A hallmark of human reaching movements is that they are appropriately tuned to the task goal and to the environmental context. This was demonstrated by the way humans flexibly respond to mechanical and visual perturbations that happen during movement. Furthermore, it was previously showed that the properties of goal-directed control can change within a movement, following abrupt changes in the goal structure. Such online adjustment was characterized by a modulation of feedback gains following switches in target shape. However, it remains unknown whether the underlying mechanism merely switches between prespecified policies, or whether it results from continuous and potentially dynamic adjustments. Here, we address this question by investigating participants’ feedback control strategies in presence of various changes in target width during reaching. More specifically, we studied whether the feedback responses to mechanical perturbations were sensitive to the rate of change in target width, which would be in...

Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer’s disease (AD), a neurodegenerative condition caused by the build-up of aggregated amyloid-β and tau proteins in the brain. Amyloid-β is produced by amyloid precursor protein ( APP), a gene located on chromosome 21. People who have Down syndrome have three copies of chromosome 21 and thus also an additional copy of APP ; this genetic change drives the early development of Alzheimer’s disease in these individuals. Here we use a combination of next-generation mouse models of Down syndrome (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of amyloid-β accumulation ( AppNL-F ) to determine how chromosome 21 genes, other than APP, modulate APP/amyloid-β in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate amyloid-β accumulation in the brain. We go on to identify a subregion of chromosome 21 that conta...

Atypical sensory processing is now thought to be a core feature of the autism spectrum. Influential theories have proposed that both increased and decreased neural response reliability within sensory systems could underlie altered sensory processing in autism. Here, we report evidence for abnormally increased reliability of visual-evoked responses in layer 2/3 neurons of adult male and female primary visual cortex in the MECP2-duplication syndrome animal model of autism. Increased response reliability was due in part to decreased response amplitude, decreased fluctuations in endogenous activity, and an abnormal decoupling of visual-evoked activity from endogenous activity. Similar to what was observed neuronally, the optokinetic reflex occurred more reliably at low contrasts in mutant mice compared to controls. Retinal responses did not explain our observations. These data suggest that the circuit mechanisms for combining sensory-evoked and endogenous signal and noise processes may be altered in this form ...

Perampanel (PMP) is a third-generation antiseizure drug reported to be a potent and selective noncompetitive negative allosteric modulator of one subfamily of ionotropic glutamate receptor (iGluR), the α-amino-3-hydroxy-S-methylisoxazole-4-propionic acid receptors (AMPARs). However, the recent structural resolution of AMPARs in complex with PMP revealed that its binding pocket is formed from residues that are largely conserved in two members of another family of iGluRs, the GluK4 and GluK5 kainate receptor (KAR) subunits. We show here that PMP inhibits both recombinant and neuronal KARs, contrary to the previous reports, and that the negative allosteric modulator (NAM) activity requires GluK5 subunits to be channel constituents. PMP inhibited heteromeric GluK1/GluK5 and GluK2/GluK5 KARs at IC50 values comparable to that for AMPA receptors but was much less potent on homomeric GluK1 or GluK2 KARs. The auxiliary subunits Neto1 or Neto2 also made GluK2-containing KARs more sensitive to inhibition. Finally, PM...

Lesion studies in macaques suggest dissociable functions of the orbitofrontal cortex (OFC) and medial frontal cortex (MFC), with OFC being essential for goal-directed decision-making and MFC supporting social cognition. Bilateral amygdala damage results in impairments in both of these domains. There are extensive reciprocal connections between these prefrontal areas and the amygdala; however, it is not known whether the dissociable roles of OFC and MFC depend on functional interactions with the amygdala. To test this possibility, we compared the performance of male rhesus macaques ( Macaca mulatta ) with crossed surgical disconnection of the amygdala and either MFC (MFC × AMY, n = 4) or OFC (OFC × AMY, n = 4) to a group of unoperated controls (CON, n = 5). All monkeys were assessed for their performance on two tasks to measure the following: (1) food-retrieval latencies while viewing videos of social and nonsocial stimuli in a test of social interest and (2) object choices based on current food value using...

During mammalian neocortex development, nascent pyramidal neurons migrate along radial glial cells and overtake earlier-born neurons to terminate at the front of the developing cortical plate (CP), leading to the outward expansion of the CP border. While much has been learned about the cellular and molecular mechanisms that underlie the migration of pyramidal neurons, how migrating neurons bypass the preceding neurons at the end of migration to reach their final positions remains poorly understood. Here, we report that Down syndrome cell adhesion molecule (DSCAM) is required for migrating neurons to bypass their postmigratory predecessors during the expansion of the upper cortical layers. DSCAM is a type I transmembrane cell adhesion molecule. It has been linked to Down syndrome through its location on Chromosome 21 trisomy and to autism spectrum disorders through loss-of-function mutations. Ex vivo time-lapse imaging demonstrates that DSCAM is required for migrating neurons to bypass their postmigratory p...

Classical forward and reverse mouse genetics require germline mutations and, thus, are unwieldy to study sleep functions of essential genes or redundant pathways. It is also time-consuming to conduct EEG/EMG-based mouse sleep screening because of labor-intensive surgeries and genetic crosses. Here, we describe a highly accurate SleepV (video) system and adeno-associated virus (AAV)-based adult brain chimeric (ABC)-expression/KO platform for somatic genetics analysis of sleep in adult male or female mice. A pilot ABC screen identifies CREB and CRTC1, of which constitutive or inducible expression significantly reduces quantity and/or quality of non-rapid eye movement sleep. Whereas ABC-KO of exon 13 of Sik3 by AAV-Cre injection in Sik3-E13flox/flox adult mice phenocopies Sleepy (Sik3 Slp /+ ) mice, ABC-CRISPR of Slp/Sik3 reverses hypersomnia of Sleepy mice, indicating a direct role of SLP/SIK3 kinase in sleep regulation. Multiplex ABC-CRISPR of both orexin/hypocretin receptors causes narcolepsy episodes, en...

Terrestrial locomotion requires coordinated bilateral activation of limb muscles, with left-right alternation in walking or running, and synchronous activation in hopping or skipping. The neural mechanisms involved in interlimb coordination at birth are well-known in different mammalian species, but less so in humans. Here, 46 neonates (of either sex) performed bilateral and unilateral stepping with one leg blocked in different positions. By recording EMG activities of lower limb muscles, we observed episodes of left-right alternating or synchronous coordination. In most cases the frequency of EMG oscillations during sequences of consecutive steps was roughly similar between the two sides, but in some cases it was considerably different, with episodes of 2:1 interlimb coordination and episodes of activity deletions on the blocked side. Hip position of the blocked limb significantly affected ipsilateral but not contralateral muscle activities. Thus, hip extension backwards engaged hip flexor muscle, and hip...

Deciding about courses of action involves minimizing costs and maximizing benefits. Decision neuroscience studies have implicated both the ventral and dorsal medial PFC (vmPFC and dmPFC) in signaling goal value and action cost, but the precise functional role of these regions is still a matter of debate. Here, we suggest a more general functional partition that applies not only to decisions but also to judgments about goal value (expected reward) and action cost (expected effort). In this conceptual framework, cognitive representations related to options (reward value and effort cost) are dissociated from metacognitive representations (confidence and deliberation) related to solving the task (providing a judgment or making a choice). We used an original approach aimed at identifying consistencies across several preference tasks, from likeability ratings to binary decisions involving both attribute integration and option comparison. fMRI results in human male and female participants confirmed the vmPFC as a...