Down Syndrome (DS), the most common genetic cause of intellectual disability, is associated with lifelong cognitive deficits. However, the mechanisms by which triplication of chromosome 21 genes drive neuroinflammation and cognitive dysfunction are poorly understood. Here, using the Ts65Dn mouse model of DS, we performed an integrated single-nucleus ATAC and RNA-sequencing (snATAC-seq and snRNA-seq) analysis of the adult cortex. We identified cell type-specific transcriptional and chromatin-associated changes in the Ts65Dn cortex, including regulators of neuroinflammation, transcription and translation, myelination, and mitochondrial function. We discovered enrichment of a senescence-associated transcriptional signature in Ts65Dn oligodendrocyte precursor cells (OPCs) and epigenetic changes consistent with a loss of heterochromatin. We found that senescence is restricted to a subset of OPCs concentrated in deep cortical layers. Treatment of Ts65Dn mice with a senescence-reducing flavonoid rescued cortical ...

Simultaneous adaptation to opposite visuomotor perturbations is known to be difficult. It has been shown to be possible only in situations where the two tasks are associated with different contexts, being either a different colored background, a different area of workspace, or a different follow-through movement. However, many of these elements evoke explicit mechanisms that could contribute to storing separate (modular) memories. It remains to be shown whether simultaneous adaptation to multiple perturbations is possible when they are introduced in a fully implicit manner. Here we sought to test this possibility using a visuomotor perturbation small enough to eliminate explicit awareness. Participants (N=25) performed center-out reaching movements with a joystick to 5 targets located 72° apart. Depending on the target, visual feedback of cursor position was either veridical (1 target) or could be rotated by +5 or -5° (2 targets each). After 300 trials of adaptation (60 to each target), results revealed th...

We investigated morphological changes in the corticospinal tract (CST) to understand the mechanism underlying recovery of hand function after lesion of the CST at the C4/C5 border in 7 macaque monkeys. All monkeys exhibited prominent recovery of precision grip success ratio within a few months. The trajectories and terminals of CST from the contralesional (n = 4) and ipsilesional (n = 3) hand area of primary motor cortex (M1) were investigated at 5-29 months after the injury using an anterograde neural tracer, biotinylated dextran amine (BDA). Reorganization of the CST was assessed by counting the number of BDA-labeled axons and bouton-like swellings in the gray and white matters. Rostral to the lesion (at C3), the number of axon collaterals of the descending axons from both contralesional and ipsilesional M1 entering the ipsilesional and contralesional gray matter, respectively, were increased. Caudal to the lesion (at C8), axons originating from the contralesional M1, descending in the preserved gray mat...

In implicit sensorimotor adaptation, a mismatch between the predicted and actual sensory feedback results in a sensory prediction error (SPE). Sensory predictions have long been thought to be linked to descending motor commands, implying a necessary contribution of movement execution to adaptation. Yet, recent work has shown that mere motor imagery (MI) also engages predictive mechanisms, opening up the possibility that MI might be sufficient to drive implicit adaptation. In a within-subject design in humans (n=30), implicit adaptation was assessed in a center-out reaching task, following a single exposure to a visuomotor rotation. It was hypothesized that performing MI of a reaching movement while being provided with an animation of rotated visual feedback (MI condition) would lead to post-rotation biases similar to those observed when the movement is executed (Execution condition). Results revealed that both the MI and Execution conditions led to significant directional biases following rotated trials. Y...

After corticospinal tract damage, reticulospinal connections to motoneurons strengthen preferentially to flexor muscles. This could contribute to the disproportionately poor recovery of extensors often seen after spinal cord injury (SCI) and stroke. In this study, we paired electrical stimulation over the triceps muscle with auditory clicks, using a wearable device to deliver stimuli over a prolonged period of time. Healthy human volunteers wore the stimulation device for ∼6 hours and a variety of electrophysiological assessments were used to measure changes in triceps motor output. In contrast to previous results in the biceps muscle, paired stimulation: 1) did not increase the StartReact effect; 2) did not decrease the suppression of responses to transcranial magnetic brain stimulation (TMS) following a loud sound; 3) did not enhance muscle responses elicited by a TMS coil oriented to induce anterior-posterior current. In a second study, chronic cervical SCI survivors wore the stimulation device for ∼4...

The brain interprets sensory inputs to guide behavior, but behavior itself disrupts sensory inputs. Perceiving a coherent world while acting in it constitutes active perception. For example, saccadic eye movements displace visual images on the retina and yet the brain perceives visual stability. Because this percept of visual stability has been shown to be influenced by prior expectations, we tested the hypothesis that it is Bayesian. The key prediction was that priors would be used more as sensory uncertainty increases. Humans and rhesus macaques reported whether an image moved during saccades. We manipulated both prior expectations and levels of sensory uncertainty. All psychophysical data were compared with the predictions of Bayesian ideal observer models. We found that humans were Bayesian for continuous judgments. For categorical judgments, however, they were anti-Bayesian: they used their priors less with greater uncertainty. We studied this categorical result further in macaques. The animals’ judgm...

Human studies employing intracerebral and transcranial perturbations suggest that the input-output properties of cortical circuits are dramatically affected during sleep in healthy subjects as well as in awake patients with multifocal and focal brain injury. In all these conditions, cortical circuits react to direct stimulation with an initial activation followed by suppression of activity (Off-period) that disrupts the build-up of sustained causal interactions typically observed in healthy wakefulness. The transition to this stereotypical response has important clinical implications, being associated with loss of consciousness or loss of function. Here, we provide a mechanistic explanation of these findings by means of simulations of a cortical-like module endowed with activity-dependent adaptation and mean-field theory. First, we show that fundamental aspects of the local responses elicited in humans by direct cortical stimulation can be replicated by systematically varying the relationships between adap...

About one third of individuals living with epilepsy have treatment-resistant seizures. Alternative therapeutic strategies are thus urgently needed. One potential novel treatment target is microRNA-induced silencing, which is differentially regulated in epilepsy. Inhibitors (antagomirs) of specific microRNAs have shown therapeutic promise in preclinical epilepsy studies; however, these studies were mainly conducted in male rodent models, and research into microRNA regulation in females and by female hormones in epilepsy is scarce. This is problematic because female sex and the menstrual cycle can affect the disease course of epilepsy and may, therefore, also alter the efficacy of potential microRNA-targeted treatments. Here, we used the proconvulsant microRNA miR-324-5p and its target, the potassium channel Kv4.2, as an example to test how microRNA-induced silencing and the efficacy of antagomirs in epilepsy are altered in female mice. We showed that Kv4.2 protein is reduced after seizures in female mice si...

Responding rapidly to visual stimuli is fundamental for many animals. For example, predatory birds and insects alike have amazing target detection abilities, with incredibly short neural and behavioral delays, enabling efficient prey capture. Similarly, looming objects need to be rapidly avoided to ensure immediate survival, as these could represent approaching predators. Male Eristalis tenax hoverflies are non-predatory, highly territorial insects, that perform high-speed pursuits of conspecifics and other territorial intruders. During the initial stages of the pursuit the retinal projection of the target is very small, but this grows to a larger object before physical interaction. Supporting such behaviors, E. tenax and other insects have both target-tuned and loom-sensitive neurons in the optic lobes and the descending pathways. We here show that these visual stimuli are not necessarily encoded in parallel. Indeed, we describe a class of descending neurons that respond to small targets, to looming and t...

The ventral pallidum (VP) is an integral locus in the reward circuitry and a major target of GABAergic innervation of both D1-medium spiny neurons (MSNs) and D2-MSNs from the nucleus accumbens (NAc). The VP contains populations of GABAergic (VPGABA, GAD2(+) or vGlut(-)) and glutamatergic (VPglutamate, GAD2(-) or vGlut(+)) cells that facilitate positive reinforcement and behavioral avoidance, respectively. MSN efferents to the VP exert opponent control over behavioral reinforcement with activation of D1-MSN afferents promoting and D2-MSN afferents inhibiting reward seeking. How this afferent-specific and cell type-specific control of reward-seeking is integrated remains largely unknown. Besides GABA, D1-MSNs co-release substance P to stimulate NK1 receptors and D2-MSNs co-release enkephalin to activate mu-opioid and delta-opioid receptors. These neuropeptides act in the VP to alter appetitive behavior and reward-seeking. Using a combination of optogenetics and patch-clamp electrophysiology in mice we foun...