Research

Research Questions and Projects

The main focus of our research is the neurophysiology of the basal ganglia. These are structures deep in the brain that play a key role in our ability to make decisions - to select one action over another, to initiate those actions, and to learn which actions to perform in the future.
Abnormal function of neural circuits through the basal ganglia is involved in a set of human conditions classed as “neurological”, “psychiatric”, or somewhere in between. These include Parkinson’s and Huntington’s Diseases, addictions and obsessive-compulsive disorders, Tourette Syndrome and schizophrenia.
While there are many clues, how these circuits work is not yet understood. Our research aims to gain insight into how this neural machinery normally operates, and how it can malfunction.

Brief descriptions of two of our current projects:

Multiple Memory Systems in Action Selection (supported by National Institute on Drug Abuse)
This research program examines how multiple neural circuits involved in learning contribute to making a decision, and how this process may be subverted by addictive drugs. Several current models suggest that the abnormal engagement of normal learning mechanisms contributes to drug addiction. In particular, it has been argued that repeated drug-enhanced release of dopamine in the striatum produces unusually strong learned habits of drug-seeking and drug- taking. Such habits are hard to suppress, resulting in a progressive narrowing of behavioral repertoire, and greatly diminished control over drug intake. To better understand this process, we shall examine neural coding mechanisms involved in habit formation and inhibition, in striatum, hippocampus and medial frontal cortex. We shall also investigate how neural representations are altered when habits are artificially strengthened by the psychomotor stimulant drug amphetamine. Our approach has two essential features. Firstly we apply electrophysiological methods to tasks whose behavioral and neuroanatomical characteristics are relatively well understood. Secondly we perform comparisons between closely related situations, aiming to isolate aspects of neural representations that are specifically associated with distinct cognitive demands. Rats will perform two radial maze tasks that are identical in the stimuli presented to the animal, differing only in the strategies required to obtain rewards. In the 'win-stay' task (visual stimulus- response) the rat has to choose the arm that is illuminated, regardless of its recent history of choices. Learning this task has been shown to require the striatum, and can be enhanced by intra-striatal injections of amphetamine. In the other task ('win-shift'), the rat has to avoid the most- recently-visited arm, and the visual cue is irrelevant. This is a spatial working-memory task, that requires intact hippocampal function. Shifting between the visually-cued and spatial strategies requires suppression of the learned habit, and has been shown to involve the rat medial frontal cortex. By examining neural representations associated with acquisition of a visual stimulus-response habit, with drug enhancement of a habit, and with suppression of a habit, we aim to gain convergent data on how habits are encoded, and how excessively strong habits may contribute to addiction. At the same time we aim to provide a behavioral model of drug-induced loss of behavioral flexibility, that could be used by investigators testing novel drug abuse therapies. A fuller understanding of neural representations in frontal- striatal circuits, and how they are affected by dopamine, would also greatly contribute to our understanding of schizophrenia, obsessive-compulsive disorder, Tourette syndrome, and Parkinson's Disease, as well as drug abuse.

Dynamics of Striatal Microcircuits during Action Selection and Inhibition
(supported by Tourette Syndrome Association)
Tourette Syndrome is a chronic disorder of behavioral inhibition, thought to arise from altered physiology of basal ganglia circuits. A recent study found that individuals with Tourette Syndrome have fewer parvalbumin-positive interneurons in the striatum (Kalanithi et al., PNAS 102: 13307-13312). These fast-spiking interneurons have previously been suggested to have a key role in the normal suppression of unwanted responses, yet there have been no published investigations of the activity of these cells in behaving animals. We have recently shown that these interneurons can be effectively identified in extracellular recordings from freely-moving rats (Berke et al. Neuron 43: 883-896). We propose to record from these cells, as well as projection neurons, during carefully-controlled operant tasks in which rats have to make choices, inhibit premature responding, and enable/release one specific action while suppressing other well-learned actions. We will pay particular attention to the timing relationships between interneurons and projection neurons, examining the hypothesis that feed-forward inhibition serves to suppress the activity of projection neurons that do not represent the specific selected action. By examining such dynamic properties of striatal microcircuits, we aim to further our understanding of fundamental processes of action selection and suppression, and how such processes are disrupted in Tourette Syndrome.

Simplified anatomy of basal ganglia loop circuits