Evan Feinberg - US grants

PROJECT SUMMARY Abnormal synapse structure, function, and number are posited to underlie a range of diseases, from neurodevelopmental conditions such as autism to neurodegenerative disorders such as Alzheimer's. Each neuron synapses with functionally diverse upstream and downstream partner neurons to support different computations and facets of behavior, and recently discovered partner-specific synaptic abnormalities are hypothesized to drive conditions such as schizophrenia and Alzheimer's. These observations indicate that the essential subunits of neural information processing are not neurons themselves but their synaptic connections, and that understanding brain function in health and disease will require understanding how different synapses contribute to computations and behavior. In recent years, causal relationships of this sort have been established for identified cell types in neural processing and behavior using chemogenetic and optogenetic tools to manipulate identified neurons, yet these methods lack the spatial resolution necessary to selectively manipulate synaptic connections with specific partners. As a result, there is an outstanding need for methods able to manipulate communication between defined synaptic partners in health and in disease. This proposal describes a solution to this problem, a new technology termed controller locally affecting synaptic partners (CLASP). I explain the underlying concept and how we will implement and rigorously validate CLASP using a sequence of in vitro and in vivo assays. To demonstrate the power of this approach, we will then apply CLASP in vivo to investigate the functional role of a fundamental circuit motif in cortical processing. Finally, I delineate how CLASP can be applied to studies in neurological and psychiatric disease models and to investigate synapse-specific therapeutic interventions, and envision how the CLASP approach could be adapted to create additional variants for synapse-specific manipulations. The successful completion of these studies will yield a transformative new technology and illustrate its power to unravel neural circuits in health and disease with unprecedented specificity.

PROJECT SUMMARY/ABSTRACT A fundamental task of the brain is to choose what to do next, and an impaired ability to select appropriate behaviors and repress inappropriate actions is thought to underlie conditions including schizophrenia, addiction, and Huntington's disease. How the brain weighs available actions to choose and execute the most adaptive is not understood. In the canonical model, effector structures such as the superior colliculus (SC) are constantly poised to generate behaviors, but are repressed by tonically active GABAergic neurons of the basal ganglia (BG) output nuclei substantia nigra pars reticulata (SNr) and internal globus pallidus; before an action, the specific subset of BG output neurons inhibiting that action pause firing to ?release? its effector pathway. However, several studies have revealed that SNr harbors multiple GABAergic inhibitory cell types of which some are only phasically active, and both tonic and phasic inhibitory SNr neurons can converge on the same target neurons in structures such as SC. These cell types are intermingled in SNr, which has hindered efforts to apply the genetic tools of modern neuroscience to decipher how their convergent phasic and tonic inhibitory signals influence downstream neural processing to control behavioral choice and execution. To surmount this obstacle, my lab has developed approaches to selectively express genetic tools in either phasic or tonic SNr neurons. Here I propose to apply our approach to reveal how phasic and tonic inhibitory BG subtypes coordinate behavior. First, we will test the hypothesis that phasic SNr neurons encode both behavioral choice and execution by recording their activity during behavior. Second, we will test the hypothesis that phasic inhibitory neurons shape both choice and execution of the chosen behavior using targeted manipulations. Third, to understand the transcriptional basis of physiologic differences between these phasic and tonic types, we will define the genetic identities of both using a novel barcoding approach in single-cell sequencing. Collectively, these studies will provide a comprehensive portrait of how phasic and tonic inhibitory BG cell types coordinate behavioral choice and execution. The findings from these studies may help us to understand the etiology of and lead to new treatments for conditions including addiction, schizophrenia, Parkinson's, and Huntington's disease.