Activation of Npas1-neurons in the Ventral Pallidum Mediates Stress Susceptibility

Background: Altered activity of the ventral pallidum (VP) underlies disrupted motivation after stress exposure. The VP is a very heterogeneous structure comprised of many different neuron types with distinct electrophysiological properties and projections. Neuronal PAS 1-positive (Npas1+) VP neurons are thought to send projections to brain regions critical for stress response. In this study, we evaluated how activity of VP Npas1+ neurons affect emotional behaviors and responses to social stress. Methods: We used a chemogenetic approach to manipulate VP Npas1+ neurons during social defeat stress (SDS) and behavioral tasks related to anxiety and motivation in Npas1-Cre mice. We employed a similar approach in females using the chronic witness defeat stress (CWDS). Finally, to characterize VP Npas1+ neuron circuitry and molecular identity we evaluated the projection targets of the VP Npas1+ neurons and performed RNA-seq on ribosome-associated mRNA from VP Npas1+ neurons. Results: Chemogenetic activation of VP Npas1+ neurons increased susceptibility to a subthreshold (S)SDS and anxiety-like behavior in the elevated plus maze and open field. Inhibition of VP Npas1+ neurons enhanced resilience to chronic (C)SDS and CWDS. We identified VP Npas1+ projections to the nucleus accumbens (NAc), ventral tegmental area (VTA), medial and lateral habenula (LHb), lateral hypothalamus (LH), thalamus, medial and lateral septum, and periaqueductal gray area. VP Npas1+ neurons displayed distinct transcriptomes representing distinct biological processes. Conclusions: Activity, of VP Npas1+ neurons, modulates susceptibility to social stressors and anxiety-like behavior. These outcomes could be related to their projections to brain regions that modulate reward and aversion.

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Distinct properties in ventral pallidum projection neuron subtypes

10.1101/2021.11.15.468637 ◽

2021 ◽

Author(s):

Nimrod Bernat ◽

Rianne Campbell ◽

Hyungwoo Nam ◽

Mahashweta Basu ◽

Tal Odesser ◽

...

Keyword(s):

Gene Expression ◽

Expression Profiles ◽

Expression Patterns ◽

Critical Role ◽

Gene Expression Profiles ◽

Cell Types ◽

Projection Neuron ◽

Brain Regions ◽

Ventral Pallidum ◽

Lateral Habenula

The ventral pallidum (VP), a major component of the basal ganglia, plays a critical role in motivational disorders. It sends projections to many different brain regions but it is not yet known whether and how these projections differ in their cellular properties, gene expression patterns, connectivity and role in reward seeking. In this study, we focus on four major outputs of the VP - to the lateral hypothalamus (LH), ventral tegmental area (VTA), mediodorsal thalamus (MDT), and lateral habenula (LHb) - and examine the differences between them in 1) baseline gene expression profiles using projection-specific RNA-sequencing; 2) physiological parameters using whole-cell patch clamp; and 3) their influence on cocaine reward using chemogenetic tools. We show that these four VP efferents differ in all three aspects and highlight specifically differences between the projections to the LH and the VTA. These two projections originate largely from separate populations of neurons, express distinct sets of genes related to neurobiological functions, and show opposite physiological and behavioral properties. Collectively, our data demonstrates for the first time that VP neurons exhibit distinct molecular and cellular profiles in a projection-specific manner, suggesting that they represent different cell types.

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History of winning and hierarchy landscape influence stress susceptibility in mice

10.1101/2021.07.06.451249 ◽

2021 ◽

Author(s):

Katherine B LeClair ◽

Kenny L Chan ◽

Manuella P Kaster ◽

Lyonna F Parise ◽

Charles Joseph Burnett ◽

...

Keyword(s):

Social Stress ◽

Social Rank ◽

High Mobility ◽

Social Hierarchy ◽

Social Stressors ◽

Male And Female ◽

Female Mice ◽

Hierarchy Formation ◽

History Of ◽

Stress Susceptibility

Social hierarchy formation is strongly evolutionarily conserved. Across species, rank within social hierarchy has large effects on health and behavior. To investigate the relationship between social rank and stress susceptibility, we exposed ranked male and female mice to social and non-social stressors and manipulated social hierarchy position. We found that rank predicts same sex social stress outcomes: dominance in males and females confers resilience while subordination confers susceptibility. Pre-existing rank does not predict non-social stress outcomes in females and weakly does so in males, but rank emerging under stress conditions reveals social interaction deficits in male and female subordinates. Both history of winning and rank of cage mates affect stress susceptibility in males: rising to the top rank through high mobility confers resilience and mice that lose dominance lose stress resilience, though gaining dominance over a subordinate animal does not confer resilience. Overall, we have demonstrated a relationship between social status and stress susceptibility, particularly when taking into account individual history of winning and the overall hierarchy landscape in male and female mice.

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History of winning and hierarchy landscape influence stress susceptibility in mice

eLife ◽

10.7554/elife.71401 ◽

2021 ◽

Vol 10 ◽

Author(s):

Katherine B LeClair ◽

Kenny L Chan ◽

Manuella P Kaster ◽

Lyonna F Parise ◽

Charles Joseph Burnett ◽

...

Keyword(s):

Social Stress ◽

Social Rank ◽

High Mobility ◽

Social Hierarchy ◽

Social Stressors ◽

Male And Female ◽

Female Mice ◽

Hierarchy Formation ◽

History Of ◽

Stress Susceptibility

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Epigenetic signatures of chronic social stress in stress-susceptible animals

10.1101/690826 ◽

2019 ◽

Cited By ~ 1

Author(s):

Nicholas O’Toole ◽

Tie-Yuan Zhang ◽

Xianglan Wen ◽

Josie Diorio ◽

Patricia P. Silveira ◽

...

Keyword(s):

Social Stress ◽

Estrogen Receptor Alpha ◽

Cytosine Methylation ◽

Genome Wide Association Study ◽

Brain Regions ◽

Hub Gene ◽

Deleted In Colorectal Cancer ◽

Genome Wide ◽

A Genome ◽

Stress Susceptibility

AbstractExposure of mice to chronic social defeat stress (CSDS) produces depressive- and anxiety-like behaviors and widespread transcriptomic changes in several brain regions in susceptible animals. Here we present the first study of genome-wide cytosine methylation patterns of mice susceptible to CSDS using whole-genome bisulfite sequencing on DNA from the nucleus accumbens, a critical region for CSDS effects on behavior. We found extensive evidence for differential methylation following exposure to CSDS in susceptible animals, with a greater proportion of CG hypermethylation than hypomethylation in CSDS-susceptible mice compared to non-stressed controls; non-CG methylation shows the opposite trend. Several genes previously implicated in the effects of CSDS are among those with the greatest number of differentially methylated sites, including estrogen receptor alpha (Esr1), the deleted in colorectal cancer (Dcc) gene andCacna1c, which has been associated with a range of psychiatric conditions. Informatic analysis of DM sites revealed a gene network with ß-catenin as the hub gene of a network that included the ß-catenin-related WNT/frizzled signaling pathway as well as bothEsr1andDcc. Finally, we found considerable overlap between DM genes associated with CSDS in susceptible animals and those associated with human neuroticism in a genome-wide association study. Analysis of these overlapping genes revealed ‘WNT signaling’ as the top pathway, which features ß-catenin as the primary hub gene. These findings reveal a striking convergence between the molecular pathways identified through either transcriptional or epigenomic analyses of the mouse model of susceptibility to chronic stress and the genomic architecture of increased stress susceptibility reflected in neuroticism in humans.

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Childhood Adversities and Salivary Cortisol Responses to the Trier Social Stress Test: A Systematic Review of Studies Using the Children Trauma Questionnaire (CTQ)

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18010029 ◽

2020 ◽

Vol 18 (1) ◽

pp. 29

Author(s):

Chuk Ling Julian Lai ◽

Daryl Yu Heng Lee ◽

Monique On Yee Leung

Keyword(s):

Salivary Cortisol ◽

Social Stress ◽

Stress Test ◽

Trier Social Stress Test ◽

Future Research ◽

Cortisol Response ◽

Childhood Adversities ◽

Social Stressors ◽

Childhood Trauma Questionnaire ◽

Cortisol Responses

Alteration in cortisol response to acute social stressors has been hypothesized to mediate childhood adversities (CA) and increased morbidity in adulthood. However, the evidence supporting an association between CA and cortisol response to social stressors is inconclusive. The present review addressed this issue by reviewing the literature on CA and cortisol response to acute social stressors, with a focus on studies with adolescents or adults, using the Childhood Trauma Questionnaire (CTQ) to assess CA, and examining salivary cortisol response to the Trier Social Stress Test (TSST). Systematic searches of relevant articles in PsycINFO, PubMed, Web of Science and ScienceDirect in February and March 2020 identified 12 articles including 1196 participants with mean ages ranging from 15.3 to 52.3 yrs. across studies. CTQ scores were significantly associated with cortisol response in 2 studies. In addition, the physical abuse and emotional neglect subscales were associated with cortisol response respectively in 2 separate studies. The lack of association between CA and cortisol response calls for more longitudinal studies, and the use of formal records of maltreatment or informant reports in future research to complement information collected by retrospective measures. In addition, increased attention to biological mechanisms other than that associated with the regulation of cortisol in explaining the connection between CA and psychiatry morbidity is warranted.

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Hypothalamic neuronal circuits regulating hunger-induced taste modification

Nature Communications ◽

10.1038/s41467-019-12478-x ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 6

Author(s):

Ou Fu ◽

Yuu Iwai ◽

Masataka Narukawa ◽

Ayako W. Ishikawa ◽

Kentaro K. Ishii ◽

...

Keyword(s):

Lateral Hypothalamus ◽

Critical Role ◽

Taste Preference ◽

Lateral Septum ◽

Gustatory System ◽

Lateral Habenula ◽

Mechanistic Insight ◽

Aversive Taste ◽

Neuronal Mechanisms ◽

Internal States

Abstract The gustatory system plays a critical role in sensing appetitive and aversive taste stimuli for evaluating food quality. Although taste preference is known to change depending on internal states such as hunger, a mechanistic insight remains unclear. Here, we examine the neuronal mechanisms regulating hunger-induced taste modification. Starved mice exhibit an increased preference for sweetness and tolerance for aversive taste. This hunger-induced taste modification is recapitulated by selective activation of orexigenic Agouti-related peptide (AgRP)-expressing neurons in the hypothalamus projecting to the lateral hypothalamus, but not to other regions. Glutamatergic, but not GABAergic, neurons in the lateral hypothalamus function as downstream neurons of AgRP neurons. Importantly, these neurons play a key role in modulating preferences for both appetitive and aversive tastes by using distinct pathways projecting to the lateral septum or the lateral habenula, respectively. Our results suggest that these hypothalamic circuits would be important for optimizing feeding behavior under fasting.

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Dysfunction in Ribosomal Gene Expression in the Hypothalamus and Hippocampus following Chronic Social Defeat Stress in Male Mice as Revealed by RNA-Seq

Neural Plasticity ◽

10.1155/2016/3289187 ◽

2016 ◽

Vol 2016 ◽

pp. 1-6 ◽

Cited By ~ 22

Author(s):

Dmitry A. Smagin ◽

Irina L. Kovalenko ◽

Anna G. Galyamina ◽

Anatoly O. Bragin ◽

Yuriy L. Orlov ◽

...

Keyword(s):

Gene Expression ◽

Social Stress ◽

Ribosome Biogenesis ◽

Social Defeat ◽

Brain Regions ◽

Ribosomal Gene ◽

Rna Seq ◽

Male Mice ◽

Social Defeat Stress ◽

Chronic Social Defeat Stress

Chronic social defeat stress leads to the development of anxiety- and depression-like states in male mice and is accompanied by numerous molecular changes in brain. The influence of 21-day period of social stress on ribosomal gene expression in five brain regions was studied using the RNA-Seq database. MostRps, Rpl, Mprs, andMprlgenes were upregulated in the hypothalamus and downregulated in the hippocampus, which may indicate ribosomal dysfunction following chronic social defeat stress. There were no differentially expressed ribosomal genes in the ventral tegmental area, midbrain raphe nuclei, or striatum. This approach may be used to identify a pharmacological treatment of ribosome biogenesis abnormalities in the brain of patients with “ribosomopathies.”

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Peripheral nerve injury-induced alterations in VTA neuron firing properties

Molecular Brain ◽

10.1186/s13041-019-0511-y ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 2

Author(s):

Shuo Huang ◽

Stephanie L. Borgland ◽

Gerald W. Zamponi

Keyword(s):

Neuropathic Pain ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Brain Regions ◽

Action Potential Firing ◽

Electrophysiological Properties ◽

Reporter Mice ◽

Potential Firing ◽

Firing Properties

Abstract The ventral tegmental area (VTA) is one of the main brain regions harboring dopaminergic (DA) neurons, and plays important roles in reinforcement and motivation. Recent studies have indicated that DA neurons not only respond to rewarding stimuli, but also to noxious stimuli. Furthermore, VTA DA neurons undergo plasticity during chronic pain. Lateral and medial VTA neurons project to different brain areas, and have been characterized via their distinct electrophysiological properties. In this study, we characterized electrophysiological properties of lateral and medial VTA DA neurons using DAT-cre reporter mice, and examined their plasticity during neuropathic pain states. We observed various DA subpopulations in both the lateral and medial VTA, as defined by action potential firing patterns, independently of synaptic inputs. Our results demonstrated that lateral and medial VTA DA neurons undergo differential plasticity after peripheral nerve injury that leads to neuropathic pain. However, these changes only reside in specific DA subpopulations. This study suggests that lateral and medial VTA DA neurons are differentially affected during neuropathic pain conditions, and emphasizes the importance of subpopulation specificity when targeting VTA DA neurons for treatment of neuropathic pain.

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