A novel framework for the functional dissection of motor systems

Tritsch, Nicolas

Abstract

The capacity to physically interact with the surrounding world is a fundamental feature of the nervous system. Detecting an appetizing odor, seeing a predator, hearing the song of a potential mate or feeling pain only represent the first of many steps that ultimately lead to the generation of a motor behavior. Our current knowledge of the brain, however, is not commensurate with this division of labor between sensory and motor functions: we have a much greater appreciation for how the nervous system detects and perceives sensory stimuli compared to how it produces motor responses. While technical limitations have played an important role, the foremost problem has been a lack of approaches capable of systematically and directly triggering complex movements without confounding influences from perception, attention and motivation. Indeed, a prerequisite for mechanistic investigations of any biological, physical and chemical process is the ability to create experimental conditions that reproducibly elicit an observable phenomenon. This proposal describes a novel experimental framework that fulfills this important requirement, offering the ability to reliably trigger, and precisely quantify complex forelimb movements in mice while optogenetically manipulating the activity of specific neurons with great spatial and temporal precision. Using this approach in combination with 2-photon Ca2+ imaging and multi-site silicone probe recordings, we propose to reveal how a collection of subcortical nuclei known as the basal ganglia (BG) contributes to the selection and production of complex movements. We will test the hypothesis that midbrain dopaminergic neurons and striatal cholinergic neurons control the overall gain of ongoing movements through phasic modulation of striatal projection neuron excitability and collateral synaptic transmission efficacy. We will then determine how dopamine neurons mediate instrumental learning, looking at their ability to specifically reinforce past actions that lead to desirable outcomes, as well as the capacity for the BG to subsequently bias future behavioral decisions. If successful, this proposal will not only redefine our understanding of the BG, it will establish a powerful and versatile experimental approach to study the neurological basis of behavior in many species, including humans.

Public Health Relevance

The basal ganglia are a collection of brain regions intimately involved in the control of motor actions; their dysfunction underlies Parkinson's disease, obsessive-compulsive disorder and drug addiction, amongst many others. Understanding how the basal ganglia function will prove essential to improve the diagnosis and treatment of these neurological illnesses. This proposal describes the development of a new experimental approach that will provide unprecedented insights into the precise mechanism of action of basal ganglia circuits.