of research achievements during FY 2008.? ? A. The dorsolateral striatum and endocannabinoid signaling are critical for habit formation? Extended training can induce a shift in behavioral control from voluntary goal-directed actions, which are governed by action-outcome contingencies and sensitive to the value of the outcome, to habits which are insensitive to the outcome value. Previous studies in rats have shown that interval schedules of reinforcement favor habit formation while ratio schedules favor goal-directed behavior. Furthermore, we showed that lesions of the dorsolateral striatum rendered the mice less predisposed for habit formation. The molecular mechanisms underlying habit formation are not well understood. Endocannabinoids, which can function as retrograde messengers acting through presynaptic CB1 receptors, are highly expressed in the dorsolateral striatum. Using a reversible devaluation paradigm, we confirmed that in mice random interval schedules also favor habit formation compared with random ratio schedules. We also found that training with interval schedules resulted in a preference for exploration of a novel lever, whereas training with ratio schedules resulted in more exploitation of the reinforced lever. Furthermore, mice carrying either a heterozygous or a homozygous null mutation of the cannabinoid receptor type I (CB1) showed reduced habit formation, and enhanced exploitation. The impaired habit formation in CB1 mutant mice cannot be attributed to chronic developmental or behavioral abnormalities, because pharmacological blockade of CB1 receptors specifically during training also impairs habit formation. Taken together our data suggest that endocannabinoid signaling is critical for habit formation.? ? B. Dynamic reorganization of striatal circuits via region-specific plasticity? during the acquisition and consolidation of a skill.? The learning of novel skills like riding a bicycle or playing a piano is characterized by an initial stage of rapid improvement in performance, followed by a phase of more gradual improvements as the skills are automatized and performance asymptotes. Although the striatum has been implicated in skill learning, the detailed physiological mechanisms underlying its role in the acquisition and consolidation of skills are not understood. We uncovered the first direct evidence of synaptic plasticity and excitability changes in striatum during skill learning. Ex vivo recordings from striatal neurons in brain slices of mice trained on a skill showed profound and training-specific changes in excitatory synaptic transmission. Furthermore, these changes were specific to different regions of the dorsal striatum and evolved dynamically between the early and late phases of skill learning. There was an increase in synaptic strength in the associative striatum early in training, which decreased after extended training when long-lasting potentiation of glutamatergic transmission emerged in the sensorimotor striatum. Similar region-specific changes were observed using in vivo recordings of striatal neural activity during the different phases of skill learning. This functional reorganization of the striatal circuitry observed both in vivo and ex vivo lead to a shift in the relative involvement of each striatal region as training progressed. These findings demonstrate the dynamic nature of skill memories, with a greater involvement of the associative striatum during initial acquisition, and the gradual engagement of the sensorimotor striatum with extensive training.? ? C. In vivo detection of changes in Arc expression in the striatum using fiber optics in awake behaving mice undergoing amphetamine sensitization (In collaboration with Dr. Steve Vogel).? Most techniques used to detect changes in gene expression in behaving animals, such as in situ hybridization, western blot and immunocytochemistry, require posthoc processing of tissues obtained from the animals. To monitor real time local gene expression in awake and freely moving mice at different stages of behavioral training, we have designed a fiber optics system, which uses the principles of Time Correlated Single Photon Counting (TCSPC) to allow acquisition of emission spectra as well as lifetimes. The system is based on delivering pulse laser light of 473 nm through a single mode optical fiber to excite a sample, while a multimode fiber is used to collect the excitation emission. By using this system, we have been able to accurately differentiate GFP and Venus signals in solutions containing these two proteins at different ratios as well as calculate taus for GFP averaging 2.95 +/- 0.4 ns. This average correlates with the published taus of between 2.4 and 2.6 ns. We were also able to use this system to detect GFP expression in subcortical brain structures, like the striatum of GAD-GFP mice. We have implanted several mice and have been applying this system to monitor the expression of Arc in the dorsal striatum during amphetamine sensitization. By monitoring the relative ratios of GFP (in an Arc-GFP mouse where GFP is a reporter of the expression of Arc) to Venus (in a CAG-Venus mouse where Venus is constitutively active) we are investigating the rise time and levels of expression of arc across days in real time genes during repeated administration of amphetamine.
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