Thursday, November 21, 2024
11/21/2024
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.
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