PROJECT SUMMARY
Neural dynamics in motor cortex are necessary for dexterous behavior, but the mechanisms that generate
these activity patterns are unclear. The long-term goal of our research is to understand how cortical dynamics
are constructed to control movement, so that therapies could be developed to identify and repair aberrant
activity patterns associated with motor disorders. My laboratory recently showed that these cortical dynamics
arise from a collaboration between the intrinsic properties of cortex and inputs from the rest of the brain, but
how distinct input streams are received and processed by the cortex remains poorly understood. To
characterize these operations, we must understand the identity of the contributing inputs and their relationship
to cortical dynamics. The objective of this proposal is to directly test the role of two major inputs, from ventral
anterior (VA) and ventral lateral (VL) thalamic nuclei, to primary motor cortex. VA and VL have distinguishable
input/output features: VA receives more input from basal ganglia, VL receives more input from cerebellum, VA
and VL project to distinct cortical targets, and their intrinsic physiological properties differ. The central
hypothesis to be tested here is that the VA-to-cortex pathway modulates, while the VL-to-cortex pathway
drives, cortical dynamics and control of movement. To test the roles of VA and VL in the construction of cortical
dynamics and behavior, we produced and validated genetic tools in the mouse that allow selective monitoring
and manipulation of specific thalamic nuclei. With these tools, we will assess the relationship between a
cortically dependent prehension task and the activity patterns of VA and VL neurons. We will then determine
how activity in VL and VA drive or modulate cortical activity. Efforts to model the production of cortical
commands have focused almost exclusively on firing patterns of cortex, leaving aside the influence of external
inputs, leading to a cortico-centric view of pattern generation. With the data we collect, we will generate a more
realistic computational model for pattern generation that considers the role of both intrinsic cortical dynamics
and external inputs. Thus completion of these aims will advance understanding of how the cortical dynamics
underlying prehension are constructed through interactions with the basal ganglia and cerebellum. The
proposed research is innovative because it will use a new genetic toolbox for exploring thalamus, will produce
an in-depth assessment of thalamocortical dynamics during a new complex prehension task, will advance the
use of causal perturbations for testing interactions between brain regions, and will generate a more holistic
model for pattern generation for dexterous behavior. The proposed work is significant because understanding
the relationships among cortex, cerebellum, and basal ganglia can elucidate how their damage or disease
leads to motor disorders and support the development of therapies designed to replace lost or corrupted
signals.
