Currently my lab is focusing on 2 specific research projects. The first concerns understanding the organization, dynamics and behavioral function of neostriatal interneurons, in particular the cholinergic (ChAT) interneurons. The second is aimed at establishing a paradigm for the investigation of the cellular and circuit mechanisms of dopaminergic reinforcement.
The neostriatal circuitry (including the circuitry of the ventral striatum) plays a central role in the functioning of the basal ganglia as the site of integration of cortical information and motivationally relevant subcortical signals. ChAT interneurons are of particular interest because they encode reinforcement related information (such as the valance and magnitude of reinforcement) in brief population responses that are precisely coordinated and mechanistically linked with transient dopaminergic signals in the neostriatum. Our primary interest is the cellular and circuit mechanisms that mediate the effect of these cholinergic signals.
We have shown that ChAT interneurons form a circuit with 4 types of GABAergic interneurons whose activity is likely driven to a significant extent by the ChAT interneurons. The GABAergic circuits in turn innervate projection neurons and consequently can contribute to the control of the activity of the striatum and to the regulation of synaptic plasticity underlying reinforcement mediated learning in this brain area.
The second major project in my lab aims at developing an experimental strategy for understanding how phasic, reinforcement related signals of dopaminergic (DA) neurons control the functioning of the striatal circuitry. Midbrain DA neurons exhibit transient firing rate changes that encode reward prediction errors (RPE) which can be thought of with some simplification as the difference between the predicted and immediately available reward. RPE signals are believed to be central for learning from the outcome of behavior and most theories of operant conditioning, in particular temporal difference learning models incorporate “teaching” signals with closely similar properties to RPE signals of DA neurons. This observation, taken in the context of an extensive body of evidence that links dopamine to positive reinforcement and reinforcement mediated learning, led to the general hypothesis that dopaminergic RPE signals affect synaptic or other properties of the striatal circuit in a way that results in adaptive change in behavior (i.e.: increased probability of obtaining a positive outcome). Although different theories have been proposed and many candidates exist (regulation of set points for synaptic plasticity, for instance) studying whether and how dopaminergic transients contribute to learning has been significantly complicated by the problem that very little is known about the specific contribution of striatal neuronal activity to the selection of actions. Consequently, it may be difficult or impossible to identify which dopamine dependent cellular changes are instrumental in the emergence of learned behavior.
These projects involve a variety of techniques. Most importantly we use in vitro multi-neuronal whole-cell recordings in combination with optogenetics to analyze neuronal circuits in transgenic mice. Further, we use in vivo tetrode recordings in behaving mice in combination of optogenetics and pharmacogenetics to characterize the firing response of genetically identified neuron populations. Finally, we also use a number of molecular biological techniques including single-cell multiple RT-PCR, and construction of virus vectors for delivery of optogenetic and pharmacogenetic tools.