Biology subjects

Woodard, C. L.

Publications and source records attributed to Woodard, C. L..

3 recordsLinked to original sources

bioRxiv2026

A Novel Cortico-Striatal NREM Sleep Rhythm in Mice and Non-Human Primates

With practice, rapid early gains in performance are followed by a slower phase marked by kinematic refinement, automaticity and enhanced cortical and striatal interactions. While sleep is known to support early learning, its causal role in the slow phase of learning is not known. Here we recorded neuronal activity in primary motor cortex (M1) and the dorsolateral striatum (DLS) during long-term skill acquisition and interleaved sleep. Surprisingly, the slow phase of learning was marked by the emergence of a previously unrecognized 5-10 Hz oscillatory activity during NREM sleep that was coherent across M1 and DLS. This oscillation resulted in repeated joint reactivation of task-specific information in cortex and striatum. Strikingly, during later stages of training, such joint reactivation of task activity increased over the course of NREM sleep, suggesting that sleep-dependent processing strengthens cortico-striatal interactions. The strength of M1-DLS coherence was predictive of next-day performance gains and increased cortico-striatal coupling during task performance. Targeted closed-loop disruption of this oscillation during NREM sleep abolished performance gains, whereas switching to a dose matched random stimulation paradigm enabled performance improvements in the same animals. Importantly, the same cortico-striatal 5-10 Hz rhythm was also found in sleeping non-human primates, where it was selectively enhanced following learning. Together, we identify, across species, a novel NREM sleep oscillation that is important for sleep-dependent performance gains which depend on cortico-striatal processing.

neuroscience↗

bioRxiv2024

Effect of chronic upregulation of endocannabinoid signaling in vivo with JZL184 on striatal synaptic plasticity and motor learning in YAC128 Huntington disease mice

Synaptic dysfunction underlies early sensorimotor and cognitive deficits, and precedes neurodegeneration in a variety of disorders, including Alzheimer, Parkinson and Huntington disease (HD). A monogenic inherited disorder, HD manifests with cognitive, motor and mood disorders associated with progressive degeneration of striatal spiny projection neurons and cortical pyramidal neurons. Cortico-basal ganglia-thalamic loops regulate movement selection and motor learning, which are impaired early in HD. Skilled motor learning is mediated in part by plasticity at cortico-striatal synapses, including endocannabinoid-mediated, high-frequency stimulation induced long-term depression (HFS-LTD). Previously, we found impaired HFS-LTD in brain slice recordings from pre-manifest HD mouse models, which was corrected by JZL184, an inhibitor of endocannabinoid 2-arachidonoyl glycerol (2-AG) degradation. Here, we tested the effects of JZL184 administered in vivo to YAC128 HD model and wild-type (WT) littermate mice. JZL184, given orally daily over a 3-week period, significantly increased levels of 2-AG in striatal tissue. While JZL184 treatment had no impact on open field behavior which was similar for the two genotypes, the treatment improved motor learning on the rotarod task in YAC128 mice to the level observed in WT mice. Moreover, HFS-induced striatal plasticity measured by field potential recording in acute brain slice from YAC128 mice was normalized to WT levels after JZL184 treatment. These results suggest a novel target for mitigating early symptoms of HD, and support the need for clinical trials to test the efficacy of modulating the endocannabinoid system in treatment of HD.

neuroscience↗

bioRxiv2021

Impaired refinement of kinematic variability in Huntington disease mice on an automated home-cage forelimb motor task

The effective development of novel therapies in mouse models of neurological disorders relies on behavioural assessments that provide accurate read-outs of neuronal dysfunction and/or degeneration. We designed an automated behavioural testing system ( PiPaw) which integrates an operant lever-pulling task directly into the mouse home-cage. This task is accessible to group-housed mice 24-hours per day, enabling high-throughput longitudinal analysis of forelimb motor learning. Moreover, this design eliminates the need for exposure to novel environments and minimizes experimenter interaction, significantly reducing two of the largest stressors associated with animal behaviour. Mice improved their performance of this task over one week of testing by reducing inter-trial variability of reward-related kinematic parameters (pull amplitude or peak velocity). In addition, mice displayed short-term improvements in reward rate, and a concomitant decrease in movement variability, over the course of brief (<10 minutes) bouts of task engagement. We used this system to assess motor learning in mouse models of the inherited neurodegenerative disorder, Huntington disease (HD). Despite having no baseline differences in task performance, Q175-FDN HD mice were unable to modulate the variability of their movements in order to increase reward on either short or long timescales. Task training was associated with a decrease in the amplitude of spontaneous excitatory activity recorded from striatal medium spiny neurons in the hemisphere contralateral to the trained forelimb in wildtype mice; however, no such changes were observed in Q175-FDN mice. This behavioural screening platform should prove useful for preclinical drug trials towards improved treatments in HD and other neurological disorders. Significance StatementIn order to develop effective therapies for neurological disorders such as Huntington disease (HD), its important to be able to accurately and reliably assess the behaviour of mouse models of these conditions. Moreover, these behavioural assessments should provide an accurate readout of underlying neuronal dysfunction and/or degeneration. In this paper, we employed an automated behavioural testing system to assess motor learning in mice within their home-cage. Using this system, we were able to study motor abnormalities in HD mice with an unprecedented level of detail, and identified a specific behavioural deficit associated with an underlying impairment in striatal neuronal plasticity. These results validate the usefulness of this system for assessing behaviour in mouse models of HD and other neurological disorders.

neuroscience↗