Kv4.2(V404M) Mutation Induces Epileptiform Activity and Multiple Behavioral Abnormalities in Heterozygous Knock-in Mice.

The neural circuits responsible for selecting, initiating, and executing movements have been studied for decades but remain poorly understood. Coordinated lateralized movements are a fundamental component of natural orienting behavior and provide convenient behavioral readouts of decision making in animal model studies. While many brain regions, including cortical, cerebellar and midbrain structures, have been implicated in “orienting movements” (), a key node in the network is the intermediate and deep layers of the superior colliculus (dSC), which receives a wide range of cell-type-specific input (; ; ), performs computations to select spatial targets for movement, and coordinates downstream motor circuits to initiate and execute lateralized movements (; ; ). The dSC thus provides an excellent model for understanding how integrating input from multiple systems subserves a well-defined function (). In particular, examining neural activity in dSC and its upstream inputs during orienting behavior can elucidate whether, when, and how the strength of input from specific regions depends on behaviorally-relevant variables. A prominent inhibitory input to the dSC from the substantia nigra (SNr), an output nucleus of the basal ganglia, is proposed to permit orienting movements via phasic release of dSC from tonic inhibition (; ; ; ) and to modulate dSC output based on the value and kinematics of the movement (; ; ). The preponderance of this foundational work was performed in restrained primates making saccades while either dSC or SNr activity was recorded (; ; ; ; ; ; ). However, the extent to which these findings translate to other movements that also underlie orienting behavior (e.g. bilaterally coordinated directional limb movements), or to other species, is unclear. Thus, much remains unknown about how SNr influences dSC computations underlying directional motor output. To address this knowledge gap, we developed several variants of a head-fixed behavioral task requiring mice to perform an directional orienting forelimb movement to either the left or right. This task leverages the amenability of the mouse nervous system to cell-type-specific recording and perturbation during behavior (), complementing work in primate and other model systems (). We examined how SNr and dSC activity were related to behavioral events by recording with high-density electrode arrays. In addition, we replicated our analyses on publicly available data recorded in mouse SNr and dSC during a similar behavioral task developed by the International Brain Laboratory (IBL) (; ). Across data sets we found that mice exhibited reward-maximizing behavioral strategies, SNr and dSC activity reflected several task-related variables throughout the trial, and that SNr modulated, rather than strongly suppressed, task-relevant dSC activity.