Clinical research has increasingly emphasized the importance of ascending viscerosensory pathways from the caudal brainstem, including noradrenergic (NA) pathways, in stress responses and affective/emotional state. Dysregulated NA signaling is implicated in the pathophysiology of stress-related psychiatric illnesses, including depression and anxiety disorders. The proposed research will test hypotheses about the structure and function of ascending NA pathways that modulate neural activity within interconnected regions of the paraventricular nucleus of the hypothalamus (PVN), central nucleus of the amygdala (CeA), and anterolateral bed nucleus of the stria terminalis (alBST). These pathways arise from NA neurons in viscerosensory regions of the nucleus of the solitary tract (NST) and ventrolateral medulla (VLM), with little or no direct contribution from the pontine locus coeruleus. Revealing the functional organization of these systems in rats has clinical relevance, and may contribute to the development of new therapeutic options for treating stress-related emotional dysregulation. Our working hypothesis is that both physiological (interoceptive) and cognitive/emotional stressors alter viscerosensory signals that are relayed by medullary NA neurons to the hypothalamus and limbic forebrain, and that these signals are critical for shaping emotional state as evidenced by stress responsiveness, motivated behavior, and emotional learning. NA neurons within the NST and VLM have branching axons that target more than one hypothalamic and limbic forebrain target. Retrograde tract-tracing experiments in Aim 1 will simultaneously examine NA axonal collateralization and ascending pathway recruitment by a malaise- inducing agent, lithium chloride (LiCl). The anatomical data obtained in Aim 1 will facilitate interpretation of functional data obtained in Aim 2, in which NA inputs to the PVN, CeA, and/or alBST will be selectively destroyed before rats are assayed for behavioral and physiological responses to three distinct challenges: (1) LiCl, (2) exposure to a fear- and anxiety-inducing predator odor, trimethylthiazoline (TMT), or (3) systemic yohimbine (YO), a pharmacological agent that robustly increases NA signaling throughout the brain. Parallel experiments in Aim 3 will test the hypothesis that direct communication between the CeA and alBST is necessary for behavioral and physiological responses to LiCl, TMT, and YO in rats with otherwise intact central NA circuitry. The proposed research will reveal new aspects of the functional organization of viscerosensory NA inputs to the hypothalamus and limbic forebrain that play a critical role in mediating physiological and behavioral responses to emotionally significant events. Dysregulated noradrenergic signaling in the brain is implicated in stress-related psychiatric illnesses, including depression and anxiety disorders. The proposed research will test hypotheses about the structure and function of noradrenergic pathways that modulate neural activity within interconnected regions of the hypothalamus and limbic forebrain. Experimental outcomes could lead to the development of new therapeutic options for treating stress-related emotional pathologies.

Public Health Relevance

Dysregulated noradrenergic signaling in the brain is implicated in stress-related psychiatric illnesses, including depression and anxiety disorders. The proposed research will test hypotheses about the structure and function of noradrenergic pathways that modulate neural activity within interconnected regions of the hypothalamus and limbic forebrain. Experimental outcomes could lead to the development of new therapeutic options for treating stress-related emotional pathologies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH059911-15
Application #
8440841
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Simmons, Janine M
Project Start
1999-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
15
Fiscal Year
2013
Total Cost
$289,753
Indirect Cost
$109,565
Name
University of Pittsburgh
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Zheng, Huiyuan; Cai, Li; Rinaman, Linda (2015) Distribution of glucagon-like peptide 1-immunopositive neurons in human caudal medulla. Brain Struct Funct 220:1213-9
Horn, Charles C; Meyers, Kelly; Lim, Audrey et al. (2014) Delineation of vagal emetic pathways: intragastric copper sulfate-induced emesis and viral tract tracing in musk shrews. Am J Physiol Regul Integr Comp Physiol 306:R341-51
Kreisler, Alison D; Davis, Elizabeth A; Rinaman, Linda (2014) Differential activation of chemically identified neurons in the caudal nucleus of the solitary tract in non-entrained rats after intake of satiating vs. non-satiating meals. Physiol Behav 136:47-54
Maniscalco, James W; Rinaman, Linda (2014) Systemic leptin dose-dependently increases STAT3 phosphorylation within hypothalamic and hindbrain nuclei. Am J Physiol Regul Integr Comp Physiol 306:R576-85
Bienkowski, Michael S; Rinaman, Linda (2013) Common and distinct neural inputs to the medial central nucleus of the amygdala and anterior ventrolateral bed nucleus of stria terminalis in rats. Brain Struct Funct 218:187-208
Zheng, Huiyuan; Rinaman, Linda (2013) Yohimbine anxiogenesis in the elevated plus maze requires hindbrain noradrenergic neurons that target the anterior ventrolateral bed nucleus of the stria terminalis. Eur J Neurosci 37:1340-9
Maniscalco, James W; Rinaman, Linda (2013) Overnight food deprivation markedly attenuates hindbrain noradrenergic, glucagon-like peptide-1, and hypothalamic neural responses to exogenous cholecystokinin in male rats. Physiol Behav 121:35-42
Bienkowski, Michael S; Wendel, Elizabeth S; Rinaman, Linda (2013) Organization of multisynaptic circuits within and between the medial and the central extended amygdala. J Comp Neurol 521:3406-31
Rinaman, Linda; Banihashemi, Layla; Koehnle, Thomas J (2011) Early life experience shapes the functional organization of stress-responsive visceral circuits. Physiol Behav 104:632-40
Bienkowski, Michael S; Rinaman, Linda (2011) Immune challenge activates neural inputs to the ventrolateral bed nucleus of the stria terminalis. Physiol Behav 104:257-65

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