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Principal Investigator: Troy Adam Roepke
Organization: RUTGERS, THE STATE UNIV OF N.J.
Fiscal Year: 2024
Award: $409,883
Funding agency: National Institute of Mental Health
Project Summary
Chronic exposure to stressful experiences can result in maladaptive affective states that yield behavioral
disturbances in rodents and stress-related mood disorders in humans. Over the last decade, the neural circuits
underlying these maladaptive effects of stress have become better defined. One region of importance is the bed
nucleus of the stria terminalis (BNST), which is a major output pathway connecting the central amygdala to the
ventromedial nucleus of the hypothalamus that also receives direct projections from other limbic areas.
Therefore, BNST may be an integrative center for limbic information and valence monitoring. Psychological and
physiological stressors affect males and females differently. The BNST is a sexually dimorphic structure that
may contribute to distinct chronic stress responses in males and females because expression of aromatase and
both estrogen receptors (ER) differs in male and female BNST. Direct activation of neurons within the oval
nucleus of the BNST (ovBNST) increases anxiety-associated negative valence behaviors in male rodents, and
our preliminary data demonstrates that exposure of C57BL/6J male mice to chronic variable mild stress (CVMS)
results in increased corticotropin releasing hormone (CRH/CRF) signaling, increased mEPSC amplitude, altered
resting membrane potential, and diminished M-currents in ovBNST neurons. While these data suggest that
ovBNST may be a nexus for the effects of chronic stress on affective states, many questions remain unanswered.
Our overall hypothesis is that CRH-expressing ovBNST neurons are critical mediators of the chronic stress
response and that sexual dimorphism in the BNST underlies the distinct chronic stress responses found in males
and females. The proposed specific aims will directly answer these questions and increase our understanding
of how ovBNST mediates the maladaptive effects of chronic stress. In Aim 1, we will identify the cell populations
that are impacted by chronic stressors (CVMS, chronic nondiscriminatory social defeat stress [CNSDS]) and the
neurophysiological consequences in male and female mice. In Aim 2, we will assess how chronic stress affects
ER signaling in BNST and whether optogenetic modulation of ER-positive BNST neurons mimics and/or
reverses the effects of chronic stress on behavior. In Aim 3, we will determine the necessity and sufficiency of
CRH-signaling in ovBNST neurons in mediating the behavioral effects of CVMS and CNSDS.
Terms: <ACTH-Releasing Factor><ARO><ARO1><Address><Affect><Affective><Affective Disorders><Ammon Horn><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Anxiety><Area><Aromatase><Arousal><Bed Nucleus of Stria Terminalis><Behavior><Behavior Disorders><Behavioral><Brain region><CPV1><CRF Receptors><CRF receptor type 1><CRF-41><CRF-R1><CRF1 receptor><CRH Receptors><CRH-1><CYAR><CYP 19><CYP19><CYP19A1><CYP19A1 gene><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cells><Chronic><Chronic Disease><Chronic Illness><Chronic stress><Cognition><Collaborations><Cornu Ammonis><Corticoliberin><Corticotropin Releasing-Factor Receptors><Corticotropin-Releasing Factor><Corticotropin-Releasing Factor-41><Corticotropin-Releasing Hormone><Corticotropin-Releasing Hormone Receptors><Corticotropin-Releasing Hormone-41><Coupled><Crh1 receptor><Cytochrome P-450 CYP19><Cytochrome P450 19><Cytochrome P450 19A1><Data><Differences between sexes><Differs between sexes><Electrophysiology><Electrophysiology (science)><Estrogen Receptors><Estrogen Synthase><Estrogen Synthetase><Estrogens><Exposure to><Female><Genetic><Genomics><Hippocampus><Human><Hypothalamic structure><Hypothalamus><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Intracellular Communication and Signaling><KO mice><Knock-out Mice><Knockout Mice><Locus Coeruleus><Mediating><Mediator><Membrane Potentials><Mice><Mice Mammals><Modern Man><Molecular><Monitor><Mood Disorders><Murine><Mus><Negative Valence><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Nucleus><Nucleus Pigmentosus Pontis><Null Mouse><Output><P-450AROM><P450AROM><Pathway interactions><Population><Positive Valence><Predisposition><Property><Receptor Signaling><Rest><Resting Potentials><Rodent><Rodentia><Rodents Mammals><Role><Sex Differences><Sexual differences><Signal Transduction><Signal Transduction Systems><Signaling><Steroid Compound><Steroids><Stress><Stressful Event><Stria Terminalis Nucleus><Structure><Structure of terminal stria nuclei of preoptic region><Susceptibility><Techniques><Therapeutic Estrogen><Transgenic Mice><Transgenic Organisms><Translating><Transmembrane Potentials><Variant><Variation><Viral><amygdaloid nuclear complex><behavior outcome><behavioral disorder><behavioral outcome><biological adaptation to stress><biological signal transduction><blue nucleus><cell type><chronic disorder><corticotropin releasing hormone><corticotropin-releasing factor receptor 1><electrophysiological><global gene expression><global transcription profile><hippocampal><hormonal signals><hormone signals><hypothalamic><locus ceruleus structure><male><mouse model><murine model><neural circuit><neural circuitry><neurocircuitry><neuronal><neuronal excitability><neurophysiological><neurophysiology><novel><optogenetics><pathway><physiologic stresses><physiologic stressor><physiological stresses><prevent><preventing><psychological stresses><psychological stressor><reaction; crisis><receptor binding><receptor bound><resilient to stress><sex><sex based differences><sex dimorphism><sex-dependent differences><sex-related differences><sex-specific differences><sexual dimorphism><sexually dimorphic><social><social defeat><social role><social stresses><social stressor><stress disorder><stress resilience><stress resiliency><stress response><stress; reaction><stressful experience><stressful life event><stressful life experience><stressor><synaptic circuit><synaptic circuitry><transcriptome><transgenic>