The basal ganglia (BG) have been implicated in goal-directed locomotion for decades. However the mechanisms by which the BG regulates locomotion remain unclear. While most descriptions of the BG focus on outputs to thalamus which drive motor cortex, a more phylogenetically conserved target is the brainstem. One major brainstem target of the BG is the mesencephalic locomotor region (MLR). The MLR is defined functionally as a brainstem region in which electrical stimulation drives locomotion. Lesion of this area in humans causes akinesia and an inability to initiate locomotion. Our fundamental goal is to investigate the circuit mechanisms by which the BG regulates locomotion through the MLR. We hypothesize that neurons in this region are necessary for locomotion initiated by the BG. The BG may be broken into two pathways, the direct and indirect, which begin in the striatum. The pathways are split between populations of medium spiny neurons (MSN's) at the input nucleus of the BG, the striatum. Direct pathway MSN's express dopamine receptor D1 while indirect pathway MSN's express adenosine receptor Adora2a. The direct pathway has been hypothesized to promote movement while the indirect pathway suppresses movement. We hypothesize that these two pathways oppositely regulate the MLR to initiate or suppress locomotion. The output of the BG is the Substantia Nigra pars reticulate (SNr) which provides tonic inhibition of downstream structures thought to be responsible for motor programs such as locomotion. Release of this tonic inhibition allows a program to be activated. We hypothesize that the SNr can regulate locomotion through the MLR by modulation of its tonic inhibition. In this set of experiments I will use cutting edge optogenetic and electrophysiological methods to 1) define the cell-types responsible for the initiation of locomotion in the MLR, 2) demonstrate the SNr's control of the MLR which results in the suppression or initiation of locomotion, 3) show how the direct and indirect pathways oppositely affect locomotion through the MLR. This study will shed light on the circuits and cells responsible for the initiation of goal-directed locomotio and provide valuable circuit-level insight to aid the development of new and innovative treatments of BG and locomotor disorders.
Many gait and movement disorders originate in the basal ganglia and affect millions of people worldwide. A major barrier to developing treatments for these ailments is a fundamental understanding of the neural circuitry involved in the planning and execution of these actions. This proposal employs cutting edge techniques to uncover the circuits and cell types responsible for the successful execution of locomotion originating in the basal ganglia.
| Roseberry, Thomas; Kreitzer, Anatol (2017) Neural circuitry for behavioural arrest. Philos Trans R Soc Lond B Biol Sci 372: |
| Roseberry, Thomas K; Lee, A Moses; Lalive, Arnaud L et al. (2016) Cell-Type-Specific Control of Brainstem Locomotor Circuits by Basal Ganglia. Cell 164:526-37 |
