In the central and peripheral nervous systems, the myelin sheath promotes neuronal signal transduction. The thickness of the myelin sheath changes during development and in disease conditions like multiple sclerosis. Such changes are routinely detected using electron microscopy through g -ratio quantification. While g -ratio is one of the most critical measurements in myelin studies, a major drawback is that g -ratio quantification is extremely laborious and time-consuming. Here, we report the development and validation of MyelTracer, an installable, stand-alone software for semi-automated g -ratio quantification based on the Open Computer Vision Library (OpenCV). Compared with manual g -ratio quantification, using MyelTracer produces consistent results across multiple tissues and animal ages, as well as in remyelination after optic nerve crush, and reduces total quantification time by 40–60%. With g -ratio measurements via MyelTracer, a known hypomyelination phenotype can be detected in a Williams syndrom...

Highlighted Research Paper: [[Lewis AS, Calipari ES, Siciliano CA (2021) Toward Standardized Guidelines for Investigating Neural Circuit Control of Behavior in Animal Research.][2]][2] []: /lookup/doi/10.1523/ENEURO.0498-20.2021

Patch-clamp instruments including amplifier circuits and pipettes affect the recorded voltage signals. We hypothesized that realistic and complete in silico representation of recording instruments together with detailed morphology and biophysics of small recorded structures will reveal signal distortions and provide a tool that predicts native, instrument-free electrical signals from distorted voltage recordings. Therefore, we built a model that was verified by small axonal recordings. The model accurately recreated actual action potential (AP) measurements with typical recording artefacts and predicted the native electrical behavior. The simulations verified that recording instruments substantially filter voltage recordings. Moreover, we revealed that instrumentation directly interferes with local signal generation depending on the size of the recorded structures, which complicates the interpretation of recordings from smaller structures, such as axons. However, our model offers a straightforward approach...

The NMDA receptors are a type of glutamate receptors, which is involved in neuronal function, plasticity and development in the mammalian brain. However, how the NMDA receptors contribute to adult neurogenesis and development of the dentate gyrus is unclear. In this study, we investigate this question by examining a region-specific knock-out mouse line that lacks the NR1 gene, which encodes the essential subunit of the NMDA receptors, in granule cells of the dentate gyrus (DG-NR1KO mice). We found that the survival of newly-generated granule cells, cell proliferation and the size of the granule cell layer are significantly reduced in the dorsal dentate gyrus of adult DG-NR1KO mice. Our results also show a significant reduction in the number of immature neurons and in the volume of the granule cell layer, starting from three weeks of postnatal age. DG-NR1KO mice also showed impairment in the expression of an immediate early gene, Arc, and behavior during the novelty-suppressed feeding and open field test. T...

A point mutation in miR-96 causes non-syndromic progressive peripheral hearing loss and alters structure and physiology of the central auditory system. To gain further insight into the functions of miRNAs within the central auditory system, we investigated constitutive Mir-183/96dko mice of both sexes. In this mouse model, the genomically clustered miRs-183 and -96 are constitutively deleted. It shows significantly and specifically reduced volumes of auditory hindbrain nuclei, due to decreases in cell number and soma size. Electrophysiological analysis of the calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) demonstrated strongly altered synaptic transmission in young-adult mice. We observed an increase in quantal content and readily releasable vesicle pool size in the presynapse while the overall morphology of the calyx was unchanged. Detailed analysis of the active zones revealed differences in its molecular composition and synaptic vesicle distribution. Postsynaptically, altered c...

The central noradrenergic (NA) system is critical for the maintenance of attention, behavioral flexibility, spatial navigation, and learning and memory, those cognitive functions lost first in early Alzheimer's disease (AD). In fact, the locus coeruleus (LC), the sole source of norepinephrine (NE) for >90% of the brain, is the first site of pathologic tau accumulation in human AD with axon loss throughout forebrain, including hippocampus. The dentate gyrus is heavily innervated by LC–NA axons, where released NE acts on β-adrenergic receptors (ARs) at excitatory synapses from entorhinal cortex to facilitate long-term synaptic plasticity and memory formation. These synapses experience dysfunction in early AD before cognitive impairment. In the TgF344-AD rat model of AD, degeneration of LC–NA axons in hippocampus recapitulates human AD, providing a preclinical model to investigate synaptic and behavioral consequences. Using immunohistochemistry, Western blot analysis, and brain slice electrophysiology in 6- t...

Processing capabilities for many low-level visual features are experientially malleable, aiding sighted organisms in adapting to dynamic environments. Explicit instructions to attend a specific visual field location influence retinotopic visuocortical activity, amplifying responses to stimuli appearing at cued spatial positions. It remains undetermined both how such prioritization affects surrounding nonprioritized locations, and if a given retinotopic spatial position can attain enhanced cortical representation through experience rather than instruction. The current report examined visuocortical response changes as human observers ( N = 51, 19 male) learned, through differential classical conditioning, to associate specific screen locations with aversive outcomes. Using dense-array EEG and pupillometry, we tested the preregistered hypotheses of either sharpening or generalization around an aversively associated location following a single conditioning session. Competing hypotheses tested whether mean resp...

As we learn to perform a motor task with novel dynamics, the central nervous system must adapt motor commands and modify sensorimotor transformations. The objective of the current research is to identify the neural mechanisms underlying the adaptive process. It has been shown previously that an increase in muscle co-contraction is frequently associated with the initial phase of adaptation and that co-contraction is gradually reduced as performance improves. Our investigation focused on the neural substrates of muscle co-contraction during the course of motor adaptation using a resting-state fMRI approach in healthy human subjects of both genders. We analyzed the functional connectivity in resting-state networks during three phases of adaptation, corresponding to different muscle co-contraction levels and found that change in the strength of functional connectivity in one brain network was correlated with a metric of co-contraction, and in another with a metric of motor learning. We identified the cerebellu...

The successful recognition of familiar persons is critical for social interactions. Despite extensive research on the neural representations of familiar faces, we know little about how such representations unfold as someone becomes familiar. In three EEG experiments on human participants of both sexes, we elucidated how representations of face familiarity and identity emerge from different qualities of familiarization: brief perceptual exposure (Experiment 1), extensive media familiarization (Experiment 2), and real-life personal familiarization (Experiment 3). Time-resolved representational similarity analysis revealed that familiarization quality has a profound impact on representations of face familiarity: they were strongly visible after personal familiarization, weaker after media familiarization, and absent after perceptual familiarization. Across all experiments, we found no enhancement of face identity representation, suggesting that familiarity and identity representations emerge independently dur...

Zhanmin Lin, Bin Wu, Maarten W. Paul, Ka Wan Li, Yao Yao, et al. (see pages [5579–5594][1]) Synaptic strength is regulated partly by kinases and phosphatases that determine the phosphorylation state of various synaptic proteins. In the cerebellum, for example, protein kinase C and CaMKII