The stress response is an evolutionarily conserved mechanism critical for survival that requires orchestration of different systems in the body. Corticotropin-releasing hormone (CRH) neurons of the hypothalamic paraventricular nucleus (PVN) represent the final common pathway leading to HPA axis activation in response to stress. Noradrenergic inputs to CRH neurons in the PVN provide a powerful drive to activate the HPA axis. Previous anatomical studies have shown that noradrenergic afferents synapse directly on CRH neurons, but electrophysiological analyses indicate that the noradrenergic activation of CRH neurons is mediated primarily by the stimulation of presynaptic glutamatergic neurons. Here, using whole cell patch clamp recordings in identified CRH neurons, I demonstrate that norepinephrine (NE) stimulates excitatory synaptic inputs by activating postsynaptic α1 adrenergic receptors in CRH neurons and inducing the release of the retrograde messenger nitric oxide, which drives upstream glutamate neurons to elicit spike-dependent synaptic glutamate release onto the CRH neurons. Notably, the NE effect is dependent on ATP transmission and astrocytic function, suggesting that astrocytes serve as an intermediary in the retrograde activation of glutamateregic synaptic inputs to the CRH neurons. In addition, I also show that the NE-induced excitation of CRH neurons is stress-status sensitive and corticosterone dependent, in that stress-induced corticosterone causes internalization of membrane α1 adrenergic receptors to desensitize the CRH neurons to NE. Taken together, my findings provide evidence that NE excites CRH neurons in a stress state-dependent manner by a retrograde NO stimulation of local glutamate circuits that is dependent on glial activation. This retrograde trans-neuronal-glial regulation of excitatory synaptic inputs to CRH neurons by NE provides a mechanism for the NE activation of the HPA axis in the early stage of stress response. The stress-/corticosterone-induced desensitization of CRH neurons to NE modulation by the internalization of α1 adrenergic receptors confers a stress state-dependent resistance of the CRH neurons to repeated noradrenergic activation, which provides a mechanism for the negative feedback regulation of the CRH neurons and the HPA axis by stress and glucocorticoids, and a means to restore neuroendocrine homeostasis after stress exposure. / acase@tulane.edu
| Identifer | oai:union.ndltd.org:TULANE/oai:http://digitallibrary.tulane.edu/:tulane_27722 |
| Date | January 2014 |
| Contributors | Jiang, Zhiying (Author), Tasker, Jeffrey (Thesis advisor) |
| Publisher | Tulane University |
| Source Sets | Tulane University |
| Language | English |
| Detected Language | English |
| Format | 119 |
| Rights | Copyright is in accordance with U.S. Copyright law |
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