Xin Jin - US grants

Project Summary: It is a fundamental challenge for organisms to chunk a series of actions into sequence and acquire a large action repertoire for survival and reproduction. The organization of behavior into action sequences, and how it is realized in the nervous system has been a central question in neuroscience. Dysfunctions of the cortico- basal ganglia circuits are associated with impaired sequential behavior in many neurological and psychiatric diseases including Parkinson's disease, Huntington's disease and Obsessive-Compulsive Disorder (OCD). The striatum is the major input nuclei of the basal ganglia, which receive sensory, motor and cognitive information across cerebral cortex. Current model of basal ganglia suggested that there are two major neural subcircuits, called the ?direct? and ?indirect? pathways, for selecting and inhibiting actions respectively. Nevertheless, this over-simplified opponent view has been challenged by recent work. In addition, besides the direct and indirect pathways, it has been known for a long time that there are two compartments in the striatum, termed the patch (striosome) and matrix, which can be defined by the expression of immune- histochemical markers like mu-opioid receptors. Important functional differences have been suggested between the patch and matrix compartments based on the observations in human basal ganglia disorders. However, the functional understanding of the patch vs. matrix compartment and their roles in controlling actions are largely missing at this moment. Conventional anatomical and electrophysiological methods are ill- suited to address these questions because these compartments are irregular in shape and different cell types are mixed in distribution, making the precise lesion or physiological studies rather difficult if not impossible. This project will take advantage of a series of cutting-edge neurotechniques including in vivo recording with cell type identification, optogenetics, fast-scan cyclic voltammetry, viral tracing and miniscope imaging, combined with quantitative behavior and computational modeling, to dissect the role of specific striatal compartments in action sequence learning and execution, in comparison with the function of striatal pathways. Furthermore, it aims to systemically investigate the physiology and function of different striatal cell types and their interaction with specific cortical inputs during behavior. Firstly, a novel action sequence task in mice with quantitative behavior will be developed to determine the striatal involvement in action sequences at molecular and cellular levels. It is then followed by in vivo electro-chemical, electrophysiological and optogenetic experiments to define the activity and contribution of various striatal cell types to sequence execution. Finally modified rabies virus will be utilized to define cell-type-specific cortico-striatal pathways, and dissect the physiology and function of these pathways during behavior with advanced imaging and optogenetics. Together this project will advance the understanding of the function and logic of specific corticostriatal circuitry for both action sequence learning and execution.

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive loss of memory and other cognitive functions. Several lines of evidence suggest that neural network impairment leads to cognitive and behavioral deficits in AD, but the underlying cellular and molecular mechanisms are not completely understood. Several neurotransmitter systems are impaired in AD brain, in particular cholinergic neurons. However, drugs, such as acetylcholine esterase inhibitors, that are developed to target individual neurotransmitter systems have met with limited success. As a result, it has been suggested that prolonged and artificially elevated ambient levels of neurotransmitters may interfere with phasic synaptic signaling and lead to aberrant tonic activation of extrasynaptic receptors. Thus, elucidation of systems mechanisms may provide insights into novel strategies to develop more effective treatments for improving cognitive function, including better information on the long-range circuits and local microcircuits underlying cognitive function and better understanding of the roles and molecular basis of phasic and tonic modes of synaptic transmission elicited by individual neurotransmitters and their receptors. The advent of optogenetics coupled with large-scale in vivo recording of freely moving animals performing cognitive tasks provides an excellent opportunity to map functional circuitry and to determine the effect of different synaptic activation patterns to ameliorate cognitive deficits in AD. The prefrontal cortex (PFC) interacts with multiple cortical and subcortical structures and plays an important role in working memory, long-term memory consolidation and execution of actions. As neuronal loss in the nucleus basalis of Meynert (NBM), a component of the basal forebrain that provides long-range projections to the cortex, is a prominent feature in AD brain, we would like to focus on elucidating the cellular and molecular mechanisms of the NBM-PFC network activity underpinning cognitive deficits in AD. Toward this goal, we have provided evidence that APP41 line of AD mice, which express high levels of Amyloid peptide ¿ (A¿) in the cortex at 3 months of age, displays reduced cholinergic and GABAergic markers, cognitive deficits, altered theta and gamma oscillations and increased epileptic discharge. Furthermore, a neuregulin 1 (NRG1) mutation is associated with late-onset familial AD in patients with psychosis. Our preliminary results show that NRG1 improves cognitive deficits in APP41 mice, forms a complex with muscarinic acetylcholine receptor M2 and is required for ACh-induced neuronal excitability. Neuronal oscillations in the PFC are impaired in mice lacking NRG1 in the cholinergic neurons. To further elucidate the molecular and cellular mechanisms, three aims are proposed in the present application. Aim 1 is to characterize the network activity in the PFC during cognitive tasks in AD mice. Aim 2 is to determine the cholinergic and GABAergic contribution to network pathophysiology and behavior in AD mice. Aim 3 is to determine the role of NRG1 in the development of the NBM-PFC circuit, network activity and cognitive function in AD mice.