How do we attend to relevant auditory information in complex naturalistic scenes? Much research has focused on detecting which information is attended, without regarding underlying top-down control mechanisms. Studies investigating attentional control generally manipulate and cue specific features in simple stimuli. However, in naturalistic scenes it is impossible to dissociate relevant from irrelevant information based on low-level features. Instead, the brain has to parse and select auditory objects of interest. The neural underpinnings of object-based auditory attention remain not well understood. Here we recorded MEG while 15 healthy human subjects (9 female) prepared for the repetition of an auditory object presented in one of two overlapping naturalistic auditory streams. The stream containing the repetition was prospectively cued with 70% validity. Crucially, this task could not be solved by attending low-level features, but only by processing the objects fully. We trained a linear classifier on the...

The post-injury regenerative capacity of neurons is known to be mediated by a complex interaction of intrinsic regenerative pathways and external cues. In Caenorhabditis elegans , the initiation of axon regeneration is regulated by the non-muscle myosin light chain (MLC-4) phosphorylation signaling pathway. In this study, we have identified svh-16 / cdk-14 , a mammalian CDK14 homolog, as a positive regulator of axon regeneration in motor neurons. We then isolated the CDK-14-binding protein MIG-5/Disheveled (Dsh) and found that EGL-20/Wnt and the MIG-1/Frizzled receptor (Fz) are required for efficient axon regeneration. Further, we demonstrate that CDK-14 activates EPHX-1, the C. elegans homolog of the mammalian ephexin Rho-type GTPase guanine nucleotide-exchange factor (GEF), in a kinase-independent manner. EPHX-1 functions as a GEF for the CDC-42 GTPase, inhibiting myosin phosphatase, which maintains MLC-4 phosphorylation. These results suggest that CDK14 activates the RhoGEF–CDC42–MLC phosphorylation axi...

The role of the motor cortex in perceptual and cognitive functions is highly controversial. Here, we investigated the hypothesis that the motor cortex can be instrumental for translating foreign language vocabulary. Human participants of both sexes were trained on foreign language (L2) words and their native language translations over four consecutive days. L2 words were accompanied by complementary gestures (sensorimotor enrichment) or pictures (sensory enrichment). Following training, participants translated the auditorily-presented L2 words that they had learned. During translation, repetitive transcranial magnetic stimulation (rTMS) was applied bilaterally to a site within the primary motor cortex (Brodmann Area 4) located in the vicinity of the arm functional compartment. Responses within the stimulated motor region have previously been found to correlate with behavioral benefits of sensorimotor-enriched L2 vocabulary learning. Compared to sham stimulation, effective perturbation by rTMS slowed down t...

Microglia are resident myeloid cells of the central nervous system. Recently, single-cell RNA sequencing has enabled description of a disease-associated subtype of microglia (DAM) with a role in neurodegeneration and demyelination. In this study, we use scRNAseq to investigate the temporal dynamics of immune cells harvested from the epicenter of traumatic spinal cord injury (SCI) induced in female mice. We find that as a consequence of SCI, baseline microglia undergo permanent transcriptional re-programming into a previously uncharacterized subtype of microglia with striking similarities to previously reported DAM as well as a distinct microglial state found during development. Using a microglia depletion model we showed that DAM in SCI are derived from baseline microglia and strongly enhance recovery of hind limb locomotor function following injury. SIGNIFICANCE STATEMENT Although disease associated microglia have been the subject of strong research interest during recent years (e.g. Jordão 2019 or Ker...

In demyelinating diseases such as multiple sclerosis (MS), primary loss of myelin and subsequent neuronal degeneration throughout the central nervous system (CNS) impair patient functionality. While the importance of mechanistic target of rapamycin (mTOR) signaling during developmental myelination is known, no studies have yet directly examined the function of mTOR signaling specifically in the oligodendrocyte (OL) lineage during remyelination. Here, we conditionally deleted mTOR from adult oligodendrocyte precursor cells (OPCs) using Ng2-CreERT in male adult mice to test its function in new OLs responsible for remyelination. During early remyelination after cuprizone-induced demyelination, mice lacking mTOR in adult OPCs had unchanged OL numbers but thinner myelin. Myelin thickness recovered by late-stage repair, suggesting a delay in myelin production when mTOR is deleted from adult OPCs. Surprisingly, loss of mTOR in OPCs had no effect on efficiency of remyelination after lysophosphatidylcholine lesions...

Tuberous sclerosis complex (TSC) is a multisystem developmental disorder characterized by hamartomas in various organs such as the brain, lungs, and kidneys. Epilepsy, along with autism and intellectual disability, is one of the neurological impairments associated with TSC that has an intimate relationship with developmental outcomes and quality of life. Sustained activation of the mammalian target of rapamycin (mTOR) via TSC1 or TSC2 mutations is known to be involved in the onset of epilepsy in TSC. However, the mechanism by which mTOR causes seizures remain unknown. In this study, we showed that, human induced pluripotent stem cell-derived TSC2- deficient ( TSC2-/- ) neurons exhibited elevated neuronal activity with highly synchronized Ca2+ spikes. Notably, TSC2-/- neurons presented enhanced Ca2+ influx via L-type Ca2+ channels (LTCCs), which contributed to the abnormal neurite extension and sustained activation of cAMP response element binding protein (CREB), a critical mediator of synaptic plasticity. ...

All what we see, touch, hear, taste or smell must first be detected by the sensory elements of our nervous system. Sensory neurons, therefore, represent a critical component in all neural circuits and their correct function is essential for the generation of behaviour and adaptation to the environment. Here we report that the evolutionarily-conserved microRNA (miRNA) miR-263b , plays a key behavioural role in Drosophila melanogaster through effects on the function of larval sensory neurons. Several independent experiments (in 50:50/male:female populations) support this finding: first, miRNA expression analysis – via reporter expression and FACS-qPCR analysis – demonstrate miR-263b expression in larval sensory neurons. Second, behavioural tests in miR-263b null mutants show defects in self-righting, an innate and evolutionarily conserved posture-control behaviour that allows larvae to rectify their position if turned upside-down. Third, competitive inhibition of miR-263b in sensory neurons using a miR-263b ...

Axon regenerative failure in the mature CNS contributes to functional deficits following many traumatic injuries, ischemic injuries and neurodegenerative diseases. The complement cascade of the innate immune system responds to pathogen threat through inflammatory cell activation, pathogen opsonization, and pathogen lysis, and complement is also involved in CNS development, neuroplasticity, injury, and disease. Here, we investigated the involvement of the classical complement cascade and microglia/monocytes in CNS repair using the mouse optic nerve injury (ONI) model, in which axons arising from retinal ganglion cells (RGCs) are disrupted. We report that central complement C3 protein and mRNA, classical complement C1q protein and mRNA, and microglia/monocyte phagocytic complement receptor CR3 all increase in response to ONI, especially within the optic nerve itself. Importantly, genetic deletion of C1q, C3, or CR3 attenuates RGC axon regeneration induced by several distinct methods, with minimal effects on ...

The middle temporal (MT) area of the extrastriate visual cortex has long been studied in adulthood for its distinctive physiological properties and function as a part of the dorsal stream, yet interestingly possesses a similar maturation profile as the primary visual cortex (V1). Here we examined whether an early-life lesion to MT of marmoset monkeys (6 female & 2 male) altered the dorsal stream development and the behavioral precision of reaching to grasp sequences. We observed permanent changes in the anatomy of cortices associated with both reaching (PE and MIP) and grasping (AIP), as well as in reaching and grasping behaviors. In addition, we observed a significant impact on the anatomy of V1 and the direction sensitivity of V1 neurons in the lesion projection zone. These findings indicate that area MT is a crucial node in the development of primate vision, impacting both V1 and areas in the dorsal visual pathway known to mediate visually guided manual behaviors. Significance Statement: Previous stu...

High molecular weight hyaluronan (HMWH), a well-established treatment for osteoarthritis pain, is anti-hyperalgesic in preclinical models of inflammatory and neuropathic pain. HMWH-induced anti-hyperalgesia is mediated by its action at cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, which can signal via phosphoinositide 3-kinase (PI3K), a large family of kinases involved in diverse cell functions. We demonstrate that intrathecal administration of an oligodeoxynucleotide (ODN) antisense to mRNA for PI3Kγ (a class I PI3K isoform) expressed in dorsal root ganglia (DRG), and intradermal administration of a PI3Kγ selective inhibitor (AS605240), markedly attenuates HMWH-induced anti-prostaglandin E2 (PGE2) hyperalgesia, in male and female rats. Intradermal administration of inhibitors of mTOR (Rapamycin) and Protein Kinase B (AKT; AKT inhibitor IV), signaling molecules downstream of PI3Kγ, also attenuates HMWH-induced anti-hyperalgesia. In vitro patch-clamp electrophysiology experiments on...