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 ...

Increasing loss of structure and function of neurons and decline in cognitive function is commonly seen during the progression of neurologic diseases, although the causes and initial symptoms of individual diseases are distinct. This observation suggests a convergence of common degenerative features. In myotonic dystrophy type 1 (DM1), the expression of expanded CUG RNA induces neurotransmission dysfunction before axon and dendrite degeneration and reduced MBNL2 expression associated with aberrant alternative splicing. The role of loss of function of MBNL2 in the pathogenesis of neurodegeneration and the causal mechanism of neurodegeneration-reduced expression of MBNL2 remain elusive. Here, we show that increased MBNL2 expression is associated with neuronal maturation and required for neuronal morphogenesis and the fetal to adult developmental transition of RNA processing. Neurodegenerative conditions including NMDA receptor (NMDAR)-mediated excitotoxicity and dysregulated calcium homeostasis triggered nuc...

The integration of somatosensory signals across fingers is essential for dexterous object manipulation. Previous experiments suggest that this integration occurs in neural populations in the primary somatosensory cortex (S1). However, the integration process has not been fully characterized, as previous studies have mainly used two-finger stimulation paradigms. Here, we addressed this gap by stimulating all 31 single- and multi-finger combinations. We measured population-wide activity patterns evoked during finger stimulation in human S1 and primary motor cortex (M1) using 7T functional magnetic resonance imaging (fMRI) in female and male participants. Using multivariate fMRI analyses, we found clear evidence of unique non-linear interactions between fingers. In Brodmann area (BA) 3b, interactions predominantly occurred between pairs of neighbouring fingers. In BA 2, however, we found equally strong interactions between spatially distant fingers, as well as interactions between finger triplets and quadrupl...

Oxytocin (Oxt) neurons regulate diverse physiological responses via direct connections with different neural circuits. However, the lack of comprehensive input-output wiring diagrams of Oxt neurons and their quantitative relationship with Oxt receptor (Oxtr) expression presents challenges to understanding circuit-specific Oxt functions. Here, we establish a whole-brain distribution and anatomic connectivity map of Oxt neurons, and their relationship with Oxtr expression using high-resolution 3D mapping methods in adult male and female mice. We use a flatmap to describe Oxt neuronal expression in four hypothalamic domains including under-characterized Oxt neurons in the tuberal nucleus (TU). Oxt neurons in the paraventricular hypothalamus (PVH) broadly project to nine functional circuits that control cognition, brain state, and somatic visceral response. In contrast, Oxt neurons in the supraoptic (SO) and accessory (AN) nuclei have limited central projection to a small subset of the nine circuits. Surprisin...

Ion channels at the nodes of Ranvier (NRs) are believed to play essential roles in intrinsic electrophysiological properties and saltatory conduction of action potentials (AP) at the NRs of myelinated nerves. While we have recently shown that two-pore domain potassium (K2P) channels play a key role at the NRs of Aβ-afferent nerves, K+ channels and their functions at the NRs of mammalian motor nerves remain elusive. Here we addressed this issue by using ex vivo preparations of lumbar spinal ventral nerves from both male and female rats and the pressure-patch-clamp recordings at their NRs. We found that depolarizing voltages evoked large non-inactivating outward currents at NRs. The outward currents could be partially inhibited by voltage-gated K+ channel blockers, largely inhibited by K2P blockers and cooling temperatures. Inhibition of the outward currents by voltage-gated K+ channel blockers, K2P blockers, or cooling temperatures significantly altered electrophysiological properties measured at the NRs in...

Aging leads to degeneration of the peripheral and central auditory systems, hearing loss, and difficulty understanding sounds in noise. Aging is also associated with changes in susceptibility to or recovery from damaging noise exposures, although the effects of the interaction between acute noise exposure and age on the perception of sounds are not well studied. We tested these effects in the CBA/CaJ mouse model of age-related hearing loss using operant conditioning procedures before and after noise exposure and longitudinally measured changes in their sensitivity for detecting tones in quiet or noise backgrounds. Cochleae from a subset of the behaviorally tested mice were immunolabeled to examine organ of Corti damage relative to what is expected based on aging alone. Mice tested in both quiet and noise background conditions experienced worse behavioral sensitivity immediately after noise exposure, but mice exposed at older ages generally showed greater threshold shifts and reduced recovery over time. Sur...