Search results

Title: Transmissible Tumors: Breaking the Cancer Paradigm..
Creator: Ostrander, Elaine A, Davis, Brian W, Ostrander, Gary K
Abstract/Description: Transmissible tumors are those that have transcended the bounds of their incipient hosts by evolving the ability to infect another individual through direct transfer of cancer cells, thus becoming parasitic cancer clones. Coitus, biting, and scratching are transfer mechanisms for the two primary species studied, the domestic dog (Canis lupus familiaris) and the Tasmanian devil (Sarcophilus harrisii). Canine transmissible venereal tumors (CTVT) are likely thousands of years old, and have...
Show moreTransmissible tumors are those that have transcended the bounds of their incipient hosts by evolving the ability to infect another individual through direct transfer of cancer cells, thus becoming parasitic cancer clones. Coitus, biting, and scratching are transfer mechanisms for the two primary species studied, the domestic dog (Canis lupus familiaris) and the Tasmanian devil (Sarcophilus harrisii). Canine transmissible venereal tumors (CTVT) are likely thousands of years old, and have successfully travelled from host to host around the world, while the Tasmanian devil facial tumor disease (DFTD) is much younger and geographically localized. The dog tumor is not necessarily lethal, while the devil tumor has driven the population to near extinction. Transmissible tumors are uniform in that they have complex immunologic profiles, which allow them to escape immune detection by their hosts, sometimes for long periods of time. In this review, we explore how transmissible tumors in CTVT, DFTD, and as well as the soft-shell clam and Syrian hamster, can advance studies of tumor biology.
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Date Issued: 2016-01-01
Identifier: FSU_pmch_26686413, 10.1016/j.tig.2015.10.001, PMC4698198, 26686413, 26686413, S0168-9525(15)00187-0
Format: Citation

Title: Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats.
Creator: Sarkar, Ambalika, Kabbaj, Mohamed
Abstract/Description: The mechanistic underpinnings of sex differences in occurrence of depression and efficacy of antidepressant treatments are poorly understood. We examined the effects of isolation stress (IS) and the fast-acting antidepressant ketamine on anhedonia and depression-like behavior, spine density, and synaptic proteins in male and female rats. We used a chronic social IS paradigm to test the effects of ketamine (0, 2.5 mg/kg, and 5 mg/kg) on behavior and levels of synaptic proteins synapsin-1,...
Show moreThe mechanistic underpinnings of sex differences in occurrence of depression and efficacy of antidepressant treatments are poorly understood. We examined the effects of isolation stress (IS) and the fast-acting antidepressant ketamine on anhedonia and depression-like behavior, spine density, and synaptic proteins in male and female rats. We used a chronic social IS paradigm to test the effects of ketamine (0, 2.5 mg/kg, and 5 mg/kg) on behavior and levels of synaptic proteins synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 in male rats and female rats in diestrus. Medial prefrontal cortex spine density was also examined in male rats and female rats that received ketamine during either the diestrus or the proestrus phase of their estrous cycle. Male rats showed anhedonia and depression-like behavior after 8 weeks of IS, concomitant with decreases in spine density and levels of synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 in the medial prefrontal cortex; these changes were reversed by a single injection of ketamine (5 mg/kg). After 11 weeks of IS, female rats showed depression-like behavior but no signs of anhedonia. Although both doses of ketamine rescued depression-like behavior in female rats, the decline observed in synaptic proteins and spine density in IS and in diestrus female rats could not be reversed by ketamine. Spine density was higher in female rats during proestrus than in diestrus. Our findings implicate a role for synaptic proteins synapsin-1, postsynaptic density protein 95, and glutamate receptor 1 and medial prefrontal cortex spine density in the antidepressant effects of ketamine in male rats subjected to IS but not in female rats subjected to IS, suggesting dissimilar underlying mechanisms for efficacy of ketamine in the two sexes.
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Date Issued: 2016-09-15
Identifier: FSU_pmch_26957131, 10.1016/j.biopsych.2015.12.025, PMC4940294, 26957131, 26957131, S0006-3223(16)00010-X
Format: Citation

Title: High dietary fructose does not exacerbate the detrimental consequences of high fat diet on basilar artery function.
Creator: Toklu, H Z, Muller-Delp, J, Sakaraya, Y, Oktay, S, Kirichenko, N, Matheny, M, Carter, C S, Morgan, D, Strehler, K Y E, Tumer, N, Scarpace, P J
Abstract/Description: The objective of the study was to determine the effects of a high fat (HF) diet alone or with high fructose (HF/F) on functional and structural changes in the basilar arteries and cardiovascular health parameters in rats. Male Sprague Dawley rats were fed either a HF (30%) or HF/F (30/40%) diet for 12 weeks. The basilar artery was cannulated in a pressurized system (90 cm H2O) and vascular responses to KCl (30 - 120 mM), endothelin (10(-11) - 10(-7) M), acetylcholine (ACh) (10(-10) - 10(-4) M...
Show moreThe objective of the study was to determine the effects of a high fat (HF) diet alone or with high fructose (HF/F) on functional and structural changes in the basilar arteries and cardiovascular health parameters in rats. Male Sprague Dawley rats were fed either a HF (30%) or HF/F (30/40%) diet for 12 weeks. The basilar artery was cannulated in a pressurized system (90 cm H2O) and vascular responses to KCl (30 - 120 mM), endothelin (10(-11) - 10(-7) M), acetylcholine (ACh) (10(-10) - 10(-4) M), diethylamine (DEA)-NONO-ate (10(-10) - 10(-4) M), and papaverine (10(-10) - 10(-4) M) were evaluated. Rats were also monitored for food intake, body weight, blood lipids, blood pressure, and heart rate. At death, asymmetrical dimethyl arginine level (ADMA) and leptin were assayed in serum. Although there was no significant difference in weight gain and food intake, HF and HF/F diets increased body fat composition and decreased the lean mass. HF/F diet accelerated the development of dyslipidemia. Although resting blood pressure remained unchanged, stress caused a significant elevation in blood pressure and a modest increase in heart rate in HF fed rats. Both HF and HF/F diet resulted in decreased response to endothelium-dependent and -independent relaxation, whereas increased basilar artery wall thickness was observed only in HF group. Serum leptin levels positively correlated with wall thickness. Moreover serum ADMA was increased and eNOS immunofluorescence was significantly decreased with both diets. These data suggest that the presence of high fructose in a HF diet does not exacerbate the detrimental consequences of a HF diet on basilar artery function.
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Date Issued: 2016-04-01
Identifier: FSU_pmch_27226180, PMC5572808, 27226180, 27226180
Format: Citation

Title: Cocaine-induced neurodevelopmental deficits and underlying mechanisms.
Creator: Martin, Melissa M, Graham, Devon L, McCarthy, Deirdre M, Bhide, Pradeep G, Stanwood, Gregg D
Abstract/Description: Exposure to drugs early in life has complex and long-lasting implications for brain structure and function. This review summarizes work to date on the immediate and long-term effects of prenatal exposure to cocaine. In utero cocaine exposure produces disruptions in brain monoamines, particularly dopamine, during sensitive periods of brain development, and leads to permanent changes in specific brain circuits, molecules, and behavior. Here, we integrate clinical studies and significance with...
Show moreExposure to drugs early in life has complex and long-lasting implications for brain structure and function. This review summarizes work to date on the immediate and long-term effects of prenatal exposure to cocaine. In utero cocaine exposure produces disruptions in brain monoamines, particularly dopamine, during sensitive periods of brain development, and leads to permanent changes in specific brain circuits, molecules, and behavior. Here, we integrate clinical studies and significance with mechanistic preclinical studies, to define our current knowledge base and identify gaps for future investigation. Birth Defects Research (Part C) 108:147-173, 2016. © 2016 Wiley Periodicals, Inc.
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Date Issued: 2016-06-01
Identifier: FSU_pmch_27345015, 10.1002/bdrc.21132, PMC5538582, 27345015, 27345015
Format: Citation

Title: Prediction of individual differences in fear response by novelty seeking, and disruption of contextual fear memory reconsolidation by ketamine.
Creator: Duclot, Florian, Perez-Taboada, Iara, Wright, Katherine N, Kabbaj, Mohamed
Abstract/Description: Only a portion of the population exposed to trauma will develop persistent emotional alterations characteristic of posttraumatic stress disorder (PTSD), which illustrates the necessity for identifying vulnerability factors and novel pharmacotherapeutic alternatives. Interestingly, clinical evidence suggests that novelty seeking is a good predictor for vulnerability to the development of excessive and persistent fear. Here, we first tested this hypothesis by analyzing contextual and cued fear...
Show moreOnly a portion of the population exposed to trauma will develop persistent emotional alterations characteristic of posttraumatic stress disorder (PTSD), which illustrates the necessity for identifying vulnerability factors and novel pharmacotherapeutic alternatives. Interestingly, clinical evidence suggests that novelty seeking is a good predictor for vulnerability to the development of excessive and persistent fear. Here, we first tested this hypothesis by analyzing contextual and cued fear responses of rats selected for their high (high responders, HR) or low (low responders, LR) exploration of a novel environment, indicator of novelty seeking. While HR and LR rats exhibited similar sensitivity to the shock and cued fear memory retention, fewer extinction sessions were required in HR than LR animals to reach extinction, indicating faster contextual and cued memory extinction. In a second part, we found an effective disruption of contextual fear reconsolidation by the N-methyl-d-aspartate receptor antagonist ketamine, associated with a down-regulation of early growth response 1 (Egr1) in the hippocampal CA1 area, and up-regulation of brain-derived neurotrophic factor (Bdnf) mRNA levels in the prelimbic and infralimbic cortices. Altogether, these data demonstrate a link between novelty seeking and conditioned fear extinction, and highlight a promising novel role of ketamine in affecting established fear memory.
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Date Issued: 2016-10-01
Identifier: FSU_pmch_27343386, 10.1016/j.neuropharm.2016.06.022, PMC5017153, 27343386, 27343386, S0028-3908(16)30275-1
Format: Citation

Title: An insight into the thermodynamic characteristics of human thrombopoietin complexation with TN1 antibody.
Creator: Arai, Shigeki, Shibazaki, Chie, Adachi, Motoyasu, Honjo, Eijiro, Tamada, Taro, Maeda, Yoshitake, Tahara, Tomoyuki, Kato, Takashi, Miyazaki, Hiroshi, Blaber, Michael, Kuroki, Ryota
Abstract/Description: Human thrombopoietin (hTPO) primarily stimulates megakaryocytopoiesis and platelet production and is neutralized by the mouse TN1 antibody. The thermodynamic characteristics of TN1 antibody-hTPO complexation were analyzed by isothermal titration calorimetry (ITC) using an antigen-binding fragment (Fab) derived from the TN1 antibody (TN1-Fab). To clarify the mechanism by which hTPO is recognized by TN1-Fab the conformation of free TN1-Fab was determined to a resolution of 2.0 Å using X-ray...
Show moreHuman thrombopoietin (hTPO) primarily stimulates megakaryocytopoiesis and platelet production and is neutralized by the mouse TN1 antibody. The thermodynamic characteristics of TN1 antibody-hTPO complexation were analyzed by isothermal titration calorimetry (ITC) using an antigen-binding fragment (Fab) derived from the TN1 antibody (TN1-Fab). To clarify the mechanism by which hTPO is recognized by TN1-Fab the conformation of free TN1-Fab was determined to a resolution of 2.0 Å using X-ray crystallography and compared with the hTPO-bound form of TN1-Fab determined by a previous study. This structural comparison revealed that the conformation of TN1-Fab does not substantially change after hTPO binding and a set of 15 water molecules is released from the antigen-binding site (paratope) of TN1-Fab upon hTPO complexation. Interestingly, the heat capacity change (ΔCp) measured by ITC (-1.52 ± 0.05 kJ mol(-1) K(-1) ) differed significantly from calculations based upon the X-ray structure data of the hTPO-bound and unbound forms of TN1-Fab (-1.02 ∼ 0.25 kJ mol(-1) K(-1) ) suggesting that hTPO undergoes an induced-fit conformational change combined with significant desolvation upon TN1-Fab binding. The results shed light on the structural biology associated with neutralizing antibody recognition.
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Date Issued: 2016-10-01
Identifier: FSU_pmch_27419667, 10.1002/pro.2985, PMC5029525, 27419667, 27419667
Format: Citation

Title: 14-3-3τ promotes surface expression of Cav2.2 (α1B) Ca2+ channels.
Creator: Liu, Feng, Zhou, Qin, Zhou, Jie, Sun, Hao, Wang, Yan, Zou, Xiuqun, Feng, Lingling, Hou, Zhaoyuan, Zhou, Aiwu, Zhou, Yi, Li, Yong
Abstract/Description: Surface expression of voltage-gated Ca(2+) (Cav) channels is important for their function in calcium homeostasis in the physiology of excitable cells, but whether or not and how the α1 pore-forming subunits of Cav channels are trafficked to plasma membrane in the absence of the known Cav auxiliary subunits, β and α2δ, remains mysterious. Here we showed that 14-3-3 proteins promoted functional surface expression of the Cav2.2 α1B channel in transfected tsA-201 cells in the absence of any known...
Show moreSurface expression of voltage-gated Ca(2+) (Cav) channels is important for their function in calcium homeostasis in the physiology of excitable cells, but whether or not and how the α1 pore-forming subunits of Cav channels are trafficked to plasma membrane in the absence of the known Cav auxiliary subunits, β and α2δ, remains mysterious. Here we showed that 14-3-3 proteins promoted functional surface expression of the Cav2.2 α1B channel in transfected tsA-201 cells in the absence of any known Cav auxiliary subunit. Both the surface to total ratio of the expressed α1B protein and the current density of voltage step-evoked Ba(2+) current were markedly suppressed by the coexpression of a 14-3-3 antagonist construct, pSCM138, but not its inactive control, pSCM174, as determined by immunofluorescence assay and whole cell voltage clamp recording, respectively. By contrast, coexpression with 14-3-3τ significantly enhanced the surface expression and current density of the Cav2.2 α1B channel. Importantly, we found that between the two previously identified 14-3-3 binding regions at the α1B C terminus, only the proximal region (amino acids 1706-1940), closer to the end of the last transmembrane domain, was retained by the endoplasmic reticulum and facilitated by 14-3-3 to traffic to plasma membrane. Additionally, we showed that the 14-3-3/Cav β subunit coregulated the surface expression of Cav2.2 channels in transfected tsA-201 cells and neurons. Altogether, our findings reveal a previously unidentified regulatory function of 14-3-3 proteins in promoting the surface expression of Cav2.2 α1B channels.
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Date Issued: 2015-01-30
Identifier: FSU_pmch_25516596, 10.1074/jbc.M114.567800, PMC4317001, 25516596, 25516596, M114.567800
Format: Citation

Title: 14-3-3 proteins are required for hippocampal long-term potentiation and associative learning and memory.
Creator: Qiao, Haifa, Foote, Molly, Graham, Kourtney, Wu, Yuying, Zhou, Yi
Abstract/Description: 14-3-3 is a family of regulatory proteins highly expressed in the brain. Previous invertebrate studies have demonstrated the importance of 14-3-3 in the regulation of synaptic functions and learning and memory. However, the in vivo role of 14-3-3 in these processes has not been determined using mammalian animal models. Here, we report the behavioral and electrophysiological characterization of a new animal model of 14-3-3 proteins. These transgenic mice, considered to be a 14-3-3 functional...
Show more14-3-3 is a family of regulatory proteins highly expressed in the brain. Previous invertebrate studies have demonstrated the importance of 14-3-3 in the regulation of synaptic functions and learning and memory. However, the in vivo role of 14-3-3 in these processes has not been determined using mammalian animal models. Here, we report the behavioral and electrophysiological characterization of a new animal model of 14-3-3 proteins. These transgenic mice, considered to be a 14-3-3 functional knock-out, express a known 14-3-3 inhibitor in various brain regions of different founder lines. We identify a founder-specific impairment in hippocampal-dependent learning and memory tasks, as well as a correlated suppression in long-term synaptic plasticity of the hippocampal synapses. Moreover, hippocampal synaptic NMDA receptor levels are selectively reduced in the transgenic founder line that exhibits both behavioral and synaptic plasticity deficits. Collectively, our findings provide evidence that 14-3-3 is a positive regulator of associative learning and memory at both the behavioral and cellular level.
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Date Issued: 2014-04-02
Identifier: FSU_pmch_24695700, 10.1523/JNEUROSCI.4393-13.2014, PMC3972712, 24695700, 24695700, 34/14/4801
Format: Citation

Title: Acute BDNF treatment upregulates GluR1-SAP97 and GluR2-GRIP1 interactions: implications for sustained AMPA receptor expression..
Creator: Jourdi, Hussam, Kabbaj, Mohamed
Abstract/Description: Brain-derived neurotrophic factor (BDNF) plays several prominent roles in synaptic plasticity and in learning and memory formation. Reduced BDNF levels and altered BDNF signaling have been reported in several brain diseases and behavioral disorders, which also exhibit reduced levels of AMPAr subunits. BDNF treatment acutely regulates AMPA receptor expression and function, including synaptic AMPAr subunit trafficking, and implicates several well defined signaling molecules that are required to...
Show moreBrain-derived neurotrophic factor (BDNF) plays several prominent roles in synaptic plasticity and in learning and memory formation. Reduced BDNF levels and altered BDNF signaling have been reported in several brain diseases and behavioral disorders, which also exhibit reduced levels of AMPAr subunits. BDNF treatment acutely regulates AMPA receptor expression and function, including synaptic AMPAr subunit trafficking, and implicates several well defined signaling molecules that are required to elicit long term potentiation and depression (LTP and LTD, respectively). Long term encoding of synaptic events, as in long term memory formation, requires AMPAr stabilization and maintenance. However, factors regulating AMPAr stabilization in neuronal cell membranes and synaptic sites are not well characterized. In this study, we examine the effects of acute BDNF treatment on levels of AMPAr-associated scaffolding proteins and on AMPAr subunit-scaffolding protein interactions. We also examine the effects of BDNF-dependent enhanced interactions between AMPAr subunits with their specific scaffolding proteins on the accumulation of both types of proteins. Our results show that acute BDNF treatment upregulates the interactions between AMPAr subunits (GluR1 and GluR2) with their scaffold proteins SAP97 and GRIP1, respectively, leading to prolonged increased accumulation of both categories of proteins, albeit with distinct mechanisms for GluR1 and GluR2. Our findings reveal a new role for BDNF in the long term maintenance of AMPA receptor subunits and associated scaffolding proteins at synapses and further support the role of BDNF as a key regulator of synaptic consolidation. These results have potential implications for recent findings implicating BDNF and AMPAr subunits in various brain diseases and behavioral disorders.
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Date Issued: 2013-01-01
Identifier: FSU_pmch_23460828, 10.1371/journal.pone.0057124, PMC3584105, 23460828, 23460828, PONE-D-12-38051
Format: Citation

Title: An S116R Phosphorylation Site Mutation in Human Fibroblast Growth Factor-1 Differentially Affects Mitogenic and Glucose-Lowering Activities.
Creator: Xia, Xue, Kumru, Ozan S, Blaber, Sachiko I, Middaugh, C Russell, Li, Ling, Ornitz, David M, Suh, Jae Myoung, Atkins, Annette R, Downes, Michael, Evans, Ronald M, Tenorio, Connie...
Show moreXia, Xue, Kumru, Ozan S, Blaber, Sachiko I, Middaugh, C Russell, Li, Ling, Ornitz, David M, Suh, Jae Myoung, Atkins, Annette R, Downes, Michael, Evans, Ronald M, Tenorio, Connie A, Bienkiewicz, Ewa, Blaber, Michael
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Abstract/Description: Fibroblast growth factor-1 (FGF-1), a potent human mitogen and insulin sensitizer, signals through both tyrosine kinase receptor-mediated autocrine/paracrine pathways as well as a nuclear intracrine pathway. Phosphorylation of FGF-1 at serine 116 (S116) has been proposed to regulate intracrine signaling. Position S116 is located within a ∼17 amino acid C-terminal loop that contains a rich set of functional determinants including heparin∖heparan sulfate affinity, thiol reactivity, nuclear...
Show moreFibroblast growth factor-1 (FGF-1), a potent human mitogen and insulin sensitizer, signals through both tyrosine kinase receptor-mediated autocrine/paracrine pathways as well as a nuclear intracrine pathway. Phosphorylation of FGF-1 at serine 116 (S116) has been proposed to regulate intracrine signaling. Position S116 is located within a ∼17 amino acid C-terminal loop that contains a rich set of functional determinants including heparin∖heparan sulfate affinity, thiol reactivity, nuclear localization, pharmacokinetics, functional half-life, nuclear ligand affinity, stability, and structural dynamics. Mutational targeting of specific functionality in this region without perturbing other functional determinants is a design challenge. S116R is a non-phosphorylatable variant present in bovine FGF-1 and other members of the human FGF family. We show that the S116R mutation in human FGF-1 is accommodated with no perturbation of biophysical or structural properties, and is therefore an attractive mutation with which to elucidate the functional role of phosphorylation. Characterization of S116R shows reduction in NIH 3T3 fibroblast mitogenic stimulation, increase in fibroblast growth factor receptor-1c activation, and prolonged duration of glucose lowering in ob/ob hyperglycemic mice. A novel FGF-1/fibroblast growth factor receptor-1c dimerization interaction combined with non-phosphorylatable intracrine signaling is hypothesized to be responsible for these observed functional effects.
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Date Issued: 2016-12-01
Identifier: FSU_pmch_27773526, 10.1016/j.xphs.2016.09.005, PMC5310217, 27773526, 27773526, S0022-3549(16)41698-9
Format: Citation

Title: Fluoxetine exposure during adolescence increases preference for cocaine in adulthood.
Creator: Iñiguez, Sergio D, Riggs, Lace M, Nieto, Steven J, Wright, Katherine N, Zamora, Norma N, Cruz, Bryan, Zavala, Arturo R, Robison, Alfred J, Mazei-Robison, Michelle S
Abstract/Description: Currently, there is a high prevalence of antidepressant prescription rates within juvenile populations, yet little is known about the potential long-lasting consequences of such treatments, particularly on subsequent responses to drugs of abuse. To address this issue at the preclinical level, we examined whether adolescent exposure to fluoxetine (FLX), a selective serotonin reuptake inhibitor, results in changes to the sensitivity of the rewarding properties of cocaine in adulthood. Separate...
Show moreCurrently, there is a high prevalence of antidepressant prescription rates within juvenile populations, yet little is known about the potential long-lasting consequences of such treatments, particularly on subsequent responses to drugs of abuse. To address this issue at the preclinical level, we examined whether adolescent exposure to fluoxetine (FLX), a selective serotonin reuptake inhibitor, results in changes to the sensitivity of the rewarding properties of cocaine in adulthood. Separate groups of male c57bl/6 mice were exposed to FLX (0 or 20 mg/kg) for 15 consecutive days either during adolescence (postnatal days [PD] 35-49) or adulthood (PD 65-79). Twenty-one days after FLX treatment, behavioral responsivity to cocaine (0, 2.5, 5, 10, or 20 mg/kg) conditioned place preference was assessed. Our data shows that mice pretreated with FLX during adolescence, but not during adulthood, display an enhanced dose-dependent preference to the environment paired with cocaine (5 or 10 mg/kg) when compared to age-matched saline pretreated controls. Taken together, our findings suggest that adolescent exposure to FLX increases sensitivity to the rewarding properties of cocaine, later in life.
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Date Issued: 2015-10-09
Identifier: FSU_pmch_26449406, 10.1038/srep15009, PMC4598853, 26449406, 26449406, srep15009
Format: Citation

Title: Female mice and rats exhibit species-specific metabolic and behavioral responses to ovariectomy.
Creator: Witte, Michelina Messina, Resuehr, David, Chandler, Ashley R, Mehle, Ashlee K, Overton, J Michael
Abstract/Description: Ovariectomy (OVX) leads to hyperphagia and weight gain in rats, which can be prevented by estradiol (E2) replacement; however, the role of endogenous E2 on feeding and energy homeostasis in female mice has not been well characterized. The primary goal of this study was to assess the relative contribution of increased energy intake and decreased energy expenditure to OVX-induced weight gain in female rats and mice. OVX led to hyperphagia in rats, but did not produce daily, nor cumulative,...
Show moreOvariectomy (OVX) leads to hyperphagia and weight gain in rats, which can be prevented by estradiol (E2) replacement; however, the role of endogenous E2 on feeding and energy homeostasis in female mice has not been well characterized. The primary goal of this study was to assess the relative contribution of increased energy intake and decreased energy expenditure to OVX-induced weight gain in female rats and mice. OVX led to hyperphagia in rats, but did not produce daily, nor cumulative, hyperphagia in mice. OVX decreased mass-specific metabolic rate in mice, but not in rats. OVX decreased home cage locomotor activity in both species. Pair-feeding attenuated OVX-induced weight gain in rats and produced both short- and long-term changes in expression of key hypothalamic genes involved in food intake and energy homeostasis, i.e., the anorexigenic neuropeptide pro-opiomelanocortin (POMC) and the orexigenic neuropeptides: melanin-concentrating hormone (MCH) and agouti-related peptide (AgRP). No differences in hypothalamic gene expression were observed between OVX'd and sham mice. The results suggest that OVX-induced weight gain is mediated by hyperphagia and reduced locomotor activity in rats, but that in mice, it is primarily mediated by reduced locomotor activity and metabolic rate.
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Date Issued: 2010-05-01
Identifier: FSU_pmch_20067798, 10.1016/j.ygcen.2010.01.006, PMC2856744, 20067798, 20067798, S0016-6480(10)00009-2
Format: Citation

Title: Extracellular signal-regulated kinase 2 signaling in the hippocampal dentate gyrus mediates the antidepressant effects of testosterone.
Creator: Carrier, Nicole, Kabbaj, Mohamed
Abstract/Description: Human and animal studies suggest that testosterone may have antidepressant effects. In this study, we sought to investigate the molecular mechanisms underlying the antidepressant effects of testosterone within the hippocampus, an area that is fundamental in the etiology of depression. The effects of testosterone replacements in gonadectomized adult male rats were investigated using the sucrose preference and forced swim tests. We explored possible effects of testosterone on hippocampal...
Show moreHuman and animal studies suggest that testosterone may have antidepressant effects. In this study, we sought to investigate the molecular mechanisms underlying the antidepressant effects of testosterone within the hippocampus, an area that is fundamental in the etiology of depression. The effects of testosterone replacements in gonadectomized adult male rats were investigated using the sucrose preference and forced swim tests. We explored possible effects of testosterone on hippocampal neurogenesis and gene expression of stress-related molecules. Through the use of viral vectors, we pursued the antidepressant molecular mechanism(s) of testosterone in mediating anhedonia and manipulated extracellular signal-regulated kinase 2 (ERK2) expression in the dentate gyrus in gonadectomized rats with testosterone replacements. Testosterone had antidepressant effects, likely mediated by aromatization to estrogen metabolites, in the sucrose preference and forced swim tests despite having no effects on hippocampal cell proliferation or survival. We found a testosterone-dependent regulation of hippocampal ERK2 expression. Functionally, reducing ERK2 activity within the dentate gyrus induced anhedonia in gonadectomized rats receiving testosterone supplementation, whereas the overexpression of ERK2 rescued this behavior in gonadectomized rats. These results implicate a role for ERK2 signaling within the dentate gyrus area of the hippocampus as a key mediator of the antidepressant effects of testosterone.
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Date Issued: 2012-04-01
Identifier: FSU_pmch_22265242, 10.1016/j.biopsych.2011.11.028, PMC3307821, 22265242, 22265242, S0006-3223(11)01201-7
Format: Citation

Title: Essential roles of CKIdelta and CKIepsilon in the mammalian circadian clock.
Creator: Lee, Hyeongmin, Chen, Rongmin, Lee, Yongjin, Yoo, Seunghee, Lee, Choogon
Abstract/Description: Circadian rhythms in mammals are generated by a negative transcriptional feedback loop in which PERIOD (PER) is rate-limiting for feedback inhibition. Casein kinases Idelta and Iepsilon (CKIdelta/epsilon) can regulate temporal abundance/activity of PER by phosphorylation-mediated degradation and cellular localization. Despite their potentially crucial effects on PER, it has not been demonstrated in a mammalian system that these kinases play essential roles in circadian rhythm generation as...
Show moreCircadian rhythms in mammals are generated by a negative transcriptional feedback loop in which PERIOD (PER) is rate-limiting for feedback inhibition. Casein kinases Idelta and Iepsilon (CKIdelta/epsilon) can regulate temporal abundance/activity of PER by phosphorylation-mediated degradation and cellular localization. Despite their potentially crucial effects on PER, it has not been demonstrated in a mammalian system that these kinases play essential roles in circadian rhythm generation as does their homolog in Drosophila. To disrupt both CKIdelta/epsilon while avoiding the embryonic lethality of CKIdelta disruption in mice, we used CKIdelta-deficient Per2(Luc) mouse embryonic fibroblasts (MEFs) and overexpressed a dominant-negative mutant CKIepsilon (DN-CKIepsilon) in the mutant MEFs. CKIdelta-deficient MEFs exhibited a robust circadian rhythm, albeit with a longer period, suggesting that the cells possess a way to compensate for CKIdelta loss. When CKIepsilon activity was disrupted by the DN-CKIepsilon in the mutant MEFs, circadian bioluminescence rhythms were eliminated and rhythms in endogenous PER abundance and phosphorylation were severely compromised, demonstrating that CKIdelta/epsilon are indeed essential kinases for the clockwork. This is further supported by abolition of circadian rhythms when physical interaction between PER and CKIdelta/epsilon was disrupted by overexpressing the CKIdelta/epsilon binding domain of PER2 (CKBD-P2). Interestingly, CKBD-P2 overexpression led to dramatically low levels of endogenous PER, while PER-binding, kinase-inactive DN-CKIepsilon did not, suggesting that CKIdelta/epsilon may have a non-catalytic role in stabilizing PER. Our results show that an essential role of CKIdelta/epsilon is conserved between Drosophila and mammals, but CKIdelta/epsilon and DBT may have divergent non-catalytic functions in the clockwork as well.
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Date Issued: 2009-12-15
Identifier: FSU_pmch_19948962, 10.1073/pnas.0906651106, PMC2795500, 19948962, 19948962, 0906651106
Format: Citation

Title: Exercise training reverses aging-induced impairment of myogenic constriction in skeletal muscle arterioles.
Creator: Ghosh, Payal, Mora Solis, Fredy R, Dominguez, James M, Spier, Scott A, Donato, Anthony J, Delp, Michael D, Muller-Delp, Judy M
Abstract/Description: To investigate whether exercise training can reverse age-related impairment of myogenic vasoconstriction in skeletal muscle arterioles, young (4 mo) and old (22 mo) male Fischer 344 rats were randomly assigned to either sedentary or exercise-trained groups. The roles of the endothelium and Kv1 channels in age- and exercise training-induced adaptations of myogenic responses were assessed through evaluation of pressure-induced constriction in endothelium-intact and denuded soleus muscle...
Show moreTo investigate whether exercise training can reverse age-related impairment of myogenic vasoconstriction in skeletal muscle arterioles, young (4 mo) and old (22 mo) male Fischer 344 rats were randomly assigned to either sedentary or exercise-trained groups. The roles of the endothelium and Kv1 channels in age- and exercise training-induced adaptations of myogenic responses were assessed through evaluation of pressure-induced constriction in endothelium-intact and denuded soleus muscle arterioles in the presence and absence of the Kv1 channel blocker, correolide. Exercise training enhanced myogenic constriction in arterioles from both old and young rats. In arterioles from old rats, exercise training restored myogenic constriction to a level similar to that of arterioles from young sedentary rats. Removal of the endothelium did not alter myogenic constriction of arterioles from young sedentary rats, but reduced myogenic constriction in arterioles from young exercise-trained rats. In contrast, endothelial removal had no effect on myogenic constriction of arterioles from old exercise-trained rats, but increased myogenic vasoconstriction in old sedentary rats. The effect of Kv1 channel blockade was also dependent on age and training status. In arterioles from young sedentary rats, Kv1 blockade had little effect on myogenic constriction, whereas in old sedentary rats Kv1 blockade increased myogenic constriction. After exercise training, Kv1 channel blockade increased myogenic constriction in arterioles from both young and old rats. Thus exercise training restores myogenic constriction of arterioles from old rats and enhances myogenic constriction from young rats through adaptations of the endothelium and smooth muscle Kv1 channels.
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Date Issued: 2015-04-01
Identifier: FSU_pmch_25634999, 10.1152/japplphysiol.00277.2014, PMC4422370, 25634999, 25634999, japplphysiol.00277.2014
Format: Citation

Title: An Examination of Dynamic Gene Expression Changes in the Mouse Brain During Pregnancy and the Postpartum Period.
Creator: Ray, Surjyendu, Tzeng, Ruei-Ying, DiCarlo, Lisa M, Bundy, Joseph L, Vied, Cynthia, Tyson, Gary, Nowakowski, Richard, Arbeitman, Michelle N
Abstract/Description: The developmental transition to motherhood requires gene expression changes that alter the brain to drive the female to perform maternal behaviors. We broadly examined the global transcriptional response in the mouse maternal brain, by examining four brain regions: hypothalamus, hippocampus, neocortex, and cerebellum, in virgin females, two pregnancy time points, and three postpartum time points. We find that overall there are hundreds of differentially expressed genes, but each brain region...
Show moreThe developmental transition to motherhood requires gene expression changes that alter the brain to drive the female to perform maternal behaviors. We broadly examined the global transcriptional response in the mouse maternal brain, by examining four brain regions: hypothalamus, hippocampus, neocortex, and cerebellum, in virgin females, two pregnancy time points, and three postpartum time points. We find that overall there are hundreds of differentially expressed genes, but each brain region and time point shows a unique molecular signature, with only 49 genes differentially expressed in all four regions. Interestingly, a set of "early-response genes" is repressed in all brain regions during pregnancy and postpartum stages. Several genes previously implicated in underlying postpartum depression change expression. This study serves as an atlas of gene expression changes in the maternal brain, with the results demonstrating that pregnancy, parturition, and postpartum maternal experience substantially impact diverse brain regions.
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Date Issued: 2015-11-23
Identifier: FSU_pmch_26596646, 10.1534/g3.115.020982, PMC4704721, 26596646, 26596646, g3.115.020982
Format: Citation

Title: Male-specific Fruitless isoforms have different regulatory roles conferred by distinct zinc finger DNA binding domains.
Creator: Dalton, Justin E, Fear, Justin M, Knott, Simon, Baker, Bruce S, McIntyre, Lauren M, Arbeitman, Michelle N
Abstract/Description: Drosophila melanogaster adult males perform an elaborate courtship ritual to entice females to mate. fruitless (fru), a gene that is one of the key regulators of male courtship behavior, encodes multiple male-specific isoforms (Fru(M)). These isoforms vary in their carboxy-terminal zinc finger domains, which are predicted to facilitate DNA binding. By over-expressing individual Fru(M) isoforms in fru-expressing neurons in either males or females and assaying the global transcriptional...
Show moreDrosophila melanogaster adult males perform an elaborate courtship ritual to entice females to mate. fruitless (fru), a gene that is one of the key regulators of male courtship behavior, encodes multiple male-specific isoforms (Fru(M)). These isoforms vary in their carboxy-terminal zinc finger domains, which are predicted to facilitate DNA binding. By over-expressing individual Fru(M) isoforms in fru-expressing neurons in either males or females and assaying the global transcriptional response by RNA-sequencing, we show that three Fru(M) isoforms have different regulatory activities that depend on the sex of the fly. We identified several sets of genes regulated downstream of Fru(M) isoforms, including many annotated with neuronal functions. By determining the binding sites of individual Fru(M) isoforms using SELEX we demonstrate that the distinct zinc finger domain of each Fru(M) isoforms confers different DNA binding specificities. A genome-wide search for these binding site sequences finds that the gene sets identified as induced by over-expression of Fru(M) isoforms in males are enriched for genes that contain the binding sites. An analysis of the chromosomal distribution of genes downstream of Fru(M) shows that those that are induced and repressed in males are highly enriched and depleted on the X chromosome, respectively. This study elucidates the different regulatory and DNA binding activities of three Fru(M) isoforms on a genome-wide scale and identifies genes regulated by these isoforms. These results add to our understanding of sex chromosome biology and further support the hypothesis that in some cell-types genes with male-biased expression are enriched on the X chromosome.
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Date Issued: 2013-09-27
Identifier: FSU_pmch_24074028, 10.1186/1471-2164-14-659, PMC3852243, 24074028, 24074028, 1471-2164-14-659
Format: Citation

Title: Light-regulated translational control of circadian behavior by eIF4E phosphorylation.
Creator: Cao, Ruifeng, Gkogkas, Christos G, de Zavalia, Nuria, Blum, Ian D, Yanagiya, Akiko, Tsukumo, Yoshinori, Xu, Haiyan, Lee, Choogon, Storch, Kai-Florian, Liu, Andrew C, Amir,...
Show moreCao, Ruifeng, Gkogkas, Christos G, de Zavalia, Nuria, Blum, Ian D, Yanagiya, Akiko, Tsukumo, Yoshinori, Xu, Haiyan, Lee, Choogon, Storch, Kai-Florian, Liu, Andrew C, Amir, Shimon, Sonenberg, Nahum
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Abstract/Description: The circadian (∼24 h) clock is continuously entrained (reset) by ambient light so that endogenous rhythms are synchronized with daily changes in the environment. Light-induced gene expression is thought to be the molecular mechanism underlying clock entrainment. mRNA translation is a key step of gene expression, but the manner in which clock entrainment is controlled at the level of mRNA translation is not well understood. We found that a light- and circadian clock-regulated MAPK/MNK pathway...
Show moreThe circadian (∼24 h) clock is continuously entrained (reset) by ambient light so that endogenous rhythms are synchronized with daily changes in the environment. Light-induced gene expression is thought to be the molecular mechanism underlying clock entrainment. mRNA translation is a key step of gene expression, but the manner in which clock entrainment is controlled at the level of mRNA translation is not well understood. We found that a light- and circadian clock-regulated MAPK/MNK pathway led to phosphorylation of the cap-binding protein eIF4E in the mouse suprachiasmatic nucleus of the hypothalamus, the locus of the master circadian clock in mammals. Phosphorylation of eIF4E specifically promoted translation of Period 1 (Per1) and Period 2 (Per2) mRNAs and increased the abundance of basal and inducible PER proteins, which facilitated circadian clock resetting and precise timekeeping. Together, these results highlight a critical role for light-regulated translational control in the physiology of the circadian clock.
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Date Issued: 2015-06-01
Identifier: FSU_pmch_25915475, 10.1038/nn.4010, PMC4446158, 25915475, 25915475, nn.4010
Format: Citation

Title: Long-term caloric restriction reduces metabolic rate and heart rate under cool and thermoneutral conditions in FBNF1 rats.
Creator: Knight, W David, Witte, M M, Parsons, A D, Gierach, M, Overton, J Michael
Abstract/Description: The long-term metabolic and cardiovascular responses to caloric restriction (CR) are poorly understood. We examined the responses to one year of CR in FBNF1 rats housed in cool (COOL; T(a)=15 °C) or thermoneutral (TMN; T(a)=30 °C) conditions. Rats were acclimated to COOL or TMN for 2 months, instrumented for cardiovascular telemetry and studied in calorimeters. Baseline caloric intake, oxygen consumption (VO(2)), mean arterial blood pressure (MAP), and heart rate (HR) were determined prior to...
Show moreThe long-term metabolic and cardiovascular responses to caloric restriction (CR) are poorly understood. We examined the responses to one year of CR in FBNF1 rats housed in cool (COOL; T(a)=15 °C) or thermoneutral (TMN; T(a)=30 °C) conditions. Rats were acclimated to COOL or TMN for 2 months, instrumented for cardiovascular telemetry and studied in calorimeters. Baseline caloric intake, oxygen consumption (VO(2)), mean arterial blood pressure (MAP), and heart rate (HR) were determined prior to assignment to ad lib (AL) or CR groups (30-40% CR) within each T(a) (n = 8). Groups of rats were studied after 10 weeks CR, one year CR, and after 4 days of re-feeding. Both 10 weeks and one year of CR reduced HR and VO(2) irrespective of T(a). Evaluation of the relationship between metabolic organ mass (liver, heart, brain, and kidney mass) and energy expenditure revealed a clear shift induced by CR to reduce expenditure per unit metabolic mass in both COOL and TMN groups. Re-feeding resulted in prompt elevations of HR and VO(2) to levels observed in control rats. These findings are consistent with the hypothesis that long term CR produces sustained reductions in metabolic rate and heart rate in rats.
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Date Issued: 2011-05-01
Identifier: FSU_pmch_21513729, 10.1016/j.mad.2011.04.001, PMC3118456, 21513729, 21513729, S0047-6374(11)00046-7
Format: Citation

Title: Layer-specific modulation of entorhinal cortical excitability by presubiculum in a rat model of temporal lobe epilepsy.
Creator: Abbasi, Saad, Kumar, Sanjay S
Abstract/Description: Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and is often refractory to antiepileptic medications. The medial entorhinal area (MEA) is affected in TLE but mechanisms underlying hyperexcitability of MEA neurons require further elucidation. Previous studies suggest that inputs from the presubiculum (PrS) contribute to MEA pathophysiology. We assessed electrophysiologically how PrS influences MEA excitability using the rat pilocarpine model of TLE. PrS-MEA...
Show moreTemporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and is often refractory to antiepileptic medications. The medial entorhinal area (MEA) is affected in TLE but mechanisms underlying hyperexcitability of MEA neurons require further elucidation. Previous studies suggest that inputs from the presubiculum (PrS) contribute to MEA pathophysiology. We assessed electrophysiologically how PrS influences MEA excitability using the rat pilocarpine model of TLE. PrS-MEA connectivity was confirmed by electrically stimulating PrS afferents while recording from neurons within superficial layers of MEA. Assessment of alterations in PrS-mediated synaptic drive to MEA neurons was made following focal application of either glutamate or NBQX to the PrS in control and epileptic animals. Here, we report that monosynaptic inputs to MEA from PrS neurons are conserved in epileptic rats, and that PrS modulation of MEA excitability is layer-specific. PrS contributes more to synaptic inhibition of LII stellate cells than excitation. Under epileptic conditions, stellate cell inhibition is significantly reduced while excitatory synaptic drive is maintained at levels similar to control. PrS contributes to both synaptic excitation and inhibition of LIII pyramidal cells in control animals. Under epileptic conditions, overall excitatory synaptic drive to these neurons is enhanced while inhibitory synaptic drive is maintained at control levels. Additionally, neither glutamate nor NBQX applied focally to PrS now affected EPSC and IPSC frequency of LIII pyramidal neurons. These layer-specific changes in PrS-MEA interactions are unexpected and of significance in unraveling pathophysiological mechanisms underlying TLE.
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Date Issued: 2015-11-01
Identifier: FSU_pmch_26378210, 10.1152/jn.00823.2015, PMC4737416, 26378210, 26378210, jn.00823.2015
Format: Citation

Title: Long term ablation of protein kinase A (PKA)-mediated cardiac troponin I phosphorylation leads to excitation-contraction uncoupling and diastolic dysfunction in a knock-in mouse model of hypertrophic cardiomyopathy.
Creator: Dweck, David, Sanchez-Gonzalez, Marcos A, Chang, Audrey N, Dulce, Raul A, Badger, Crystal-Dawn, Koutnik, Andrew P, Ruiz, Edda L, Griffin, Brittany, Liang, Jingsheng, Kabbaj,...
Show moreDweck, David, Sanchez-Gonzalez, Marcos A, Chang, Audrey N, Dulce, Raul A, Badger, Crystal-Dawn, Koutnik, Andrew P, Ruiz, Edda L, Griffin, Brittany, Liang, Jingsheng, Kabbaj, Mohamed, Fincham, Frank D, Hare, Joshua M, Overton, J Michael, Pinto, Jose R
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Abstract/Description: The cardiac troponin I (cTnI) R21C (cTnI-R21C) mutation has been linked to hypertrophic cardiomyopathy and renders cTnI incapable of phosphorylation by PKA in vivo. Echocardiographic imaging of homozygous knock-in mice expressing the cTnI-R21C mutation shows that they develop hypertrophy after 12 months of age and have abnormal diastolic function that is characterized by longer filling times and impaired relaxation. Electrocardiographic analyses show that older R21C mice have elevated heart...
Show moreThe cardiac troponin I (cTnI) R21C (cTnI-R21C) mutation has been linked to hypertrophic cardiomyopathy and renders cTnI incapable of phosphorylation by PKA in vivo. Echocardiographic imaging of homozygous knock-in mice expressing the cTnI-R21C mutation shows that they develop hypertrophy after 12 months of age and have abnormal diastolic function that is characterized by longer filling times and impaired relaxation. Electrocardiographic analyses show that older R21C mice have elevated heart rates and reduced cardiovagal tone. Cardiac myocytes isolated from older R21C mice demonstrate that in the presence of isoproterenol, significant delays in Ca(2+) decay and sarcomere relaxation occur that are not present at 6 months of age. Although isoproterenol and stepwise increases in stimulation frequency accelerate Ca(2+)-transient and sarcomere shortening kinetics in R21C myocytes from older mice, they are unable to attain the corresponding WT values. When R21C myocytes from older mice are treated with isoproterenol, evidence of excitation-contraction uncoupling is indicated by an elevation in diastolic calcium that is frequency-dissociated and not coupled to shorter diastolic sarcomere lengths. Myocytes from older mice have smaller Ca(2+) transient amplitudes (2.3-fold) that are associated with reductions (2.9-fold) in sarcoplasmic reticulum Ca(2+) content. This abnormal Ca(2+) handling within the cell may be attributed to a reduction (2.4-fold) in calsequestrin expression in conjunction with an up-regulation (1.5-fold) of Na(+)-Ca(2+) exchanger. Incubation of permeabilized cardiac fibers from R21C mice with PKA confirmed that the mutation prevents facilitation of mechanical relaxation. Altogether, these results indicate that the inability to enhance myofilament relaxation through cTnI phosphorylation predisposes the heart to abnormal diastolic function, reduced accessibility of cardiac reserves, dysautonomia, and hypertrophy.
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Date Issued: 2014-08-15
Identifier: FSU_pmch_24973218, 10.1074/jbc.M114.561472, PMC4132808, 24973218, 24973218, M114.561472
Format: Citation

Title: Juvenile and adult rats differ in cocaine reward and expression of zif268 in the forebrain.
Creator: Hollis, F, Gaval-Cruz, M, Carrier, N, Dietz, D M, Kabbaj, M
Abstract/Description: Adolescents are more likely to experiment with and become addicted to drugs of abuse. A number of studies indicate that the developmental forebrain may be responsible for making adolescents vulnerable to the addictive properties of such drugs. The aim of this study was to first compare behavioral responses to novelty and cocaine between juvenile and adult rats and then compare levels of the immediate-early gene zif268 activation in several forebrain areas via in situ hybridization. We found...
Show moreAdolescents are more likely to experiment with and become addicted to drugs of abuse. A number of studies indicate that the developmental forebrain may be responsible for making adolescents vulnerable to the addictive properties of such drugs. The aim of this study was to first compare behavioral responses to novelty and cocaine between juvenile and adult rats and then compare levels of the immediate-early gene zif268 activation in several forebrain areas via in situ hybridization. We found that juveniles demonstrated higher locomotion scores and required a higher dose of cocaine than adults to establish a conditioned place preference. Additionally, at this higher dose, juvenile rats exhibited higher levels of zif268 mRNA in the prefrontal cortex compared with adults. A developmental effect for increased zif268 mRNA was also observed in the striatum and nucleus accumbens, but there was no interaction with the cocaine dose. These findings hold interesting implications for the study of the molecular mechanisms underlying juvenile drug addiction.
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Date Issued: 2012-01-03
Identifier: FSU_pmch_22056598, 10.1016/j.neuroscience.2011.10.012, PMC3249467, 22056598, 22056598, S0306-4522(11)01186-9
Format: Citation

Title: Kallikrein cascades in traumatic spinal cord injury: in vitro evidence for roles in axonopathy and neuron degeneration..
Creator: Radulovic, Maja, Yoon, Hyesook, Larson, Nadya, Wu, Jianmin, Linbo, Rachel, Burda, Joshua E, Diamandis, Eleftherios P, Blaber, Sachiko I, Blaber, Michael, Fehlings, Michael G,...
Show moreRadulovic, Maja, Yoon, Hyesook, Larson, Nadya, Wu, Jianmin, Linbo, Rachel, Burda, Joshua E, Diamandis, Eleftherios P, Blaber, Sachiko I, Blaber, Michael, Fehlings, Michael G, Scarisbrick, Isobel A
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Abstract/Description: Kallikreins (KLKs) are a family of 15 secreted serine proteases with emerging roles in neurologic diseases. To illuminate their contributions to the pathophysiology of spinal cord injury (SCI), we evaluated acute through chronic changes in the immunohistochemical appearance of 6 KLKs (KLK1, KLK5, KLK6, KLK7, KLK8, and KLK9) in postmortem human traumatic SCI cases, quantified their RNA expression levels in experimental murine SCI, and assessed the impact of recombinant forms of each enzyme...
Show moreKallikreins (KLKs) are a family of 15 secreted serine proteases with emerging roles in neurologic diseases. To illuminate their contributions to the pathophysiology of spinal cord injury (SCI), we evaluated acute through chronic changes in the immunohistochemical appearance of 6 KLKs (KLK1, KLK5, KLK6, KLK7, KLK8, and KLK9) in postmortem human traumatic SCI cases, quantified their RNA expression levels in experimental murine SCI, and assessed the impact of recombinant forms of each enzyme toward murine cortical neurons in vitro. Temporally and spatially distinct changes in KLK expression were observed with partially overlapping patterns between human and murine SCI, including peak elevations (or reductions) during the acute and subacute periods. Kallikrein 9 showed the most marked changes and remained chronically elevated. Importantly, a subset of KLKs (KLK1, KLK5, KLK6, KLK7, and KLK9) were neurotoxic toward primary neurons in vitro. Kallikrein immunoreactivity was also observed in association with swollen axons and retraction bulbs in the human SCI cases examined. Together, these findings demonstrate that elevated levels of a significant subset of KLKs are positioned to contribute to neurodegenerative changes in cases of CNS trauma and disease and, therefore, represent new potential targets for the development of neuroprotective strategies.
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Date Issued: 2013-11-01
Identifier: FSU_pmch_24128681, 10.1097/NEN.0000000000000007, PMC4097185, 24128681, 24128681
Format: Citation

Title: Kidney glycosphingolipids are elevated early in diabetic nephropathy and mediate hypertrophy of mesangial cells.
Creator: Subathra, Marimuthu, Korrapati, Midhun, Howell, Lauren A, Arthur, John M, Shayman, James A, Schnellmann, Rick G, Siskind, Leah J
Abstract/Description: Glycosphingolipids (GSLs) play a role in insulin resistance and diabetes, but their role in diabetic nephropathy (DN) has received limited attention. We used 9- and 17-wk-old nondiabetic db/m and diabetic db/db mice to examine the role of GSLs in DN. Cerebrosides or monoglycosylated GSLs [hexosylceramides (HexCers); glucosyl- and galactosylceramides] and lactosylceramide (LacCers) were elevated in db/db mouse kidney cortices, specifically in glomeruli, and also in urine. In our recent paper ...
Show moreGlycosphingolipids (GSLs) play a role in insulin resistance and diabetes, but their role in diabetic nephropathy (DN) has received limited attention. We used 9- and 17-wk-old nondiabetic db/m and diabetic db/db mice to examine the role of GSLs in DN. Cerebrosides or monoglycosylated GSLs [hexosylceramides (HexCers); glucosyl- and galactosylceramides] and lactosylceramide (LacCers) were elevated in db/db mouse kidney cortices, specifically in glomeruli, and also in urine. In our recent paper (25), we observed that the kidneys exhibited glomerular hypertrophy and proximal tubular vacuolization and increased fibrosis markers at these time points. Mesangial cells contribute to hyperglycemia-induced glomerular hypertrophy in DN. Hyperglycemic culture conditions, similar to that present in diabetes, were sufficient to elevate mesangial cell HexCers and increase markers of fibrosis, extracellular matrix proteins, and cellular hypertrophy. Inhibition of glucosylceramide synthase or lowering glucose levels decreased markers of fibrosis and extracellular matrix proteins and reversed mesangial cell hypertrophy. Hyperglycemia increased phosphorylated (p)SMAD3 and pAkt levels and reduced phosphatase and tensin homolog levels, which were reversed with glucosylceramide synthase inhibition. These data suggest that inhibition of glucosylceramide synthase reversed mesangial cell hypertrophy through decreased pAkt and pSmad3 and increased pathways responsible for protein degradation. Importantly, urinary GSL levels were higher in patients with DN compared with healthy control subjects, implicating a role for these lipids in human DN. Thus, hyperglycemia in type II diabetes leads to renal dysfunction at least in part by inducing accumulation of HexCers and LacCers in mesangial cells, resulting in fibrosis, extracellular matrix production, and hypertrophy.
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Date Issued: 2015-08-01
Identifier: FSU_pmch_26041445, 10.1152/ajprenal.00150.2015, PMC4525094, 26041445, 26041445, ajprenal.00150.2015
Format: Citation

Title: Hedonic sensitivity to low-dose ketamine is modulated by gonadal hormones in a sex-dependent manner.
Creator: Saland, Samantha K, Schoepfer, Kristin J, Kabbaj, Mohamed
Abstract/Description: We recently reported a greater sensitivity of female rats to rapid antidepressant-like effects of ketamine compared to male rats, and that ovarian-derived estradiol (E2) and progesterone (P4) are essential for this response. However, to what extent testosterone may also contribute, and whether duration of response to ketamine is modulated in a sex- and hormone-dependent manner remains unclear. To explore this, we systematically investigated the influence of testosterone, estradiol and...
Show moreWe recently reported a greater sensitivity of female rats to rapid antidepressant-like effects of ketamine compared to male rats, and that ovarian-derived estradiol (E2) and progesterone (P4) are essential for this response. However, to what extent testosterone may also contribute, and whether duration of response to ketamine is modulated in a sex- and hormone-dependent manner remains unclear. To explore this, we systematically investigated the influence of testosterone, estradiol and progesterone on initiation and maintenance of hedonic response to low-dose ketamine (2.5 mg/kg) in intact and gonadectomized male and female rats. Ketamine induced a sustained increase in sucrose preference of female, but not male, rats in an E2P4-dependent manner. Whereas testosterone failed to alter male treatment response, concurrent administration of P4 alone in intact males enhanced hedonic response low-dose ketamine. Treatment responsiveness in female rats only was associated with greater hippocampal BDNF levels, but not activation of key downstream signaling effectors. We provide novel evidence supporting activational roles for ovarian-, but not testicular-, derived hormones in mediating hedonic sensitivity to low-dose ketamine in female and male rats, respectively. Organizational differences may, in part, account for the persistence of sex differences following gonadectomy and selective involvement of BDNF in treatment response.
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Date Issued: 2016-02-18
Identifier: FSU_pmch_26888470, 10.1038/srep21322, PMC4766854, 26888470, 26888470, srep21322
Format: Citation

Title: Heterogeneous ageing of skeletal muscle microvascular function.
Creator: Muller-Delp, Judy M
Abstract/Description: The distribution of blood flow to skeletal muscle during exercise is altered with advancing age. Changes in arteriolar function that are muscle specific underlie age-induced changes in blood flow distribution. With advancing age, functional adaptations that occur in resistance arterioles from oxidative muscles differ from those that occur in glycolytic muscles. Age-related adaptations of morphology, as well as changes in both endothelial and vascular smooth muscle signalling, differ in muscle...
Show moreThe distribution of blood flow to skeletal muscle during exercise is altered with advancing age. Changes in arteriolar function that are muscle specific underlie age-induced changes in blood flow distribution. With advancing age, functional adaptations that occur in resistance arterioles from oxidative muscles differ from those that occur in glycolytic muscles. Age-related adaptations of morphology, as well as changes in both endothelial and vascular smooth muscle signalling, differ in muscle of diverse fibre type. Age-induced endothelial dysfunction has been reported in most skeletal muscle arterioles; however, unique alterations in signalling contribute to the dysfunction in arterioles from oxidative muscles as compared with those from glycolytic muscles. In resistance arterioles from oxidative muscle, loss of nitric oxide signalling contributes significantly to endothelial dysfunction, whereas in resistance arterioles from glycolytic muscle, alterations in both nitric oxide and prostanoid signalling underlie endothelial dysfunction. Similarly, adaptations of the vascular smooth muscle that occur with advancing age are heterogeneous between arterioles from oxidative and glycolytic muscles. In both oxidative and glycolytic muscle, late-life exercise training reverses age-related microvascular dysfunction, and exercise training appears to be particularly effective in reversing endothelial dysfunction. Patterns of microvascular ageing that develop among muscles of diverse fibre type and function may be attributable to changing patterns of physical activity with ageing. Importantly, aerobic exercise training, initiated even at an advanced age, restores muscle blood flow distribution patterns and vascular function in old animals to those seen in their young counterparts.
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Date Issued: 2016-04-15
Identifier: FSU_pmch_26575597, 10.1113/JP271005, PMC4933125, 26575597, 26575597
Format: Citation

Title: In Vivo Analysis of Troponin C Knock-In (A8V) Mice: Evidence that TNNC1 Is a Hypertrophic Cardiomyopathy Susceptibility Gene..
Creator: Martins, Adriano S, Parvatiyar, Michelle S, Feng, Han-Zhong, Bos, J Martijn, Gonzalez-Martinez, David, Vukmirovic, Milica, Turna, Rajdeep S, Sanchez-Gonzalez, Marcos A, Badger,...
Show moreMartins, Adriano S, Parvatiyar, Michelle S, Feng, Han-Zhong, Bos, J Martijn, Gonzalez-Martinez, David, Vukmirovic, Milica, Turna, Rajdeep S, Sanchez-Gonzalez, Marcos A, Badger, Crystal-Dawn, Zorio, Diego A R, Singh, Rakesh K, Wang, Yingcai, Jin, J-P, Ackerman, Michael J, Pinto, Jose R
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Abstract/Description: Mutations in thin-filament proteins have been linked to hypertrophic cardiomyopathy, but it has never been demonstrated that variants identified in the TNNC1 (gene encoding troponin C) can evoke cardiac remodeling in vivo. The goal of this study was to determine whether TNNC1 can be categorized as an hypertrophic cardiomyopathy susceptibility gene, such that a mouse model can recapitulate the clinical presentation of the proband. The TNNC1-A8V proband diagnosed with severe obstructive...
Show moreMutations in thin-filament proteins have been linked to hypertrophic cardiomyopathy, but it has never been demonstrated that variants identified in the TNNC1 (gene encoding troponin C) can evoke cardiac remodeling in vivo. The goal of this study was to determine whether TNNC1 can be categorized as an hypertrophic cardiomyopathy susceptibility gene, such that a mouse model can recapitulate the clinical presentation of the proband. The TNNC1-A8V proband diagnosed with severe obstructive hypertrophic cardiomyopathy at 34 years of age exhibited mild-to-moderate thickening in left and right ventricular walls, decreased left ventricular dimensions, left atrial enlargement, and hyperdynamic left ventricular systolic function. Genetically engineered knock-in (KI) mice containing the A8V mutation (heterozygote=KI-TnC-A8V(+/-); homozygote=KI-TnC-A8V(+/+)) were characterized by echocardiography and pressure-volume studies. Three-month-old KI-TnC-A8V(+/+) mice displayed decreased ventricular dimensions, mild diastolic dysfunction, and enhanced systolic function, whereas KI-TnC-A8V(+/-) mice displayed cardiac restriction at 14 months of age. KI hearts exhibited atrial enlargement, papillary muscle hypertrophy, and fibrosis. Liquid chromatography-mass spectroscopy was used to determine incorporation of mutant cardiac troponin C (≈ 21%) into the KI-TnC-A8V(+/-) cardiac myofilament. Reduced diastolic sarcomeric length, increased shortening, and prolonged Ca(2+) and contractile transients were recorded in intact KI-TnC-A8V(+/-) and KI-TnC-A8V(+/+) cardiomyocytes. Ca(2+) sensitivity of contraction in skinned fibers increased with mutant gene dose: KI-TnC-A8V(+/+)>KI-TnC-A8V(+/-)>wild-type, whereas KI-TnC-A8V(+/+) relaxed more slowly on flash photolysis of diazo-2. The TNNC1-A8V mutant increases the Ca(2+)-binding affinity of the thin filament and elicits changes in Ca(2+) homeostasis and cellular remodeling, which leads to diastolic dysfunction. These in vivo alterations further implicate the role of TNNC1 mutations in the development of cardiomyopathy.
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Date Issued: 2015-10-01
Identifier: FSU_pmch_26304555, 10.1161/CIRCGENETICS.114.000957, PMC4618104, 26304555, 26304555
Format: Citation

Title: Intracellular linkers are involved in Mg2+-dependent modulation of the Eag potassium channel.
Creator: Liu, Xinqiu, Wu, Yuying, Zhou, Yi
Abstract/Description: Modulation of activation kinetics by divalent ions is one of the characteristic features of Eag channels. Here, we report that Mg(2+)-dependent deceleration of Eag channel activation is significantly attenuated by a G297E mutation, which exhibits a gain-of-function phenotype in Drosophila by suppressing the effect of shaker mutation on behavior and neuronal excitability. The G297 residue is located in the intracellular linker of transmembrane segments S2 and S3, and is thus not involved in...
Show moreModulation of activation kinetics by divalent ions is one of the characteristic features of Eag channels. Here, we report that Mg(2+)-dependent deceleration of Eag channel activation is significantly attenuated by a G297E mutation, which exhibits a gain-of-function phenotype in Drosophila by suppressing the effect of shaker mutation on behavior and neuronal excitability. The G297 residue is located in the intracellular linker of transmembrane segments S2 and S3, and is thus not involved in direct binding of Mg(2+) ions. Moreover, mutation of the only positively charged residue in the other intracellular linker between S4 and S5 also results in a dramatic reduction of Mg(2+)-dependent modulation of Eag activation kinetics. Collectively, the two mutations in eag eliminate or even paradoxically reverse the effect of Mg(2+) on channel activation and inactivation kinetics. Together, these results suggest an important role of the intracellular linker regions in gating processes of Eag channels.
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Date Issued: 2010-07-01
Identifier: FSU_pmch_20855938, 10.4161/chan.4.4.12329, PMC3322480, 20855938, 20855938, 12329
Format: Citation

Title: Intracellular regions of the Eag potassium channel play a critical role in generation of voltage-dependent currents.
Creator: Li, Yong, Liu, Xinqiu, Wu, Yuying, Xu, Zhe, Li, Hongqin, Griffith, Leslie C, Zhou, Yi
Abstract/Description: Folding, assembly, and trafficking of ion channels are tightly controlled processes and are important for biological functions relevant to health and disease. Here, we report that functional expression of the Eag channel is temperature-sensitive by a mechanism that is independent of trafficking or surface targeting of the channel protein. Eag channels in cells grown at 37 °C exhibit voltage-evoked gating charge movements but fail to conduct K(+) ions. By mutagenesis and chimeric channel...
Show moreFolding, assembly, and trafficking of ion channels are tightly controlled processes and are important for biological functions relevant to health and disease. Here, we report that functional expression of the Eag channel is temperature-sensitive by a mechanism that is independent of trafficking or surface targeting of the channel protein. Eag channels in cells grown at 37 °C exhibit voltage-evoked gating charge movements but fail to conduct K(+) ions. By mutagenesis and chimeric channel studies, we show that the N- and C-terminal regions are involved in controlling a step after movement of the voltage sensor, as well as in regulating biophysical properties of the Eag channel. Synthesis and assembly of Eag at high temperature disrupt the ability of these domains to carry out their function. These results suggest an important role of the intracellular regions in the generation of Eag currents.
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Date Issued: 2011-01-14
Identifier: FSU_pmch_21059657, 10.1074/jbc.M110.184077, PMC3020747, 21059657, 21059657, M110.184077
Format: Citation

Title: Histone deacetylase inhibitors facilitate partner preference formation in female prairie voles.
Creator: Wang, Hui, Duclot, Florian, Liu, Yan, Wang, Zuoxin, Kabbaj, Mohamed
Abstract/Description: In the socially monogamous prairie vole (Microtus ochrogaster), mating induces enduring pair-bonds that are initiated by partner preference formation and regulated by a variety of neurotransmitters, including oxytocin, vasopressin and dopamine. We examined potential epigenetic mechanisms mediating pair-bond regulation and found that the histone deacetylase inhibitors sodium butyrate and trichostatin A (TSA) facilitated partner preference formation in female prairie voles in the absence of...
Show moreIn the socially monogamous prairie vole (Microtus ochrogaster), mating induces enduring pair-bonds that are initiated by partner preference formation and regulated by a variety of neurotransmitters, including oxytocin, vasopressin and dopamine. We examined potential epigenetic mechanisms mediating pair-bond regulation and found that the histone deacetylase inhibitors sodium butyrate and trichostatin A (TSA) facilitated partner preference formation in female prairie voles in the absence of mating. This was associated with a specific upregulation of oxytocin receptor (OTR, oxtr) and vasopressin V1a receptor (V1aR, avpr1a) in the nucleus accumbens (NAcc), through an increase in histone acetylation at their respective promoters. Furthermore, TSA-facilitated partner preference was prevented by OTR or V1aR blockade in the NAcc. Notably, mating-induced partner preference triggered the same epigenetic regulation of oxtr and avpr1a gene promoters as TSA. These observations indicate that TSA and mating facilitate partner preference through epigenetic events, providing, to the best of our knowledge, the first direct evidence for epigenetic regulation of pair-bonding.
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Date Issued: 2013-07-01
Identifier: FSU_pmch_23727821, 10.1038/nn.3420, PMC3703824, 23727821, 23727821, nn.3420
Format: Citation

Title: Inhibition of 14-3-3 Proteins Leads to Schizophrenia-Related Behavioral Phenotypes and Synaptic Defects in Mice.
Creator: Foote, Molly, Qiao, Haifa, Graham, Kourtney, Wu, Yuying, Zhou, Yi
Abstract/Description: The 14-3-3 family of proteins is implicated in the regulation of several key neuronal processes. Previous human and animal studies suggested an association between 14-3-3 dysregulation and schizophrenia. We characterized behavioral and functional changes in transgenic mice that express an isoform-independent 14-3-3 inhibitor peptide in the brain. We recently showed that 14-3-3 functional knockout mice (FKO) exhibit impairments in associative learning and memory. We report here that these 14-3...
Show moreThe 14-3-3 family of proteins is implicated in the regulation of several key neuronal processes. Previous human and animal studies suggested an association between 14-3-3 dysregulation and schizophrenia. We characterized behavioral and functional changes in transgenic mice that express an isoform-independent 14-3-3 inhibitor peptide in the brain. We recently showed that 14-3-3 functional knockout mice (FKO) exhibit impairments in associative learning and memory. We report here that these 14-3-3 FKO mice display other behavioral deficits that correspond to the core symptoms of schizophrenia. These behavioral deficits may be attributed to alterations in multiple neurotransmission systems in the 14-3-3 FKO mice. In particular, inhibition of 14-3-3 proteins results in a reduction of dendritic complexity and spine density in forebrain excitatory neurons, which may underlie the altered synaptic connectivity in the prefrontal cortical synapse of the 14-3-3 FKO mice. At the molecular level, this dendritic spine defect may stem from dysregulated actin dynamics secondary to a disruption of the 14-3-3-dependent regulation of phosphorylated cofilin. Collectively, our data provide a link between 14-3-3 dysfunction, synaptic alterations, and schizophrenia-associated behavioral deficits.
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Date Issued: 2015-09-15
Identifier: FSU_pmch_25863357, 10.1016/j.biopsych.2015.02.015, PMC4544659, 25863357, 25863357, S0006-3223(15)00125-0
Format: Citation

Title: Identification of G1-regulated genes in normally cycling human cells.
Creator: Beyrouthy, Maroun J, Alexander, Karen E, Baldwin, Amy, Whitfield, Michael L, Bass, Hank W, McGee, Dan, Hurt, Myra M
Abstract/Description: Obtaining synchronous cell populations is essential for cell-cycle studies. Methods such as serum withdrawal or use of drugs which block cells at specific points in the cell cycle alter cellular events upon re-entry into the cell cycle. Regulatory events occurring in early G1 phase of a new cell cycle could have been overlooked. We used a robotic mitotic shake-off apparatus to select cells in late mitosis for genome-wide gene expression studies. Two separate microarray experiments were...
Show moreObtaining synchronous cell populations is essential for cell-cycle studies. Methods such as serum withdrawal or use of drugs which block cells at specific points in the cell cycle alter cellular events upon re-entry into the cell cycle. Regulatory events occurring in early G1 phase of a new cell cycle could have been overlooked. We used a robotic mitotic shake-off apparatus to select cells in late mitosis for genome-wide gene expression studies. Two separate microarray experiments were conducted, one which involved isolation of RNA hourly for several hours from synchronous cell populations, and one experiment which examined gene activity every 15 minutes from late telophase of mitosis into G1 phase. To verify synchrony of the cell populations under study, we utilized methods including BrdU uptake, FACS, and microarray analyses of histone gene activity. We also examined stress response gene activity. Our analysis enabled identification of 200 early G1-regulated genes, many of which currently have unknown functions. We also confirmed the expression of a set of genes candidates (fos, atf3 and tceb) by qPCR to further validate the newly identified genes. Genome-scale expression analyses of the first two hours of G1 in naturally cycling cells enabled the discovery of a unique set of G1-regulated genes, many of which currently have unknown functions, in cells progressing normally through the cell division cycle. This group of genes may contain future targets for drug development and treatment of human disease.
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Date Issued: 2008-01-01
Identifier: FSU_pmch_19079774, 10.1371/journal.pone.0003943, PMC2600614, 19079774, 19079774
Format: Citation

Title: Individual differences in novelty-seeking behavior in rats as a model for psychosocial stress-related mood disorders.
Creator: Duclot, Florian, Hollis, Fiona, Darcy, Michael J, Kabbaj, Mohamed
Abstract/Description: Most neuropsychiatric disorders, including stress-related mood disorders, are complex multi-parametric syndromes. Diagnoses are therefore hard to establish and current therapeutic strategies suffer from significant variability in effectiveness, making the understanding of inter-individual variations crucial to unveiling effective new treatments. In rats, such individual differences are observed during exposure to a novel environment, where individuals will exhibit either high or low locomotor...
Show moreMost neuropsychiatric disorders, including stress-related mood disorders, are complex multi-parametric syndromes. Diagnoses are therefore hard to establish and current therapeutic strategies suffer from significant variability in effectiveness, making the understanding of inter-individual variations crucial to unveiling effective new treatments. In rats, such individual differences are observed during exposure to a novel environment, where individuals will exhibit either high or low locomotor activity and can thus be separated into high (HR) and low (LR) responders, respectively. In rodents, a long-lasting, psychosocial, stress-induced depressive state can be triggered by exposure to a social defeat procedure. We therefore analyzed the respective vulnerabilities of HR and LR animals to long-lasting, social defeat-induced behavioral alterations relevant to mood disorders. Two weeks after four daily consecutive social defeat exposures, HR animals exhibit higher anxiety levels, reduced body weight gain, sucrose preference, and a marked social avoidance. LR animals, however, remain unaffected. Moreover, while repeated social defeat exposure induces long-lasting contextual fear memory in both HR and LR animals, only HR individuals exhibit marked freezing behavior four weeks after a single social defeat. Combined, these findings highlight the critical involvement of inter-individual variations in novelty-seeking behavior in the vulnerability to stress-related mood disorders, and uncover a promising model for posttraumatic stress disorder.
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Date Issued: 2011-08-03
Identifier: FSU_pmch_21172365, 10.1016/j.physbeh.2010.12.014, PMC3081532, 21172365, 21172365, S0031-9384(10)00461-0
Format: Citation

Title: Individual differences in the effect of social defeat on anhedonia and histone acetylation in the rat hippocampus.
Creator: Hollis, F, Duclot, F, Gunjan, A, Kabbaj, M
Abstract/Description: Major depression is a growing problem worldwide with variation in symptoms and response to treatment. Individual differences in response to stress may contribute to such observed individual variation in behavior and pathology. Therefore, we investigated depressive-like behavior following exposure to repeated social defeat in a rat model of individual differences in response to novelty. Rats are known to exhibit either high locomotor activity and sustained exploration (high responders, HR) or...
Show moreMajor depression is a growing problem worldwide with variation in symptoms and response to treatment. Individual differences in response to stress may contribute to such observed individual variation in behavior and pathology. Therefore, we investigated depressive-like behavior following exposure to repeated social defeat in a rat model of individual differences in response to novelty. Rats are known to exhibit either high locomotor activity and sustained exploration (high responders, HR) or low activity with minimal exploration (low responders, LR) in a novel environment. We measured anhedonia using the sucrose preference test in HR and LR rats following exposure to social defeat stress or in basal, non-defeated conditions. We then compared histone acetylation in the hippocampus in HR and LR defeat and non-defeated rats and measured mRNA levels of histone deacetylases (HDAC) 3, 4, 5, and Creb binding protein (CBP). We found that basally, HR rats consumed more sucrose solution than LR rats, but reduced consumption after exposure to defeat. LR rats' preference was unaffected by social defeat. We found that HR rats had higher levels of histone acetylation on H3K14 and H2B than LR rats in non-stress conditions. Following defeat, this acetylation pattern changed differentially, with HR rats decreasing acetylation of H3K14 and H2B and LR's increasing acetylation of H3K14. Acetylation on histone H4 decreased following defeat with no individual variation. Basal differences in CBP expression levels may underlie the observed acetylation pattern; however we found no significant effects of defeat in levels of HDACs 3, 4, 5 in the hippocampus.
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Date Issued: 2011-03-01
Identifier: FSU_pmch_20851702, 10.1016/j.yhbeh.2010.09.005, PMC3037445, 20851702, 20851702, S0018-506X(10)00246-1
Format: Citation

Title: Individual differences in novelty seeking predict subsequent vulnerability to social defeat through a differential epigenetic regulation of brain-derived neurotrophic factor expression.
Creator: Duclot, Florian, Kabbaj, Mohamed
Abstract/Description: Some personality traits, including novelty seeking, are good predictors of vulnerability to stress-related mood disorders in both humans and rodents. While high-novelty-seeking rats [high responders (HRs)] are vulnerable to the induction of depressive-like symptoms by social defeat stress, low-novelty-seeking rats [low responders (LRs)] are not. Here, we show that such individual differences are critically regulated by hippocampal BDNF. While LR animals exhibited an increase in BDNF levels...
Show moreSome personality traits, including novelty seeking, are good predictors of vulnerability to stress-related mood disorders in both humans and rodents. While high-novelty-seeking rats [high responders (HRs)] are vulnerable to the induction of depressive-like symptoms by social defeat stress, low-novelty-seeking rats [low responders (LRs)] are not. Here, we show that such individual differences are critically regulated by hippocampal BDNF. While LR animals exhibited an increase in BDNF levels following social defeat, HR individuals did not. This difference in hippocampal BDNF expression promoted the vulnerability of HR and the resilience of LR rats. Indeed, preventing activation of BDNF signaling by infusing the BDNF scavenger TrkB-Fc into the dentate gyrus of the hippocampus of LR rats led to social defeat-induced social avoidance, whereas its activation in HR rats by the TrkB agonist 7,8-dihydroxyflavone promoted social approach. Along with the changes in BDNF expression following defeat, we report in LR animals a downregulation of the inactive BDNF receptor TrkB.T1, associated with an activation of CREB through Akt-mediated signaling, but not MSK1-mediated signaling. In HR animals, none of these molecules were affected by social defeat. Importantly, the BDNF upregulation involved an epigenetically controlled transcription of bdnf exon VI, associated with a coherent regulation of relevant epigenetic factors. Altogether, our data support the importance of hippocampal BDNF regulation in response to stressful events. Moreover, we identify a specific and adaptive regulation of bdnf exon VI in the hippocampus as a critical regulator of stress resilience, and strengthen the importance of epigenetic factors in mediating stress-induced adaptive and maladaptive responses in different individuals.
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Date Issued: 2013-07-03
Identifier: FSU_pmch_23825410, 10.1523/JNEUROSCI.0199-13.2013, PMC3718363, 23825410, 23825410, 33/27/11048
Format: Citation

Title: Melatonin in the mammalian olfactory bulb.
Creator: Corthell, J T, Olcese, J, Trombley, P Q
Abstract/Description: Melatonin is a neurohormone associated with circadian rhythms. A diurnal rhythm in olfactory sensitivity has been previously reported and melatonin receptor mRNAs have been observed in the olfactory bulb, but the effects of melatonin in the olfactory bulb have not been explored. First, we corroborated data from a previous study that identified melatonin receptor messenger RNAs in the olfactory bulb. We then investigated whether melatonin treatment would affect cells in the olfactory bulbs of...
Show moreMelatonin is a neurohormone associated with circadian rhythms. A diurnal rhythm in olfactory sensitivity has been previously reported and melatonin receptor mRNAs have been observed in the olfactory bulb, but the effects of melatonin in the olfactory bulb have not been explored. First, we corroborated data from a previous study that identified melatonin receptor messenger RNAs in the olfactory bulb. We then investigated whether melatonin treatment would affect cells in the olfactory bulbs of rats. Using a combination of polymerase chain reaction (PCR), quantitative PCR (qPCR), cell culture, and electrophysiology, we discovered that melatonin receptors and melatonin synthesis enzymes were present in the olfactory bulb and we observed changes in connexin43 protein, GluR1 mRNA, GluR2 mRNA, Per1 mRNA, Cry2 mRNA, and K(+) currents in response to 2-iodomelatonin. Via qPCR, we observed that messenger RNAs encoding melatonin receptors and melatonin biosynthesis enzymes fluctuated in the olfactory bulb across 24h. Together, these data show that melatonin receptors are present in the olfactory bulb and likely affect olfactory function. Additionally, these data suggest that melatonin may be locally synthesized in the olfactory bulb.
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Date Issued: 2014-03-07
Identifier: FSU_pmch_24365461, 10.1016/j.neuroscience.2013.12.033, PMC3939688, 24365461, 24365461, S0306-4522(13)01056-7
Format: Citation

Title: Methyl supplementation attenuates cocaine-seeking behaviors and cocaine-induced c-Fos activation in a DNA methylation-dependent manner.
Creator: Wright, Katherine N, Hollis, Fiona, Duclot, Florian, Dossat, Amanda M, Strong, Caroline E, Francis, T Chase, Mercer, Roger, Feng, Jian, Dietz, David M, Lobo, Mary Kay, Nestler,...
Show moreWright, Katherine N, Hollis, Fiona, Duclot, Florian, Dossat, Amanda M, Strong, Caroline E, Francis, T Chase, Mercer, Roger, Feng, Jian, Dietz, David M, Lobo, Mary Kay, Nestler, Eric J, Kabbaj, Mohamed
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Abstract/Description: Epigenetic mechanisms, such as histone modifications, regulate responsiveness to drugs of abuse, such as cocaine, but relatively little is known about the regulation of addictive-like behaviors by DNA methylation. To investigate the influence of DNA methylation on the locomotor-activating effects of cocaine and on drug-seeking behavior, rats receiving methyl supplementation via chronic l-methionine (MET) underwent either a sensitization regimen of intermittent cocaine injections or...
Show moreEpigenetic mechanisms, such as histone modifications, regulate responsiveness to drugs of abuse, such as cocaine, but relatively little is known about the regulation of addictive-like behaviors by DNA methylation. To investigate the influence of DNA methylation on the locomotor-activating effects of cocaine and on drug-seeking behavior, rats receiving methyl supplementation via chronic l-methionine (MET) underwent either a sensitization regimen of intermittent cocaine injections or intravenous self-administration of cocaine, followed by cue-induced and drug-primed reinstatement. MET blocked sensitization to the locomotor-activating effects of cocaine and attenuated drug-primed reinstatement, with no effect on cue-induced reinstatement or sucrose self-administration and reinstatement. Furthermore, upregulation of DNA methyltransferase 3a and 3b and global DNA hypomethylation were observed in the nucleus accumbens core (NAc), but not in the medial prefrontal cortex (mPFC), of cocaine-pretreated rats. Glutamatergic projections from the mPFC to the NAc are critically involved in the regulation of cocaine-primed reinstatement, and activation of both brain regions is seen in human addicts when reexposed to the drug. When compared with vehicle-pretreated rats, the immediate early gene c-Fos (a marker of neuronal activation) was upregulated in the NAc and mPFC of cocaine-pretreated rats after cocaine-primed reinstatement, and chronic MET treatment blocked its induction in both regions. Cocaine-induced c-Fos expression in the NAc was associated with reduced methylation at CpG dinucleotides in the c-Fos gene promoter, effects reversed by MET treatment. Overall, these data suggest that drug-seeking behaviors are, in part, attributable to a DNA methylation-dependent process, likely occurring at specific gene loci (e.g., c-Fos) in the reward pathway.
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Date Issued: 2015-06-10
Identifier: FSU_pmch_26063926, 10.1523/JNEUROSCI.5227-14.2015, PMC4461693, 26063926, 26063926, 35/23/8948
Format: Citation

Title: The NMDA receptor NR1 subunit is critically involved in the regulation of NMDA receptor activity by C-terminal Src kinase (Csk).
Creator: Fang, Xiao-Qian, Xu, Jindong, Feng, Shuang, Groveman, Bradley R, Lin, Shuang-Xiu, Yu, Xian-Min
Abstract/Description: Previous studies have shown that Csk plays critical roles in the regulation of neural development, differentiation and glutamate-mediated synaptic plasticity. It has been found that Csk associates with the NR2A and 2B subunits of N-methyl-D-aspartate receptors (NMDARs) in a Src activity-dependent manner and serves as an intrinsic mechanism to provide a "brake" on the induction of long-term synaptic potentiation (LTP) mediated by NMDARs. In contrast to the NR2A and 2B subunits, no apparent...
Show morePrevious studies have shown that Csk plays critical roles in the regulation of neural development, differentiation and glutamate-mediated synaptic plasticity. It has been found that Csk associates with the NR2A and 2B subunits of N-methyl-D-aspartate receptors (NMDARs) in a Src activity-dependent manner and serves as an intrinsic mechanism to provide a "brake" on the induction of long-term synaptic potentiation (LTP) mediated by NMDARs. In contrast to the NR2A and 2B subunits, no apparent tyrosine phosphorylation is found in the NR1 subunit of NMDARs. Here, we report that Csk can also associate with the NR1 subunit in a Src activity-dependent manner. The truncation of the NR1 subunit C-tail which contains only one tyrosine (Y837) significantly reduced the Csk association with the NR1-1a/NR2A receptor complex. Furthermore, we found that either the truncation of NR2A C-tail at aa 857 or the mutation of Y837 in the NR1-1a subunit to phenylalanine blocked the inhibition of NR1-1a/NR2A receptors induced by intracellular application of Csk. Thus, both the NR1 and NR2 subunits are required for the regulation of NMDAR activity by Csk.
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Date Issued: 2011-02-01
Identifier: FSU_pmch_21113815, 10.1007/s11064-010-0330-0, PMC3032389, 21113815, 21113815
Format: Citation

Title: Neurogenesis and neuronal migration in the forebrain of the TorsinA knockout mouse embryo.
Creator: McCarthy, Deirdre M, Gioioso, Valeria, Zhang, Xuan, Sharma, Nutan, Bhide, Pradeep G
Abstract/Description: Early-onset generalized torsion dystonia, also known as DYT1 dystonia, is a childhood onset heritable neurological movement disorder involving painful, involuntary muscle contractions, sustained abnormal postures, and repetitive movements. It is caused by a GAG deletion in the Tor1A gene located on chromosome 9. TorsinA, the product of the Tor1A gene, is expressed throughout the brain beginning early in embryonic development. It plays a role in the regulation of nuclear envelope-cytoskeletal...
Show moreEarly-onset generalized torsion dystonia, also known as DYT1 dystonia, is a childhood onset heritable neurological movement disorder involving painful, involuntary muscle contractions, sustained abnormal postures, and repetitive movements. It is caused by a GAG deletion in the Tor1A gene located on chromosome 9. TorsinA, the product of the Tor1A gene, is expressed throughout the brain beginning early in embryonic development. It plays a role in the regulation of nuclear envelope-cytoskeletal interactions, and presumably nuclear translocation. Since nuclear translocation, powered by cytoskeletal traction, is critical for cell proliferation and migration, we examined whether neurogenesis and neuronal migration are affected in Tor1A-/- mouse brain. Our data show that interkinetic nuclear migration and the pattern of migration of newly generated neurons are impaired in the dorsal forebrain of the Tor1A-/- embryo. However, neurogenesis is not altered significantly. The rate of migration of cells from explants of the medial ganglionic eminence is also impaired in the Tor1A-/- embryo. Thus, loss of torsinA results in subtle but significant alterations in cell proliferation and migration in the embryonic forebrain. These subtle developmental changes are consistent with a lack of significant changes in neuronal numbers, neuronal positioning or size of brain regions in DYT1 dystonia patients.
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Date Issued: 2012-01-01
Identifier: FSU_pmch_23018676, 10.1159/000342260, PMC3712350, 23018676, 23018676, 000342260
Format: Citation

Title: New methods for investigation of neuronal migration in embryonic brain explants.
Creator: Nery, Flávia C, da Hora, Cintia C, Yaqub, Uzma, Zhang, Xuan, McCarthy, Deirdre M, Bhide, Pradeep G, Irimia, Daniel, Breakefield, Xandra O
Abstract/Description: Proper migration of neurons is essential for the formation and normal functioning of the nervous system. Defects in neuronal migration underlie a number of neurologic diseases in humans. Although cell migration is crucial for neural development, molecular mechanisms guiding neuronal migration remain to be elucidated fully. Newborn neurons from the embryonic medial ganglionic eminence (MGE) migrate a long distance dorsally in the developing brain, giving rise to several types of interneurons...
Show moreProper migration of neurons is essential for the formation and normal functioning of the nervous system. Defects in neuronal migration underlie a number of neurologic diseases in humans. Although cell migration is crucial for neural development, molecular mechanisms guiding neuronal migration remain to be elucidated fully. Newborn neurons from the embryonic medial ganglionic eminence (MGE) migrate a long distance dorsally in the developing brain, giving rise to several types of interneurons in the neocortex. In this study, we developed an immunocytochemistry (ICC) protocol to stain neurons migrating out of the MGE explant embedded in Matrigel. We also established a protocol to efficiently transfect cells in MGE explants, achieving a transduction efficiency of more than 30%. In addition, we developed microfluidic chambers for explants that allow visualization of the vectorial migration of individual neurons from mouse embryonic MGE explants. Our microfluidic system allows monitoring of the distribution of cellular organelles (e.g. Golgi) within migrating neurons which have been stained with commercial molecular dyes or transfected with adeno-associated virus (AAV) expressing reporter proteins. These methods provide new paradigms to study neuronal migration in real-time.
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Date Issued: 2015-01-15
Identifier: FSU_pmch_25291524, 10.1016/j.jneumeth.2014.09.028, PMC4268085, 25291524, 25291524, S0165-0270(14)00353-7
Format: Citation

Title: Myelin basic protein induces neuron-specific toxicity by directly damaging the neuronal plasma membrane.
Creator: Zhang, Jie, Sun, Xin, Zheng, Sixin, Liu, Xiao, Jin, Jinghua, Ren, Yi, Luo, Jianhong
Abstract/Description: The central nervous system (CNS) insults may cause massive demyelination and lead to the release of myelin-associated proteins including its major component myelin basic protein (MBP). MBP is reported to induce glial activation but its effect on neurons is still little known. Here we found that MBP specifically bound to the extracellular surface of the neuronal plasma membrane and induced neurotoxicity in vitro. This effect of MBP on neurons was basicity-dependent because the binding was...
Show moreThe central nervous system (CNS) insults may cause massive demyelination and lead to the release of myelin-associated proteins including its major component myelin basic protein (MBP). MBP is reported to induce glial activation but its effect on neurons is still little known. Here we found that MBP specifically bound to the extracellular surface of the neuronal plasma membrane and induced neurotoxicity in vitro. This effect of MBP on neurons was basicity-dependent because the binding was blocked by acidic lipids and competed by other basic proteins. Further studies revealed that MBP induced damage to neuronal membrane integrity and function by depolarizing the resting membrane potential, increasing the permeability to cations and other molecules, and decreasing the membrane fluidity. At last, artificial liposome vesicle assay showed that MBP directly disturbed acidic lipid bilayer and resulted in increased membrane permeability. These results revealed that MBP induces neurotoxicity through its direct interaction with acidic components on the extracellular surface of neuronal membrane, which may suggest a possible contribution of MBP to the pathogenesis in the CNS disorders with myelin damage.
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Date Issued: 2014-09-25
Identifier: FSU_pmch_25255088, 10.1371/journal.pone.0108646, PMC4177931, 25255088, 25255088, PONE-D-14-18395
Format: Citation

Title: Anti-Inflammatory Mechanism of Neural Stem Cell Transplantation in Spinal Cord Injury.
Creator: Cheng, Zhijian, Zhu, Wen, Cao, Kai, Wu, Fei, Li, Jin, Wang, Guoyu, Li, Haopen, Lu, Ming, Ren, Yi, He, Xijing
Abstract/Description: Neural stem cell (NSC) transplantation has been proposed to promote functional recovery after spinal cord injury. However, a detailed understanding of the mechanisms of how NSCs exert their therapeutic plasticity is lacking. We transplanted mouse NSCs into the injured spinal cord seven days after SCI, and the Basso Mouse Scale (BMS) score was performed to assess locomotor function. The anti-inflammatory effects of NSC transplantation was analyzed by immunofluorescence staining of neutrophil...
Show moreNeural stem cell (NSC) transplantation has been proposed to promote functional recovery after spinal cord injury. However, a detailed understanding of the mechanisms of how NSCs exert their therapeutic plasticity is lacking. We transplanted mouse NSCs into the injured spinal cord seven days after SCI, and the Basso Mouse Scale (BMS) score was performed to assess locomotor function. The anti-inflammatory effects of NSC transplantation was analyzed by immunofluorescence staining of neutrophil and macrophages and the detection of mRNA levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interleukin-12 (IL-12). Furthermore, bone marrow-derived macrophages (BMDMs) were co-cultured with NSCs and followed by analyzing the mRNA levels of inducible nitric oxide synthase (iNOS), TNF-α, IL-1β, IL-6 and IL-10 with quantitative real-time PCR. The production of TNF-α and IL-1β by BMDMs was examined using the enzyme-linked immunosorbent assay (ELISA). Transplanted NSCs had significantly increased BMS scores (p < 0.05). Histological results showed that the grafted NSCs migrated from the injection site toward the injured area. NSCs transplantation significantly reduced the number of neutrophils and iNOS+/Mac-2+ cells at the epicenter of the injured area (p < 0.05). Meanwhile, mRNA levels of TNF-α, IL-1β, IL-6 and IL-12 in the NSCs transplantation group were significantly decreased compared to the control group. Furthermore, NSCs inhibited the iNOS expression of BMDMs and the release of inflammatory factors by macrophages in vitro (p < 0.05). These results suggest that NSC transplantation could modulate SCI-induced inflammatory responses and enhance neurological function after SCI via reducing M1 macrophage activation and infiltrating neutrophils. Thus, this study provides a new insight into the mechanisms responsible for the anti-inflammatory effect of NSC transplantation after SCI.
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Date Issued: 2016-08-23
Identifier: FSU_pmch_27563878, 10.3390/ijms17091380, PMC5037660, 27563878, 27563878, ijms17091380
Format: Citation

Title: The Anxiolytic and Antidepressant-like Effects of Testosterone and Estrogen in Gonadectomized Male Rats.
Creator: Carrier, Nicole, Saland, Samantha K, Duclot, Florian, He, Huan, Mercer, Roger, Kabbaj, Mohamed
Abstract/Description: While the influence of testosterone levels on vulnerability to affective disorders is not straightforward, research suggests this hormone may confer some degree of resiliency in men. We recently demonstrated a role for the dentate gyrus in mediating testosterone's protective effects on depressive-like behavior in gonadectomized male rats. Here, testosterone may exert its effects through androgen receptor-mediated mechanisms or via local aromatization to estradiol. Gonadectomized male rats...
Show moreWhile the influence of testosterone levels on vulnerability to affective disorders is not straightforward, research suggests this hormone may confer some degree of resiliency in men. We recently demonstrated a role for the dentate gyrus in mediating testosterone's protective effects on depressive-like behavior in gonadectomized male rats. Here, testosterone may exert its effects through androgen receptor-mediated mechanisms or via local aromatization to estradiol. Gonadectomized male rats were implanted with a placebo, testosterone, or estradiol pellet, and subsequent protective anxiolytic- and antidepressant-like effects of testosterone and its aromatized metabolite, estradiol, were then investigated in the open field and sucrose preference tests, respectively. Moreover, their influence on gene expression in the hippocampus was analyzed by genome-wide complementary DNA microarray analysis. Finally, the contribution of testosterone's aromatization within the dentate gyrus was assessed by local infusion of the aromatase inhibitor fadrozole, whose efficacy was confirmed by liquid chromatography-tandem mass spectrometry. Both hormones had antidepressant-like effects associated with a substantial overlap in transcriptional regulation, particularly in synaptic plasticity- and mitogen-activated protein kinase pathway-related genes. Further, chronic aromatase inhibition within the dentate gyrus blocked the protective effects of testosterone. Both testosterone and estradiol exhibit anxiolytic- and antidepressant-like effects in gonadectomized male rats, while similarly regulating critical mediators of these behaviors, suggesting common underlying mechanisms. Accordingly, we demonstrated that testosterone's protective effects are mediated, in part, by its aromatization in the dentate gyrus. These findings thus provide further insight into a role for estradiol in mediating the protective anxiolytic- and antidepressant-like effects of testosterone.
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Date Issued: 2015-08-15
Identifier: FSU_pmch_25683735, 10.1016/j.biopsych.2014.12.024, PMC4501899, 25683735, 25683735, S0006-3223(15)00040-2
Format: Citation

Title: Balancing sex chromosome expression and satisfying the sexes.
Creator: Horabin, Jamila I
Abstract/Description: Equalizing sex chromosome expression between the sexes when they have largely differing gene content appears to be necessary, and across species, is accomplished in a variety of ways. Even in birds, where the process is less than complete, a mechanism to reduce the difference in gene dose between the sexes exists. In early development, while the dosage difference is unregulated and still in flux, it is frequently exploited by sex determination mechanisms. The Drosophila female sex...
Show moreEqualizing sex chromosome expression between the sexes when they have largely differing gene content appears to be necessary, and across species, is accomplished in a variety of ways. Even in birds, where the process is less than complete, a mechanism to reduce the difference in gene dose between the sexes exists. In early development, while the dosage difference is unregulated and still in flux, it is frequently exploited by sex determination mechanisms. The Drosophila female sex determination process is one clear example, determining the sexes based on X chromosome dose. Recent data show that in Drosophila, the female sex not only reads this gene balance difference, but at the same time usurps the moment. Taking advantage of the transient default state of male dosage compensation, the sex determination master-switch Sex-lethal which resides on the X, has its expression levels enhanced before it works to correct the gene imbalance. Intriguingly, key developmental genes which could create developmental havoc if their levels were unbalanced show more exquisite regulation, suggesting nature distinguishes them and ensures their expression is kept in the desirable range.
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Date Issued: 2012-01-01
Identifier: FSU_pmch_22388008, 10.4161/fly.18822, PMC3365834, 22388008, 22388008, 18822
Format: Citation

Title: Cdk5rap2 exposes the centrosomal root of microcephaly syndromes.
Creator: Megraw, Timothy L, Sharkey, James T, Nowakowski, Richard S
Abstract/Description: Autosomal recessive primary microcephaly (MCPH) is characterized by small brain size as a result of deficient neuron production in the developing cerebral cortex. Although MCPH is a rare disease, the questions surrounding its etiology strike at the core of stem cell biology. The seven genes implicated in MCPH all encode centrosomal proteins and disruption of the MCPH gene Cdk5rap2 in mice revealed its role in neural progenitor proliferation and in maintaining normal centriole replication...
Show moreAutosomal recessive primary microcephaly (MCPH) is characterized by small brain size as a result of deficient neuron production in the developing cerebral cortex. Although MCPH is a rare disease, the questions surrounding its etiology strike at the core of stem cell biology. The seven genes implicated in MCPH all encode centrosomal proteins and disruption of the MCPH gene Cdk5rap2 in mice revealed its role in neural progenitor proliferation and in maintaining normal centriole replication control. We discuss here the impact that centrosome regulation has upon neural progenitors in the developing brain. We integrate the impact of centriole replication defects with the functions of Cdk5rap2 and other MCPH proteins, propose mechanisms for progenitor loss in MCPH, and discuss links to two other microcephaly syndromes.
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Date Issued: 2011-08-01
Identifier: FSU_pmch_21632253, 10.1016/j.tcb.2011.04.007, PMC3371655, 21632253, 21632253, S0962-8924(11)00083-3
Format: Citation

Title: Cenexin1 and Odf2: splice variants with diverged cilium functions..
Creator: Chen, Jieyan V, Megraw, Timothy L
Date Issued: 2013-03-15
Identifier: FSU_pmch_23470458, 10.4161/cc.24152, PMC3637342, 23470458, 23470458, 24152
Format: Citation

Title: Pharmacokinetic properties of 2nd-generation fibroblast growth factor-1 mutants for therapeutic application.
Creator: Xia, Xue, Babcock, Joseph P, Blaber, Sachiko I, Harper, Kathleen M, Blaber, Michael
Abstract/Description: Fibroblast growth factor-1 (FGF-1) is an angiogenic factor with therapeutic potential for the treatment of ischemic disease. FGF-1 has low intrinsic thermostability and is characteristically formulated with heparin as a stabilizing agent. Heparin, however, adds a number of undesirable properties that negatively impact safety and cost. Mutations that increase the thermostability of FGF-1 may obviate the need for heparin in formulation and may prove to be useful "2nd-generation" forms for...
Show moreFibroblast growth factor-1 (FGF-1) is an angiogenic factor with therapeutic potential for the treatment of ischemic disease. FGF-1 has low intrinsic thermostability and is characteristically formulated with heparin as a stabilizing agent. Heparin, however, adds a number of undesirable properties that negatively impact safety and cost. Mutations that increase the thermostability of FGF-1 may obviate the need for heparin in formulation and may prove to be useful "2nd-generation" forms for therapeutic use. We report a pharmacokinetic (PK) study in rabbits of human FGF-1 in the presence and absence of heparin, as well as three mutant forms having differential effects upon thermostability, buried reactive thiols, and heparin affinity. The results support the hypothesis that heparan sulfate proteoglycan (HSPG) in the vasculature of liver, kidney and spleen serves as the principle peripheral compartment in the distribution kinetics. The addition of heparin to FGF-1 is shown to increase endocrine-like properties of distribution. Mutant forms of FGF-1 that enhance thermostability or eliminate buried reactive thiols demonstrate a shorter distribution half-life, a longer elimination half-life, and a longer mean residence time (MRT) in comparison to wild-type FGF-1. The results show how such mutations can produce useful 2nd-generation forms with tailored PK profiles for specific therapeutic application.
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Date Issued: 2012-01-01
Identifier: FSU_pmch_23133616, 10.1371/journal.pone.0048210, PMC3486806, 23133616, 23133616, PONE-D-12-24821
Format: Citation

Title: Pathogenesis associated with a restrictive cardiomyopathy mutant in cardiac troponin T is due to reduced protein stability and greatly increased myofilament Ca2+ sensitivity.
Creator: Parvatiyar, Michelle S, Pinto, Jose Renato
Abstract/Description: Dilated and hypertrophic cardiomyopathy mutations in troponin can blunt effects of protein kinase A (PKA) phosphorylation of cardiac troponin I (cTnI), decreasing myofilament Ca2+-sensitivity; however this effect has never been tested for restrictive cardiomyopathy (RCM) mutants. This study explores whether an RCM cardiac troponin T mutant (cTnT-ΔE96) interferes with convergent PKA regulation and if TnT instability contributes to greatly enhanced Ca2+-sensitivity in skinned fibers. Force of...
Show moreDilated and hypertrophic cardiomyopathy mutations in troponin can blunt effects of protein kinase A (PKA) phosphorylation of cardiac troponin I (cTnI), decreasing myofilament Ca2+-sensitivity; however this effect has never been tested for restrictive cardiomyopathy (RCM) mutants. This study explores whether an RCM cardiac troponin T mutant (cTnT-ΔE96) interferes with convergent PKA regulation and if TnT instability contributes to greatly enhanced Ca2+-sensitivity in skinned fibers. Force of contraction in skinned cardiac porcine fiber and spectroscopic studies were performed. A decrease of -0.26 and -0.25 pCa units in Ca2+-sensitivity of contraction after PKA incubation was observed for skinned fibers incorporated with WT or cTnT-ΔE96, respectively. To further assess whether cTnT-ΔE96 interferes solely with transmission of cTnI phosphorylation effects, skinned fibers were reconstituted with PKA pseudo-phosphorylated cTnI (cTnI-SS/DD.cTnC). Fibers displaced with cTnT-WT, reconstituted with cTnI-SS/DD.cTnC decreased Ca2+-sensitivity of force (pCa50=5.61) compared to control cTnI-WT.cTnC (pCa50=5.75), similarly affecting cTnT-ΔE96 (pCa50=6.03) compared to control \cTnI-WT.cTnC (pCa50=6.14). Fluorescence studies measuring cTnC(IAANS) Ca2+-affinity changes due to cTnT-ΔE96 indicated that higher complexity (thin filament) better recapitulates skinned fiber Ca2+ sensitive changes. Circular dichroism revealed reduced α-helicity and earlier thermal unfolding for cTnT-ΔE96 compared to WT. Although ineffective in decreasing myofilament Ca2+-sensitivity to normal levels, cTnT-ΔE96 does not interfere with PKA cTnI phosphorylation mediated effects; 2) cTnT-ΔE96 requires actin to increase cTnC Ca2+-affinity; and 3) deletion of E96 reduces cTnT stability, likely disrupting crucial thin filament interactions. The pathological effect of cTnT-ΔE96 is largely manifested by dramatic myofilament Ca2+-sensitization which still persists even after PKA phosphorylation mediated Ca2+-desensitization.
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Date Issued: 2015-02-01
Identifier: FSU_pmch_25450489, 10.1016/j.bbagen.2014.09.029, PMC4276470, 25450489, 25450489, S0304-4165(14)00366-3
Format: Citation

Title: Cellular distribution of the fragile X mental retardation protein in the mouse brain.
Creator: Zorio, Diego A R, Jackson, Christine M, Liu, Yong, Rubel, Edwin W, Wang, Yuan
Abstract/Description: The fragile X mental retardation protein (FMRP) plays an important role in normal brain development. Absence of FMRP results in abnormal neuronal morphologies in a selected manner throughout the brain, leading to intellectual deficits and sensory dysfunction in the fragile X syndrome (FXS). Despite FMRP importance for proper brain function, its overall expression pattern in the mammalian brain at the resolution of individual neuronal cell groups is not known. In this study we used FMR1...
Show moreThe fragile X mental retardation protein (FMRP) plays an important role in normal brain development. Absence of FMRP results in abnormal neuronal morphologies in a selected manner throughout the brain, leading to intellectual deficits and sensory dysfunction in the fragile X syndrome (FXS). Despite FMRP importance for proper brain function, its overall expression pattern in the mammalian brain at the resolution of individual neuronal cell groups is not known. In this study we used FMR1 knockout and isogenic wildtype mice to systematically map the distribution of FMRP expression in the entire mouse brain. Using immunocytochemistry and cellular quantification analyses, we identified a large number of prominent cell groups expressing high levels of FMRP at the subcortical levels, in particular sensory and motor neurons in the brainstem and thalamus. In contrast, many cell groups in the midbrain and hypothalamus exhibit low FMRP levels. More important, we describe differential patterns of FMRP distribution in both cortical and subcortical brain regions. Almost all major brain areas contain high and low levels of FMRP cell groups adjacent to each other or between layers of the same cortical areas. These differential patterns indicate that FMRP expression appears to be specific to individual neuronal cell groups instead of being associated with all neurons in distinct brain regions, as previously considered. Taken together, these findings support the notion of FMRP differential neuronal regulation and strongly implicate the contribution of fundamental sensory and motor processing at subcortical levels to FXS pathology. J. Comp. Neurol. 525:818-849, 2017. © 2016 Wiley Periodicals, Inc.
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Date Issued: 2017-03-01
Identifier: FSU_pmch_27539535, 10.1002/cne.24100, PMC5558202, 27539535, 27539535
Format: Citation

Title: Impact of Maternal Serotonin Transporter Genotype on Placental Serotonin, Fetal Forebrain Serotonin, and Neurodevelopment.
Creator: Muller, Christopher L, Anacker, Allison Mj, Rogers, Tiffany D, Goeden, Nick, Keller, Elizabeth H, Forsberg, C Gunnar, Kerr, Travis M, Wender, Carly LA, Anderson, George M,...
Show moreMuller, Christopher L, Anacker, Allison Mj, Rogers, Tiffany D, Goeden, Nick, Keller, Elizabeth H, Forsberg, C Gunnar, Kerr, Travis M, Wender, Carly LA, Anderson, George M, Stanwood, Gregg D, Blakely, Randy D, Bonnin, Alexandre, Veenstra-VanderWeele, Jeremy
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Abstract/Description: Biomarker, neuroimaging, and genetic findings implicate the serotonin transporter (SERT) in autism spectrum disorder (ASD). Previously, we found that adult male mice expressing the autism-associated SERT Ala56 variant have altered central serotonin (5-HT) system function, as well as elevated peripheral blood 5-HT levels. Early in gestation, before midbrain 5-HT projections have reached the cortex, peripheral sources supply 5-HT to the forebrain, suggesting that altered maternal or placenta 5...
Show moreBiomarker, neuroimaging, and genetic findings implicate the serotonin transporter (SERT) in autism spectrum disorder (ASD). Previously, we found that adult male mice expressing the autism-associated SERT Ala56 variant have altered central serotonin (5-HT) system function, as well as elevated peripheral blood 5-HT levels. Early in gestation, before midbrain 5-HT projections have reached the cortex, peripheral sources supply 5-HT to the forebrain, suggesting that altered maternal or placenta 5-HT system function could impact the developing embryo. We therefore used different combinations of maternal and embryo SERT Ala56 genotypes to examine effects on blood, placenta and embryo serotonin levels and neurodevelopment at embryonic day E14.5, when peripheral sources of 5-HT predominate, and E18.5, when midbrain 5-HT projections have reached the forebrain. Maternal SERT Ala56 genotype was associated with decreased placenta and embryonic forebrain 5-HT levels at E14.5. Low 5-HT in the placenta persisted, but forebrain levels normalized by E18.5. Maternal SERT Ala56 genotype effects on forebrain 5-HT levels were accompanied by a broadening of 5-HT-sensitive thalamocortical axon projections. In contrast, no effect of embryo genotype was seen in concepti from heterozygous dams. Blood 5-HT levels were dynamic across pregnancy and were increased in SERT Ala56 dams at E14.5. Placenta RNA sequencing data at E14.5 indicated substantial impact of maternal SERT Ala56 genotype, with alterations in immune and metabolic-related pathways. Collectively, these findings indicate that maternal SERT function impacts offspring placental 5-HT levels, forebrain 5-HT levels, and neurodevelopment.
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Date Issued: 2017-01-01
Identifier: FSU_pmch_27550733, 10.1038/npp.2016.166, PMC5399236, 27550733, 27550733, npp2016166
Format: Citation

Program in Neuroscience (5)	+ -
Center for Brain Repair (2)	+ -
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Department of Statistics (1)	+ -
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Sex Characteristics (9)	+ -
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text (101)	+ -
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