STATE-DEPENDENT MODULATION OF CEREBELLAR FUNCTION

About This Grant

PROJECT SUMMARY Proper cerebellar function is important for many aspects of mental health, as evidenced by the wide range of neurological and neuropsychiatric disorders that have been associated with impaired neural processing in the cerebellum, from ataxia and dystonia to schizophrenia, autism and attention-deficit/hyperactivity disorder (ADHD). To understand how the cerebellum contributes to both motor control and cognitive functions it is necessary to define what kind of inputs it receives, particularly via the massive mossy fiber system, which carries the bulk of all sensory, motor and cognitive signals sent to the cerebellum from the rest of the brain. Furthermore, variations in brain state are likely to alter the information content of mossy fiber inputs and have a major impact on how well and reliably the cerebellum can perform its function. Unfortunately, conventional extracellular recording methods do not offer enough stability and often fail to distinguish signals of mossy fibers from other cell types in the cerebellar cortex. As a result, there is very limited knowledge about mossy fiber activity in cerebellar tasks, and no information at all about state-dependent modulation of mossy fiber responses or which mossy fiber states may be associated with enhanced cerebellar function. The experiments in this application take advantage of Neuropixels probes and a recent semi-supervised deep learning algorithm to overcome previous technical limitations and record for the first time from identified mossy fiber populations while mice perform a cerebellar-dependent eyeblink conditioning task. The analysis of mossy fiber activity, both before and during conditioning trials, is meant to achieve the following goals: (1) to provide new biological insight into the moment-to-moment variability of mossy fiber states, (2) to help define which mossy fiber states are associated with ‘faulty’ vs ‘reliable’ cerebellar function and, (3) to reveal how locomotion and non-invasive stimulation of the prefrontal cortex can be used to steer mossy fibers toward favorable states that are linked to improved performance of cerebellar-driven motor responses. Thus, the findings will have important implications for enhancing cerebellar function, both in health and disease, by developing new therapeutic interventions that can be used to promote beneficial mossy fiber states. Given the well-established role of the cerebellum in the control of movement, it is expected that the findings will impact patients with motor problems most directly. However, cerebellar dysfunction has also been associated with impairments in executive function, abstract reasoning, working memory, high-level language processing and attentional control. To the extent that the neural signature of ‘faulty’ and ‘reliable’ mossy fiber states is similar in regions of the cerebellum involved in these cognitive functions, the aims of this application and the implications for future treatments may apply to them as well.