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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Stoeckel, Luke
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University of Cincinnati
Schools of Medicine
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Egan, Ann E; Thompson, Abigail M K; Buesing, Dana et al. (2018) Palatable Food Affects HPA Axis Responsivity and Forebrain Neurocircuitry in an Estrous Cycle-specific Manner in Female Rats. Neuroscience 384:224-240
Packard, Amy E B; Di, Shi; Egan, Ann E et al. (2017) Sucrose-induced plasticity in the basolateral amygdala in a 'comfort' feeding paradigm. Brain Struct Funct 222:4035-4050
Packard, Amy E B; Zhang, Jintao; Myers, Brent et al. (2017) Apolipoprotein A-IV constrains HPA and behavioral stress responsivity in a strain-dependent manner. Psychoneuroendocrinology 86:34-44
Ulrich-Lai, Yvonne M; Christiansen, Anne M; Wang, Xia et al. (2016) Statistical modeling implicates neuroanatomical circuit mediating stress relief by 'comfort' food. Brain Struct Funct 221:3141-56
Packard, Amy E B; Egan, Ann E; Ulrich-Lai, Yvonne M (2016) HPA Axis Interactions with Behavioral Systems. Compr Physiol 6:1897-1934
Ulrich-Lai, Yvonne M (2016) Self-medication with sucrose. Curr Opin Behav Sci 9:78-83
Gutierrez-Aguilar, Ruth; Thompson, Abigail; Marchand, Nathalie et al. (2015) The obesity-associated transcription factor ETV5 modulates circulating glucocorticoids. Physiol Behav 150:38-42
Ulrich-Lai, Yvonne M; Fulton, Stephanie; Wilson, Mark et al. (2015) Stress exposure, food intake and emotional state. Stress 18:381-99
Egan, Ann E; Ulrich-Lai, Yvonne M (2015) Activation of physiological stress responses by a natural reward: Novel vs. repeated sucrose intake. Physiol Behav 150:43-52
Thompson, Abigail K; Fourman, Sarah; Packard, Amy E B et al. (2015) Metabolic consequences of chronic intermittent mild stress exposure. Physiol Behav 150:24-30

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