Understanding the Neural Mechanisms Controlling Brain-wide Dynamics

PROJECT SUMMARY/ABSTRACT Behavior emerges from the flow of information between brain regions. For example, finding a friend in a crowd requires the interaction of brain regions performing sensory processing, memory processing, and motor responses. Disrupting how neural activity flows through the brain is thought to lead to deficits in several neuropsychiatric and neurological disorders, including schizophrenia and autism spectrum disorder. However, the neural mechanisms controlling the flow of information through the brain are not well understood. To capture how information flows through the brain, we recently used mesoscale calcium imaging to record the dynamics of neural activity across the dorsal cortex of mice. Surprisingly, we found cortex-wide neural dynamics could be captured in 14 unique spatiotemporal patterns of neural activity. These ‘motifs’ of activity occurred repeatedly, were common to all mice, and were associated with specific behaviors. Importantly, identifying these motifs allows us to quantify how neural activity is flowing across cortex. Here, we will leverage this ability to understand the neural mechanisms that control the expression of different motifs and, thus, control the flow of neural activity across the brain. Our Aims will address three key components of control: First, information must be routed between brain regions. Activity from a brain region can flow to several possible downstream regions (to support different behaviors). Using mesoscale calcium imaging, we will quantify how activity is routed through the brain at each moment in time. Simultaneous electrophysiology and optogenetics will then test two prominent hypotheses that predict activity is routed differently depending on 1) how information is represented in the population of neurons and 2) the frequency of synchronous oscillations. Second, the brain must be able to control how neural activity flows through cortex. Prefrontal cortex and the basal ganglia are two regions thought to provide such control. However, their role in guiding cortex-wide neural dynamics has never been directly tested. Therefore, our second aim will combine mesoscale imaging, electrophysiology, and optogenetics to test whether neurons in prefrontal cortex or basal ganglia control the expression of different motifs and, thus, control how neural activity flows through the brain. Third, in order to learn a new behavior, one must learn the pattern of neural activity that supports that behavior. Neuromodulation is thought to be critical for such learning: current models propose norepinephrine explores new patterns while dopamine refines patterns. To test this, our third aim will combine mesoscale imaging with recording and stimulation of noradrenergic/dopaminergic midbrain neurons while animals learn new behaviors. In this way, we aim to understand how neuromodulation changes behavior and cortex-wide neural dynamics. Our innovative combination of mesoscale imaging, electrophysiology, and optogenetics will provide insight into how neural activity is routed (Aim 1) and how cortex-wide dynamics are controlled (Aim 2) and learned (Aim 3). By understanding these mechanisms, we hope to improve treatments for diseases disrupting cognitive control.