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Diverse Intrinsic Properties Shape Functional Phenotype Of Low-frequency Neurons In The Auditory Brainstem
Title
Diverse Intrinsic Properties Shape Functional Phenotype Of Low-frequency Neurons In The Auditory Brainstem.
Creator
Hong, Hui, Wang, Xiaoyu, Lu, Ting, Zorio, Diego A. R., Wang, Yuan, Sanchez, Jason Tait
Abstract/Description
In the auditory system, tonotopy is the spatial arrangement of where sounds of different frequencies are processed. Defined by the organization of neurons and their inputs, tonotopy emphasizes distinctions in neuronal structure and function across topographic gradients and is a common feature shared among vertebrates. In this study we characterized action potential firing patterns and ion channel properties from neurons located in the extremely low-frequency region of the chicken nucleus...
Show moreIn the auditory system, tonotopy is the spatial arrangement of where sounds of different frequencies are processed. Defined by the organization of neurons and their inputs, tonotopy emphasizes distinctions in neuronal structure and function across topographic gradients and is a common feature shared among vertebrates. In this study we characterized action potential firing patterns and ion channel properties from neurons located in the extremely low-frequency region of the chicken nucleus magnocellularis (NM), an auditory brainstem structure. We found that NM neurons responsible for encoding the lowest sound frequencies (termed NMc neurons) have enhanced excitability and fired bursts of action potentials to sinusoidal inputs <= 10 Hz; a distinct firing pattern compared to higher-frequency neurons. This response property was due to lower amounts of voltage dependent potassium (K-v) conductances, unique combination of K-v subunits and specialized sodium (Na-v) channel properties. Particularly, NMc neurons had significantly lower K(v)1 and K(v)3 currents, but higher K(v)2current. NMc neurons also showed larger and faster transient Nav current (I-NaT) with different voltage dependence of inactivation from higher-frequency neurons. In contrast, significantly smaller resurgent sodium current (I-NaR) was present in NMc with kinetics and voltage dependence that differed from higher-frequency neurons. Immunohistochemistry showed expression of Na(v)1.6 channel subtypes across the tonotopic axis. However, various immunoreactive patterns were observed between regions, likely underlying some tonotopic differences in I-N(aT) and I-NaR. Finally, using pharmacology and computational modeling, we concluded that K(v)3, K(v)2 channels and I-NaR work synergistically to regulate burst firing in NMc.
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Date Issued
2018-06-26
Identifier
FSU_libsubv1_wos_000436338700001, 10.3389/fncel.2018.00175
Format
Citation
Mtor Signaling Regulates Central And Peripheral Circadian Clock Function
Title
Mtor Signaling Regulates Central And Peripheral Circadian Clock Function.
Creator
Ramanathan, Chidambaram, Kathale, Nimish D., Liu, Dong, Lee, Choogon, Freeman, David A., Hogenesch, John B., Cao, Ruifeng, Liu, Andrew C.
Abstract/Description
The circadian clock coordinates physiology and metabolism. mTOR (mammalianmechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Given that mTOR activities exhibit robust circadian oscillations in a variety of...
Show moreThe circadian clock coordinates physiology and metabolism. mTOR (mammalianmechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Given that mTOR activities exhibit robust circadian oscillations in a variety of tissues and cells including the SCN, here we continued to investigate the role of mTOR in orchestrating autonomous clock functions in central and peripheral circadian oscillators. Using a combination of genetic and pharmacological approaches we show that mTOR regulates intrinsic clock properties including period and amplitude. In peripheral clock models of hepatocytes and adipocytes, mTOR inhibition lengthens period and dampens amplitude, whereas mTOR activation shortens period and augments amplitude. Constitutive activation of mTOR in Tsc2(-/-)fibroblasts elevates levels of core clock proteins, including CRY1, BMAL1 and CLOCK. Serum stimulation induces CRY1 upregulation in fibroblasts in an mTOR-dependent but Bmal1- and Period-independent manner. Consistent with results from cellular clock models, mTOR perturbation also regulates period and amplitude in the ex vivo SCN and liver clocks. Further, mTOR heterozygous mice show lengthened circadian period of locomotor activity in both constant darkness and constant light. Together, these results support a significant role for mTOR in circadian timekeeping and in linking metabolic states to circadian clock functions.
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Date Issued
2018-05-01
Identifier
FSU_libsubv1_wos_000434016500019, 10.1371/journal.pgen.1007369
Format
Citation
Reinforcing properties of an intermittent, low dose of ketamine in rats
Title
Reinforcing properties of an intermittent, low dose of ketamine in rats: effects of sex and cycle..
Creator
Wright, Katherine N, Strong, Caroline E, Addonizio, Marjorie N, Brownstein, Naomi C, Kabbaj, Mohamed
Abstract/Description
Repeated intermittent exposure to ketamine has rapid and long-lasting antidepressant effects, but the abuse potential has only been assessed at high doses. Furthermore, while females are more susceptible to depression and more sensitive to ketamine's antidepressant-like effects, the abuse potential for ketamine in females is unknown. The objectives of this study are to determine the reinforcing properties of low-dose intermittent ketamine in adult rats of both sexes and determine whether...
Show moreRepeated intermittent exposure to ketamine has rapid and long-lasting antidepressant effects, but the abuse potential has only been assessed at high doses. Furthermore, while females are more susceptible to depression and more sensitive to ketamine's antidepressant-like effects, the abuse potential for ketamine in females is unknown. The objectives of this study are to determine the reinforcing properties of low-dose intermittent ketamine in adult rats of both sexes and determine whether cycling gonadal hormones influence females' response to ketamine. In male rats, we also aimed to determine whether reinstatement to intermittent ketamine is comparable to intermittent cocaine. Male rats intravenously self-administered cocaine (0.75 mg/kg/infusion) or ketamine (0.1 mg/kg/infusion) once every fourth day, while intact cycling female rats self-administered ketamine only during preidentified stages of their 4-day estrus cycle, when gonadal hormones are either high (proestrus) or low (diestrus). After acquiring self-administration, rats underwent daily extinction training followed by cue-primed and drug-primed reinstatement to assess drug-seeking behavior. Diestrus-trained females fail to maintain ketamine self-administration and did not display reinstatement to ketamine-paired cues. Males and proestrus-trained females reinstated to ketamine-paired cues. Ketamine-primed reinstatement was dependent on simultaneous cue presentation. Male rats reinstated to cocaine priming independent of cue presentation. These findings indicate that females's responsivity to this dose of ketamine depends on stage of cycle, as only proestrus-trained females and males respond to ketamine's reinforcing effects under this treatment paradigm.
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Date Issued
2017-02-01
Identifier
FSU_pmch_27837330, 10.1007/s00213-016-4470-z, PMC5384643, 27837330, 27837330, 10.1007/s00213-016-4470-z
Format
Citation
Viral-mediated Zif268 expression in the prefrontal cortex protects against gonadectomy-induced working memory, long-term memory, and social interaction deficits in male rats.
Title
Viral-mediated Zif268 expression in the prefrontal cortex protects against gonadectomy-induced working memory, long-term memory, and social interaction deficits in male rats.
Creator
Dossat, Amanda M, Jourdi, Hussam, Wright, Katherine N, Strong, Caroline E, Sarkar, Ambalika, Kabbaj, Mohamed
Abstract/Description
In humans, some males experience reductions in testosterone levels, as a natural consequence of aging or in the clinical condition termed hypogonadism, which are associated with impaired cognitive performance and mood disorder(s). Some of these behavioral deficits can be reversed by testosterone treatment. Our previous work in rats reported that sex differences in the expression of the transcription factor Zif268, a downstream target of testosterone, within the medial prefrontal cortex (mPFC)...
Show moreIn humans, some males experience reductions in testosterone levels, as a natural consequence of aging or in the clinical condition termed hypogonadism, which are associated with impaired cognitive performance and mood disorder(s). Some of these behavioral deficits can be reversed by testosterone treatment. Our previous work in rats reported that sex differences in the expression of the transcription factor Zif268, a downstream target of testosterone, within the medial prefrontal cortex (mPFC) mediates sex differences in social interaction. In the present study, we aimed to examine the effects of gonadectomy (GNX) in male rats on mPFC Zif268 expression, mood and cognitive behaviors. We also examined whether reinstitution of Zif268 in GNX rats will correct some of the behavioral deficits observed following GNX. Our results show that GNX induced a downregulation of Zif268 protein in the mPFC, which was concomitant with impaired memory in the y-maze and spontaneous object recognition test, reduced social interaction time, and depression-like behaviors in the forced swim test. Reinstitution of mPFC Zif268, using a novel adeno-associated-viral (AAV) construct, abrogated GNX-induced working memory and long-term memory impairments, and reductions in social interaction time, but not GNX-induced depression-like behaviors. These findings suggest that mPFC Zif268 exerts beneficial effects on memory and social interaction, and could be a potential target for novel treatments for behavioral impairments observed in hypogonadal and aged men with declining levels of gonadal hormones.
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Date Issued
2017-01-06
Identifier
FSU_pmch_27816701, 10.1016/j.neuroscience.2016.10.062, PMC5154846, 27816701, 27816701, S0306-4522(16)30603-0
Format
Citation
Prediction of individual differences in fear response by novelty seeking, and disruption of contextual fear memory reconsolidation by ketamine.
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
Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats.
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
Reversal Learning Deficits Associated with Increased Frontal Cortical Brain-Derived Neurotrophic Factor Tyrosine Kinase B Signaling in a Prenatal Cocaine Exposure Mouse Model.
Title
Reversal Learning Deficits Associated with Increased Frontal Cortical Brain-Derived Neurotrophic Factor Tyrosine Kinase B Signaling in a Prenatal Cocaine Exposure Mouse Model.
Creator
McCarthy, Deirdre M, Bell, Genevieve A, Cannon, Elisa N, Mueller, Kaly A, Huizenga, Megan N, Sadri-Vakili, Ghazaleh, Fadool, Debra A, Bhide, Pradeep G
Abstract/Description
Prenatal cocaine exposure remains a major public health concern because of its adverse impact on cognitive function in children and adults. We report that prenatal cocaine exposure produces significant deficits in reversal learning, a key component of cognitive flexibility, in a mouse model. We used an olfactory reversal learning paradigm and found that the prenatally cocaine-exposed mice showed a marked failure to learn the reversed paradigm. Because brain-derived neurotrophic factor (BDNF)...
Show morePrenatal cocaine exposure remains a major public health concern because of its adverse impact on cognitive function in children and adults. We report that prenatal cocaine exposure produces significant deficits in reversal learning, a key component of cognitive flexibility, in a mouse model. We used an olfactory reversal learning paradigm and found that the prenatally cocaine-exposed mice showed a marked failure to learn the reversed paradigm. Because brain-derived neurotrophic factor (BDNF) is a key regulator of cognitive functions, and because prenatal cocaine exposure increases the expression of BDNF and the phosphorylated form of its receptor, tyrosine kinase B (TrkB), we examined whether BDNF-TrkB signaling is involved in mediating the reversal learning deficit in prenatally cocaine-exposed mice. Systemic administration of a selective TrkB receptor antagonist restored normal reversal learning in prenatally cocaine-exposed mice, suggesting that increased BDNF-TrkB signaling may be an underlying mechanism of reversal learning deficits. Our findings provide novel mechanistic insights into the reversal learning phenomenon and may have significant translational implications because impaired cognitive flexibility is a key symptom in psychiatric conditions of developmental onset.
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Date Issued
2016-01-01
Identifier
FSU_pmch_27951531, 10.1159/000452739, PMC5360472, 27951531, 27951531, 000452739
Format
Citation