The ability to learn dexterous motor skills is a fundamental aspect of human behavior. However, the underlying neural circuit mechanisms for dexterous skill learning are unclear. Advancing our understanding of motor skill learning requires the integration of modern neuroscientific techniques with a rigorously characterized dexterous task. The development of automated rodent skilled reaching with paw tracking allows detailed analysis of how reach-to-grasp kinematics evolve during learning. We assessed how both “gross” forelimb and “fine” digit kinematics changed as rats learned skilled reaching. Rats whose success rates increased (learners) consistently reduced the variability in their reach trajectories. Refinement of fine digit control generally continued after consistency in gross hand transport to the pellet plateaued. Interestingly, most rats whose success rates did not increase (non-learners) also converged on consistent reach kinematics. Some non-learners, however, maintained substantial variability ...

The V-ATPase is a highly conserved enzymatic complex that ensures appropriate levels of organelle acidification in virtually all eukaryotic cells. While the general mechanisms of this proton pump have been well studied, little is known about the specific regulations of neuronal V-ATPase. Here, we studied CG31030, a previously uncharacterized Drosophila protein predicted from its sequence homology to be part of the V-ATPase family. In contrast to its ortholog ATP6AP1/VhaAC45 which is ubiquitous, we observed that CG31030 expression is apparently restricted to all neurons, and using CRISPR/Cas9-mediated gene tagging, that it is mainly addressed to synaptic terminals. In addition, we observed that CG31030 is essential for fly survival and that this protein co-immunoprecipitates with identified V-ATPase subunits, and in particular ATP6AP2. Using a genetically-encoded pH probe (VMAT-pHluorin) and electrophysiological recordings at the larval neuromuscular junction, we show that CG31030 knock-down induces a major...

The transcription factor cAMP response element-binding protein (CREB) is involved in a myriad of cellular functions in the central nervous system. For instance, the role of CREB via phosphorylation at the amino-acid residue Serine (Ser)133 in expressing plasticity-related genes and activity-dependent neuronal plasticity processes has been extensively demonstrated. However, much less is known about the role of CREB phosphorylation at Ser142 and Ser143. Here, we employed a viral vector containing a dominant negative form of CREB, with serine-to-alanine mutations at residue 142 and 143 to specifically block phosphorylation at both sites. We then transfected this vector into primary neurons in vitro or intracortically injected it into mice in vivo , to test whether these phosphorylation events were important for activity-dependent plasticity. We demonstrated by immunohistochemistry of cortical neuronal cultures that the expression of Arc, a known plasticity-related gene, requires triple phosphorylation of CREB...

Humans can use their previous experience in form of statistical priors to improve decisions. It is, however, unclear how such priors are learned and represented. Importantly, it has remained elusive whether prior learning is independent of the sensorimotor system involved in the learning process or not, as both modality-specific and modality-general learning have been reported in the past. Here, we used a saccadic eye movement task to probe the learning and representation of a spatial prior across a few trials. In this task, learning occurs in an unsupervised manner and through encountering trial-by-trial visual hints drawn from a distribution centered on the target location. Using a model-comparison approach, we found that participants’ prior knowledge is largely represented in the form of their previous motor actions, with minimal influence from the previously seen visual hints. By using two different motor contexts for response (looking either at the estimated target location, or exactly opposite to it)...

Bilateral convergence of external stimuli is a common feature of vertebrate sensory systems. This convergence of inputs from the bilateral receptive fields allows higher order sensory perception, such as depth perception in the vertebrate visual system and stimulus localization in the auditory system. The functional role of such bilateral convergence in the olfactory system is unknown. To test whether each olfactory bulb (OB) contributes a separate piece of olfactory information, and whether information from the bilateral OB is integrated, we synchronized the activation of OBs with blue light in mice expressing ChIEF in the olfactory sensory neurons (OSNs) and behaviorally assessed the relevance of dual OBs in olfactory perception. Our findings suggest that each OB contributes separate components of olfactory information, and the mice integrate the bilaterally synchronized olfactory information for olfactory identity.

The opioid epidemic led to an increase in the number of neonatal opioid withdrawal syndrome (NOWS) cases in infants born to opioid-dependent mothers. Hallmark features of NOWS include weight loss, severe irritability, respiratory problems, and sleep fragmentation. Mouse models provide an opportunity to identify brain mechanisms that contribute to NOWS. Neonatal outbred Swiss Webster Cartworth Farms White (CFW) mice were administered morphine (15 mg/kg, s.c.) twice daily from postnatal day 1 (P1) to P14, an approximation of the third trimester of human gestation. Female and male mice underwent behavioral testing on P7 and P14 to determine the impact of opioid exposure on anxiety and pain sensitivity. Ultrasonic vocalizations (USVs) and daily body weights were also recorded. Brainstems containing pons and medulla were collected during morphine withdrawal on P14 for RNA sequencing. Morphine induced weight loss from P2 to P14, which persisted during adolescence (P21) and adulthood (P50). USVs markedly increase...

Convincing evidence of blood-spinal cord barrier (BSCB) alterations has been demonstrated in amyotrophic lateral sclerosis (ALS) and barrier repair is imperative to prevent motor neuron dysfunction. We showed benefits of human bone marrow-derived CD34+ cells (hBM34+) and endothelial progenitor cells (hBM-EPCs) intravenous transplantation into symptomatic G93A SOD1 mutant mice on barrier reparative processes. These gains likely occurred by replacement of damaged endothelial cells, prolonging motor neuron survival. However, additional investigations are needed to confirm the effects of administered cells on integrity of the microvascular endothelium. The aim of this study was to determine tight junction protein levels, capillary pericyte coverage, microvascular basement membrane, and endothelial filamentous actin (F-actin) status in spinal cord capillaries of G93A SOD1 mutant mice treated with human bone marrow-derived stem cells. Tight junction proteins were detected in the spinal cords of cell-treated vers...

Recent evidence suggests that alteration of axon initial segment (AIS) geometry (i.e., length or location along the axon) contributes to CNS dysfunction in neurological diseases. For example, AIS length is shorter in the prefrontal cortex of type 2 diabetic mice with cognitive impairment. To determine the key type 2 diabetes-related factor that produces AIS shortening we modified levels of insulin, glucose, or the reactive glucose metabolite methylglyoxal in cultures of dissociated cortices from male and female mice and quantified AIS geometry using immunofluorescent imaging of the AIS proteins AnkyrinG and βIV spectrin. Neither insulin nor glucose modification altered AIS length. Exposure to 100 but not 1 or 10 μm methylglyoxal for 24 h resulted in accumulation of the methylglyoxal-derived advanced glycation end-product hydroimidazolone and produced reversible AIS shortening without cell death. Methylglyoxal-evoked AIS shortening occurred in both excitatory and putative inhibitory neuron populations and i...

Prolonged exposure to a stimulus causes desensitization of cortical neurons and results in perceptual changes. One example of this phenomenon is contrast adaptation, in which perceived differences between light and dark regions of a stimulus decrease. Blakemore, Muncey, and Ridley reported evidence for the “perceptual fading of a stabilized cortical image” in a 1971 Nature paper. Our goal was to replicate their second experiment, in which adaptation was measured across many contrasts, and develop an active learning exercise for undergraduate students. The experiment was coded using an open-source python package and psychophysical data were collected from two observers. On each trial, a sinusoidally modulated luminance grating appeared above fixation, and the task of the observer was to adjust the contrast of a grating below fixation until the two appeared identical. Between trials in the adaptation condition, a high contrast grating was presented in the top location; no such grating appeared between trials...

Repetition is an indispensable component of motor skill acquisition. However, it is unknown how consistent repeated movement patterns must be to engage an implicit “use-dependent” learning mechanism. In this Registered Report, we tackled this question through a combination of computational modeling, simulations, and behavioral experiments involving visually-guided treadmill walking. Our hypotheses were formalized by two distinct computational models: in the two-process Strategy plus Use-Dependent model, use-dependent learning is viewed as a slowly updating and slowly decaying bias in the direction of repeated movements. The Adaptive Bayesian model frames use-dependent learning as an emergent property of quickly adapting prior probabilities of target step lengths. Critically, the Adaptive Bayesian model is much more sensitive to variable practice than the Strategy plus Use-Dependent model. To test these hypotheses, human participants ( N  = 18, 10 females) learned a novel asymmetric stepping pattern under t...