The proposed 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's syndrome, and Parkinson's Disease, as well as drug abuse.
| Schmidt, Robert; Berke, Joshua D (2017) A Pause-then-Cancel model of stopping: evidence from basal ganglia neurophysiology. Philos Trans R Soc Lond B Biol Sci 372: |
| Schmidt, Robert; Leventhal, Daniel K; Mallet, Nicolas et al. (2013) Canceling actions involves a race between basal ganglia pathways. Nat Neurosci 16:1118-24 |
| Leventhal, Daniel K; Gage, Gregory J; Schmidt, Robert et al. (2012) Basal ganglia beta oscillations accompany cue utilization. Neuron 73:523-36 |
| Lau, Troy; Gage, Gregory J; Berke, Joshua D et al. (2010) Local dynamics of gap-junction-coupled interneuron networks. Phys Biol 7:16015 |
| van der Meer, Matthijs A A; Kalenscher, Tobias; Lansink, Carien S et al. (2010) Integrating early results on ventral striatal gamma oscillations in the rat. Front Neurosci 4:300 |
| Stoetzner, C R; Pettibone, J R; Berke, J D (2010) State-dependent plasticity of the corticostriatal pathway. Neuroscience 165:1013-8 |
| Wiltschko, Alexander B; Pettibone, Jeffrey R; Berke, Joshua D (2010) Opposite effects of stimulant and antipsychotic drugs on striatal fast-spiking interneurons. Neuropsychopharmacology 35:1261-70 |
| Feldt, Sarah; Wang, Jane X; Hetrick, Vaughn L et al. (2010) Memory formation: from network structure to neural dynamics. Philos Trans A Math Phys Eng Sci 368:2251-67 |
| Gage, Gregory J; Stoetzner, Colin R; Wiltschko, Alexander B et al. (2010) Selective activation of striatal fast-spiking interneurons during choice execution. Neuron 67:466-79 |
| Feldt, S; Waddell, J; Hetrick, V L et al. (2009) Functional clustering algorithm for the analysis of dynamic network data. Phys Rev E Stat Nonlin Soft Matter Phys 79:056104 |
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