Convergent findings suggest that the stress-related neurohormone, corticotropin-releasing factor (CRF) serves as a neuromodulator in the noradrenergic nucleus locus coeruleus (LC) to regulate the activity of this forebrain-projecting system during stress. CRF-induced LC activation may be important for cognitive aspects of the stress response, such as increased arousal and alterations in attention, and therefore may be adaptive. However, a history of stress alters the sensitivity of the LC-noradrenergic system to CRF and this may underlie certain symptoms of stress-related psychiatric disorders (e.g., hyperarousal, difficulty concentrating). This proposal will advance our understanding of the cellular mechanisms by which CRF alters LC activity, the mechanisms underlying stress-induced plasticity and consequences of CRF-LC interactions that may impact on cognition. An antiserum directed against the CRF-R1 receptor that has recently become available will be used to characterize and quantify the localization of CRF-R1 on neurochemically identified cellular processes within the LC (AIM 1). Internalization and trafficking of the CRF-R1 receptor will be examined at the ultrastructural level in rats that have been administered CRF in the LC or that have been acutely exposed to stressors. Changes in LC activity will be correlated to indices of CRF-R1 cellular translocation (AIM 2). A variety of approaches will be used to determine the cellular mechanisms underlying postsynaptic changes in LC sensitivity to CRF that are observed in rats with a history of stress (AIM 3). These include 1) reverse transcriptase-polymerase chain reaction (RT-PCR) to measure changes in CRF-receptor mRNA in the LC, 2) Western blot analysis to measure protein levels in the LC of CRF receptors, as well as levels of components of the signaling cascade linked to CRF-R1 activation, and 3) ultrastructural analysis of receptor internalization and recycling. Finally, AIM 4 is designed to determine the consequences of CRF modulation of the LC-noradrenergic system on forebrain activity and behavior controlled by attention to sensory stimuli. The effect of CRF in the LC on activity of ensembles of neurons in a functionally-connected network (whiskerpad-barrelfield cortex) during sensory stimulation (whiskerpad stimulation) will be quantified. Additionally, the effect of CRF in the LC on behavior controlled by whiskerpad stimulation will be determined. Together these studies will advance our understanding of the cellular mechanisms underlying the acute effects of stress on the LC-norepinephrine system, mechanisms underlying stress-induced plasticity of this system and the role of this system in cognitive responses to stress.
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