In humans, the control of voluntary movements is critically dependent on neuronal communication between dopamine-containing neurons in the midbrain and target neurons in the striatum. Indeed, the degeneration of midbrain dopamine neurons in Parkinson's disease results in tremor, slowness of movement and rigidity. Conversely, excessive dopaminergic stimulation induces hyperactivity, impulsiveness and compulsive drug use. Despite the importance of these neurons, the mechanisms by which they shape the activity of target neurons in the striatum are poorly understood. My immediate goal is to shed light on the powerful influence that midbrain dopamine neurons exert on movement-related striatal circuits. In the long run, I wish to use this knowledge to understand how dysfunction of dopamine neuron signaling engenders neurological illnesses. Under the mentorship of Drs. Bernardo Sabatini and Christopher Harvey and with the support of Dr. Mark Andermann, I will acquire the scientific and professional training necessary to address these long-standing questions and to succeed as an independent researcher. The resources and facilities within the Harvard Medical School Department of Neurobiology are ideal to ensure I realize my research and career objectives. My research plan is divided into three main aims: 1) To dissect the synaptic and cellular effects of dopamine neurons on striatal projection neurons, 2) To define the spatial and temporal activity patterns of striatal neurons in behaving mice, and 3) To determine how dopamine neurons modulate striatal activity in vivo. I will first use electrophysiology, two-photon calcium imaging and two-photon glutamate uncaging to determine how optogenetic stimulation of dopamine neurons impacts the excitability of striatal projection neurons and the strength of excitatory synapses that impinge on them (Aim 1). In parallel, I will develop a striatal window preparation to monitor neural activity en masse in the striatum of mice running on a spherical treadmill using two-photon calcium imaging. I will then use this technique to reveal the spatial and temporal patterns of activity of identified striatal neurons during sensory and motor behaviors (Aim 2). These experiments will not only uncover canonical features of striatal circuit dynamics in vivo, but they will also serve as a template for the detection of circuit elements that are modified by dopamine neurons.
In Aim 3, I will identify these modifications by optically monitoring the activity of striatal neurons in behaving mice before and after optogenetic or pharmacogenetic manipulation of dopamine neuron discharge. By revealing how brief and prolonged changes in dopamine neuron activity impact striatal neurons at the synaptic, cellular and circuit levels, the proposed work will shed light on the mechanisms employed by dopamine neurons to influence voluntary movements and the disturbances that lead to motor impairments in Parkinson's disease. Importantly, this knowledge will guide the development of therapeutic interventions for this and other neurological diseases.
Neurons that produce the neurotransmitter dopamine represent only a tiny fraction of all neurons in the mammalian brain, yet the signals they convey are essential for fundamental behaviors and cognitive processes such as motivation, arousal, learning and memory, decision-making, and the control of voluntary movements. This proposal seeks to uncover how dopaminergic neurons influence the activity of the cells in the striatum, a brain region that controls the selection and initiation of movements. Understanding this will guide the development of novel therapies for Parkinson's disease as well as other neurological disorders.
|Tritsch, Nicolas X; Carter, Adam G (2016) Parkinson's Disease: A Thalamostriatal Rebalancing Act? Neuron 89:675-7|