Chronic stress is a factor in psychiatric diseases, such as depression, PTSD and other anxiety disorders. The brain noradrenergic system plays an important role in arousal and acute stress reactivity, and has been implicated in the etiology and symptoms of such stress-related psychiatric disorders. In the previous project, we showed that norepinephrine (NE) acts in limbic and hypothalamic brain regions to facilitate adaptive behavioral and neuroendocrine responses to acute stress. We found that differences in this modulatory influence may account for genetic vulnerability to stress in WKY rats, and that interactions between genetic predisposition and environmental stress can lead to maladaptive changes in behavioral and endocrine stress reactivity that resemble stress-related pathology. In this renewal, we continue this investigation, shifting focus from the beneficial modulatory effect of NE in acute stress to examine its role in the detrimental effects of chronic stress, specifically on emotion and cognition.
Aims 1 and 2 address possible changes in acute NE modulatory function as a consequence of chronic unpredictable stress (CUS).
Aim 1 will test the hypothesis that CUS-induced sensitization of acute NE reactivity in the bed nucleus of the stria terminals underlies the CUS-induced increase in anxiety-like behavior.
Aim 2 will address cognitive function in medial prefrontal cortex (mPFC). We have shown that enhancing NE function in mPFC facilitates cognitive set-shifting, an executive process that is disrupted in depression and anxiety disorders. By contrast, CUS causes a set-shifting deficit.
In aim 2, we determine whether the facilitatory influence of NE on cognitive function in mPFC is intact after CUS, when the cognitive deficit is evident. If intact, we will investigate if increased NE is recruited to compensate for the cognitive deficit after CUS. But if deficient, we will determine if the deficit is pre-synaptic (NE release) or post-synaptic (adrenergic receptor expression or function in mPFC). These studies will employ microdialysis, behavioral pharmacology, and anatomical approaches.
In aim 3, we will explore the potential role of repeated activation of noradrenergic facilitatory activity during chronic stress as a causative factor in the CUS-induced cognitive deficit, rather than simply an effect. We hypothesize that repeatedly evoked NE activity during CUS may be responsible for changes in mPFC function that underlie the deficit in cognition. This will be tested by blocking noradrenergic influence in mPFC during CUS, but leaving the facilitatory function intact at testing. A complementary battery of approaches will be used, including systemic adrenergic antagonist treatment during CUS, lesioning noradrenergic innervation of mPFC, and blocking adrenergic receptors locally in mPFC before each CUS stress treatment. Understanding how maladaptive changes in NE function induced by chronic stress may account for cognitive and affective dimensions of depression and anxiety disorders may lead to more effective strategies for the treatment or prevention of these devastating neuropsychiatric disorders. Chronic stress is an important factor in the development of many serious psychiatric disorders, and the brain noradrenergic system, which is involved in the response to stress, is a target for many therapeutic agents used in the treatment of stress-related illnesses such as depression, PTSD and anxiety disorders. In this project, we investigate how the modulatory function of norepinephrine, which is normally beneficial in the short-term, can become detrimental if activated repeatedly in the context of chronic stress. This is important to understanding the processes leading to stress-related psychopathology, and the results will hopefully inform the future development of novel strategies for more effective treatment or even prevention of these devastating and costly stress-related neuropsychiatric disorders.
|Girotti, Milena; Adler, Samantha M; Bulin, Sarah E et al. (2017) Prefrontal cortex executive processes affected by stress in health and disease. Prog Neuropsychopharmacol Biol Psychiatry :|
|Jett, Julianne D; Bulin, Sarah E; Hatherall, Lauren C et al. (2017) Deficits in cognitive flexibility induced by chronic unpredictable stress are associated with impaired glutamate neurotransmission in the rat medial prefrontal cortex. Neuroscience 346:284-297|
|Patton, Michael S; Lodge, Daniel J; Morilak, David A et al. (2017) Ketamine Corrects Stress-Induced Cognitive Dysfunction through JAK2/STAT3 Signaling in the Orbitofrontal Cortex. Neuropsychopharmacology 42:1220-1230|
|Radley, Jason; Morilak, David; Viau, Victor et al. (2015) Chronic stress and brain plasticity: Mechanisms underlying adaptive and maladaptive changes and implications for stress-related CNS disorders. Neurosci Biobehav Rev 58:79-91|
|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|
|Jett, Julianne D; Morilak, David A (2013) Too much of a good thing: blocking noradrenergic facilitation in medial prefrontal cortex prevents the detrimental effects of chronic stress on cognition. Neuropsychopharmacology 38:585-95|
|Roth, Megan K; Bingham, Brian; Shah, Aparna et al. (2012) Effects of chronic plus acute prolonged stress on measures of coping style, anxiety, and evoked HPA-axis reactivity. Neuropharmacology 63:1118-26|
|Morilak, David A (2012) Modulating the modulators: interaction of brain norepinephrine and cannabinoids in stress. Exp Neurol 238:145-8|
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