A Novel Approach to Crack Neuronal Mechanisms that Shape Computations in the Brain

Project Summary Living in this ever-changing environment, we continually adapt and learn new behaviors. The computation mechanisms in our brain must be highly plastic to support such flexibility. Problems with this adaptive process, on the other hand, result in inflexible and maladaptive behaviors, the main symptoms of Attention-Deficit / Hyperactivity Disorder (ADHD), Obsessive-Compulsive Disorder (OCD), and other brain disorders. The goal of this proposal is to establish an experimental method to approach what neuronal substrates and mechanisms support our flexible behavior. Neuronal computations are mediated by coordinated activity patterns across neurons, referred to as neuronal dynamics. When we learn/adapt behavior, underlying neuronal dynamics change. This reconfiguration of neuronal dynamics is constrained by synaptic interactions among neurons. Thus, changes in synaptic interactions, or synaptic plasticity, likely mediate the shaping of neuronal dynamics and behavior. Therefore, neuronal dynamics and synaptic plasticity are two pillars of brain functions that cooperate to flexibly adapt behaviors. Yet, dynamics and plasticity have rarely been studied together due to the lack of appropriate behavioral paradigms and experimental methods to examine them. To bridge this gap, I have established a novel behavioral paradigm along with a proposal for a molecular screening method to identify the brain areas where synaptic plasticity is responsible for adapting actions. Electrophysiological recordings at such brain areas combined with manipulation of plasticity will allow us to crack a causal relationship between plasticity and neuronal dynamics: we will identify what kinds of changes in neuronal dynamics are induced by synaptic plasticity and how those changes result in improved behavior. By combining molecular, systems, and theoretical neuroscience methods, our experimental approach will link plasticity, dynamics, and behavior to explain the algorithmic basis of flexible computations in the brain. Identifying neural substrates controlling flexible behaviors provides a foundation for examining how dysfunctions of such substrates result in maladaptive behaviors observed in various brain disorders. Our novel approach to combine electrophysiology with manipulations of plasticity has the potential to become a new standard in neuroscience; and, linking neuronal dynamics and plasticity may inspire novel methods in machine learning and artificial intelligence. Thus, our findings and unconventional approach will have a broad impact in neuroscience and beyond.