The robust, reciprocal anatomical connections between the cerebellum and contralateral sensorimotor cerebral hemisphere underscores the strong physiological interdependence between these two regions in relation to human behavior. Previous studies have shown that damage to sensorimotor cortex can result in a lasting reduction of cerebellar metabolism, the magnitude of which has been linked to poor rehabilitative outcomes. A better understanding of movement-related cerebellar physiology as well as cortico-cerebellar coherence (CCC) in the chronic, post-stroke state may be key to developing novel neuromodulatory techniques that promote upper limb motor rehabilitation. As a part of the first in-human phase-I trial investigating the effects of deep brain stimulation of the cerebellar dentate nucleus (DN) on chronic, post-stroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG in subjects (both sexes) with middle cerebral artery stroke during a visuo-motor tracking task. We investigat...

Motor skills learning is classically associated with brain regions including cerebral and cerebellar cortices and basal ganglia nuclei. Less is known about the role of the hippocampus in the acquisition and storage of motor skills. Here we show that mice receiving a long-term training in the accelerating rotarod display marked hippocampal transcriptional changes and reduced pyramidal neurons activity in the CA1 region when compared with naïve mice. Then, we use mice in which neural ensembles are permanently labeled in an Egr1 activity-dependent fashion. Using these mice, we identify a subpopulation of Egr1 -expressing pyramidal neurons in CA1 activated in short- and long-term trained mice in the rotarod task. When Egr1 is downregulated in the CA1 or these neuronal ensembles are depleted, motor learning is improved whereas their chemogenetic stimulation impairs motor learning performance. Thus, Egr1 organizes specific CA1 neuronal ensembles during the accelerating rotarod task that limit motor learning. The...

Midbrain dopaminergic neurons include many subtypes characterised by their location, connectivity and function. Surprisingly, mechanisms underpinning the specification of A9 neurons (responsible for motor function, including within ventral midbrain (VM) grafts for treating Parkinson’s disease) over adjacent A10, remains largely speculated. We assessed the impact of synaptic targeting on survival, integration, and phenotype acquisition of dopaminergic neurons within VM grafts generated from fetal tissue or human pluripotent stem cells. VM progenitors were grafted into female mice with 6OHDA-lesions of host midbrain dopamine neurons, with some animals also receiving intrastriatal quinolinic acid injections to ablate medium spiny neurons (MSN) – the A9 neuron primary target. While loss of MSNs variably affected graft survival, it significantly reduced striatal yet increased cortical innervation. Consequently, grafts showed reduced A9 and increased A10-specification, with more dopamine neurons failing to matur...

Because of their ease of use, Adeno-Associated Viruses (AAV) are indispensable tools for much of neuroscience. Yet AAVs have been used relatively little to study the identities and connectivity of peripheral sensory neurons, principally because methods to selectively target peripheral neurons have been limited. The introduction of the AAV-PHP.S capsid with enhanced tropism for peripheral neurons (Chan et al., 2017) offered a solution, which we further elaborate here. Using AAV-PHP.S with GFP or mScarlet fluorescent proteins, we show that the mouse sensory ganglia for cranial nerves V, VII, IX and X, are targeted. Pseudounipolar neurons of both somatic and visceral origin, but not satellite glia, express the reporters. One week after virus injection, ≈66% of geniculate ganglion neurons were transduced. Fluorescent reporters were transported along the central and peripheral axons of these sensory neurons, permitting visualization of terminals at high resolution, and/or in intact, cleared brain using light sh...

Actions have consequences. Motor learning involves correcting actions that lead to movement errors and remembering these actions for future behavior. In most laboratory situations, movement errors have no physical consequences and simply indicate the progress of learning. Here we asked how experiencing a physical consequence when making a movement error affects motor learning. Two groups of participants adapted to a new, prism-induced mapping between visual input and motor output while performing a precision walking task. Importantly, one group experienced an unexpected slip perturbation when making foot-placement errors during adaptation. Because of our innate drive for safety, and the fact that balance is fundamental to movement, we hypothesized that this experience would enhance motor memory. Learning generalized to different walking tasks to a greater extent in the group who experienced the adverse physical consequence. This group also showed faster relearning one week later despite exposure to a compe...

Synaptic abnormality is an important pathologic feature of autism spectrum disorders (ASDs) and responsible for various behavioral defects in these neurodevelopmental disorders. Microglia are the major immune cells in the brain and also play an important role in synapse refinement. Although dysregulated synaptic pruning by microglia during the brain development has been associated with ASDs, the underlying mechanism has yet to be fully elucidated. Herein, we observed that expression of Transmembrane protein 59 (TMEM59), a protein recently shown to regulate microglial function, was decreased in autistic patients. Furthermore, we found that both male and female mice with either complete or microglia-specific loss of Tmem59 developed ASD-like behaviors. Microglial TMEM59-deficient mice also exhibited enhanced excitatory synaptic transmission, increased dendritic spine density, and elevated levels of excitatory synaptic proteins in synaptosomes. TMEM59-deficient microglia had impaired capacity for synapse engu...

Populations of cortical neurons generate rhythmic fluctuations in their ongoing spontaneous activity. These fluctuations can be seen in the local field potential (LFP), which reflects summed return currents from synaptic activity in the local population near a recording electrode. The LFP is spectrally broad and many researchers view this breadth as containing many narrowband oscillatory components which may have distinct functional roles. This view is supported by the observation that the phase of narrowband oscillations are often correlated with cortical excitability and can relate to the timing of spiking activity and the fidelity of sensory evoked responses. Accordingly, researchers commonly “tune in'' to these channels by narrowband filtering the LFP. Alternatively, neural activity may be fundamentally broadband and composed of transient, non-stationary rhythms that are difficult to approximate as oscillations. In this view, the instantaneous state of the broad ensemble relates directly to the excitab...

Effective planning involves knowing where different actions take us. However natural environments are rich and complex, leading to an exponential increase in memory demand as a plan grows in depth. One potential solution is to filter out features of the environment irrelevant to the task at hand. This enables a shared model of transition dynamics to be used for planning over a range of different input features. Here, we asked human participants (13 male, 16, female) to perform a sequential decision-making task, designed so that knowledge should be integrated independently of the input features (visual cues) present in one case but not in another. Participants efficiently switched between using a low (cue independent) and a high (cue specific) dimensional representation of state transitions. fMRI data identified the medial temporal lobe as a locus for learning state transitions. Within this region, multivariate patterns of BOLD responses as state associations changed (via trial-by-trial learning) were less ...