Biochemical data suggest that noradrenergic (NA) neurons in the locus ceruleus (LC) are activated by stress-inducing conditions. Recent biochemical, immunohistochemical and electrophysiological data suggest that this activation may be mediated by neurotransmitter corticotropin-releasing hormone (CRH) secreted from axons terminating in LC. The proposed experiments will extend these observations and test three hypotheses: a) LC is activated during stress, producing certain components of stress responses, b) neurotransmitter CRH is released during stress, also producing components of stress responses, c) stress-induced LC activation is mediated by neurotransmitter CRH. The proposed aims are: 1) To further characterize, at the light microscopic level, the CRH innervation of LC and other brain regions in both rat and monkey. Immunohistochemical and transport methods will determine the source of CRH innervation of LC, map CRH-containing neurons and processes in monkey neocortex, and verify that CRH is contained in the primate olivocerebellar pathway. 2) To determine whether particular """"""""stressors"""""""" electrophysiologically activate rat LC neurons and whether this activation can be antagonized by pharmacologic means. Microelectrode recordings in LC of anesthetized and unanesthetized rats will determine whether hemorrhage, temperature fluctuations and audiogenic stress activate LC neurons and whether this activation can be blocked by CRH antagonists, CRH antisera, or steroid treatment. 3) To determine, utilizing in vitro intracellular recording, the membrane events which mediate CRH effects on LC activity. A slice preparation will be used. 4) To characterize the involvement of LC neurons in generating behavioral components of stress responses utilizing an audiogenic stress paradigm. Verifiable, reversible manipulations of LC activity by discrete drug infusions will test whether LC activation and/or CRH infusion produce stress-induced behaviors, and whether these effects can be blocked by LC inactivation and/or CRH antagonist infusion. 5) To test the hypothesis that CRH innervation of a subpopulation of dopamine-containing neurons functions to activate these neurons in response to stressful stimuli. Anatomic observations suggest a dense CRH innervation of a subpopulation of DA neurons. Methods similar to those in Aims 1-4 will be used to study possible CRH-DA interactions. The proposed studies will furnish cellular anatomic and physiologic information about NA, DA, and CRH functions and interactions in stress.
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