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Principal Investigator: James P Herman
Organization: UNIVERSITY OF CINCINNATI
Fiscal Year: 2024
Award: $578,180
Funding agency: National Institute of Mental Health
Summary
Traumatic stress exposure elicits behavioral and physiological responses that can compromise health and
well-being, generating brain and bodily changes that can intrude on appropriate emotional regulation.
Numerous disease states, most notably post-traumatic stress disorder, share behavioral and physiological
dysfunctions typical of traumatic stress exposure, indicative of a link between stress and disease. The long-
term objective of this research line is to understand brain mechanisms that control behavioral stress
responses, knowledge that will be essential for designing strategies for management of maladaptive behaviors
in stress-linked disorders. This proposal queries the neurocircuitry underlying lasting behavioral pathologies
linked to severe stress, focusing on the role of intralimbic cortex (IL) connections in driving pathology. Prior
research and our preliminary data present strong evidence for reduced IL excitability following severe stress
exposure, and functional hypoactivity of the human IL homolog is associated with PTSD. This proposal is
designed to understand the mechanisms underlying stress-induced IL hypofunction, concentrating on changes
in intrinsic processes and afferent connectivity. Aim 1 is designed to test the necessity and sufficiency of IL
afferent input in causing long-lasting severe stress-induced impairments in fear adaptation (extinction) and
reinstatement of fear following stress reminders, using a rat model of trauma exposure (single prolonged
stress). The role of IL afferent connections from the prelimbic cortex (PL) and ventral hippocampus (vHPA) in
SPS-induced fear pathology will be tested using viral vector mediated expression of excitatory and inhibitory
DREADDs, and circuit mapping employed to test engagement PL-IL and vHPC-IL circuitry . Aim 2 will use
electrophysiological approaches to explore cellular and connectional mechanisms driving IL hypoactivity
following SPS, focusing on intrinsic neuronal excitabilty and synaptic drive by PL and vHPC projections to the
IL. Aim 3 will use a multi-dimensional approach to identify molecular processes underlying IL hypoexcitability,
using an analysis platform integrating genomic, proteome and kinome data. Studies will use bioinformatic
approaches to determine possible drug targets for intervention in males and females. Results of these studies
will inform development of new pharmacological and/or circuit-targeting intervention strategies to promote
stress resilience in individuals exposed to traumatic or severe stress.
Terms: <Address><Aldesleukin Gene><Ammon Horn><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Anatomic Sites><Anatomic structures><Anatomy><Animals><Anterior><Attenuated><Automobile Driving><Behavior><Behavior Control><Behavioral><Behavioral Manipulation><Bio-Informatics><Bioinformatics><Biological><Brain><Brain Nervous System><CNS plasticity><Cell Communication and Signaling><Cell Signaling><Chemosensitization><Chemosensitization/Potentiation><Common Rat Strains><Connector Neuron><Cornu Ammonis><Cues><DREADDs><Data><Data Set><Development><Dimensions><Disease><Disorder><Drug Targeting><Dysfunction><Electrophysiology><Electrophysiology (science)><Emotional><Encephalon><Experimental Designs><Exposure to><Extinction><Fear><Female><Fright><Functional disorder><GeneHomolog><Genes><Genomics><Health><Hippocampus><Homolog><Homologous Gene><Homologue><Human><IL-2 Gene><IL2><IL2 gene><Image><Immediate-Early Genes><Impairment><Individual><Informatics><Intercalary Neuron><Intercalated Neurons><Interleukin 2 Precursor Gene><Interleukin-2 Gene><Interneurons><Internuncial Cell><Internuncial Neuron><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knowledge><Learning><Link><Maintenance><Maps><Mediating><Modeling><Modern Man><Modification><Molecular><Negative Valence><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neuronal Plasticity><Neurons><Neurophysiology / Electrophysiology><Output><PTSD><Parvalbumins><Pathologic><Pathology><Personal Satisfaction><Physiologic><Physiological><Physiopathology><Play><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Posttraumatic Neuroses><Potentiation><Prefrontal Cortex><Prevention><Process><Proteins><Proteome><Proteomics><RNA Seq><RNA sequencing><RNAseq><Rat><Rats Mammals><Rattus><Regimen><Research><Rodent><Rodentia><Rodents Mammals><Role><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Synapses><Synaptic><T-Cell Growth Factor Gene><TCGF Gene><Testing><Viral Vector><Woman><amygdaloid nuclear complex><attenuate><attenuates><behavioral control><behavioral plasticity><biologic><biological adaptation to stress><biological signal transduction><cell type><central nervous system plasticity><cingulate cortex><conditioned fear><design><designer receptors exclusively activated by designer drugs><designing><developmental><driving><electrophysiological><emotion regulation><emotional regulation><exposure to trauma><fear conditioning><fear memory><genetic approach><genetic strategy><hippocampal><human disease><imaging><insight><interventional strategy><learning extinction><maladaptive behavior><male><men><multiomics><multiple omics><neural circuit><neural circuitry><neural plasticity><neurocircuitry><neuronal><neuroplastic><neuroplasticity><optogenetics><panomics><pathophysiology><pharmacologic><physical conditioning><physical health><post-trauma stress disorder><posttrauma stress disorder><prevent><preventing><reaction; crisis><recruit><resilient to stress><response><sex><social role><stress reduction><stress resilience><stress resiliency><stress response><stress; reaction><synapse><synapse function><synaptic circuit><synaptic circuitry><synaptic function><transcriptome sequencing><transcriptomic sequencing><trauma exposure><traumatic neurosis><traumatic stress><well-being><wellbeing>