Functional Segregation Within the Whisker-Barrel Neuraxis

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 DESCRIPTION (provided by applicant): The long-term objectives of this multi-PI R01 proposal are two-fold. First, the functions of specific parallel neural pathways (lemniscal, paralemniscal) linking brainstem and forebrain trigeminal (V) representations will be revealed. This will be done in the rodent whisker-to-barrel cortex neuraxis, which has become the model of choice for discovery of information processing mechanisms, due to the prominence of barrels in the cerebral cortex of transgenic mice. Yet, there are major gaps in our knowledge of subcortical components that hamper our grasp of the whisker-barrel circuit. These gaps will be filled by applying a set of multidisciplinary tools to studies of the neural control of whisker-related sensation and movement. Our overarching hypothesis is that neural activity in the spinal V subnucleus interpolaris (SpVi, paralemniscal) is necessary for whisker-mediated object detection and orientation responses, while whisker-mediated object identification and discrimination require neural activity in a topographically patterned (barrelettes) V nucleus principalis (PrV, lemniscal). Three Specific Aims employ: a) transgenic mice that lack barrelettes in PrV, but not in SpVi, b) reversible allatostatin- induced silencing of adenovirus transduced multi-whisker responsive SpVi cells or single-whisker PrV cells, and c) anatomical and electrophysiological assessments of the integrity and neurotransmission properties of V brainstem neurons in animals studied in the above 2 Aims. Thus, "gene deletion" and "neural silencing" approaches are coupled with parallel validation of the extent to which these 2 approaches produce "functional lesions" in V brainstem neurons. This permits discovery of components of the barrel neuraxis that are unequivocally responsible for whisker-mediated detection, orientation, identification and discrimination behaviors. Second, this research will als provide technical 'proof of principle' for the potential use of above- listed allatostatin-induced silencing of adenovirus infected neurons to treat human neurological disorders, such as epilepsy, chronic pain, obesity and addiction, where hyperexcitability characterizes defined neuronal populations, reduction or elimination of which could constitute a new treatment strategy. Self-administration of allatostatin could be a transformative treatment option, the efficacy of which will be evaluated here in a simple model system, with an eye towards possible side effects. A collaborative venture is offered with 3 PIs that are indispensable to the accomplishment of all 3 Specific Aims. Dr. Zeigler developed the "head-fixed" technology required to deliver stimuli to single whiskers, to monitor their movements and to bring such movements under voluntary control. These tools will be used in Aims 1 and 2. Dr. Hartmann developed the "head-free" technology required to measure and control movements of single whiskers, as well as means to analyze video materials of such. These tools will be used in Aims 1 and 2. Dr. Jacquin's career has been largely devoted to the trigeminal system and brings expertise on transgenic mice, allatostatin/adenoviruses and single unit recording to bear upon the behavioral issues and technology offered here by Drs. Hartmann and Zeigler.