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Principal Investigator: ANTHONY A GRACE
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $705,367
Funding agency: National Institute of Mental Health
Stress and the resultant anxiety can provide motivation and prevent reckless behavior. However, when
experience in excess can be deleterious. This is particularly true when stressors occur during the peripubertal
period, when the brain is undergoing substantial plastic changes. In addition, there are significant male/female
differences in experience with stress. Thus, our studies in rats show that, although males and females show
similar impacts of peripubertal stress immediately after the stress, early stress preferentially impacts
cognitive/salience processes in males as adults and postpubertal stress impacting affective behaviors in females
as adults. Our preliminary results suggest that both male and female rats exposed to neurodevelopmental stress
show parvalbumin (PV) neuron loss in the ventral hippocampus (vHipp) leading to a hyperdopaminergic state,
this occurs via different pathways and different periods within puberty depending on sex. Thus, prepubertal
(PreP) stress in males but not females leads to parvalbumin (PV) neuron loss in the basolateral amygdala (BLA)
and mesoassociative striatal dopamine hyperactivity, whereas postpubertal (PostP) stress in females but not
males leads to hyperactivity in the reuniens (RE) nucleus of the thalamus and medial mesolimbic dopamine
overdrive. We propose that this difference is due to a differential impact of medial prefrontal cortical (mPFC)
regulation, with infralimbic PFC (ilPFC) controlling RE activity and prelimbic PFC (plPFC) impacting the BLA.
Thus, our preliminary data suggest that stress has timing- and sex-specific impacts that elicit distinct pathologies
via different circuits in the adult. Our overarching hypothesis is that PreP stress causes males to be selectively
vulnerable to VTA-associative striatal DA hyperactivity in the adult via precocious maturation of the plPFC-
BLA pathway and loss of BLA PV interneurons. In contrast, PostP stress causes selective activation of the
RE, potentially via PV loss in the reticular thalamic nucleus innervated by the ilPFC, in females leading to
hyperactivation of the mesolimbic DA system in adults. We will examine this along three specific aims: 1)
Examine how PreP vs PostP stress impacts the BLA-vHipp projection in male and female rats. 2) Examine how
PreP vs PostP stress impacts the RE-vHipp projection in male and female rats, and 3) Examine how the plPFC
and ilPFC regulate BLA-vHIpp and RE-vHipp response to PreP and PostP stress. This will give substantial insight
into how early stress leads to circuit-wide disruptions that render an individual more susceptible to pathological
states as adults.
Terms: <21+ years old><Adolescent><Adolescent Youth><Adult><Adult Human><Affect><Affective><Ammon Horn><Amygdala><Amygdaloid Body><Amygdaloid Nucleus><Amygdaloid structure><Anxiety><Behavior><Brain><Brain Nervous System><Brain region><Cell Nucleus><Cognitive><Common Rat Strains><Connector Neuron><Cornu Ammonis><Corpus Striatum><Corpus striatum structure><DA Neuron><DREADDs><Data><Development><Differences between sexes><Differs between sexes><Disease><Disorder><Dopamine><Dopamine neuron><Dysfunction><Early Intervention><Encephalon><Estrogen Replacements><Exposure to><Female><Functional disorder><Hippocampus><Human><Hydroxytyramine><Hyperactivity><Individual><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Lateral><Lesion><Life><Link><Medial><Mental Depression><Mental disorders><Mental health disorders><Modeling><Modern Man><Motivation><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nucleus><Nucleus Accumbens><Nucleus Reuniens Thalami><Oophorectomy><Outcome><Ovariectomy><Parvalbumins><Pathologic><Pathology><Pathway interactions><Physiopathology><Predisposition><Prefrontal Cortex><Prepuberal state><Process><Productivity><Psychiatric Disease><Psychiatric Disorder><Puberty><Rat><Rats Mammals><Rattus><Regulation><Reuniens Nucleus><Reuniens Thalamic Nucleus><Schizophrenia><Schizophrenic Disorders><Sex Differences><Sexual differences><Staining method><Stains><Stress><Striate Body><Striatum><Susceptibility><System><Testing><Thalamic Nuclei><Thalamic structure><Thalamus><Ventral Tegmental Area><adulthood><amygdaloid nuclear complex><comparative><dementia praecox><depression><designer receptors exclusively activated by designer drugs><developmental><dopaminergic neuron><early experience><experience><female gonadectomy><female prevention><hippocampal><insight><juvenile><juvenile human><male><mental illness><nerve cell death><nerve cell loss><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><pathophysiology><pathway><peripubertal period><prepubertal><prepuberty><prevent><prevent in females><prevent in women><preventing><prevention among females><prevention among women><prevention in females><prevention in women><psychiatric illness><psychological disorder><response><schizophrenic><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><stressor><striatal><thalamic><ventral tegmentum><women's prevention>