A body of evidence assembled over the past several years indicates persuasively that GABAergic circuits in the nucleus accumbens shell (AcbSh) play an important role in the control of food intake. For example, injections of GABA agonists into the AcbSh result in a large and very specific increase in feeding, a surprising result given that the AcbSh is often assumed to exert a generalized influence on motivational or reward mechanisms. The magnitude and specificity of the effects produced by AcbSh manipulations suggest both that pathology of the neural circuitry underlying the AcbSh feeding effects may play a role in some human eating disorders, and that this circuit may be a promising target for the development of novel approaches to the treatment of disturbances in food intake and body weight. The long-term goal of the proposed research project is to identify and characterize the neural circuits through which the AcbSh produces changes in Feeding behavior. Our fundamental working hypothesis is that the AcbSh affects feeding by potently regulating neural activity in a distributed, but lateralized, network of structures that includes the medial ventral pallidum (VPm), and the lateral (LH), arcuate (Arc), and paraventricular (PVN) hypothalamic regions. The proposed experiments involve the use of complementary neuroanatomical, behavioral, pharmacological, and molecular techniques to better understand the flow of information through the circuit and the functional contribution of each structure to the expression of AcbSh-mediated feeding. Specifically, we propose to examine the ability of excitotoxic lesions of each of these structures to modify the amount and pattern of food intake elicited by unilateral intra-AcbSh injections of muscimol. These studies will be carried out using an """"""""ipsilateral-contralateral disruption"""""""" (ICD) design which will allow us to avoid many of the interpretative difficulties usually encountered in studies of this type. Because intra-AcbSh injections of muscimol induce intense Fos expression in all of the structures listed above, we will also use the ICD design to determine the manner in which lesions of these structures alter the patterns of neuronal activation produced by the intra- AcbSh injections. We will also establish whether LH neurons activated by intra-AcbSh muscimol project directly to the Arc or PVN. Additional studies will examine whether the feeding response can be altered by intracerebral injections of orexin and neuropeptide Y antagonists, and whether bicuculline injections into the VPm induce Fos expression and feeding similar to that seen after muscimol injections in the AcbSh. The prevalence of obesity and eating disorders has made these conditions a major public health concern and progress in treating them depends on our having a detailed understanding of the brain mechanisms controlling feeding. The results of these investigations will allow us to understand more clearly the functional organization of brain mechanisms that regulate feeding behavior and may provide information critical to the effort to discover effective treatments to reduce the suffering caused by dysregulation of feeding in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071738-04
Application #
7864326
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Hyde, James F
Project Start
2007-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$278,205
Indirect Cost
Name
University of Illinois at Chicago
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Shim, Insop; Stratford, Thomas R; Wirtshafter, David (2014) Dopamine is differentially involved in the locomotor hyperactivity produced by manipulations of opioid, GABA and glutamate receptors in the median raphe nucleus. Behav Brain Res 261:65-70
Covelo, Ignacio R; Patel, Zaid I; Luviano, Jennifer A et al. (2014) Manipulation of GABA in the ventral pallidum, but not the nucleus accumbens, induces intense, preferential, fat consumption in rats. Behav Brain Res 270:316-25
Stratford, Thomas R; Wirtshafter, David (2013) Lateral hypothalamic involvement in feeding elicited from the ventral pallidum. Eur J Neurosci 37:648-53
Stratford, Thomas R; Wirtshafter, David (2013) Injections of muscimol into the paraventricular thalamic nucleus, but not mediodorsal thalamic nuclei, induce feeding in rats. Brain Res 1490:128-33
Stratford, Thomas R; Wirtshafter, David (2012) Effects of muscimol, amphetamine, and DAMGO injected into the nucleus accumbens shell on food-reinforced lever pressing by undeprived rats. Pharmacol Biochem Behav 101:499-503
Covelo, Ignacio R; Wirtshafter, David; Stratford, Thomas R (2012) GABA(A) and dopamine receptors in the nucleus accumbens shell differentially influence performance of a water-reinforced progressive ratio task. Pharmacol Biochem Behav 101:57-61
Wirtshafter, David; Covelo, Ignacio R; Salija, Inga et al. (2012) Effects of muscimol in the nucleus accumbens shell on salt appetite and sucrose intake: a microstructural study with a comment on the sensitization of salt intake. Behav Neurosci 126:699-709
Jones-Cage, Chris; Stratford, Thomas R; Wirtshafter, David (2012) Differential effects of the adenosine AýýýA agonist CGS-21680 and haloperidol on food-reinforced fixed ratio responding in the rat. Psychopharmacology (Berl) 220:205-13
Stratford, Thomas R; Wirtshafter, David (2012) Evidence that the nucleus accumbens shell, ventral pallidum, and lateral hypothalamus are components of a lateralized feeding circuit. Behav Brain Res 226:548-54
Wirtshafter, David; Davis, John D; Stratford, Thomas R (2011) Inactivation of the median raphe nucleus increases intake of sucrose solutions: a microstructural analysis. Behav Neurosci 125:529-40

Showing the most recent 10 out of 12 publications