Mediator protein complex subunit 12 (Med12) is a core component of the basal transcriptional apparatus and plays a critical role in the development of many tissues. Mutations in Med12 are associated with X-linked intellectual disability syndromes and hearing loss; however, its role in nervous system function remains undefined. Here, we show that temporal conditional deletion of Med12 in astrocytes in the adult CNS results in region-specific alterations in astrocyte morphology. Surprisingly, behavioral studies revealed rapid hearing loss after adult deletion of Med12 that was confirmed by a complete abrogation of auditory brainstem responses. Cellular analysis of the cochlea revealed degeneration of the stria vascularis, in conjunction with disorganization of basal cells adjacent to the spiral ligament and downregulation of key cell adhesion proteins. Physiologic analysis revealed early changes in endocochlear potential, consistent with strial-specific defects. Together, our studies reveal that Med12 regula...

Up states are the best studied example of an emergent neural dynamic regime. Computational models based on a single class of inhibitory neurons indicate that Up states reflect bistable dynamic systems in which positive feedback is stabilized by strong inhibition and predict a paradoxical effect in which increased drive to inhibitory neurons results in decreased inhibitory activity. To date, however, computational models have not incorporated empirically defined properties of parvalbumin (PV) and somatostatin (SST) neurons. Here we first experimentally characterized the frequency–current ( F–I ) curves of pyramidal (Pyr), PV, and SST neurons from mice of either sex, and confirmed a sharp difference between the threshold and slopes of PV and SST neurons. The empirically defined F–I curves were incorporated into a three-population computational model that simulated the empirically derived firing rates of pyramidal, PV, and SST neurons. Simulations revealed that the intrinsic properties were sufficient to pred...

Previously, studies using human neuroimaging and excitotoxic lesions in non-human primate have demonstrated an important role of ventrolateral prefrontal cortex (vlPFC) in higher order cognitive functions such as cognitive flexibility and the planning of behavioral sequences. In the present experiments, we tested effects on performance of temporary inactivation (using GABA receptor agonists) and dopamine (DA) D2 and 5-HT2A-receptor (R) blockade of vlPFC via local intracerebral infusions in the marmoset. We trained common marmosets to perform spatial self-ordered sequencing tasks in which one cohort of animals performed two and three response sequences on a continuously varying spatial array of response options on a touch-sensitive screen. Inactivation of vlPFC produced a marked disruption of accuracy of sequencing which also exhibited significant error perseveration. There were somewhat contrasting effects of D2 and 5-HT2A-R blockade, with the former producing error perseveration on incorrect trials, thoug...

Adaptive reward-related decision making requires accurate prospective consideration of the specific outcome of each option and its current desirability. Often this information must be inferred based on the presence of predictive environmental events. The basolateral amygdala (BLA) and medial orbitofrontal cortex (mOFC) are two key nodes in the circuitry supporting such outcome expectations, but very little is known about the function of direct connections between these regions. Here, in male rats, we first anatomically confirmed the existence of bidirectional, direct projections between the mOFC and BLA and found that BLA projections to mOFC are largely distinct from those to lateral OFC (lOFC). Next, using pathway-specific chemogenetic inhibition and the outcome-selective Pavlovian-to-instrumental transfer and devaluation tests, we interrogated the function of the bidirectional mOFC–BLA connections in reward-directed behavior. We found evidence that the mOFC→BLA pathway mediates the use of environmental c...

JNeurosci is publishing an Expression of Concern for the article, “TACE/ADAM17 Is Essential for Oligodendrocyte Development and CNS Myelination,” by Javier Palazuelos, Howard C. Crawford, Michael Klingener, Bingru Sun, Jason Karelis, Elaine W. Raines, and Adan Aguirre, which appeared on pages [

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...