The Impact of Repeated Stress on Neuropeptidergic Regulation of Monoamine Systems
Lemos, Julia Cristine
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To promote an organism's evolutionary fitness, neurocircuitry has developed that encodes and responds to stressors. Stress motivates appropriate responding to environmental challenges through a diverse array of mechanisms that integrate cognitive, emotional and motor functions. Neuropeptides are released in an activity-dependent fashion throughout the brain in response to acute stressors and other arousing environmental stimuli and impinge on monoaminergic systems to allow processing of stimuli and produce appropriate behavioral responses. Here I show that corticotropin releasing factor causes the release of dynorphin, the endogenous ligand for kappa opioid receptors, in limbic brain regions including the basolateral amygdala (BLA) and dorsal raphe nucleus (DRN) to produce a negative affective state. The DRN is the major serotonergic projection nucleus in the brain. We demonstrate that the dynorphin-KOR system has net inhibitory regulation of serotonergic DRN neuronal excitability. While CRF acting in some limbic regions produces negative affect, when CRF acts specifically in the nucleus accumbens, a subcortical region that is critical for interfacing cognitive, emotional and motor inputs, it promotes appetitive behaviors. I found that intra-nucleus accumbens infusions of CRF produce conditioned place preference and and promotes exploration of novel stimuli. CRF does this by potentiating dopamine release within the nucleus accumbens through co-activation of CRF R1 and R2. Severe or chronic stress produces an affective shift in responses to subsequent stressors from engagement to withdrawal, a hallmark symptom of major depressive disorder. Stressful trauma may lead to this shift by amplifying the negative affective component of stress and ablating the motivation components. Repeated stress leads to several neuroadaptations, many of which target the functionality of stress-related neuropeptides themselves. I discovered that repeated swim stress dysregulates both CRF and dynorphin-KOR regulation of dopamine and serotonin systems respectively. Stress exposure causes a net reduction in KOR-mediated inhibitory regulation of serotonergic neuronal excitability through a p38α MAPK-dependent mechanism. While stress-induced alterations in KOR regulation of serotonin cells was relatively transient, stress-induced ablation of CRF's ability to potentiate dopamine release was remarkably long-lasting, not recovering for at least 90 days. The behavioral consequence of this long-term dysregulation of CRF-dopamine interactions was a switch in the subjective perception of CRF actions in the nucleus accumbens such that CRF was now experienced as aversive. This dysregulation of CRF signaling in the nucleus accumbens is dependent on stress-induced glucocorticoid activity. The following body of work characterizes how neuropeptides impinge on monoamine systems to produce motivated behaviors in responses to arousing environmental stimuli and importantly, offers biological substrates that are underlie the etiology of stress-induced psychopathologies such as Major Depressive Disorder.