Benjamin B. Land - US grants

DESCRIPTION (provided by applicant): The number of obese individuals continues to increase worldwide, contributing to millions of deaths each year. Research investigating the neural underpinnings of overnutrition has traditionally focused on the hypothalamus, where metabolism is thought to be regulated. However, parts of the brain involved in decision making (prefrontal cortex) and reward processing (nucleus accumbens) are now hypothesized to play an important role in compulsive, or habitual, feeding. The goal of this proposal is to investigate how the prefrontal cortex and the nucleus accumbens may be working together to control food intake. We will use a novel, "optogenetic" technique that uses two special types of ion channels, halorhodopsin and channelrhodopsin, that are activated by light. By employing viral injection techniques, we will express these light-activated channels selectively in prefrontal cortical neurons and their projections, which terminate in the nucleus accumbens. We can then use laser light with specific wavelengths to either excite (with channelrhodopsin) or inhibit (with halorhodopsin) only those presynaptic terminals arriving from the prefrontal cortex in accumbens, allowing unprecedented spatial selectivity. We predict that yellow light, which activates halorhodopsin, will inhibit the firing of glutamate-releasing cortical neurons and thus promote food intake in normal, sated animals. We believe that this is similar to what is occurring in obese, habitually eating individuals- a reduction in firing of the prefrontal cortical neurons. The second half of the proposal seeks to reverse this aberrant behavior. We will first demonstrate that overnutrition, as a result of a high-fat diet, induces habit-like responses to food intake. We will then reverse this habit behavior by using blue light, which will activate the prefrontal cortical neurons via the channelrhodopsin and restore glutamate to the accumbens. By resolving this important connection between these brain areas, we hope to provide new insights into the treatment of obesity and related disorders. PUBLIC HEALTH RELEVANCE: This research attempts to better understand how obesity may alter decision making to reinforce detrimental eating habits. By determining how this occurs in the brain, we will be better able to provide therapeutic interventions that may help control weight gain and diseases associated with obesity.

Project Summary Stress is a known risk factor for clinical depression, and stress can exacerbate depressive symptoms in vulnerable individuals. By better understanding the molecular mechanisms by which stress can drive pro-depressive behaviors, we will be able to generate novel/tailored therapeutics to combat this prevalent disease. Both the kappa-opioid receptor (KOR) and mammalian target of rapamycin (mTOR) systems have been shown to mediate elements of stress-induced, depression-like behaviors in mice. However, these two systems have never been linked, representing a major gap in our knowledge of a complete pathway from stress to pathophysiology and behavior. Understanding how KOR activity is related to mTOR function will be critical in refining drugs that target these systems. One possible intermediate protein in these pathways is p38 MAPK, which is activated by KOR and whose activity is necessary for stress-induced immobility, aversion, and social avoidance. The proposed experiments will directly test the relationship between KOR, p38 MAPK, and mTOR as a functional signaling pathway mediating depression-like behaviors and neuronal plasticity. Specifically, we propose to first validate preliminary data demonstrating that mTOR levels are modulated by KOR activation. In Aim 1, we will use pharmacological inhibitors/antagonists and genetic models to test whether p38 MAPK is necessary for the changes in mTOR level seen by KOR activation. We will then assess whether mTOR mediates KOR/p38-induced place aversion and changes in swim stress immobility. In aim 2, we will test whether KOR changes markers of neuronal plasticity including dendrite length, spine density/shape, and synaptic proteins. We will use both pharmacological activation of KOR and stress to test dependence of p38 MAPK and mTOR, and finally determine if KOR antagonism is able to attenuate changes in stress-induced plasticity. The proposed studies described here will better define the molecular pathways from stress exposure to depression-like behaviors, and possibly uncover novel targets for therapeutic action that could be used in the clinical population to treat stress-vulnerable individuals.