Chronic stress is a factor in many psychiatric diseases, such as depression, PTSD and other anxiety disorders. The brain noradrenergic (NE) system is important in arousal and acute stress reactivity, and is implicated in the etiology of stress-related psychiatric disorders. In the previus grant period, we showed that increasing NE transmission acutely in the prefrontal cortex (PFC) of rats facilitates cognitive flexibility on an attentional setshifting test (AST). By contrast, chonic unpredictable stress (CUS) compromised cognitive flexibility. We also showed that after CUS, elevating NE acutely still facilitates PFC function, but blocking NE receptors in the PFC during CUS protects cognitive flexibility. This suggests that after chronic stress, evoking NE activity acutely is still beneficial in the short term, but this comes at a cost. Over time, this repeated facilitation takes a toll, compromising the same circuits that are facilitated acutely, ultimately inducing a cognitive deficit. The purpose of this project is to identify the mechanisms by which the processes that mediate cognitive flexibility in PFC are compromised by repeated NE modulation during chronic stress. We focus on glutamate neurotransmission in the PFC, both pre- and post-synaptically.
In Aim 1, we will first determine the adrenergic receptor subtype by which repeated elicitation of NE activity during CUS compromises cognitive flexibility and function of the medial prefrontal cortex (mPFC), which mediates cognitive set-shifting, and the orbitofrontal cortex (OFC), which mediates reversal learning. Rats will be exposed to 2 weeks of CUS, with or without local administration of selective ?1- or -adrenergic receptor antagonists into mPFC or OFC prior to each stress session. They will be tested drug free for cognitive performance on the AST after CUS is terminated. The effective antagonist will be used in all subsequent aims.
In Aim 2, we will use microdialysis to measure CUS-induced changes in, and adrenergic antagonist protection of glutamate release in PFC in response to acute stress, excitatory afferent activation, or during cognitive performance on the AST.
In Aim 3, changes in post-synaptic PFC response to glutamate activity will be assessed. We will measure changes in fos induction in the PFC in response to activation of excitatory glutamate afferents from the thalamus, hippocampus and contralateral PFC. We will identify the glutamate receptors responsible for different aspects of cognitive flexibility in PFC, then measure CUS-induced changes in expression, phosphorylation and membrane localization of those receptors, and their protection by adrenergic antagonist treatment during CUS. We will measure changes in expression of PSD95, a post-synaptic protein important in regulating glutamate synaptic plasticity. And in Aim 4, we will assess changes in downstream JAK2-STAT3 signaling and its modulation of cognitive flexibility. These results will help us better understand the mechanisms of stress-induced pathology that underlie dysregulation of PFC function and cognitive capability, and will help us identify novel therapeutic targets for treatment of stress-related psychiatric disorders in patients who are only partially-responsive or resistant to existing approaches.

Public Health Relevance

These preclinical studies address the neurobiological mechanisms underlying the detrimental consequences of chronic stress. Specifically, we will investigate how the modulatory effects of norepinephrine in the prefrontal cortex, which facilitates cognitive flexibility acutely, and contributes to adaptive and effective responding to acute stress, can have detrimental consequences on cognition when elicited repeatedly by chronic stress. The results will add to our understanding of the mechanisms of stress-related neuropsychiatric pathology, and may reveal novel entry points for more selective, more effective, or complementary therapeutic strategies.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Winsky, Lois M
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University of Texas Health Science Center
Schools of Medicine
San Antonio
United States
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Girotti, Milena; Adler, Samantha M; Bulin, Sarah E et al. (2018) Prefrontal cortex executive processes affected by stress in health and disease. Prog Neuropsychopharmacol Biol Psychiatry 85:161-179
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Jett, Julianne D; Boley, Angela M; Girotti, Milena et al. (2015) Antidepressant-like cognitive and behavioral effects of acute ketamine administration associated with plasticity in the ventral hippocampus to medial prefrontal cortex pathway. Psychopharmacology (Berl) 232:3123-33
Donegan, Jennifer J; Girotti, Milena; Weinberg, Marc S et al. (2014) A novel role for brain interleukin-6: facilitation of cognitive flexibility in rat orbitofrontal cortex. J Neurosci 34:953-62
Girotti, Milena; Donegan, Jennifer J; Morilak, David A (2013) Influence of hypothalamic IL-6/gp130 receptor signaling on the HPA axis response to chronic stress. Psychoneuroendocrinology 38:1158-69

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