Our Work
The Tritsch laboratory studies synaptic mechanisms underlying the control of movement. Our goal is to reveal how the nervous system generates movement and how disorders of movement control—such as Parkinson’s disease—corrupt this process.
In vivo dopamine and acetylcholine dynamics
The neuromodulators dopamine (DA) and acetylcholine (ACh) are famous for signaling reward and promoting reinforcement learning. Yet, their dynamics and the factors that shape them remain poorly understood, especially outside reward-based experimental paradigms. Our laboratory uses simultaneous dual-color photometry of fluorescent DA and ACh reporters from multiple regions in the brain of mice in combination with high-density silicon probe recordings to reveal how extracellular DA and ACh fluctuate in vivo.
Our findings challenge the pervasive notion that there exists a stable, basal tone of DA and ACh. Instead, we found that striatal circuits are constantly exposed to large, sub-second transients in DA and ACh that share the characteristics of reward-evoked responses, endowing them with the necessary attributes to modify striatal activity and behavior. Interestingly, our data indicate that rewards and salient sensory stimuli do not generate DA and ACh transients de novo, but rather engage intrinsic, persistent network dynamics that have so far remained undetected. This realization fundamentally transforms our understanding of phasic DA and ACh from ‘outside-in’ (i.e. DA and ACh teach the brain about external sensory stimuli that must be valued, attended to or acted on) to ‘inside-out’ (i.e. DA and ACh dynamically reflect what the brain internally values, attends to and acts on), and provides a simple solution to the long-standing question of how phasic DA and ACh responses develop to conditioned stimuli during Pavlovian conditioning. Intrinsic fluctuations in DA and ACh may also open and close windows for the initiation of self-paced volitional action, and their disruption may contribute to neuropsychiatric conditions like schizophrenia and obsessive-compulsive disorder.
Modulation of striatal activity
Dopamine (DA) and acetylcholine (ACh) are powerful modulators of behavior, yet the mechanisms through which they influence neural activity remain poorly understood. We use two-photon calcium imaging and extracellular electrophysiology in combination with optogenetic and pharmacogenetic modulation DA- and ACh-releasing neurons to investigate how DA and ACh alter neural activity on short and long timescales. We found that DA modifies the overall number of target neurons that encode motor actions, and that chronic loss of DA neurons in a model of Parkinson’s disease severely alters how target neurons respond to DA. Our findings point to a novel and unexpected dimension of DA modulation in controlling how many target neurons are eligible for synaptic plasticity. In addition, our findings provides a likely explanation for why treatment of Parkinson’s disease with levodopa induces uncontrolled involuntary movements (i.e. levodopa-induced dyskinesia).
Synaptic transmission from dopamine neurons
How do midbrain dopamine (DA) neurons synaptically modulate the activity of target neurons? We discovered that they co-release the inhibitory transmitter GABA along with DA. Suprisingly, midbrain DA neurons lack enzymes that typically define GABAergic synapses and are classically thought to be required for synthetizing GABA and packaging it into synaptic vesicles.
Using a combination of genetic and molecular manipulations with optogenetics and whole-cell electrophysiological recordings in mice, we recently established that DA neurons acquire GABA exclusively through presynaptic uptake using the membrane transporter Gat1 (encoded by Slc6a1). GABA is then packaged for vesicular release using the vesicular monoamine transporter Vmat2. Our data therefore show that presynaptic transmitter recycling can substitute for de novo GABA synthesis and that Vmat2 contributes to vesicular GABA transport, expanding the range of molecular mechanisms available to neurons to support inhibitory synaptic communication.
Dopamine's contribution to the control of motor vigor
Ever since the discovery that degeneration of DA neurons impairs the speed and amplitude of voluntary movements in Parkinson’s disease, DA has become synonymous with motor vigor. However, its mechanisms of action are still debated. To elucidate the role of DA in the production vigorous actions, we designed a dexterous forelimb motor task in mice based on standard clinical tests used to score bradykinesia in Parkinson's disease. We use optogenetic manipulations of DA neuron activity to uncover the specific kinematic parameters that DA modulates and the speed with which this modulation occurs.
How does neurodegeneration alter striatal circuit function?
Parkinson’s disease (PD) is caused by the slow, progressive degeneration of brain cells that produce dopamine. The brain circuits that normally receive dopamine continually adapt to its gradual loss: they initially learn to operate until dopamine levels decline in half, at which point brain circuits begin to malfunction, giving rise to the motor symptoms that define PD. As the disease progresses and degeneration worsens further, the brain continues to change, until it no longer responds favorably to levodopa --the most effective and widely prescribed drug in the treatment of PD– producing instead abnormal involuntary movements called dyskinesia. Our research aims to uncover exactly how brain circuits change as dopamine neurons gradually degenerate in the hopes of developing new and better tolerated therapeutics.