Advances in molecular genetic techniques are revealing new details of the neuronatomical organization of brain circuitry and the functional role of these circuits in behavior. Engineered viral vector constructs have been developed to label axonal projections of targeted neurons with unprecedented clarity, while others allow for retrograde transynaptic labeling of neurons providing inputs or anterograde transynaptic labeling of post-synatpic targets of axonal projections. Development of optogenetic and DREADD techniques provide the ability to functionally manipulate neural circuits to study their role in behavior while calcium indicators provide the ability to analyze the physiologic activity in targeted neuron populations. Together these approaches are providing new insights into the functional organization of neural circuits. For example, optogenetic studies, using light activation of Channel Rhodopsin (ChR), have demonstrated the ability to functionally manipulate specific neural pathways to determine their role in behaviors including fear memory, anxiety, feeding, and movement. The analytic potential of these approaches is enhanced by the ability to target specific neuron populations, which are defined components of neural circuits. One approach involves the use of transgenic Cre-driver mouse lines in which Cre-recombinase is expressed under the control of gene-specific promoters. During the past year we characterized BAC-Cre driver lines from the GENSAT project that allow for targeting components of the neural circuits of the cerebral cortex and basal ganglia. Lines were characterized with selective labeling in cortical layer 2/3, in layer 4, in layer 5 and in layer 6. Moreover, layer specific lines were identified with expression throughout the cerebral cortex, in specific cortical areas and in subtypes of layer 5 cortical projection. Subtypes of layer 5 lines characterized include those with expression selective for pyramidal tract (PT) and intertelencephalic (IT) corticostriatal neurons. PT and IT corticostriatal neuron subtypes have been the focus of a number of recent studies concerning the functional organization of the cerebral cortex and basal ganglia, and will be used in proposed studies described below. In this study some 20 BAC-Cre lines are characterized with expression in the striatum, including those with expression in both direct and indirect striatal pathway neurons, selective for the direct and indirect pathway, selective for the patch and matrix striatal compartments, and those with distinct regional distributions within the striatum. Characterization of other BAC-Cre lines include over 10 lines with expression in select thalamic nuclei, and in other components of the basal ganglia including the amygdala, habenula, subthalamic nucleus, dopaminergic neurons and the superior colliculus. Together these lines that target specific components of circuits within the cerebral cortex and basal ganglia provide a resource for neuroscientists to study the functional organization of these circuits in animal models of neurologic and mental disorders.

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U.S. National Institute of Mental Health
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