Sascha du Lac - US grants

[unreadable] DESCRIPTION (provided by applicant): The long-range goal of this research is to understand the cellular and molecular mechanisms that mediate the normal performance and adaptive plasticity in eye movements. The vestibulo-ocular and optokinetic reflexes (VOR and OKR, respectively) prevent blurred vision during self-motion by producing eye movements that precisely compensate for motion of the head. Neuronal mechanisms of plasticity enable these reflexes to perform accurately in the face of development, trauma, and disease. Although the roles of particular classes of neurons to signal transformations and plasticity have been identified, little is understood about how cellular mechanisms contribute to the day-to-day performance and adaptive capabilities of the oculomotor system. The objective of this proposal is to elucidate the role of a particular type of ion channel, the BK-type calcium activated potassium channel, in the induction and maintenance of oculomotor plasticity. The central hypothesis is that regulation of BK currents plays a critical role in adaptive changes in the VOR and OKR induced both by peripheral dysfunction and by prolonged visual-vestibular mismatch experience. The proposed research will use a combination of behavioral and electrophysiological analyses in transgenic mice to investigate the forms of oculomotor plasticity that require BK channels and the critical locations of BK channels within the oculomotor circuit. Extracellular recordings from the cerebellar flocculus will complement behavioral analyses of mice in which BK channels are deleted either globally or specifically in Purkinje cells. These studies will provide foundations for targeted investigations of the molecular mechanisms that underlie cerebellar-dependent plasticity as well as for pharmacological treatments of oculomotor disorders that cause nystagmus. [unreadable] [unreadable]

Project Summary The long-range goal of this research is to understand the cellular and molecular mechanisms that mediate the normal performance and adaptive plasticity of smooth eye movements. The optokinetic reflex (OKR) prevents blurred vision during self-motion by producing smooth eye movements that compensate for full field image motion. Neuronal mechanisms of plasticity enable the OKR to adapt in the face of development, trauma, and disease. Although the roles of particular classes of neurons to signal transformations and plasticity have been identified, little is understood about how cellular mechanisms contribute to the day-to-day performance and adaptive capabilities of the OKR and other smooth eye movements. The objective of the proposed research is to elucidate how cerebellar activity influences signaling and plasticity in distinct classes of brainstem neurons responsible for smooth eye movements. The central hypothesis is that cerebellar and visual pathway synapses onto vestibular nucleus and nucleus prepositus hypoglossi neurons are differentially responsible for rapid initiation vs maintained components of smooth eye movements. The proposed research will examine the influence of cerebellar activity on eye movements evoked by moving visual stimuli. Cellular and synaptic physiological experiments in brainstem slice preparations will examine the short and long term dynamics of cerebellar and visual synapses onto cerebellar recipient neurons, which mediate cerebellar influences on signaling and plasticity on smooth eye movements. Distinct classes of cerebellar target neurons will be identified by their axonal projections and patterns of cerebellar synaptic cell terminals. The influence of visual pathway and cerebellar synaptic activity will be examined in cerebellar target neurons in the vestibular and prepositus nuclei. These studies will provide foundations for targeted investigations of the molecular mechanisms that mediate smooth eye movements as well as for pharmacological treatments of cerebellar disorders and of oculomotor disorders that cause nystagmus.

? DESCRIPTION (provided by applicant): The goal of this project is to generate cellular and molecular information critical for improving clinical treatments of cerebellar disorders and for fundamental understanding of the mechanisms responsible for cerebellar control of oculomotor, skeletomotor, autonomic, and cerebral cortical circuits. Although much is known about cerebellar physiology, anatomy, and vulnerability to damage and disease, clinical treatments of cerebellar disorders are limited by the paucity of cellular and molecular information on cerebellar output neurons required to identify specific drug targets. The specific objectives of the project are to elucidate molecular and synaptic information in functionally distinct types of cerebellar output neurons. To achieve these objectives, quantitative, single-cell gene expression analyses of specific classes of cerebellar output neurons will be performed. Complementary anatomical circuit analyses will identify differential synaptic connectivity, and in vitro physiological experiments will probe the impact of cerebellar cortical computations on spike timing and rate in distinct classes of cerebellar output neurons. These experiments will provide a critical foundation for rational pharmacological therapies for postural instability and autonomic dysfunction and other debilitating sequelae of cerebellar disorders. Revealing the expression of neurotransmitter receptors, ion channels and other drug targets on physiologically and anatomically-defined subsets of cerebellar output neurons will enable enhanced specificity and efficacy in restoring postural and oculomotor stability, autonomic regulation, and cognitive functions while minimizing side effects

Proposal Summary DESCRIPTION (provided by applicant): Impairments in prefrontal cortical function are associated with many psychiatric disorders, including schizophrenia, mood disorders, and autism. Surprisingly, the vermis - a small part of the cerebellum best known for its role in posture and eye movements - has been strongly implicated in each of these disorders. Deficits in executive control of saccadic eye movements are used as biomarkers for schizophrenia, autism, and depression, consistent with a dual role of the vermis in regulating both motoric and prefrontal cortical function. However, neither the neural circuit substrates that link the cerebellar vermis with the prefrontal cortex nor the functional impact of these connections are understood. The central hypothesis of this proposal is that the affective and cognitive functions of the cerebellar vermis are mediated by a specific class of cerebellar nucleus neuron that makes circuit connections with the reticular activating system, a critical regulator of arousal and cortical state, as well as with neurons of the medial thalamus that are essential for prefrontal cortical function. The proposed experiments will test this hypothesis with a combination of modern anatomical, physiological, pharmacological, optogenetic, and behavioral strategies. Deficits in cerebellar engagement with the reticular activating system and the thalamus could account for mood dysregulation and cognitive deficits common to several psychiatric disorders. Accomplishing the aims of the proposed research will result in unprecedented cell type specific information about the long-range circuit connections that link the cerebellar vermis with the prefrontal cortex that account for cerebellar modulation of affective and cognitive function. This research will thus generate new insights into the mechanisms that mediate currently unexplained efficacy of transcranial stimulation of the cerebellum in improving cognitive and mood dysfunction in psychiatric disorders.

PROJECT SUMMARY/ABSTRACT: Signal processing in central auditory pathways depends both on acoustic information transmitted from the auditory periphery and on contextual modulation by distributed brain circuits. Healthy hearing throughout the lifespan relies on the ability to adaptively modify central auditory gain under conditions of ambiguous or degraded acoustic information, such as in noisy environments or after hearing loss. Auditory perception is also influenced by where we look and what we pay attention to, but the mechanisms mediating these contextual effects are poorly understood. Increasing evidence indicates that neural circuits outside of the classical auditory pathways may be particularly important for adaptive gain control in the auditory system. This proposal focuses on the role of the cerebellum, a brain structure historically associated with motor control but more recently recognized for its involvement in optimizing sensory processing. The long-term goal of this exploratory project is to identify the influence of the cerebellum on auditory function, with a particular interest in harnessing cerebellar plasticity mechanisms for therapeutic improvements in hearing. Little is known about the anatomical substrates or physiological effects of the cerebellum on the auditory system. The specific aims of the proposed research are to (1) Identify the neural circuit substrates for cerebellar modulation of the auditory system and (2) Examine the physiological influence of the cerebellum on midbrain auditory activity. Experiments in Aim 1 will take advantage of modern viral anterograde, retrograde, and transsynaptic circuit tracing reagents to identify brainstem and thalamic neurons that are anatomically positioned to connect the cerebellum with the inferior colliculus. Aim 2 will leverage optogenetic stimulation of the cerebellum to assess the physiological influence of manipulating cerebellar activity on spontaneous firing and auditory evoke responses in inferior colliculus neurons. This research will lay the foundation for understanding the circuits, mechanisms, and functional effects of cerebellar-auditory interactions. There are strong clinical implications for adaptive cerebellar control of hearing, as non-invasive cerebellar stimulation could provide a new therapeutic strategy for improving auditory sensitivity after hearing loss.

Project Summary The cerebellum has been implicated in a remarkable number of neurological and neuropsychiatric disorders that range from motoric deficits such as ataxia, tremor, and disequilibrium to autism, schizophrenia, and impulsivity. We do not know why some patients with dysfunction in the cerebellum experience primarily motoric symptoms while others suffer from dysregulated mood and mental health challenges. In this proposal, we examine the specific neural circuits that are responsible for diverse cerebellar motoric and non-motoric dysfunctions. Using a combination of rigorous anatomical methods, including specialized viral circuit tracing vectors that provide new information about brainwide neuronal connections, this research will test the hypothesis that specialized types of cerebellar output neurons are differentially responsible for the diverse disorders associated with the cerebellum. Accomplishments of these experimental goals will generate important new information about the brain- wide connections made by different types of cerebellar output neurons which will enable the development of new diagnostic and therapeutic strategies for patients with a wide range of motoric and neuropsychiatric disorders.