Mapping a CART neuropeptide circuit mediating Hunger-Fear interactions

Abstract

Survival requires constant trade-offs. An animal must decide, within seconds, whether to forage for food or flee from a predator. These decisions are not random, and they are influenced by the animal’s internal energy state. They reconfigure how sensory information and prior experience are evaluated, biasing behaviour toward either risk-taking or avoidance, depending on the organism’s energy state. CART (Cocaine- and amphetamine-regulated transcript) is a neuropeptide involved in a range of physiological and behavioral functions, including hunger regulation, energy balance, reward, and anxiety. CART is widely expressed in hypothalamic regions such as the arcuate nucleus (ARC), as well as in limbic and midbrain structures, including the central amygdala (CeA), bed nucleus of the stria terminalis (BNST), and periaqueductal gray (PAG), all of which are central components of defensive circuitry. Given CART’s established role in metabolic regulation, it is plausible that CART expressing neurons integrate energy state information with threat processing networks to modulate defensive behaviour in an energy-dependent manner. However, it remains unclear whether ARC CART neurons directly link metabolic state to defensive circuits. This thesis tests whether ARC CART neurons modulate innate fear and identifies their downstream projection targets. Chemogenetic activation of ARC CART neurons enhanced innate fear responses, supporting a functional role for this population in fear modulation. To identify the downstream regions that mediate these effects, non-transsynaptic viral tracing methods were used to map the projections and connectivity of ARC CART neurons. These analyses identified prominent projections from ARC CART neurons to areas of the brain that process threats, including the BNST, CeA, and PAG, with varying projection densities across targets. These findings suggest that CART neurons in the hypothalamus play a crucial role in linking metabolic states to defensive behaviors. By influencing important areas within fear and anxiety circuits, ARC CART neurons adjust behavioral priorities based on the organism's internal energy levels.