About

The overall goal of the lab is to understand the origin of motivations— why do we do what we do? How do brains set priorities for an organism’s behavior? The lab is uncovering elegant mechanisms sculpted by natural selection in the brain that ensure compliance with the body’s essential survival needs. We have discovered molecular, synaptic, and motivational principles underlying the neurobiology of homeostasis– away from innate (reflexive) behaviors and towards an emphasis on learning mechanisms. These discoveries are enabled by new tools for precisely monitoring, mapping, and manipulating neurons.

 

The lab is focused on mechanisms of hunger, but we also study other behavioral states, such as thirst, to distinguish hunger-specific principles from more broadly tuned properties of need states. Hunger and thirst states are represented by brain-wide neural ensembles that drive food- or water-seeking, enhance reward and learning during consumption, and engage satiety processes. We take a reductionist approach to deconstruct these neural ensembles by concentrating on molecularly defined neuron populations that sense physiological signals of energy or hydration deficit and are sufficient to elicit avid food or water intake.

 

We have uncovered motivational mechanisms for need-sensing neurons that elicit avid food- or water-seeking behaviors by identifying neurons responsible for the unpleasant feelings of hunger and thirst. Our results indicate a simple mechanism where the unpleasant output of need-activated drive neurons coerces an animal to perform behaviors that reduce these neurons’ activity. These findings challenged widespread ideas about the role of innate behaviors controlled by homeostasis and instead emphasized a primary role for learning. This work raised a related question of how animals identify their need states to choose appropriate behaviors. We developed a framework to explore need-state decision-making and discovered that the prefrontal cortex guides need-state-dependent choice for food or water.

 

We are also interested in methods that can extend neural circuit discoveries in model organisms to human clinical therapies. Leveraging the lab’s interdisciplinary expertise in chemistry and neurobiology, we engineered chemogenetic receptors and ultrapotent small molecule agonists to selectively control neuron function. This drug-controlled, chimeric ion channel platform is highly effective in mice and monkeys, but also was designed to translate modern neural circuit research into human therapies for neurological disorders.

 

Survival need-regulating brain regions use different cell types to encode three temporally distinct behavioral phases of motivated behavior: drive (seeking), consumption (reward/learning), and satiety. Neuron dynamics measurements are essential to establish the relationship of molecularly defined cell types to these phases. Also, we examine neuron dynamics across multiple need states to understand their selectivity for hunger vs. other needs. For this, we developed a new imaging pipeline called CaRMA imaging to monitor the dynamics of all the molecularly defined cell types in a deep brain region at the same time to determine these relationships. Our goal is to develop a mechanistic framework for homeostatic control over learning, reward, and satiety. The lab’s emphasis is on the basic science of neural circuits, but our reductionist, molecular approaches facilitate the extension to clinical therapies.