Stress is known to be a factor in the etiology or exacerbation of psychiatric disorders, and plays an important role in reinstatement of drug-taking behavior. This proposal will use primarily electrophysiological recordings in anesthetized rats to examine the effects of acute and chronic stress on the regulation of the locus coeruleus (LC) by the amygdalar complex. Norepinephrine and corticotropin releasing hormone have been identified as central factors in the response to stress. In particular, the noradrenergic neurons of the LC are known to have a major role in central mediation of stress responses. These neurons are driven by a number of afferent influences. One set of afferents that appears to have a primary role in stress as it relates to psychiatric disorders and relapse to drug abuse are the projections that involve the amygdala. We propose to examine amygdalar regulation of LC neuron activity, and how this system is modified by acute and chronic stress. Our central hypothesis is that chronic stress causes a sensitization of LC neuron responsivity via its effects on amygdalofugal pathways. This will be done along four specific aims: 1) to examine the physiology of projection systems connecting the basolateral amygdala complex with the LC, 2) to examine the response of this system to acute stressors (footshock), and how these responses are modified following chronic cold exposure, 3) to evaluate the nature of the change in LC neuron responsivity following chronic stress, and 4) to determine whether the alteration in LC responsivity following chronic stress can be altered by selective interruption of these amygdalar efferents. We will use primarily in vivo single unit and intracellular recording methods to examine systems-level interactions, with in vitro recordings used to measure persistent changes in LC neuronal activity and to address specific pathway-related questions as they arise. We will independently verify the behavioral effects of chronic cold exposure by measuring acoustic startle, a response that is sensitive to manipulations of the central amygdala and forebrain NE systems. We hope that a better understanding of amygdalar-coerulear systems will lead to insights into how stress-induced pathophysiology in these pathways can, in part, mediate some of the behavioral symptoms of psychiatric disease and drug-abuse disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015408-02
Application #
6721245
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Pilotte, Nancy S
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2004-07-15
Budget End
2005-03-31
Support Year
2
Fiscal Year
2004
Total Cost
$328,809
Indirect Cost
Name
University of Pittsburgh
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Lipski, Witold J; Grace, Anthony A (2013) Footshock-induced responses in ventral subiculum neurons are mediated by locus coeruleus noradrenergic afferents. Eur Neuropsychopharmacol 23:1320-8
Lipski, Witold J; Grace, Anthony A (2013) Activation and inhibition of neurons in the hippocampal ventral subiculum by norepinephrine and locus coeruleus stimulation. Neuropsychopharmacology 38:285-92
McCracken, Clinton B; Grace, Anthony A (2013) Persistent cocaine-induced reversal learning deficits are associated with altered limbic cortico-striatal local field potential synchronization. J Neurosci 33:17469-82
Chang, Chun-hui; Grace, Anthony A (2013) Amygdala ýý-noradrenergic receptors modulate delayed downregulation of dopamine activity following restraint. J Neurosci 33:1441-50
Valenti, Ornella; Gill, Kathryn M; Grace, Anthony A (2012) Different stressors produce excitation or inhibition of mesolimbic dopamine neuron activity: response alteration by stress pre-exposure. Eur J Neurosci 35:1312-21
Ungless, Mark A; Grace, Anthony A (2012) Are you or aren't you? Challenges associated with physiologically identifying dopamine neurons. Trends Neurosci 35:422-30
Lodge, Daniel J; Grace, Anthony A (2012) Divergent activation of ventromedial and ventrolateral dopamine systems in animal models of amphetamine sensitization and schizophrenia. Int J Neuropsychopharmacol 15:69-76
Lodge, Daniel J; Grace, Anthony A (2011) Hippocampal dysregulation of dopamine system function and the pathophysiology of schizophrenia. Trends Pharmacol Sci 32:507-13
Lisman, John; Grace, Anthony A; Duzel, Emrah (2011) A neoHebbian framework for episodic memory; role of dopamine-dependent late LTP. Trends Neurosci 34:536-47
Gill, Kathryn M; Grace, Anthony A (2011) Heterogeneous processing of amygdala and hippocampal inputs in the rostral and caudal subregions of the nucleus accumbens. Int J Neuropsychopharmacol 14:1301-14

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