Hypothalamic neuronal circuits controlling survival behaviors

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

Our interest is to understand how genetically identified cell types and their projections drive behaviors essential for survival. Using the mouse as our model system, we apply optogenetics and chemogenetics to manipulate neuronal circuits in awake, behaving mice. In addition, we use a combination of electrophysiology, fluorescence endomicroscopy, and behavioral assays to elucidate the neuronal basis of survival behaviors (e.g., feeding and nociception) and to determine how these neuronal circuits drive the rewarding and addictive nature of food intake. Evidence for the addictive properties of food and opioids has been growing progressively throughout the last decade. Both addiction and overeating are disorders by which individuals learn rewarding associations between stimuli such as drugs of abuse and highly palatable food. Therefore, our laboratory is interested in understanding the addictiveness aspects of feeding behaviors and opioids. We study this topic at the level of neuronal circuits in the context of behaviors, cell types, and synaptic connectivity. Neuronal circuits are composed of diverse collections of cell types, each having a distinct set of synaptic connections and performing specific functions. To understand how neuronal circuits drive behaviors, it is essential to examine the function of specific cell types in the circuit. However, studies have been mostly unable to identify the cell types involved in specific behaviors. Furthermore, experiments to date have largely been unable to determine when specific cell types are active to provide quantitative relationships between circuit activity and behavior. Ultimately, understanding the mechanisms regulating food intake and the rewarding and addictive nature of food and opioids will enhance our ability to battle disorders such as obesity, diabetes, anorexia, bulimia, and addiction. Recently, we showed how two of the lateral hypothalamic neuronal populations identified by the expression of the calcium-binding protein parvalbumin (PVALB; LH-PV) or leptin receptor (LH-LEPR) modulate pain and appetitive behaviors, respectively, in mice. Our work revealed LH-PV neurons as regulators of the LH glutamatergic circuitry orchestrating pain behaviors and identified LH-LEPR neurons as modulators of a hypothalamic-ventral tegmental midbrain circuit involved in controlling motivation and appetitive behaviors. Furthermore, we used a behavioral paradigm for mice to discriminate feelings of "hunger" from satiety and found that arcuate nucleus AGRP neurons drive a hunger-like internal state, whereas GABAergic and glutamatergic lateral hypothalamic neurons do not. Our study calls attention to the complexity of hypothalamic feeding regulation and can be used as a versatile framework to characterize how other neuronal circuits affect hunger and identify potential therapeutic targets for eating disorders. In addition, we demonstrated that (a) activation of agouti-related peptide (AGRP)-expressing neurons in the arcuate nucleus (ARC-AGRP) attenuated opioid-induced weight loss but did not evoke weight gain during opioid dependence and that (b) anterior hypothalamic parvalbumin neurons are glutamatergic and promote escape behavior. Together, these studies highlight our commitment to determine how specific neuronal types regulate behaviors that are essential for survival.