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

Introduction

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.

Research Question

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?

The Role of Zona Incerta

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.

Hypothesis

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.

Methodology

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.

Objectives

The ultimate objective is to uncover how distinct internal state changes:

1. Are processed in defined cell types and circuits
2. Drive behavioral flexibility
3. Are influenced by deep brain stimulation, motivated by the fact that the zona incerta is one of the few established targets in humans for this therapeutic approach.

Conclusion

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.