Individuals often engage in rewarding behaviors, including consuming highly-palatable, calorically- dense "comfort" foods or taking drugs of abuse, as a means of self-medication for stress relief, but the neural mechanisms underlying stress relief by palatable foods are largely unknown. We propose to study these mechanisms using a model in which rats with free access to food and water are given twice-daily access to a small amount of palatable sucrose solution or water as a control. Using this model, we have found that sucrose rats have attenuated hypothalamic-pituitary-adrenal (HPA) axis and behavioral-anxiety responses to stress and diminished stress-induced neuronal activation in brain reward regions. Moreover, the calories and other post- ingestive consequences of sucrose are neither sufficient nor necessary for the HPA dampening, suggesting that brain reward per se may mediate the response. The basolateral amygdala (BLA) is a key brain reward region that is also implicated in driving stress responses. Moreover, neural activity in the BLA is necessary for stress-dampening by sucrose, and genes related to structural and functional plasticity are up-regulated in the BLA following a history of sucrose intake. In support of this idea, immunolabeling for synaptophysin (a marker of presynaptic terminals), phosphorylated cAMP response element-binding protein (pCREB;a postsynaptic marker associated with synaptic plasticity), and gephyrin (a postsynaptic marker of inhibitory postsynaptic densities) are all increased in the BLA following sucrose. The current proposal addresses the hypothesis that palatable food dampens stress responses via pCREB-dependent synaptic remodeling in the BLA. We predict that sucrose intake increases BLA inhibitory tone, leading to attenuated stress-excitatory output. We will test this hypothesis in three specific aims.
The first aim will use intra-BLA blockade of CREB/pCREB expression to determine whether this signaling pathway mediates sucrose-induced synaptic reorganization and stress- dampening.
The second aim will assess structural and functional plasticity in the BLA after sucrose (using dual immunolabeling with confocal microscopy to quantify synaptic appositions onto BLA neurons, as well as whole- cell electrophysiological recordings from BLA slice preparations) to test the hypothesis that sucrose-induced synaptic remodeling results in increased inhibitory tone in BLA.
The third aim will combine tract-tracing and lesion approaches to test the hypothesis that medial prefrontal cortex (mPFC) projections to BLA are necessary for sucrose-mediated synaptic remodeling and stress dampening.

Public Health Relevance

When under stress, many people engage in pleasurable behaviors (e.g., drug taking or eating tasty, high-calorie comfort foods), presumably to help calm or comfort themselves. However, this self-medicating behavior can have negative side-effects (e.g., persistent increased caloric intake and the development of obesity). This project seeks to understand how pleasurable behaviors reduce stress, thereby providing insight into the motivation driving these behaviors and potentially offering new strategies for the prevention and/or treatment of obesity, drug addiction, and other stress-related disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK091425-02
Application #
8334571
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Hyde, James F
Project Start
2011-09-20
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$337,060
Indirect Cost
$99,365
Name
University of Cincinnati
Department
Psychiatry
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Ulrich-Lai, Yvonne M; Ryan, Karen K (2014) Neuroendocrine circuits governing energy balance and stress regulation: functional overlap and therapeutic implications. Cell Metab 19:910-25
Ryan, Karen K; Mul, Joram D; Clemmensen, Christoffer et al. (2014) Loss of melanocortin-4 receptor function attenuates HPA responses to psychological stress. Psychoneuroendocrinology 42:98-105
Packard, Amy E B; Ghosal, Sriparna; Herman, James P et al. (2014) Chronic variable stress improves glucose tolerance in rats with sucrose-induced prediabetes. Psychoneuroendocrinology 47:178-88
Grayson, Bernadette E; Hakala-Finch, Andrew P; Kekulawala, Melani et al. (2014) Weight loss by calorie restriction versus bariatric surgery differentially regulates the hypothalamo-pituitary-adrenocortical axis in male rats. Stress 17:484-93
Ryan, Karen K; Grayson, Bernadette E; Jones, Kenneth R et al. (2012) Physiological responses to acute psychological stress are reduced by the PPAR? agonist rosiglitazone. Endocrinology 153:1279-87