Publications by authors named "Ryan W Logan"

52 Publications

Sex Differences in Molecular Rhythms in the Human Cortex.

Biol Psychiatry 2021 Mar 8. Epub 2021 Mar 8.

Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania; Translational Neuroscience Program, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania. Electronic address:

Background: Diurnal rhythms in gene expression have been detected in the human brain. Previous studies found that males and females exhibit 24-hour rhythms in known circadian genes, with earlier peak expression in females. Whether there are sex differences in large-scale transcriptional rhythms in the cortex that align with observed sex differences in physiological and behavioral rhythms is currently unknown.

Methods: Diurnal rhythmicity of gene expression was determined for males and females using RNA sequencing data from human postmortem dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). Sex differences among rhythmic genes were determined using significance cutoffs, threshold-free analyses, and R difference. Phase concordance was assessed across the DLPFC and ACC for males and females. Pathway and transcription factor analyses were also conducted on significantly rhythmic genes.

Results: Canonical circadian genes had diurnal rhythms in both sexes with similar amplitude and phase. When analyses were expanded to the entire transcriptome, significant sex differences in transcriptional rhythms emerged. There were nearly twice as many rhythmic transcripts in the DLPFC in males and nearly 4 times as many rhythmic transcripts in the ACC in females. Results suggest a diurnal rhythm in synaptic transmission specific to the ACC in females (e.g., GABAergic [gamma-aminobutyric acidergic] and cholinergic neurotransmission). For males, there was phase concordance between the DLPFC and ACC, while phase asynchrony was found in females.

Conclusions: There are robust sex differences in molecular rhythms of genes in the DLPFC and ACC, providing potential mechanistic insights into how neurotransmission and synaptic function are modulated in a circadian-dependent and sex-specific manner.
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http://dx.doi.org/10.1016/j.biopsych.2021.03.005DOI Listing
March 2021

Vesicular glutamate transporter modulates sex differences in dopamine neuron vulnerability to age-related neurodegeneration.

Aging Cell 2021 Apr 28:e13365. Epub 2021 Apr 28.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Age is the greatest risk factor for Parkinson's disease (PD) which causes progressive loss of dopamine (DA) neurons, with males at greater risk than females. Intriguingly, some DA neurons are more resilient to degeneration than others. Increasing evidence suggests that vesicular glutamate transporter (VGLUT) expression in DA neurons plays a role in this selective vulnerability. We investigated the role of DA neuron VGLUT in sex- and age-related differences in DA neuron vulnerability using the genetically tractable Drosophila model. We found sex differences in age-related DA neurodegeneration and its associated locomotor behavior, where males exhibit significantly greater decreases in both DA neuron number and locomotion during aging compared with females. We discovered that dynamic changes in DA neuron VGLUT expression mediate these age- and sex-related differences, as a potential compensatory mechanism for diminished DA neurotransmission during aging. Importantly, female Drosophila possess higher levels of VGLUT expression in DA neurons compared with males, and this finding is conserved across flies, rodents, and humans. Moreover, we showed that diminishing VGLUT expression in DA neurons eliminates females' greater resilience to DA neuron loss across aging. This offers a new mechanism for sex differences in selective DA neuron vulnerability to age-related DA neurodegeneration. Finally, in mice, we showed that the ability of DA neurons to achieve optimal control over VGLUT expression is essential for DA neuron survival. These findings lay the groundwork for the manipulation of DA neuron VGLUT expression as a novel therapeutic strategy to boost DA neuron resilience to age- and PD-related neurodegeneration.
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http://dx.doi.org/10.1111/acel.13365DOI Listing
April 2021

VGLUT2 is a determinant of dopamine neuron resilience in a rotenone model of dopamine neurodegeneration.

J Neurosci 2021 Apr 23. Epub 2021 Apr 23.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA

Parkinson's disease (PD) is characterized by progressive dopamine (DA) neuron loss in the substantia nigra (SNc). In contrast, DA neurons in the ventral tegmental area (VTA) are relatively protected from neurodegeneration, but the underlying mechanisms for this resilience remain poorly understood. Recent work suggests that expression of the vesicular glutamate transporter 2 (VGLUT2) selectively impacts midbrain DA neuron vulnerability. We investigated whether altered DA neuron VGLUT2 expression determines neuronal resilience in rats exposed to rotenone, a mitochondrial complex I inhibitor and toxicant model of PD. We discovered that VTA/SNc DA neurons that expressed VGLUT2 are more resilient to rotenone-induced DA neurodegeneration. Surprisingly, the density of neurons with detectable VGLUT2 expression in the VTA and SNc increases in response to rotenone. Furthermore, dopaminergic terminals within the nucleus accumbens, where the majority of VGLUT2-expressing DA neurons project, exhibit greater resilience compared to DA terminals in the caudate/putamen. More broadly, VGLUT2-expressing terminals are protected throughout the striatum from rotenone-induced degeneration. Together, our data demonstrate that a distinct subpopulation of VGLUT2-expressing DA neurons are relatively protected from rotenone neurotoxicity. Rotenone-induced upregulation of the glutamatergic machinery in VTA and SNc neurons and their projections may be part of a broader neuroprotective mechanism. These findings offer a putative new target for neuronal resilience that can be manipulated to prevent toxicant-induced DA neurodegeneration in PD.Environmental exposures to pesticides contribute significantly to pathological processes that culminate in Parkinson's disease (PD). The pesticide rotenone has been used to generate a PD model that replicates key features of the illness including dopamine neurodegeneration. To date, longstanding questions remain: are there dopamine neuron subpopulations resilient to rotenone, and if so, what are the molecular determinants of this resilience? Here we show that the subpopulation of midbrain dopaminergic neurons that express the vesicular glutamate transporter 2 (VGLUT2) are more resilient to rotenone-induced neurodegeneration. Rotenone also upregulates VGLUT2 more broadly in the midbrain, suggesting VGLUT2 expression generally confers increased resilience to rotenone. VGLUT2 may therefore be a new target for boosting neuronal resilience to prevent toxicant-induced DA neurodegeneration in PD.
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http://dx.doi.org/10.1523/JNEUROSCI.2770-20.2021DOI Listing
April 2021

Experimentally imposed circadian misalignment alters the neural response to monetary rewards and response inhibition in healthy adolescents.

Psychol Med 2021 Mar 17:1-9. Epub 2021 Mar 17.

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Background: Sleep and circadian timing shifts later during adolescence, conflicting with early school start times, and resulting in circadian misalignment. Although circadian misalignment has been linked to depression, substance use, and altered reward function, a paucity of experimental studies precludes the determination of causality. Here we tested, for the first time, whether experimentally-imposed circadian misalignment alters the neural response to monetary reward and/or response inhibition.

Methods: Healthy adolescents (n = 25, ages 13-17) completed two in-lab sleep schedules in counterbalanced order: An 'aligned' condition based on typical summer sleep-wake times (0000-0930) and a 'misaligned' condition mimicking earlier school year sleep-wake times (2000-0530). Participants completed morning and afternoon functional magnetic resonance imaging scans during each condition, including monetary reward (morning only) and response inhibition (morning and afternoon) tasks. Total sleep time and circadian phase were assessed via actigraphy and salivary melatonin, respectively.

Results: Bilateral ventral striatal (VS) activation during reward outcome was lower during the Misaligned condition after accounting for the prior night's total sleep time. Bilateral VS activation during reward anticipation was lower during the Misaligned condition, including after accounting for covariates, but did not survive correction for multiple comparisons. Right inferior frontal gyrus activation during response inhibition was lower during the Misaligned condition, before and after accounting for total sleep time and vigilant attention, but only during the morning scan.

Conclusions: Our findings provide novel experimental evidence that circadian misalignment analogous to that resulting from school schedules may have measurable impacts on healthy adolescents' reward processing and inhibition of prepotent responses.
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http://dx.doi.org/10.1017/S0033291721000787DOI Listing
March 2021

Dopamine regulates pancreatic glucagon and insulin secretion via adrenergic and dopaminergic receptors.

Transl Psychiatry 2021 Feb 16;11(1):59. Epub 2021 Feb 16.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA.

Dopamine (DA) and norepinephrine (NE) are catecholamines primarily studied in the central nervous system that also act in the pancreas as peripheral regulators of metabolism. Pancreatic catecholamine signaling has also been increasingly implicated as a mechanism responsible for the metabolic disturbances produced by antipsychotic drugs (APDs). Critically, however, the mechanisms by which catecholamines modulate pancreatic hormone release are not completely understood. We show that human and mouse pancreatic α- and β-cells express the catecholamine biosynthetic and signaling machinery, and that α-cells synthesize DA de novo. This locally-produced pancreatic DA signals via both α- and β-cell adrenergic and dopaminergic receptors with different affinities to regulate glucagon and insulin release. Significantly, we show DA functions as a biased agonist at α-adrenergic receptors, preferentially signaling via the canonical G protein-mediated pathway. Our findings highlight the interplay between DA and NE signaling as a novel form of regulation to modulate pancreatic hormone release. Lastly, pharmacological blockade of DA D-like receptors in human islets with APDs significantly raises insulin and glucagon release. This offers a new mechanism where APDs act directly on islet α- and β-cell targets to produce metabolic disturbances.
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http://dx.doi.org/10.1038/s41398-020-01171-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884786PMC
February 2021

High-throughput measurement of fibroblast rhythms reveals genetic heritability of circadian phenotypes in diversity outbred mice and their founder strains.

Sci Rep 2021 Jan 28;11(1):2573. Epub 2021 Jan 28.

Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, 600 Main Street, Bar Harbor, 04609, ME, USA.

Circadian variability is driven by genetics and Diversity Outbred (DO) mice is a powerful tool for examining the genetics of complex traits because their high genetic and phenotypic diversity compared to conventional mouse crosses. The DO population combines the genetic diversity of eight founder strains including five common inbred and three wild-derived strains. In DO mice and their founders, we established a high-throughput system to measure cellular rhythms using in vitro preparations of skin fibroblasts. Among the founders, we observed strong heritability for rhythm period, robustness, phase and amplitude. We also found significant sex and strain differences for these rhythms. Extreme differences in period for molecular and behavioral rhythms were found between the inbred A/J strain and the wild-derived CAST/EiJ strain, where A/J had the longest period and CAST/EiJ had the shortest. In addition, we measured cellular rhythms in 329 DO mice, which displayed far greater phenotypic variability than the founders-80% of founders compared to only 25% of DO mice had periods of ~ 24 h. Collectively, our findings demonstrate that genetic diversity contributes to phenotypic variability in circadian rhythms, and high-throughput characterization of fibroblast rhythms in DO mice is a tractable system for examining the genetics of circadian traits.
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http://dx.doi.org/10.1038/s41598-021-82069-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843998PMC
January 2021

Roles of inflammation in intrinsic pathophysiology and antipsychotic drug-induced metabolic disturbances of schizophrenia.

Behav Brain Res 2021 Mar 14;402:113101. Epub 2021 Jan 14.

Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA; Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address:

Schizophrenia is a debilitating psychiatric illness that remains poorly understood. While the bulk of symptomatology has classically been associated with disrupted brain functioning, accumulating evidence demonstrates that schizophrenia is characterized by systemic inflammation and disturbances in metabolism. Indeed, metabolic disease is a major determinant of the high mortality rate associated with schizophrenia. Antipsychotic drugs (APDs) have revolutionized management of psychosis, making it possible to rapidly control psychotic symptoms. This has ultimately reduced relapse rates of psychotic episodes and improved overall quality of life for people with schizophrenia. However, long-term APD use has also been associated with significant metabolic disturbances including weight gain, dysglycemia, and worsening of the underlying cardiometabolic disease intrinsic to schizophrenia. While the mechanisms for these intrinsic and medication-induced metabolic effects remain unclear, inflammation appears to play a key role. Here, we review the evidence for roles of inflammatory mechanisms in the disease features of schizophrenia and how these mechanisms interact with APD treatment. We also discuss the effects of common inflammatory mediators on metabolic disease. Then, we review the evidence of intrinsic and APD-mediated effects on systemic inflammation in schizophrenia. Finally, we speculate about possible treatment strategies. Developing an improved understanding of inflammatory processes in schizophrenia may therefore introduce new, more effective options for treating not only schizophrenia but also primary metabolic disorders.
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http://dx.doi.org/10.1016/j.bbr.2020.113101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882027PMC
March 2021

Circadian-Dependent and Sex-Dependent Increases in Intravenous Cocaine Self-Administration in Mutant Mice.

J Neurosci 2021 02 2;41(5):1046-1058. Epub 2020 Dec 2.

Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219

Substance use disorder (SUD) is associated with disruptions in circadian rhythms. The circadian transcription factor neuronal PAS domain protein 2 (NPAS2) is enriched in reward-related brain regions and regulates reward, but its role in SU is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration (acquisition, dose-response, progressive ratio, extinction, cue-induced reinstatement) in wild-type (WT) and mutant mice at different times of day. In the light (inactive) phase, cocaine self-administration, reinforcement, motivation and extinction responding were increased in all mutants. Sex differences emerged during the dark (active) phase with mutation increasing self-administration, extinction responding, and reinstatement only in females as well as reinforcement and motivation in males and females. To determine whether circulating hormones are driving these sex differences, we ovariectomized WT and mutant females and confirmed that unlike sham controls, ovariectomized mutant mice showed no increase in self-administration. To identify whether striatal brain regions are activated in mutant females, we measured cocaine-induced ΔFosB expression. Relative to WT, ΔFosB expression was increased in D1+ neurons in the nucleus accumbens (NAc) core and dorsolateral (DLS) striatum in mutant females after dark phase self-administration. We also identified potential target genes that may underlie the behavioral responses to cocaine in mutant females. These results suggest NPAS2 regulates reward and activity in specific striatal regions in a sex and time of day (TOD)-specific manner. Striatal activation could be augmented by circulating sex hormones, leading to an increased effect of mutation in females. Circadian disruptions are a common symptom of substance use disorders (SUDs) and chronic exposure to drugs of abuse alters circadian rhythms, which may contribute to subsequent SU. Diurnal rhythms are commonly found in behavioral responses to drugs of abuse with drug sensitivity and motivation peaking during the dark (active) phase in nocturnal rodents. Emerging evidence links disrupted circadian genes to SU vulnerability and drug-induced alterations to these genes may augment drug-seeking. The circadian transcription factor neuronal PAS domain protein 2 (NPAS2) is enriched in reward-related brain regions and regulates reward, but its role in SU is unclear. To examine the role of NPAS2 in drug taking, we measured intravenous cocaine self-administration in wild-type (WT) and mutant mice at different times of day.
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http://dx.doi.org/10.1523/JNEUROSCI.1830-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880289PMC
February 2021

Valproate reverses mania-like behaviors in mice via preferential targeting of HDAC2.

Mol Psychiatry 2020 Nov 24. Epub 2020 Nov 24.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.

Valproate (VPA) has been used in the treatment of bipolar disorder since the 1990s. However, the therapeutic targets of VPA have remained elusive. Here we employ a preclinical model to identify the therapeutic targets of VPA. We find compounds that inhibit histone deacetylase proteins (HDACs) are effective in normalizing manic-like behavior, and that class I HDACs (e.g., HDAC1 and HDAC2) are most important in this response. Using an RNAi approach, we find that HDAC2, but not HDAC1, inhibition in the ventral tegmental area (VTA) is sufficient to normalize behavior. Furthermore, HDAC2 overexpression in the VTA prevents the actions of VPA. We used RNA sequencing in both mice and human induced pluripotent stem cells (iPSCs) derived from bipolar patients to further identify important molecular targets. Together, these studies identify HDAC2 and downstream targets for the development of novel therapeutics for bipolar mania.
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http://dx.doi.org/10.1038/s41380-020-00958-2DOI Listing
November 2020

Critical roles for developmental hormones and genetic sex in stress-induced transcriptional changes associated with depression.

Neuropsychopharmacology 2021 01;46(1):221-222

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.

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http://dx.doi.org/10.1038/s41386-020-00792-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689456PMC
January 2021

Roles of dopamine and glutamate co-release in the nucleus accumbens in mediating the actions of drugs of abuse.

FEBS J 2021 Mar 11;288(5):1462-1474. Epub 2020 Aug 11.

Department of Psychiatry, Translational Neuroscience Program, University of Pittsburgh, Pittsburgh, PA, USA.

Projections of ventral tegmental area dopamine (DA) neurons to the medial shell of the nucleus accumbens have been increasingly implicated as integral to the behavioral and physiological changes involved in the development of substance use disorders (SUDs). Recently, many of these nucleus accumbens-projecting DA neurons were found to also release the neurotransmitter glutamate. This glutamate co-release from DA neurons is critical in mediating the effect of drugs of abuse on addiction-related behaviors. Potential mechanisms underlying the role(s) of dopamine/glutamate co-release in contributing to SUDs are unclear. Nevertheless, an important clue may relate to glutamate's ability to potentiate loading of DA into synaptic vesicles within terminals in the nucleus accumbens in response to drug-induced elevations in neuronal activity, enabling a more robust release of DA after stimulation. Here, we summarize how drugs of abuse, particularly cocaine, opioids, and alcohol, alter DA release in the nucleus accumbens medial shell, examine the potential role of DA/glutamate co-release in mediating these effects, and discuss future directions for further investigating these mechanisms.
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http://dx.doi.org/10.1111/febs.15496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854787PMC
March 2021

Substrain specific behavioral responses in male C57BL/6N and C57BL/6J mice to a shortened 21-hour day and high-fat diet.

Chronobiol Int 2020 06 13;37(6):809-823. Epub 2020 May 13.

Department of Biological Sciences, Bridgewater State University , Bridgewater, Massachusetts, USA.

Altered circadian rhythms have negative consequences on health and behavior. Emerging evidence suggests genetics influences the physiological and behavioral responses to circadian disruption. We investigated the effects of a 21 h day (T = 21 cycle), with high-fat diet consumption, on locomotor activity, explorative behaviors, and health in male C57BL/6J and C57BL/6N mice. Mice were exposed to either a T = 24 or T = 21 cycle and given standard rodent chow (RC) or a 60% high-fat diet (HFD) followed by behavioral assays and physiological measures. We uncovered numerous strain differences within the behavioral and physiological assays, mainly that C57BL/6J mice exhibit reduced susceptibility to the obesogenic effects of (HFD) and anxiety-like behavior as well as increased circadian and novelty-induced locomotor activity compared to C57BL/6N mice. There were also substrain-specific differences in behavioral responses to the T = 21 cycle, including exploratory behaviors and circadian locomotor activity. Under the 21-h day, mice consuming RC displayed entrainment, while mice exposed to HFD exhibited a lengthening of activity rhythms. In the open-field and light-dark box, mice exposed to the T = 21 cycle had increased novelty-induced locomotor activity with no further effects of diet, suggesting daylength may affect mood-related behaviors. These results indicate that different circadian cycles impact metabolic and behavioral responses depending on genetic background, and despite circadian entrainment.
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http://dx.doi.org/10.1080/07420528.2020.1756840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758871PMC
June 2020

Sex differences in adult mood and in stress-induced transcriptional coherence across mesocorticolimbic circuitry.

Transl Psychiatry 2020 02 6;10(1):59. Epub 2020 Feb 6.

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Women are approximately two times as likely to be diagnosed with major depressive disorder (MDD) compared to men. While sex differences in MDD might be driven by circulating gonadal hormones, we hypothesized that developmental hormone exposure and/or genetic sex might play a role. Mice were gonadectomized in adulthood to isolate the role of developmental hormones. We examined the effects of developmental gonadal and genetic sex on anhedonia-/depressive-like behaviors under non-stress and chronic stress conditions and performed RNA-sequencing in three mood-relevant brain regions. We used an integrative network approach to identify transcriptional modules and stress-specific hub genes regulating stress susceptibility, with a focus on whether these differed by sex. After identifying sex differences in anhedonia-/depressive-like behaviors (female > male), we show that both developmental hormone exposure (gonadal female > gonadal male) and genetic sex (XX > XY) contribute to the sex difference. The top biological pathways represented by differentially expressed genes were related to immune function; we identify which differentially expressed genes are driven by developmental gonadal or genetic sex. There was very little overlap in genes affected by chronic stress in males and females. We also identified highly co-expressed gene modules affected by stress, some of which were affected in opposite directions in males and females. Since all mice had equivalent hormone exposure in adulthood, these results suggest that sex differences in gonadal hormone exposure during sensitive developmental periods program adult sex differences in mood, and that these sex differences are independent of adult circulating gonadal hormones.
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http://dx.doi.org/10.1038/s41398-020-0742-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026087PMC
February 2020

Prospects for finding the mechanisms of sex differences in addiction with human and model organism genetic analysis.

Genes Brain Behav 2020 03 11;19(3):e12645. Epub 2020 Feb 11.

Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, Maine.

Despite substantial evidence for sex differences in addiction epidemiology, addiction-relevant behaviors and associated neurobiological phenomena, the mechanisms and implications of these differences remain unknown. Genetic analysis in model organism is a potentially powerful and effective means of discovering the mechanisms that underlie sex differences in addiction. Human genetic studies are beginning to show precise risk variants that influence the mechanisms of addiction but typically lack sufficient power or neurobiological mechanistic access, particularly for the discovery of the mechanisms that underlie sex differences. Our thesis in this review is that genetic variation in model organisms are a promising approach that can complement these investigations to show the biological mechanisms that underlie sex differences in addiction.
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http://dx.doi.org/10.1111/gbb.12645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060801PMC
March 2020

Male C57BL6/N and C57BL6/J Mice Respond Differently to Constant Light and Running-Wheel Access.

Front Behav Neurosci 2019 10;13:268. Epub 2019 Dec 10.

Department of Biological Sciences, Bridgewater State University, Bridgewater, MA, United States.

Previous studies have shown that exposure to circadian disruption produces negative effects on overall health and behavior. More recent studies illustrate that strain differences in the behavioral and physiological responses to circadian disruption exist, even if the strains have similar genetic backgrounds. As such, we investigated the effects of constant room-level light (LL) with running-wheel access on the behavior and physiology of male C57BL6/J from Jackson Laboratories and C57BL6/N from Charles River Laboratories mice. Mice were exposed to either a 12:12 light-dark (LD) cycle or LL and given either a standard home cage or a cage with a running-wheel. Following 6 weeks of LD or LL, their response to behavioral assays (open-field, light-dark box, novel object) and measures of metabolism were observed. Under standard LD, C57BL6/J mice exhibited increased locomotor activity and reduced exploratory behavior compared to C57BL6/N mice. In LL, C57BL6/J mice had greater period lengthening and increased anxiety, while C57BL6/N mice exhibited increased weight gain and no change in exploratory behavior. C57BL6/J mice also decreased exploration with running-wheel access while C57BL6/N mice did not. These results further demonstrate that C57BL/6 substrains exhibit different behavioral and physiological responses to circadian disruption and wheel-running access.
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http://dx.doi.org/10.3389/fnbeh.2019.00268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914853PMC
December 2019

Characterization of genetically complex Collaborative Cross mouse strains that model divergent locomotor activating and reinforcing properties of cocaine.

Psychopharmacology (Berl) 2020 Apr 3;237(4):979-996. Epub 2020 Jan 3.

Department of Genetics, School of Medicine, University of North Carolina, 120 Mason Farm Road, CB7361, Chapel Hill, NC, 27599, USA.

Rationale: Few effective treatments exist for cocaine use disorders due to gaps in knowledge about its complex etiology. Genetically defined animal models provide a useful tool for advancing our understanding of the biological and genetic underpinnings of addiction-related behavior and evaluating potential treatments. However, many attempts at developing mouse models of behavioral disorders were based on overly simplified single gene perturbations, often leading to inconsistent and misleading results in pre-clinical pharmacology studies. A genetically complex mouse model may better reflect disease-related behaviors.

Objectives: Screening defined, yet genetically complex, intercrosses of the Collaborative Cross (CC) mice revealed two lines, RIX04/17 and RIX41/51, with extreme high and low behavioral responses to cocaine. We characterized these lines as well as their CC parents, CC004/TauUnc and CC041/TauUnc, to evaluate their utility as novel model systems for studying the biological and genetic mechanisms underlying behavioral responses to cocaine.

Methods: Behavioral responses to acute (initial locomotor sensitivity) and repeated (behavioral sensitization, conditioned place preference, intravenous self-administration) exposures to cocaine were assessed. We also examined the monoaminergic system (striatal tissue content and in vivo fast scan cyclic voltammetry), HPA axis reactivity, and circadian rhythms as potential mechanisms for the divergent phenotypic behaviors observed in the two strains, as these systems have a previously known role in mediating addiction-related behaviors.

Results: RIX04/17 and 41/51 show strikingly divergent initial locomotor sensitivity to cocaine with RIX04/17 exhibiting very high and RIX41/51 almost no response. The lines also differ in the emergence of behavioral sensitization with RIX41/51 requiring more exposures to exhibit a sensitized response. Both lines show conditioned place preference for cocaine. We determined that the cocaine sensitivity phenotype in each RIX line was largely driven by the genetic influence of one CC parental strain, CC004/TauUnc and CC041/TauUnc. CC004 demonstrates active operant cocaine self-administration and CC041 is unable to acquire under the same testing conditions, a deficit which is specific to cocaine as both strains show operant response for a natural food reward. Examination of potential mechanisms driving differential responses to cocaine show strain differences in molecular and behavioral circadian rhythms. Additionally, while there is no difference in striatal dopamine tissue content or dynamics, there are selective differences in striatal norepinephrine and serotonergic tissue content.

Conclusions: These CC strains offer a complex polygenic model system to study underlying mechanisms of cocaine response. We propose that CC041/TauUnc and CC004/TauUnc will be useful for studying genetic and biological mechanisms underlying resistance or vulnerability to the stimulatory and reinforcing effects of cocaine.
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http://dx.doi.org/10.1007/s00213-019-05429-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542678PMC
April 2020

Adapting Social Defeat Stress for Female Mice Using Species-Typical Interfemale Aggression.

Authors:
Ryan W Logan

Biol Psychiatry 2019 11;86(9):e31-e32

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, and the Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, Maine. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2019.08.007DOI Listing
November 2019

Diurnal rhythms in gene expression in the prefrontal cortex in schizophrenia.

Nat Commun 2019 08 9;10(1):3355. Epub 2019 Aug 9.

Translational Neuroscience Program, Department of Psychiatry, Center for Neuroscience, University of Pittsburgh, Pittsburgh, 15213, PA, USA.

Schizophrenia is associated with disrupted cognitive control and sleep-wake cycles. Here we identify diurnal rhythms in gene expression in the human dorsolateral prefrontal cortex (dlPFC), in schizophrenia and control subjects. We find significant diurnal (24 h) rhythms in control subjects, however, most of these transcripts are not rhythmic in subjects with schizophrenia. Instead, subjects with schizophrenia have a different set of rhythmic transcripts. The top pathways identified in transcripts rhythmic only in subjects with schizophrenia are associated with mitochondrial function. Importantly, these rhythms drive differential expression patterns of these and several other genes that have long been implicated in schizophrenia (including BDNF and GABAergic-related transcripts). Indeed, differential expression of these transcripts is only seen in subjects that died during the night, with no change in subjects that died during the day. These data provide insights into a potential mechanism that underlies changes in gene expression in the dlPFC with schizophrenia.
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http://dx.doi.org/10.1038/s41467-019-11335-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689017PMC
August 2019

Sex-Specific Effects of Stress on Mood-Related Gene Expression.

Mol Neuropsychiatry 2019 Jun 30;5(3):162-175. Epub 2019 Apr 30.

Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, Pennsylvania, USA.

Women are twice as likely as men to be diagnosed with major depressive disorder (MDD). Recent studies report distinct molecular changes in depressed men and women across mesocorticolimbic brain regions. However, it is unclear which sex-related factors drive distinct MDD-associated pathology. The goal of this study was to use mouse experimental systems to investigate sex-specific mechanisms underlying the distinct molecular profiles of MDD in men and women. We used unpredictable chronic mild stress to induce an elevated anxiety-/depressive-like state and "four core genotypes" (FCG) mice to probe for sex-specific mechanisms. As predicted, based on previous implications in mood, stress impacted the expression of several dopamine-, GABA-, and glutamate-related genes. Some of these effects, specifically in the prefrontal cortex, were genetic sex-specific, with effects in XX mice but not in XY mice. Stress also impacted gene expression differently across the mesocorticolimbic circuit, with increased expression of mood-related genes in the prefrontal cortex and nucleus accumbens, but decreased expression in basolateral amygdala. Our results suggest that females are sensitive to the effects of chronic stress, partly due to their genetic sex, independent of gonadal hormones. Furthermore, these results point to the prefrontal cortex as the node in the mesocorticolimbic circuitry with the strongest female-specific effects.
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http://dx.doi.org/10.1159/000499105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597924PMC
June 2019

Cell-Type-Specific Regulation of Nucleus Accumbens Synaptic Plasticity and Cocaine Reward Sensitivity by the Circadian Protein, NPAS2.

J Neurosci 2019 06 8;39(24):4657-4667. Epub 2019 Apr 8.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219, and

The circadian transcription factor neuronal PAS domain 2 (NPAS2) is linked to psychiatric disorders associated with altered reward sensitivity. The expression of is preferentially enriched in the mammalian forebrain, including the nucleus accumbens (NAc), a major neural substrate of motivated and reward behavior. Previously, we demonstrated that downregulation of NPAS2 in the NAc reduces the conditioned behavioral response to cocaine in mice. We also showed that is preferentially enriched in dopamine receptor 1 containing medium spiny neurons (D1R-MSNs) of the striatum. To extend these studies, we investigated the impact of NPAS2 disruption on accumbal excitatory synaptic transmission and strength, along with the behavioral sensitivity to cocaine reward in a cell-type-specific manner. Viral-mediated knockdown of in the NAc of male and female C57BL/6J mice increased the excitatory drive onto MSNs. Using -tdTomato mice in combination with viral knockdown, we determined these synaptic adaptations were specific to D1R-MSNs relative to non-D1R-MSNs. Interestingly, NAc-specific knockdown of blocked cocaine-induced enhancement of synaptic strength and glutamatergic transmission specifically onto D1R-MSNs. Last, we designed, validated, and used a novel Cre-inducible short-hairpin RNA virus for MSN-subtype-specific knockdown of Cell-type-specific knockdown in D1R-MSNs, but not D2R-MSNs, in the NAc reduced cocaine conditioned place preference. Together, our results demonstrate that NPAS2 regulates excitatory synapses of D1R-MSNs in the NAc and cocaine reward-related behavior. Drug addiction is a widespread public health concern often comorbid with other psychiatric disorders. Disruptions of the circadian clock can predispose or exacerbate substance abuse in vulnerable individuals. We demonstrate a role for the core circadian protein, NPAS2, in mediating glutamatergic neurotransmission at medium spiny neurons (MSNs) in the nucleus accumbens (NAc), a region critical for reward processing. We find that NPAS2 negatively regulates functional excitatory synaptic plasticity in the NAc and is necessary for cocaine-induced plastic changes in MSNs expressing the dopamine 1 receptor (D1R). We further demonstrate disruption of NPAS2 in D1R-MSNs produces augmented cocaine preference. These findings highlight the significance of cell-type-specificity in mechanisms underlying reward regulation by NPAS2 and extend our knowledge of its function.
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http://dx.doi.org/10.1523/JNEUROSCI.2233-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561687PMC
June 2019

The Intertwined Roles of Circadian Rhythms and Neuronal Metabolism Fueling Drug Reward and Addiction.

Curr Opin Physiol 2018 Oct 5;5:80-89. Epub 2018 Sep 5.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh, pittsburgh, PA, USA 15219.

Drug addiction is a highly prevalent and devastating disorder with few effective treatments, resulting in enormous burdens on family and society. The cellular and behavioral effects of drugs of abuse are related to their abilities to elevate synaptic dopamine levels. Midbrain dopaminergic neurons projecting from the ventral tegmental area to the nucleus accumbens play crucial roles in substance-induced neural and behavioral plasticity. Significantly, increasing work suggests that interplay between the brain circadian system and the cellular bioenergetic machinery in these dopamine neurons plays a critical role in mediating the actions of drugs of abuse. Here, we describe recent progress in elucidating the interconnections between circadian and metabolic systems at the molecular and cellular levels and their relationships to modulation of drug reward and addiction.
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http://dx.doi.org/10.1016/j.cophys.2018.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322667PMC
October 2018

Rhythms of life: circadian disruption and brain disorders across the lifespan.

Nat Rev Neurosci 2019 01;20(1):49-65

University of Pittsburgh School of Medicine, Department of Psychiatry, Pittsburgh, PA, USA.

Many processes in the human body - including brain function - are regulated over the 24-hour cycle, and there are strong associations between disrupted circadian rhythms (for example, sleep-wake cycles) and disorders of the CNS. Brain disorders such as autism, depression and Parkinson disease typically develop at certain stages of life, and circadian rhythms are important during each stage of life for the regulation of processes that may influence the development of these disorders. Here, we describe circadian disruptions observed in various brain disorders throughout the human lifespan and highlight emerging evidence suggesting these disruptions affect the brain. Currently, much of the evidence linking brain disorders and circadian dysfunction is correlational, and so whether and what kind of causal relationships might exist are unclear. We therefore identify remaining questions that may direct future research towards a better understanding of the links between circadian disruption and CNS disorders.
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http://dx.doi.org/10.1038/s41583-018-0088-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338075PMC
January 2019

Improved identification of concordant and discordant gene expression signatures using an updated rank-rank hypergeometric overlap approach.

Sci Rep 2018 06 25;8(1):9588. Epub 2018 Jun 25.

Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Recent advances in large-scale gene expression profiling necessitate concurrent development of biostatistical approaches to reveal meaningful biological relationships. Most analyses rely on significance thresholds for identifying differentially expressed genes. We use an approach to compare gene expression datasets using 'threshold-free' comparisons. Significance cut-offs to identify genes shared between datasets may be too stringent and may miss concordant patterns of gene expression with potential biological relevance. A threshold-free approach gaining popularity in several research areas, including neuroscience, is Rank-Rank Hypergeometric Overlap (RRHO). Genes are ranked by their p-value and effect size direction, and ranked lists are compared to identify significantly overlapping genes across a continuous significance gradient rather than at a single arbitrary cut-off. We have updated the previous RRHO analysis by accurately detecting overlap of genes changed in the same and opposite directions between two datasets. Here, we use simulated and real data to show the drawbacks of the previous algorithm as well as the utility of our new algorithm. For example, we show the power of detecting discordant transcriptional patterns in the postmortem brain of subjects with psychiatric disorders. The new R package, RRHO2, offers a new, more intuitive visualization of concordant and discordant gene overlap.
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http://dx.doi.org/10.1038/s41598-018-27903-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018631PMC
June 2018

Cocaine Self-administration Alters Transcriptome-wide Responses in the Brain's Reward Circuitry.

Biol Psychiatry 2018 12 25;84(12):867-880. Epub 2018 Apr 25.

Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address:

Background: Global changes in gene expression underlying circuit and behavioral dysregulation associated with cocaine addiction remain incompletely understood. Here, we show how a history of cocaine self-administration (SA) reprograms transcriptome-wide responses throughout the brain's reward circuitry at baseline and in response to context and/or cocaine re-exposure after prolonged withdrawal (WD).

Methods: We assigned male mice to one of six groups: saline/cocaine SA + 24-hour WD or saline/cocaine SA + 30-day WD + an acute saline/cocaine challenge within the previous drug-paired context. RNA sequencing was conducted on six interconnected brain reward regions. Using pattern analysis of gene expression and factor analysis of behavior, we identified genes that are strongly associated with addiction-related behaviors and uniquely altered by a history of cocaine SA. We then identified potential upstream regulators of these genes.

Results: We focused on three patterns of gene expression that reflect responses to 1) acute cocaine, 2) context re-exposure, and 3) drug + context re-exposure. These patterns revealed region-specific regulation of gene expression. Further analysis revealed that each of these gene expression patterns correlated with an addiction index-a composite score of several addiction-like behaviors during cocaine SA-in a region-specific manner. Cyclic adenosine monophosphate response element binding protein and nuclear receptor families were identified as key upstream regulators of genes associated with such behaviors.

Conclusions: This comprehensive picture of transcriptome-wide regulation in the brain's reward circuitry by cocaine SA and prolonged WD provides new insight into the molecular basis of cocaine addiction, which will guide future studies of the key molecular pathways involved.
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http://dx.doi.org/10.1016/j.biopsych.2018.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6202276PMC
December 2018

NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward.

Mol Psychiatry 2019 11 4;24(11):1668-1684. Epub 2018 May 4.

Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh Medical School, Pittsburgh, PA, 15219, USA.

The diurnal regulation of dopamine is important for normal physiology and diseases such as addiction. Here we find a novel role for the CLOCK protein to antagonize CREB-mediated transcriptional activity at the tyrosine hydroxylase (TH) promoter, which is mediated by the interaction with the metabolic sensing protein, Sirtuin 1 (SIRT1). Additionally, we demonstrate that the transcriptional activity of TH is modulated by the cellular redox state, and daily rhythms of redox balance in the ventral tegmental area (VTA), along with TH transcription, are highly disrupted following chronic cocaine administration. Furthermore, CLOCK and SIRT1 are important for regulating cocaine reward and dopaminergic (DAergic) activity, with interesting differences depending on whether DAergic activity is in a heightened state and if there is a functional CLOCK protein. Taken together, we find that rhythms in cellular metabolism and circadian proteins work together to regulate dopamine synthesis and the reward value for drugs of abuse.
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http://dx.doi.org/10.1038/s41380-018-0061-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215755PMC
November 2019

Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge-Like Alcohol Drinking in Mice.

Alcohol Clin Exp Res 2018 05 18;42(5):879-888. Epub 2018 Apr 18.

Research and Development Service, Portland Veterans Affairs Medical Center, Portland, Oregon.

Background: Chronic alcohol intake leads to long-lasting changes in reward- and stress-related neuronal circuitry. The nucleus accumbens (NAc) is an integral component of this circuitry. Here, we investigate the effects of DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) on neuronal activity in the NAc and binge-like drinking.

Methods: C57BL/6J mice were stereotaxically injected with AAV2 hSyn-HA hM3Dq, -hM4Di, or -eGFP bilaterally into NAc [core + shell, core or shell]. We measured clozapine-n-oxide (CNO)-induced changes in NAc activity and assessed binge-like ethanol (EtOH) or tastant/fluid intake in a limited access Drinking in the Dark (DID) schedule.

Results: We found that CNO increased NAc firing in hM3Dq positive cells and decreased firing in hM4Di cells, confirming the efficacy of these channels to alter neuronal activity both spatially and temporally. Increasing NAc core + shell activity decreased binge-like drinking without altering intake of other tastants. Increasing activity specifically in the NAc core reduced binge-like drinking, and decreasing activity in the NAc core increased drinking. Manipulation of NAc shell activity did not alter DID. Thus, we find that increasing activity in the entire NAc, or just the NAc core is sufficient to decrease binge drinking.

Conclusions: We conclude that the reduction in EtOH drinking is not due to general malaise, altered perception of taste, or reduced calorie-seeking. Furthermore, we provide the first evidence for bidirectional control of NAc core and binge-like drinking. These findings could have promising implications for treatment.
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http://dx.doi.org/10.1111/acer.13626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034712PMC
May 2018

Opposite Molecular Signatures of Depression in Men and Women.

Biol Psychiatry 2018 07 19;84(1):18-27. Epub 2018 Feb 19.

Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Neurobiology of Depression and Aging, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada; Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Major depressive disorder (MDD) affects women approximately twice as often as men. Women are three times as likely to have atypical depression, with hypersomnia and weight gain. This suggests that the molecular mechanisms of MDD may differ by sex.

Methods: To test this hypothesis, we performed a large-scale gene expression meta-analysis across three corticolimbic brain regions: the dorsolateral prefrontal cortex, subgenual anterior cingulate cortex, and basolateral amygdala (26 men, 24 women with MDD and sex-matched control subjects). Results were further analyzed using a threshold-free approach, Gene Ontology, and cell type-specific analyses. A separate dataset was used for independent validation (13 MDD subjects/sex and 22 control subjects [13 men, 9 women]).

Results: Of the 706 genes differentially expressed in men with MDD and 882 genes differentially expressed in women with MDD, only 21 were changed in the same direction in both sexes. Notably, 52 genes displayed expression changes in opposite directions between men and women with MDD. Similar results were obtained using a threshold-free approach, in which the overall transcriptional profile of MDD was opposite in men and women. Gene Ontology indicated that men with MDD had decreases in synapse-related genes, whereas women with MDD exhibited transcriptional increases in this pathway. Cell type-specific analysis indicated that men with MDD exhibited increases in oligodendrocyte- and microglia-related genes, while women with MDD had decreases in markers of these cell types.

Conclusions: The brain transcriptional profile of MDD differs greatly by sex, with multiple transcriptional changes in opposite directions between men and women with MDD.
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http://dx.doi.org/10.1016/j.biopsych.2018.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014892PMC
July 2018

Impact of Sleep and Circadian Rhythms on Addiction Vulnerability in Adolescents.

Biol Psychiatry 2018 06 15;83(12):987-996. Epub 2017 Dec 15.

Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Center for Neuroscience, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; The Jackson Laboratory, Bar Harbor, Maine. Electronic address:

Sleep homeostasis and circadian function are important maintaining factors for optimal health and well-being. Conversely, sleep and circadian disruptions are implicated in a variety of adverse health outcomes, including substance use disorders. These risks are particularly salient during adolescence. Adolescents require 8 to 10 hours of sleep per night, although few consistently achieve these durations. A mismatch between developmental changes and social/environmental demands contributes to inadequate sleep. Homeostatic sleep drive takes longer to build, circadian rhythms naturally become delayed, and sensitivity to the phase-shifting effects of light increases, all of which lead to an evening preference (i.e., chronotype) during adolescence. In addition, school start times are often earlier in adolescence and the use of electronic devices at night increases, leading to disrupted sleep and circadian misalignment (i.e., social jet lag). Social factors (e.g., peer influence) and school demands further impact sleep and circadian rhythms. To cope with sleepiness, many teens regularly consume highly caffeinated energy drinks and other stimulants, creating further disruptions in sleep. Chronic sleep loss and circadian misalignment enhance developmental tendencies toward increased reward sensitivity and impulsivity, increasing the likelihood of engaging in risky behaviors and exacerbating the vulnerability to substance use and substance use disorders. We review the neurobiology of brain reward systems and the impact of sleep and circadian rhythms changes on addiction vulnerability in adolescence and suggest areas that warrant additional research.
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http://dx.doi.org/10.1016/j.biopsych.2017.11.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972052PMC
June 2018

Neural Mechanisms of Circadian Regulation of Natural and Drug Reward.

Neural Plast 2017 21;2017:5720842. Epub 2017 Nov 21.

Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Circadian rhythms are endogenously generated near 24-hour variations of physiological and behavioral functions. In humans, disruptions to the circadian system are associated with negative health outcomes, including metabolic, immune, and psychiatric diseases, such as addiction. Animal models suggest bidirectional relationships between the circadian system and drugs of abuse, whereby desynchrony, misalignment, or disruption may promote vulnerability to drug use and the transition to addiction, while exposure to drugs of abuse may entrain, disrupt, or perturb the circadian timing system. Recent evidence suggests natural (i.e., food) and drug rewards may influence overlapping neural circuitry, and the circadian system may modulate the physiological and behavioral responses to these stimuli. Environmental disruptions, such as shifting schedules or shorter/longer days, influence food and drug intake, and certain mutations of circadian genes that control cellular rhythms are associated with altered behavioral reward. We highlight the more recent findings associating circadian rhythms to reward function, linking environmental and genetic evidence to natural and drug reward and related neural circuitry.
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http://dx.doi.org/10.1155/2017/5720842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5735684PMC
September 2018

NPAS2 Regulation of Anxiety-Like Behavior and GABAA Receptors.

Front Mol Neurosci 2017 3;10:360. Epub 2017 Nov 3.

Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA, United States.

Abnormal circadian rhythms and circadian genes are strongly associated with several psychiatric disorders. Neuronal PAS Domain Protein 2 (NPAS2) is a core component of the molecular clock that acts as a transcription factor and is highly expressed in reward- and stress-related brain regions such as the striatum. However, the mechanism by which NPAS2 is involved in mood-related behaviors is still unclear. We measured anxiety-like behaviors in mice with a global null mutation in (Npas2 null mutant mice) and found that Npas2 null mutant mice exhibit less anxiety-like behavior than their wild-type (WT) littermates (in elevated plus maze, light/dark box and open field assay). We assessed the effects of acute or chronic stress on striatal expression, and found that both stressors increased levels of . Moreover, knockdown of in the ventral striatum resulted in a similar reduction of anxiety-like behaviors as seen in the Npas2 null mutant mouse. Additionally, we identified genes as transcriptional targets of NPAS2, found that Npas2 null mutant mice exhibit reduced sensitivity to the GABAa positive allosteric modulator, diazepam and that knockdown of reduced expression and response to diazepam in the ventral striatum. These results: (1) implicate in the response to stress and the development of anxiety; and (2) provide functional evidence for the regulation of GABAergic neurotransmission by NPAS2 in the ventral striatum.
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http://dx.doi.org/10.3389/fnmol.2017.00360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675889PMC
November 2017