Anatol Kreitzer, PhD
Department of Physiology and Gladstone Institute of Neurological Disease
University of California, San Francisco
(October 1, 2014)
Basal Ganglia Circuit Mechanisms Underlying Motor Function & Dysfunction
What neuronal networks are responsible for controlling the movements we make? How does the brain progress from the decision to make a movement to the action of making the movement? The basal ganglia are the structures necessary for this function, and these neuronal networks are affected in disorders such as Parkinson’s and Huntington’s disease. In his talk, Dr. Kreitzer presented his work on how the cells of the basal ganglia and cells in the brain stem form networks critical for locomotion. Using multiple techniques, including recording from single cells and genetically modified animal models, Dr. Kreitzer is investigating how the neurons of the basal ganglia control motor movements.
The basal ganglia (BG) are critical for adaptive motor control, but the circuit principles underlying their pathway- specific modulation of target regions are not well understood. We dissected the mechanisms underlying BG direct- and indirect-pathway-mediated control of the mesencephalic locomotor region (MLR), a brainstem target of BG that is critical for locomotion. We optogenetically deconstructed the locomotor function of the three neurochemically distinct cell types within the MLR.
We found that the glutamatergic subpopulation encodes locomotor state and speed, is necessary and sufficient for locomotion, and is selectively innervated by BG. We further showed activation and suppression, respectively, of MLR glutamatergic neurons by direct and indirect pathways, which is required for bidirectional control of locomotion by BG circuits. These findings provide a fundamental understanding of how the BG can initiate or suppress a motor program through cell-type- specific regulation of neurons linked to specific actions.
Previous work has demonstrated that subsets of neurons in the MLR are correlated with locomotion, and a recent optogenetic study indicates that MLR glutamate neurons are sufficient to induce locomotion. However, less is known about the activity of identified MLR glutamate neurons in vivo, and whether their activity is actually necessary for locomotion. Moreover, the function of the cholinergic and GABAergic populations is not clear, and debate still remains as to whether some or all of the effects seen during electrical stimulation can be attributed to the glutamatergic or cholinergic population.
To investigate the locomotor function of MLR cell types and their control by BG circuitry, we combined cell-type- specific optogenetic manipulations, in vivo single-unit recordings from identified cells, viral-based circuit mapping, and high-resolution behavioral assays to explore how signals from the BG are transduced into locomotion through the MLR. Our results highlight the functional differences among cell types in the MLR and the remarkable specificity of BG-brainstem projections. In addition to defining the pathway through which the BG regulate locomotion, these results provide a more general framework for how the BG can initiate or suppress action by specific modulation of neuronal subtypes associated with a motor program.