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...

The effective development of novel therapies in mouse models of neurological disorders relies on behavioural assessments that provide accurate read-outs of neuronal dysfunction and/or degeneration. We designed an automated behavioural testing system (‘PiPaw’) which integrates an operant lever-pulling task directly into the mouse home-cage. This task is accessible to group-housed mice 24-hours per day, enabling high-throughput longitudinal analysis of forelimb motor learning. Moreover, this design eliminates the need for exposure to novel environments and minimizes experimenter interaction, significantly reducing two of the largest stressors associated with animal behaviour. Male mice improved their performance of this task over one week of testing by reducing inter-trial variability of reward-related kinematic parameters (pull amplitude or peak velocity). In addition, mice displayed short-term improvements in reward rate, and a concomitant decrease in movement variability, over the course of brief bouts of...

Rhythmic rest-activity cycles are controlled by an endogenous clock. In Drosophila , this clock resides in ∼150 neurons organized in clusters whose hierarchy changes in response to environmental conditions. The concerted activity of the circadian network is necessary for the adaptive responses to synchronizing environmental stimuli. Thus far work was devoted to unravel the logic of the coordination of different clusters focusing on neurotransmitters and neuropeptides. We further explored communication in the adult male brain through ligands belonging to the Bone Morphogenetic Protein (BMP) pathway. Herein we show that the Lateral Neurons ventral (LNvs) express the small morphogen DECAPENTAPLEGIC (DPP). DPP expression in the large LNvs triggered a period lengthening phenotype, while its downregulation caused reduced rhythmicity and affected anticipation at dawn and dusk, underscoring DPP per se conveys time-of-day relevant information. Surprisingly, its expression in the large LNvs impaired circadian remode...

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...

Opsin 3 ( Opn3 ) is highly expressed in the adult brain, however, information for spatial and temporal expression patterns during embryogenesis is significantly lacking. Here an Opn3 -eGFP reporter mouse line was utilized to monitor cell body expression and axonal projections during embryonic and early postnatal to adult stages. By applying 2D and 3D fluorescence imaging techniques, we have identified the onset of Opn3 expression, which predominantly occurred during embryonic stages, in various structures during brain/head development. In addition, this study defines over twenty Opn3 -eGFP positive neural structures never reported before. Opn3 -eGFP was first observed at E9.5 in neural regions, including the ganglia that will ultimately form the trigeminal, facial and vestibulocochlear cranial nerves. As development proceeds, expanded Opn3 -eGFP expression coincided with the formation and maturation of critical components of the central and peripheral nervous systems, including various motor-sensory tracts...