The recent recognition that symptoms of behavioral depression form an integral component of the sickness response to many infectious and inflammatory conditions expanded views on the powerful influence of the immune system on the brain. It is now clear that immune activation not only contributes to classic host defense responses, such as fever, but also modulates cognitive and affective states. Whereas studies using the neuronal activation marker c-Fos have identified a constellation of brain nuclei that respond to immune activation, the roles that any of these regions play in the induction of sickness-induced behavioral depression remains undetermined. Our preliminary studies have shown that treatment with an immune stimulant suppresses behavior-related activation of forebrain nuclei associated with arousal, attention and memory, which may underlie the behavioral effects of immune activation. We have also shown that inactivation of the dorsal vagal complex in the brainstem blocks symptoms of behavioral depression and rescues behaviorally associated forebrain activation, i.e. it prevents illness-induced suppression of forebrain nuclei. These findings suggest that incoming neural signals regarding immune activation drive an active inhibition of forebrain regions that is initiated or mediated by the dorsal vagal complex. We intend to tease apart neurocircuitry that drives symptoms of behavioral depression by combining neuroanatomical tract tracers with immunohistochemical detection of neurotransmitter substances and c-Fos expression to identify the connections and neurochemical phenotypes of neurons driven by immune activation. We will then inactivate the neurons associated with the dorsal vagal complex to determine whether they contribute to the symptoms of illness-induced behavioral depression. The experiments designed for this proposal are directed toward developing a clearer picture of the structural and functional organization of brain regions driven by immune activation, and the neurochemical signals involved, that contribute to symptoms of behavioral depression. Findings from these experiments can provide a framework for the understanding and management of cognitive and affective sequelae to illness and chronic inflammatory disorders. An ultimate goal is to be able to predict which type or component of an immune or inflammatory stimulus may trigger anhedonic/depressive symptoms, and be able to predict effective treatments, based on the neurochemistry of the activated immunosensory pathways in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH068834-04
Application #
7341764
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Desmond, Nancy L
Project Start
2005-04-01
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
4
Fiscal Year
2008
Total Cost
$279,123
Indirect Cost
Name
University of Virginia
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Kinser, Patricia Anne; Goehler, Lisa Elane; Taylor, Ann Gill (2012) How might yoga help depression? A neurobiological perspective. Explore (NY) 8:118-26
Gaykema, Ronald P A; Goehler, Lisa E (2011) Ascending caudal medullary catecholamine pathways drive sickness-induced deficits in exploratory behavior: brain substrates for fatigue? Brain Behav Immun 25:443-60
Taylor, Ann Gill; Goehler, Lisa E; Galper, Daniel I et al. (2010) Top-down and bottom-up mechanisms in mind-body medicine: development of an integrative framework for psychophysiological research. Explore (NY) 6:29-41
Gaykema, Ronald P A; Daniels, Teresa E; Shapiro, Nathan J et al. (2009) Immune challenge and satiety-related activation of both distinct and overlapping neuronal populations in the brainstem indicate parallel pathways for viscerosensory signaling. Brain Res 1294:61-79
Gaykema, Ronald P A; Goehler, Lisa E (2009) Lipopolysaccharide challenge-induced suppression of Fos in hypothalamic orexin neurons: their potential role in sickness behavior. Brain Behav Immun 23:926-30
Park, Su-Mi; Gaykema, Ron P A; Goehler, Lisa E (2008) How does immune challenge inhibit ingestion of palatable food? Evidence that systemic lipopolysaccharide treatment modulates key nodal points of feeding neurocircuitry. Brain Behav Immun 22:1160-72
Gaykema, R P A; Park, S M; McKibbin, C R et al. (2008) Lipopolysaccharide suppresses activation of the tuberomammillary histaminergic system concomitant with behavior: a novel target of immune-sensory pathways. Neuroscience 152:273-87
Goehler, Lisa E; Park, Su Mi; Opitz, Noel et al. (2008) Campylobacter jejuni infection increases anxiety-like behavior in the holeboard: possible anatomical substrates for viscerosensory modulation of exploratory behavior. Brain Behav Immun 22:354-66
Gaykema, Ronald P A; Balachandran, Madhu K; Godbout, Jonathan P et al. (2007) Enhanced neuronal activation in central autonomic network nuclei in aged mice following acute peripheral immune challenge. Auton Neurosci 131:137-42
Goehler, Lisa E; Lyte, Mark; Gaykema, Ronald P A (2007) Infection-induced viscerosensory signals from the gut enhance anxiety: implications for psychoneuroimmunology. Brain Behav Immun 21:721-6

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