UCSF

Animals must maintain internal state within narrow limits to survive. This process, known as homeostasis, is coordinated by specialized neural circuits that sense deviations in internal state and respond with compensatory physiological and behavioral outputs. Two important examples are hunger and thirst, which are generated in response to energy deficit and dehydration. However, surprisingly little is known about the neural circuits controlling hunger and thirst, in part because the brain contains many intermingled neural cell types with different functions. In this dissertation, we describe two studies that take advantage of the power of mouse genetics to study feeding and drinking behavior, as well as the underlying neural cell types and circuits. We also describe the development of mouse genetic tools to identify gene expression markers for uncharacterized neural cell types.

In our first study, we identify forebrain neural populations that are activated by dehydration, including an excitatory population in the median preoptic nucleus (MnPO). We show that activation of these neurons promotes drinking and increases blood pressure. We also demonstrate that reduction of their activity is negatively reinforcing, supporting a theory called drive reduction and resolving decades of debate about the motivational mechanism of thirst. In addition, we examine outputs to three regions downstream of the MnPO and find that they partially dissociate the behavioral and cardiovascular effects.

In our second study, we examine dietary amino acid sensing in mice. Prior to our work, it was proposed that animals rejected food lacking a single essential amino acid (EAA) within minutes of feeding. However, we are unable to replicate this result and therefore systematically reinvestigate the effects of dietary EAA deficiency. Our main findings are that dietary amino acid sensing depends on physiological need and that distinct mechanisms are responsible for sensing of different EAAs.

Together, the work described in this dissertation sheds light on neural control of feeding and drinking behavior. It will be important in future studies to elucidate the neural circuit downstream of the MnPO that controls thirst and the mechanisms underlying detection of individual dietary amino acids.