Abigail L. Person - US grants

DESCRIPTION (provided by applicant): An enormous amount of energy has been targeted at elucidating basal ganglia function yet almost nothing is known about the mechanisms that govern the relay of basal-ganglia output through the thalamus. The basic thrust of this research proposal is to explore how information is transferred through a thalamic nucleus, which lies within a basal ganglia loop required for song learning in zebra finches. This problem is interesting because the most substantial input to this thalamic area (DLM), is GABAergic and strongly inhibitory to DLM neurons. How, then, might DLM relay GABAergic inputs? A robust feature of thalamic neurons could render inhibitory post-synaptic potentials (IPSPs) excitatory, namely post-inhibitory rebound. In fact, short barrages of IPSPs have been shown to elicit rebound spikes in DLM neurons. In this study, we plan to systematically explore the capacity of thalamic neurons to translate IPSPs into superthreshold output. These experiments will provide powerful insight into the function of thalamic areas important for motor learning in vertebrates, as well as thalamic-basal ganglia relay. This information is necessary to completely understand basal ganglia circuitry, which is pathological in human disorders such as Parkinson's disease.

DESCRIPTION (provided by applicant): The cerebellum is a highly conserved brain structure involved in motor learning and behavior. The aim of this research proposal is to elucidate the cellular mechanisms underlying synaptic plasticity in the cerebellar nuclei, the output of the cerebellum. This research will support the broader long-term goal of understanding the cellular mechanisms of learning and memory in cerebellum-dependent behaviors. Lesion studies suggest that the nuclei are a locus of learning and memory which specifically involve mossy fiber afferents carrying sensory information. We propose to investigate how two disparate forms of mossy fiber synaptic plasticity - potentiation and depression - are coordinated at the level of single neurons. These opposing forms of synaptic plasticity are generated following afferent stimulation patterns that differ only slightly, and thus likely converge on at least partly the same signaling pathways. Specifically, potentiation follows coincident excitation and inhibition while depression occurs after excitation alone. The requirement for inhibition in the potentiation protocol sets this form of plasticity apart from others investigated elsewhere in the brain and therefore promises to broaden our understanding of how synaptic plasticity is generated across different neuronal cell types. Our specific aims target h/vo levels of mechanistic organization: enzymatic signaling and transmitter receptor delivery to synapses. Whole cell voltage- and current-clamp recordings are made from neurons in an acute mouse brain slice preparation and electrical stimulation is used to elicit synaptic currents. Various pharmacological agents will be used to test the roles of molecular cascades mediating plasticity. PUBLIC HEALTH RELEVANCE: Several human pathologies are linked to cerebellar dysfunction such as ataxias, dystonias, autism and some forms of mental retardation. Understanding how cerebellar circuitry supports healthy behavior is essential to decipher the roots of neural pathologies. By targeting specific enzymes and proteins involved in a cellular function that likely underlies behavior, we lay the groundwork for linking gene mutations to observable pathologies.

Project Summary/Abstract: Corollary discharge (CD), or a copy of efferent motor commands, is integral to numerous models cerebellar motor control. CD is hypothesized to provide a reference signal to update internal models of current motor state and modify reafferent sensory input that is predicted by the motor command, placing it at the center of sensorimotor integration. Our understanding of the specific anatomical and physiological circuitry of CD in the mammalian cerebellum is limited, however, owing to anatomical constraints that complicate studying motor cortex-derived CD signals. Our approach bypasses these obstacles by focusing on a neglected pathway consisting of collaterals from the premotor cerebellar nuclei to the cerebellar granule cell layer. This experimentally accessible nucleocortical pathway has all of the hallmarks of a CD pathway in that it consists of motor output neurons that also project to sensory receptive areas. We propose to investigate the organization and function of this pathway in mice as a means to understand the mechanisms and role of corollary discharge in sensory processing in mammalian cerebellum. To test the hypothesis that CD both updates internal models and suppresses sensory reafference, we will use anatomical and physiological approaches to examine whether the nucleocortical pathway forms excitatory synapses onto feedforward excitatory granule neurons and feedforward inhibitory Golgi neurons. This arrangement would provide a mechanism for the proposed roles of CD in motor control. To further test the prediction that CD can modify sensory reafference, we will examine whether sensory responses in the granule cell layer are sensitive to concurrent activation or inactivation of the nucleocortical pathway. We expect that the motor CD pathway from the cerebellar nuclei contacts granule cells and Golgi cells, converges with other sensory cerebellar afferents, and modifies sensory processing by the granule cell layer. These studies will aid in our long term goal of understanding the circuit mechanisms of feedforward motor control in mammals, which is critical for precise movement and hypothesized to be impaired in movement disorders that involve the cerebellum.

PROJECT SUMMARY/ABSTRACT Reaching movements are fundamental to human interactions with the environment. Cerebellar damage impairs reach precision and accuracy, but the mechanistic contribution of cerebellum to reach control is unclear. Recent work has illuminated principles of cerebellar feedforward control, where Purkinje cells learn predictive contingencies, termed forward models, but our understanding of control signals issued from the cerebellar nuclei, particularly to improve reach precision, is poor. The proposed studies leverage our discoveries made in the previous grant cycle, identifying and characterizing internal motor copy pathways, to test mechanisms of cerebellar predictive control. Outcomes of these studies will reconcile diverse hypotheses of cerebellar motor control and identify circuit mechanisms by which feedforward motor control is produced. We have identified strong endpoint-aligned neural activity in the cerebellar interposed nucleus of reaching mice and showed, using closed-loop optogenetics that this activity exerts a causal pull on the limb, sculpting reach endpoint. In the proposed studies we will explore this code to test its role in real-time control, learning and sequencing. In aim 1 we will identify the cell-types that produce this activity and its role in shaping reach kinematics on a trial- by-trial basis to improve precision. In aim 2, we explore whether reach adaptation changes neural patterns in the cerebellar nuclei associated with endpoint control. Finally, in Aim 3 we leverage findings from the previous grant cycle where we characterized anatomical and physiological properties of a feedback pathway from cerebellar output neurons back to the cerebellar cortex ending as mossy fibers. We will examine the contribution of this internal feedback pathway in reach control, testing the hypothesis that this fast feedback regulates time-varying neural and behavioral sequencing. The outcomes of these studies will advance our long term goal of understanding the circuit mechanisms of feedforward motor control in mammals, which is critical for precise movement and hypothesized to be impaired in movement disorders that involve the cerebellum.