The cellular and synaptic mechanisms of midbrain initiation of locomotion in mammals - PROJECT SUMMARY
Locomotion is important behavior for humans and all animals. Rhythmic movements are executed by
microcircuits of the spinal cord. Setting movement goals and selecting motor programs requires higher brain
planning centers that funnel inputs through the basal ganglia. Intercalated between the basal ganglia and
spinal cord is a critical midbrain region dubbed the mesencephalic locomotor region (MLR), which initiates
movements and controls their form and intensity. At present, we know a great deal about spinal cord and basal
ganglia microcircuits, and both are well represented in the neuroscience literature. However, the MLR is much
less well understood, particularly at the level of ion channels and synapses that animate MLR function. This
project steps in to fill that knowledge gap.
Aim 1 examines the cellular ionic mechanisms used by excitatory MLR interneurons to initiate motor programs.
We hypothesize that low voltage-activated Ca2+ currents produce low-threshold spike (LTS) bursts and plateau
potentials to trigger motor programs. We will test this hypothesis in adult brain slices in vitro and via Cre-
dependent short-hairpin RNA (shRNA) experiments to attenuate ion channel expression in excitatory MLR
interneurons in unanaesthetized freely behaving adult mice. Aim 1 will also involve next-generation deep
sequencing of the transcriptome of MLR neurons. We will harness those data for this project while also
releasing them into the Commons for general use among neuroscientists.
Aim 2 examines the synaptic mechanisms that activate MLR neurons, which we hypothesize is disinhibition via
GABAB receptors. That mechanism aligns with expectations that disinhibition via the direct path of the basal
ganglia evokes motor programs via the MLR. We will test our hypothesis in adult brain slices in vitro and via
Cre-dependent shRNA experiments that attenuate GABAB-GIRK channel synaptic function in unanaesthetized
freely behaving adult mice.
If successful, this project will explain how key midbrain microcircuits initiate locomotor behaviors at the level of
ion channels and synapses, and thus bridge a major knowledge gap in motor control. Given that basal ganglia,
MLR, and spinal cord circuits are ubiquitous features in the brains of all vertebrates during 500 MY of
evolution, the insights we develop in a genetically and electrophysiological advantageous mammalian animal
model (mouse) will be generally applicable to understanding motor control across a wide array of vertebrate
animals. There may be translational significance for the treatment of movement disorders as well.
The PIs of the project share complementary expertise in electrophysiology and behavioral experimentation in
adult mice. The PIs have an established collaboration with considerable pilot data, which led to the specific
aims and hypotheses above. Regardless of experimental outcomes, this project will elucidate the cellular and
synaptic bases of MLR function and advance understanding in motor control.
