Determining the neuroplasticity role of inhibitory NDNF neurons in motor execution and learning

ABSTRACT Neuroplasticity is a key feature of cortical systems allowing for flexible shaping of pyramidal cell activity necessary for learning, adaptation, and recovery from injury. A shared feature of neuroplasticity across cortical and subcortical regions is the involvement of inhibitory interneurons in refining pyramidal cell activity. In the motor cortex, pyramidal cells tile their activity to skilled behaviors, likely being shaped by local inhibitory interneurons. However, how pyramidal cell sequencing emerges in the motor cortex to produce and adapt skilled behaviors remains unknown. Delineating the mechanisms and circuitry involved in shaping pyramidal cell sequencing is crucial to understanding the fundamental rules of motor plasticity, and to inform future therapeutic interventions to enhance neuroplasticity. While previous studies have investigated the role of interneuron subtypes in motor plasticity; the predominant interneuron in layer 1 of cortex, neuron-derived neurotrophic factor (NDNF) neurons, has yet to be researched. NDNF neurons have been characterized across cortical regions including auditory, visual, somatosensory, and prefrontal cortex. While their functional role across these cortical regions continues to be explored, there is evidence these neurons regulate pyramidal cell inputs, attenuating top-down inputs and gain-controlling bottom-up inputs. Skilled behavior learning and execution involves the dynamic combination of top-down inputs originating from the basal ganglia and bottom-up inputs deriving from the cerebellum to shape pyramidal cell activity. Our overall hypothesis in this proposal is that motor learning and execution rely on NDNF neurons to refine pyramidal cell activity through regulation of top-down and bottom-up inputs. To test this, I will first determine the anatomical localization of NDNF neuron somata, dendrites, and axons. Then, I will establish the dynamics of NDNF neurons in M1 during motor execution and learning using two-photon calcium imaging. Lastly, I will casually test the role of NDNF neurons on shaping pyramidal cell activity by optogenetically activating and suppressing NDNF neurons while performing large-scale neural recording of pyramidal cells. In all, this work will establish the role of motor cortex NDNF neurons in neuroplasticity.