Stressful life events promote anxiety and hypertension and significantly increase the risk for cardiovascular disease which the leading cause of death in the U.S. Developing strategies that limit stress responding to prevent affective and cardiovascular disorders is the long-term goal of this project. Anxiety, hypothalamic pituitary adrenal (HPA) axis dysfunction and enhanced cardiovascular reactivity to stress contribute to the onset of affective and cardiovascular disorders and limiting these indices of stress responding may be therapeutic. Oxytocin (OT) is being used to treat stress-related disorders; however, activation of oxytocin receptors (OTRs) can have diverse effects, and consequently, identifying specific OTRs regulating stress responding may improve treatments. Magnocellular OT neurons are excited by hypernatremia, increases in the plasma sodium concentration (pNa+), and this results in long-lasting increases in central levels of OT. Driving endogenous OT release by elevating the pNa+ in rodents causes activation of OTRs that inhibit corticotropin-releasing-factor (CRF) neurons in the central amygdala (CeA) and paraventricular nucleus of the hypothalamus (PVN). These neurons are implicated in the etiology of anxiety and hypertension, and intriguingly, OTR mediated inhibition of CRF neurons decreased anxiety-like behavior, blunted HPA activation and attenuated cardiovascular responses to stress. Determining the neural mechanism(s) by which this occurs is the main objective of this proposal. In this regard, hypernatremia interacts with stress to increase neuronal activation in the bed nucleus of the stria terminalis (BNST) and the lateral ventral septum (LVS), which express OTRs and connect to brain regions mediating stress responding. Ongoing studies suggest that OTR expressing neurons in the BNST and LVS project to the CeA or function as GABAergic interneurons. These results suggest that hypernatremia activates magnocellular oxytocinergic neurons that release OT in the BNST and LVS, stimulating OTRs expressed on GABAergic neurons that inhibit CRF neurons, thereby attenuating anxiety, HPA activation and cardiovascular responses to stress.
Aim 1 will use mice with OTR-specific Cre expression, neuroanatomical tract-tracing and in vitro patch-clamp electrophysiology to test the hypothesis that magnocellular OT neurons send axons that depolarize neurons in the BNST and LVS by activating OTRs.
Aim 2 will utilize Cre-inducible adenoassociated virus (AAV) and optogenetics to test the hypothesis that neurons expressing OTRs in the BNST and LVS have GABAergic efferents that inhibit CRF neurons in the CeA and PVN.
Aim 3 will delete OTRs in the BNST and LVS of mice to test the hypothesis that these receptors mediate the stress dampening effects of hypernatremia. Completion of these experiments will determine the specific population of OTRs that are activated by endogenously released OT to limit stress responding, thereby producing important information that may guide the development of therapeutics for comorbid affective and cardiovascular disorders.
Anxiety disorders increase the risk for hypertension and cardiovascular disease, which is the leading cause of death in the U.S. This project investigates how slightly elevated body sodium levels elicit neurochemical changes that decrease the impact of psychological stress. The results may identify novel therapeutic targets to reduce anxiety and prevent hypertension and cardiovascular disease.
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|Peris, Joanna; MacFadyen, Kaley; Smith, Justin A et al. (2017) Oxytocin receptors are expressed on dopamine and glutamate neurons in the mouse ventral tegmental area that project to nucleus accumbens and other mesolimbic targets. J Comp Neurol 525:1094-1108|
|de Kloet, Annette D; Wang, Lei; Pitra, Soledad et al. (2017) A Unique ""Angiotensin-Sensitive"" Neuronal Population Coordinates Neuroendocrine, Cardiovascular, and Behavioral Responses to Stress. J Neurosci 37:3478-3490|
|Krause, Eric G; Pati, Dipanwita; Frazier, Charles J (2017) Chronic salt-loading reduces basal excitatory input to CRH neurons in the paraventricular nucleus and accelerates recovery from restraint stress in male mice. Physiol Behav 176:189-194|
|de Kloet, Annette D; Pitra, Soledad; Wang, Lei et al. (2016) Angiotensin Type-2 Receptors Influence the Activity of Vasopressin Neurons in the Paraventricular Nucleus of the Hypothalamus in Male Mice. Endocrinology 157:3167-80|
|Wang, Lei; de Kloet, Annette D; Pati, Dipanwita et al. (2016) Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors. Neuropharmacology 105:114-123|