Combinatorial neuromodulation of internal states

Introduction

Being sleepy, hungry, afraid, or happy impacts our daily experience and defines our behavior and actions. Such internal states are characterized by unique signatures of activity across neural circuits and are actively shaped by neuromodulators, such as dopamine, serotonin, acetylcholine, and norepinephrine, that are released widely throughout the brain to alter the function of target neural circuits.

Neuromodulator Dynamics

At any moment, distinct combinations of neuromodulators are being released in each brain region. Changes in the neuromodulator balance have a powerful impact on the brain-wide configurations that underlie internal and behavioral states. Most mood disorders are associated with neuromodulator imbalance, and most therapeutic strategies attempt to restore this balance. However, how combinations of neuromodulators define distinct brain configurations and shape internal states remains unknown.

Role of the Prefrontal Cortex and Hippocampus

The prefrontal cortex and the hippocampus are two interconnected regions that are essential for cognitive processing and memory. They receive converging neuromodulatory inputs, and synaptic alterations in these regions are critical for learning, while dysfunction of this pathway is involved in most mood disorders. Despite the vital role of these circuits for brain function, little is known about how combinatorial neuromodulation regulates circuit configuration and coordinates information flow between these regions.

Project Objectives

In this project, we will combine neuromodulator monitoring with large-scale in vivo electrophysiology, optogenetics, and in vivo genome editing to answer the following questions and resolve the contribution of neuromodulators to the organization of neuronal ensembles and information gating in the hippocampus-prefrontal circuit in behaving mice:

1. What is the neuromodulatory landscape across behavioral states?
2. How does state-specific neuromodulation sculpt neuronal dynamics?
3. What are the circuit elements underlying combinatorial neuromodulatory action?