Overall Goals:? The Section on In Vivo Neural Function of the Laboratory for Integrative Neuroscience is a new section of the National Institute on Alcohol Abuse and Alcoholism established in January 2006. This section studies the neurobiology of action in health and disease. Our overall goal is to understand how changes in molecular networks in the brain modify neural circuits to produce experience-dependent changes in actions. We are particularly interested in investigating the corticostriatal mechanisms - from molecules to circuits - underlying the learning and flexible use of actions; from new skills, to associations between actions and outcomes, and to habits. We chose to implement this integrative approach in mice because they combine the power of genetics, a mammalian brain with layered structures that can generate oscillatory activity, the possibility of accurately quantifying simple behaviors like action initiation (with EMG activity) and stereotypic skill learning, and also more elaborate behaviors like goal-directed actions. Our section is currently composed of Rui Costa (Acting Chief), Shweta Prasad-Mulcare (Post baccalaureate IRTA), and Christine White (Summer IRTA). Since the Section on In Vivo Neural Function was just recently established, this report will mainly consist on preliminary data from our proposed studies.? ? Pharmacogenetic approach to study the role of dopamine in voluntary movement: We have previously used a pharmacogenetic approach in DAT-KO to investigate in-vivo the corticostriatal mechanisms controlling voluntary movement. We are now expanding this model to manipulate DA levels specifically in particular subregions of the corticostriatal circuitry by infusing AMPT and L-Dopa into specific corticostriatal areas through indwelling cannuli. We are also using the same DA depletion approach in DAT-KD mice (AMPT, (250 mg/kg), which preserve 10% of normal DA transporter levels [20] (DA levels about 170% of controls). Finally, although slightly less effective than DA depletion, we are confirm the results obtained with DAT-KO and DAT-KD mice by using pharmacological blockade of D1 and D2 receptor antagonists in WT mice. ? We have been using these tools to investigate how movements can become non-voluntary and dopamine-independent. Our preliminary data shows that blockade of both D1 and D2 type dopamine receptors in naive animals renders the unable of performing in the accelerating rotarod task. However, with training, performance in the accelerating rotarod can become somewhat independent of dopaminergic function. Therefore, overtraining can make the performance of particular movements more automated and independent of DA. Our results are in agreement with recent studies showing that extensive training of a behavior until it becomes habitual renders the performance of that behavior DA-independent. ? ? Development of new multielectrode arrays:? To achieve the goal of simultaneously recording from different striatal and cortical areas within the same behaving mouse model, we have started to develop new electrode arrays with different configurations. We adapted technology that we have previously used consisting of arrays of tungsten isonel-coated microwires that we can implant into brain. These arrays and head-stage are miniaturized (<0.26 g/array), allowing mice to move freely. We have developed arrays to specifically record from the motor cortex and dorsolateral striatum, from their most anterior portion to its most posterior. We have also developed arrays with a specific configuration that allow us to simultaneously record from dorsomedial and dorsolateral striatum in the same hemisphere). Additionally we have developed 32 electrode arrays for simultaneous multi-cortical and striatal recordings, so that we can monitor the activity of more than one cortical area and the striatum simultaneously (example prefrontal cortex, dorsomedial striatum, and motor cortex).
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| Nagy, Vanja; Bozdagi, Ozlem; Matynia, Anna et al. (2006) Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J Neurosci 26:1923-34 |
| Costa, Rui M; Lin, Shih-Chieh; Sotnikova, Tatyana D et al. (2006) Rapid alterations in corticostriatal ensemble coordination during acute dopamine-dependent motor dysfunction. Neuron 52:359-69 |
