Thyroid hormone controls the timely differentiation of oligodendrocytes (OLs), and its deficiency can delay myelin development and cause mental retardation. Previous studies showed that the active thyroid hormone T3 is converted from its prohormone T4 by the selenoprotein DIO2, whose mRNA is primarily expressed in astrocytes in the central nervous system. In the present study, we discovered that SECISBP2L is highly expressed in differentiating OLs and is required for DIO2 translation. Conditional knockout of Secisbp2l in OL lineage resulted in a decreased level of DIO2 and T3, accompanied by impaired OL differentiation, hypomyelination and motor deficits in both sexes of mice. Moreover, the defective differentiation of OLs in Secisbp2l mutants can be alleviated by T3 or its analog, but not the prohormone T4. The present study has provided strong evidence for the autonomous regulation of OL differentiation by its intrinsic T3 production mediated by the novel SECISBP2L-DIO2-T3 pathway during myelin developme...

Speech perception in noisy environments is enhanced by seeing facial movements of communication partners. However, the neural mechanisms by which audio and visual speech are combined are not fully understood. We explore MEG phase locking to auditory and visual signals in MEG recordings from 14 human participants (6 females, 8 males) that reported words from single spoken sentences. We manipulated the acoustic clarity and visual speech signals such that critical speech information is present in auditory, visual or both modalities. MEG coherence analysis revealed that both auditory and visual speech envelopes (auditory amplitude modulations and lip aperture changes) were phase-locked to 2-6Hz brain responses in auditory and visual cortex, consistent with entrainment to syllable-rate components. Partial coherence analysis was used to separate neural responses to correlated audio-visual signals and showed non-zero phase locking to auditory envelope in occipital cortex during audio-visual (AV) speech. Furthermo...

Cognitive decline is a debilitating aspect of aging and neurodegenerative diseases such as Alzheimer’s disease that is closely associated with mitochondrial dysfunction, increased reactive oxygen species (ROS), neuroinflammation and astrogliosis. This study investigated the effects of decreased mitochondrial antioxidant response specifically in astrocytes on cognitive performance and neuronal function in C57Bl/6J mice using a tamoxifen-inducible astrocyte-specific knockout of manganese superoxide dismutase (aSOD2-KO), a mitochondrial matrix antioxidant that detoxifies superoxide generated during mitochondrial respiration. We reduced astrocyte SOD2 levels in male and female mice at 11-12 months of age and tested in an automated home-cage (PhenoTyper) apparatus for diurnal patterns, spatial learning and memory function at 15 months of age. Astrocyte-specific SOD2-knockout impaired hippocampal-dependent spatial working memory and decreased cognitive flexibility in the reversal phase of the testing paradigm in...

When making a turn at a familiar intersection, we know what items and landmarks will come into view. These perceptual expectations, or predictions, come from our knowledge of the context, however it’s unclear how memory and perceptual systems interact to support the prediction and reactivation of sensory details in cortex. To address this, human participants learned the spatial layout of animals positioned in a cross maze. During fMRI, participants of both sexes navigated between animals to reach a target, and in the process saw a predictable sequence of five animal images. Critically, to isolate activity patterns related to item predictions, rather than bottom-up inputs, one quarter of trials ended early, with a blank screen presented instead. Using multivariate pattern similarity analysis, we reveal that activity patterns in early visual cortex, posterior medial regions, and the posterior hippocampus showed greater similarity when seeing the same item compared to different items. Further, item effects in...

We tested the hypothesis that the pallidum contributes to the control of both posture and movement. We recorded neuronal activity from the pallidum in a task in which male cats reached forward from a standing posture to depress a lever. In agreement with previous studies, we found that a majority of pallidal cells (91/116 78%), including neurons in both the entopeduncular nucleus and the globus pallidus, showed significant modulations of their activity during reaching with the contralateral limb. Mostly different populations of cells were active during the transport (flexion) and lever press (extension) phase of the task. Most cells showed dynamic patterns of activity related to the movement. However, a modest proportion of modulated cells (18/91, 20%) showed properties consistent with a contribution to the control of anticipatory postural responses while a further 10% showed activity consistent with a contribution to postural support during the movement. While some cells that showed modified activity only...

The posteromedial cortex (PMC) is a major hub of the brain’s default mode network, and is implicated in a broad range of internally driven cognitions, including visuospatial working memory. However, its precise contribution to these cognitive processes remains unclear. Using magnetoencephalography (MEG), we measured PMC activity in healthy human participants (young adults of both sexes) while they performed a visuospatial working memory task. Multivariate pattern classification analyses revealed stimulus-related information during encoding and retrieval in a set of a priori defined cortical regions of interest, including prefrontal, occipital and ventrotemporal cortices, in addition to PMC. We measured the extent to which this stimulus information was exchanged between areas in an information flow analysis, measuring Granger-causal relationships between areas over time. Consistent with the visual nature of the task, information from occipital cortex shaped other regions across most epochs. However, the PMC...

Temporal lobe epilepsy (TLE), the most common focal seizure disorder in adults, can be instigated in experimental animals by convulsant-induced status epilepticus (SE). Principal hippocampal neurons from SE-experienced epileptic male rats (post-SE neurons) display markedly augmented spike output compared to neurons from nonepileptic animals (non-SE neurons). This enhanced firing results from a c-AMP-dependent protein kinase A (PKA)-mediated inhibition of KCa3.1, a subclass of Ca2+-gated K+ channels generating the slow afterhyperpolarizing Ca2+-gated K+ current ( I sAHP). The inhibition of KCa3.1 in post-SE neurons leads to a marked reduction in amplitude of the I sAHP that evolves during repetitive firing, as well as in amplitude of the associated Ca2+-dependent component of the slow afterhyperpolarization potential (KCa-sAHP). Here we show that KCa3.1 inhibition in post-SE neurons, is induced by corticotropin releasing factor (CRF) through its type 1 receptor (CRF1R). Acute application of CRF1R antagonist...

Perceptual decisions depend both on the features of the incoming stimulus and on the ongoing brain activity at the moment the stimulus is received. Specifically, trial-to-trial fluctuations in cortical excitability have been linked to fluctuations in the amplitude of prestimulus α oscillations (∼8-13 Hz), which are in turn are associated with fluctuations in subjects' tendency to report the detection of a stimulus. It is currently unknown whether α oscillations bias postperceptual decision-making, or even bias subjective perception itself. To answer this question, we used a contrast discrimination task in which both male and female human subjects reported which of two gratings (one in each hemifield) was perceived as having a stronger contrast. Our EEG analysis showed that subjective contrast was reduced for the stimulus in the hemifield represented in the hemisphere with relatively stronger prestimulus α amplitude, reflecting reduced cortical excitability. Furthermore, the strength of this spontaneous hem...

Endosomal sorting plays a fundamental role in directing neural development. By altering the temporal and spatial distribution of membrane receptors, endosomes regulate signaling pathways that control the differentiation and function of neural cells. Several genes linked to inherited demyelinating peripheral neuropathies, known as Charcot-Marie-Tooth (CMT) disease, encode proteins that directly interact with components of the endosomal sorting complex required for transport (ESCRT). Our previous studies demonstrated that a point mutation in the ESCRT component hepatocyte growth-factor-regulated tyrosine kinase substrate (HGS), an endosomal scaffolding protein that identifies internalized cargo to be sorted by the endosome, causes a peripheral neuropathy in the neurodevelopmentally impaired teetering mice. Here, we constructed a Schwann cell-specific deletion of Hgs to determine the role of endosomal sorting during myelination. Inactivation of HGS in Schwann cells resulted in motor and sensory deficits, slow...