Ted M. Hsu, PhD - US grants

? DESCRIPTION (provided by applicant): Over two-thirds of the US population is categorized as overweight or obese. This obesity epidemic is largely driven by the excessive intake of palatable and unhealthy foods. Both the size of an individual meal and the frequency of meal or snack initiation are heavily influenced by previous experience and by exposure to environmental food-associated stimuli (e.g. visual, olfactory) that can override homeostatic mechanisms of feeding. Therefore, the development of effective pharmacological treatments for obesity requires a deeper understanding of the neurobiological systems that integrate previous experience with external cues to control feeding behavior. Preliminary data in this proposal together with recent published work implicate the ventral subregion of the hippocampus (vHP) as a mediator of these higher-order aspects of feeding behavior. The vHP expresses receptors for the gut-derived hormone, ghrelin (GHSR1-As), that when pharmacologically activated, potently increases overall food intake, meal size and frequency, and food-motivated behavior. However, whether ghrelin signaling in the vHP is physiologically relevant for excessive food intake and obesity development is unknown. Furthermore, a comprehensive understanding of the downstream neural substrates involved in vHP ghrelin signaling also requires deeper examination. The primary goals of this proposal are to test the novel hypotheses that chronic down-regulation of ghrelin signaling in the vHP will reduce meal size and frequency, attenuate learned associations between rewarding food and external stimuli, and increase resistance to obesity development (Aim I), as well as to determine the important neural targets and neural circuitry mediating vHP ghrelin signaling (Aim II). To address these hypotheses, experiments in Aim 1 will use localized virogenetic knockdown of GHSR1-As in the vHP in conjunction with novel behavioral paradigms that examine learned associations between the environment and palatable food. Aim II will utilize neuroanatomical, immunohistochemistry methods as well as virogenetic, neuropharmacological, and behavioral techniques to determine the downstream neural targets mediating these hyperphagic effects, focusing on the lateral hypothalamus (LHA) and medial prefrontal cortex (mPFC). Experiments in Aim II will also examine the interaction between vHP ghrelin signaling and reward-related neuropeptidergic systems present in the LHA (orexin) and the mPFC (dopaminergic type-1 receptor signaling).

Project title: The effects of context and physiological state on mesolimbic encoding of reward PROJECT SUMMARY/ABSTRACT The encoding of reward is a complex process that is regulated by a variety of factors that extend beyond primary stimulus features to include interactions between contextual and discrete cues in the environment and changes to physiological state. In general, the encoding of reward and subsequent goal-oriented behaviors are often adaptive and essential for survival. However, humans world-wide are often bombarded with environmental contextual cues that can trigger maladaptive reward-seeking behaviors that are rampant in prominent health issues like obesity and drug addiction. While many have studied the mesolimbic system under the lens of both adaptive and maladaptive goal-directed behaviors, surprisingly little is known about the contribution of contextual cues in modulating the mesolimbic system. Moreover, the functions of the mesolimbic system are powerfully modulated by physiological state and can influence how mesolimbic phasic dopamine responses encode particular outcomes (e.g. food, water, and drugs of abuse). [[Thus, a major aim of this proposal is to delineate the neural substrates that integrate information about contextual cues, discrete cues, and physiological state, which subsequently guide goal- oriented behaviors. VTA-NAc phasic dopamine activity has been strongly implicated in goal-directed behaviors and is robustly influenced by physiological state. In Aim I, we utilize in vivo fiber photometry in awake, behaving animals to generate real-time recordings from VTA dopamine neurons while animals learn to associate water availability with discrete cues. We then examine the thirst neurons of the subfornical organ (SFO) as a primary neural substrate that relays physiological state information to VTA dopamine neurons using fiber photometry and chemogenetic manipulations. Based on previous work and pilot data, we anticipate that the SFO is necessary and sufficient for the modulation of water-cue evoked VTA phasic dopamine activity. We will also determine the multi-synaptic path by which the SFO communicates with the VTA. In Aim II, we consider VTA phasic dopamine signaling as an integrator of both physiological state and contextual cues that is in part modulated by input from the ventral hippocampus (vHP). Here we use fiber photometry in VTA dopamine neurons in conjunction with vHP chemogenetics during a novel behavioral task where animals learn to associate water availability with contexts paired with either water-deprivation or water- satiation. When water-satiated, we expect water-deprivation contexts to augment water-cue evoked VTA phasic dopamine signaling and that this response is dependent on vHP mediated context processing. Taken together, the novel findings from these studies will allow for a greater understanding of how goal-directed behaviors are acquired and expressed within the brain and provide important mechanistic data that will strongly impact the treatment of health issues such as obesity and drug addiction.]]