Internal state drivers of behavioral flexibility and their underlying neural circuitry in the zona incerta

Survival requires accurate and rapid implementation of adaptive behavior.

In a world where our physiological needs and surrounding environment are ever changing, one wrong move could make the difference between life and death.

How does the brain successfully compute changes in internal state and external cues, while factoring in experience, to drive the most appropriate behavioral outcome from moment-to-moment?

Mounting evidence suggests that the zona incerta, a little studied region, is a central switchboard for such adaptive behavior.

This subthalamic nucleus has widespread connections and was recently found to regulate an astounding range of behaviors critical for survival including defense, sleep, feeding and much more.

It also encodes associated changes in internal states, such as anxiety, fatigue and hunger, and integrates sensory inputs across modalities.

These features suggest that a central function of the zona incerta might be to locally compute needed transitions in behavior based on internal state changes, which are then broadcast to downstream targets to convert this into action.

To address this hypothesis, CERTASTATES will employ cutting-edge molecular, circuit tracing, recording and in vivo imaging technologies in mice together with diverse behavioral paradigms and rich behavioral state readouts.

The ultimate objective is to uncover how distinct internal state changes: (i) are processed in defined cell types and circuits, (ii) drive behavioral flexibility and (iii) are influenced by deep brain stimulation, motivated by the fact that the zona incerta is one of few established targets in humans for this therapeutic approach.

Together, this work will advance our understanding of how neural circuits generate internal states, and in turn process, broadcast and use this information to guide adaptive behavior.

Moreover, it will open an entry point for translation by exploring how clinically-applied neuromodulation can transform these vital computations.