Understanding masseter muscle (MM) innervation is critical for the study of cell-specific mechanisms of pain induced by temporomandibular disorder or after facial surgery. Here, we identified trigeminal (TG) sensory neuronal subtypes (MM TG neurons) innervating masseter muscle fibers, masseteric fascia, tendons, and adjusted tissues. A combination of patch clamp electrophysiology and immunohistochemistry on TG neurons backtraced from reporter mouse MM found 9 distinct subtypes of MM TG neurons. Of these neurons, 24% belonged to non-peptidergic IB-4+/TRPA1- or IB-4+/TRPA1+ groups, while two TRPV1+ small-sized neuronal groups were classified as peptidergic/CGRP+. One small-sized CGRP+ neuronal group had a unique electrophysiological profile and were recorded from Nav1.8- or trkC+ neurons. The remaining CGRP+ neurons were medium-sized, could be divided into Nav1.8-/trkC- and Nav1.8low/trkC+ clusters, and showed large 5HT-induced current. The final two MM TG neuronal groups were trkC+ and had no Nav1.8 and CGR...

Epilepsy-Aphasia Syndromes (EAS) are a spectrum of childhood epileptic, cognitive, and language disorders of unknown etiology. CNKSR2 is a strong X-linked candidate gene implicated in EAS, however, there have been no studies of genetic models to dissect how its absence may lead to EAS. Here we develop a novel Cnksr2 knockout (KO) mouse line and show that male mice exhibit increased neural activity and have spontaneous electrographic seizures. Cnksr2 KO mice also display significantly increased anxiety, impaired learning and memory, and a progressive and dramatic loss of ultrasonic vocalizations. We find that Cnksr2 is expressed in cortical, striatal, and cerebellar regions and is localized at both excitatory and inhibitory postsynapses. Proteomics analysis reveals Cnksr2 anchors key binding partners at synapses, and its loss results in significant alterations of the synaptic proteome, including proteins implicated in epilepsy disorders. Our results validate that loss of CNKSR2 leads to EAS and highlights t...

Older adults tend to display greater brain activation in the non-dominant hemisphere during even basic sensorimotor responses. It is debated whether this Hemispheric Asymmetry Reduction in Older Adults (HAROLD) reflects a compensatory mechanism. Across two independent fMRI experiments involving adult-lifespan human samples (N = 586 and N = 81; approximately half female) who performed right hand finger responses, we distinguished between these hypotheses using behavioural and multivariate Bayes (MVB) decoding approaches. Standard univariate analyses replicated a HAROLD pattern in motor cortex, but in- and out-of-scanner behavioural results both demonstrated evidence against a compensatory relationship, in that reaction time measures of task performance in older adults did not relate to ipsilateral motor activity. Likewise, MVB showed that this increased ipsilateral activity in older adults did not carry additional information, and if anything, combining ipsilateral with contralateral activity patterns reduc...

Hippocampal CA2, an inconspicuously positioned area between the well-studied CA1 and CA3 subfields, has captured research interest in recent years due to its role in social memory formation. However, the role of cholinergic inputs to the CA2 area for the regulation of synaptic plasticity remains to be fully understood. We show that cholinergic receptor activation with the non-selective cholinergic agonist, carbachol (CCh), triggers a protein synthesis-dependent and NMDAR-independent long-term synaptic depression (CCh-LTD) at entorhinal cortical (EC)-CA2 and Schaffer collateral (SC)-CA2 synapses in the hippocampus of adult male Wistar rats. The activation of muscarinic acetylcholine receptors (mAChRs) is critical for the induction of CCh-LTD with the results suggesting an involvement of M3 and M1 mAChRs in the early facilitation of CCh-LTD, while nicotinic acetylcholine receptor activation plays a role in the late maintenance of CCh-LTD at CA2 synapses. Remarkably, we find that CCh priming lowers the thresh...

Two novel short-interval intracortical inhibition (SICI) protocols, assessing SICI across a range of interstimulus intervals (ISI) using either parallel threshold-tracking transcranial magnetic stimulation (TT-TMS) or automated conventional TMS (cTMS), were recently introduced. However, the test-retest reliability of these protocols has not been investigated, which is important if they are to be introduced in the clinic. SICI was recorded in 18 healthy subjects using TT-TMS (T-SICI) and cTMS (A-SICI). All subjects were examined at four identical sessions, i.e. morning and afternoon sessions on two days, five to seven days apart. Both SICI protocols were performed twice at each session by the same observer. In one of the sessions, another observer performed additional examinations. Neither intra- nor inter-observer measures of SICI differed significantly between examinations, except for T-SICI at ISI 3ms (P=0.00035) and A-SICI at ISI 2.5ms (P=0.0103). Intra-day reliability was poor-to-good for A-SICI and m...

Sex steroid hormones act on hypothalamic kisspeptin neurons to regulate reproductive neural circuits in the brain. Kisspeptin neurons start to express estrogen receptors (ERs) in utero , suggesting steroid hormone action on these cells early during development. Whether neurosteroids are locally produced in the embryonic brain and impinge onto kisspeptin/reproductive neural circuitry is not known. To address this question, we analyzed aromatase expression, a key enzyme in estrogen synthesis, in male and female mouse embryos. We identified an aromatase neuronal network comprising ∼6000 neurons in the hypothalamus and amygdala. By birth, this network has become sexually dimorphic in a cluster of aromatase neurons in the arcuate nucleus adjacent to kisspeptin neurons. We demonstrate that male arcuate aromatase neurons convert testosterone to estrogen to regulate kisspeptin neuron activity. We provide spatio-temporal information on aromatase neuronal network development and highlight a novel mechanism whereby a...

The basolateral amygdala (BLA) is obligatory for fear learning. This learning is linked to BLA excitatory projection neurons whose activity is regulated by complex networks of inhibitory interneurons, dominated by parvalbumin (PV) expressing GABAergic neurons. The roles of these GABAergic interneurons in learning to fear and learning not to fear, their activity profiles across the course of fear learning, and whether or how these change across the course of learning each remain poorly understood. Here we used PV cell-type specific recording and manipulation approaches in male transgenic PV-Cre rats during Pavlovian fear conditioning to address these issues. We show that activity of BLA PV neurons during the moments of aversive reinforcement controls fear learning about aversive events but their activity during moments of non-reinforcement does not control fear extinction learning. Furthermore, we show expectation-modulation of BLA PV neurons during fear learning, with greater activity to unexpected than ex...

Results from item-method directed forgetting suggest that individuals are able to intentionally forget processed information. Most research suggests that either selective rehearsal of to-be-remembered or inhibitory control of to-be-forgotten information is accountable for effects of intentional forgetting. Some research, however, hypothesized that the time to process information mediates the underlying mechanism. To test this hypothesis, the current study investigated associations between oscillatory power in theta (3 – 7.5 Hz) and alpha frequencies (8 – 13 Hz) and intentional forgetting in human participants and explored whether or not these mechanisms depended on processing time. Previously, theta power was shown to be associated with the creation of episodic memory traces and alpha power with inhibition. We therefore expected to find associations between these neural signatures and behavioral effects. Consistent with our hypotheses, we revealed increased theta power for to-be-remembered and increased al...

Recent technological advances have enabled neural recordings consisting of hundreds to thousands of channels. As the pace of these developments continues to grow rapidly, it is imperative to have fast, flexible tools supporting the analysis of neural data gathered by such large scale modalities. Here we introduce ghostipy ( g eneral h ub o f s pectral t echniques i n Py thon), a Python open source software toolbox implementing various signal processing and spectral analyses including optimal digital filters and time-frequency transforms. ghostipy prioritizes performance and efficiency by using parallelized, blocked algorithms. As a result, it is able to outperform commercial software in both time and space complexity for high channel count data and can handle out-of-core computation in a user-friendly manner. Overall, our software suite reduces frequently encountered bottlenecks in the experimental pipeline, and we believe this toolset will enhance both the portability and scalability of neural data analys...

The non-human primate (NHP) constitutes an extraordinarily important model in neuroscience research for understanding the neuronal underpinnings of perceptual, motor, cognitive, and executive functions of the primate brain, and to study the physiological causes, effects, and potential treatments of brain disorders. Due to their cognitive capabilities, NHPs receive special attention in Animal Welfare Regulations around the world, and their well-being is a benchmark for the evaluation, monitoring, and refinement of experimental procedures. As a consequence, many typical neuroscientific procedures are considered only mildly severe by animal welfare boards. There is, however, an ongoing debate about possible long-term and cumulative effects. Due to a lack of longitudinal data, it is unclear whether mildly severe procedures may cause more significant harm on the long-term, and to what extent they may impact animal well-being and healthiness over time. We here make use of a database of blood samples drawn over a...