Neuromodulatory Control of Motivated Behavior in the Larval Zebrafish

Abstract

An animal’s behavior is strongly influenced by homeostatic drives that are crucial for survival and reproduction, such as the drive to eat, or to escape from harmful threats. In vertebrates, an evolutionarily ancient brain structure, the hypothalamus, is particularly important for coordinating these essential survival functions. Here, I leverage the simple and transparent brain of the vertebrate larval zebrafish to dissect the conserved hypothalamic networks that regulate appetite and defensive behaviors, focusing on how these overlapping circuits interact with and influence each other.

By using an unbiased brain-wide activity mapping approach, I pinpoint hypothalamic oxytocin (OXT) neurons as a key hub for the control of defensive behaviors against pain. I show that OXT neurons integrate multiple noxious stimuli, in particular input from TRPA1 damage-sensing receptors, to drive pain avoidance behavior via co-release of OXT and glutamate in the hindbrain and spinal cord. Furthermore, OXT neurons can also integrate information about the animal’s social context to control appetite, a separate homeostatic drive. These findings provide insight into how a single neuromodulatory circuit can exert flexible, context-dependent control over diverse social and non-social behaviors.

To further probe the hypothalamic networks controlling appetite, I have utilized whole-brain activity mapping to identify hypothalamic neural populations encoding hunger and satiety. My results indicate that, similar to mammals, medial and lateral regions of the hypothalamus show anti-correlated activity patterns, which likely regulate distinct phases of appetite. In hungry fish, medial hypothalamic nuclei report an energy deficit, whereas more lateral regions may be involved in voracious eating. I demonstrate that one medial hypothalamic population, the serotonergic caudal periventricular hypothalamus, is an important regulator of lateral hypothalamic (LH) activity and food intake, and a separate serotonergic population, the superior raphe nucleus, is important for regulating food intake during satiety, also via the LH, but is dispensable during hunger. Thus, by dissecting serotonin circuit function in the context of other hypothalamic feeding networks, I show how a single neuromodulator can control food intake in a satiation state-dependent manner. Overall, these studies provide insights into the underlying evolutionary principles and logic governing hypothalamic function, and demonstrate how diverse neuromodulatory circuits in the hypothalamus and beyond can exert state-dependent control over an animal’s most primitive, yet essential, survival drives.