Post-tetanic potentiation (PTP) is a form of short-term plasticity that lasts for tens of seconds following a burst of presynaptic activity. It has been proposed that PTP arises from protein kinase C (PKC) phosphorylation of Munc18-1, an SM (Sec1/Munc-18 like) family protein that is essential for release. To test this model, we made a knock-in mouse in which all Munc18-1 PKC phosphorylation sites were eliminated through serine-to-alanine point mutations (Munc18-1SA mice), and we studied mice of either sex. The expression of Munc18-1 was not altered in Munc18-1SA mice, and there were no obvious behavioral phenotypes. At the hippocampal CA3-to-CA1 synapse and the granule cell parallel fiber (PF)-to-Purkinje cell (PC) synapse, basal transmission was largely normal except for small decreases in paired-pulse facilitation that are consistent with a slight elevation in release probability. Phorbol esters that mimic the activation of PKC by diacylglycerol still increased synaptic transmission in Munc18-1SA mice. I...

Understanding masseter muscle (MM) innervation is critical for the study of cell-specific mechanisms of pain induced by temporomandibular disorder (TMDs) or after facial surgery. Here, we identified trigeminal (TG) sensory neuronal subtypes (MM TG neurons) innervating MM fibers, masseteric fascia, tendons, and adjusted tissues. A combination of patch clamp electrophysiology and immunohistochemistry (IHC) on TG neurons back-traced from reporter mouse MM found nine 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...

Team flow occurs when a group functions in a high task engagement to achieve a goal, commonly seen in performance and sports. Team flow can enable enhanced positive experiences, as compared with individual flow or regular socializing. However, the neural basis for this enhanced behavioral state remains unclear. Here, we identified neural correlates (NCs) of team flow in human participants using a music rhythm task with electroencephalogram hyperscanning. Experimental manipulations held the motor task constant while disrupting the corresponding hedonic music to interfere with the flow state or occluding the partner’s positive feedback to impede team interaction. We validated these manipulations by using psychometric ratings and an objective measure for the depth of flow experience, which uses the auditory-evoked potential (AEP) of a task-irrelevant stimulus. Spectral power analysis at both the scalp sensors and anatomic source levels revealed higher β-γ power specific to team flow in the left middle tempora...

Glycogen synthase kinase 3 (GSK3) proteins (GSK3α and GSK3β) are key mediators of signaling pathways, with crucial roles in coordinating fundamental biological processes during neural development. Here we show that the complete loss of GSK3 signaling in mouse retinal progenitors leads to microphthalmia with broad morphologic defects. A single wild-type allele of either Gsk3α or Gsk3β is able to rescue this phenotype. In this genetic context, all cell types are present in a functional retina. However, we unexpectedly detected a large number of cells in the inner nuclear layer expressing retinal ganglion cell (RGC)-specific markers (called displaced RGCs, dRGCs) when at least one allele of Gsk3α is expressed. The excess of dRGCs leads to an increased number of axons projecting into the ipsilateral medial terminal nucleus, an area of the brain belonging to the non-image-forming visual circuit and poorly targeted by RGCs in wild-type retina. Transcriptome analysis and optomotor response assay suggest that at l...

The subthalamic nucleus (STN) is an essential component of the basal ganglia and has long been considered to be a part of the ventral thalamus. However, recent neurodevelopmental data indicated that this nucleus is of hypothalamic origin which is now commonly acknowledged. In this work, we aimed to verify whether the inclusion of the STN in the hypothalamus could influence the way we understand and conduct research on the organization of the whole ventral and posterior diencephalon. Developmental and neurochemical data indicate that the STN is part of a larger glutamatergic posterior hypothalamic region that includes the premammillary and mammillary nuclei. The main anatomic characteristic common to this region involves the convergent cortical and pallidal projections that it receives, which is based on the model of the hyperdirect and indirect pathways to the STN. This whole posterior hypothalamic region is then integrated into distinct functional networks that interact with the ventral mesencephalon to a...

Autism spectrum disorders (ASDs) are characterized by abnormal behavioral traits arising from neural circuit dysfunction. While a number of genes have been implicated in ASDs, in most cases, a clear understanding of how mutations in these genes lead to circuit dysfunction and behavioral abnormality is absent. The autism susceptibility candidate 2 ( AUTS2 ) gene is one such gene, associated with ASDs, intellectual disability and a range of other neurodevelopmental conditions. However, the role of AUTS2 in neural development and circuit function is not at all known. Here, we undertook functional analysis of Auts2a, the main homolog of AUTS2 in zebrafish, in the context of the escape behavior. Escape behavior in wild-type zebrafish is critical for survival and is therefore, reliable, rapid, and has well-defined kinematic properties. auts2a mutant zebrafish are viable, have normal gross morphology and can generate escape behavior with normal kinematics. However, the behavior is unreliable and delayed, with hig...

Detection of an unexpected, novel, or salient stimulus typically leads to an orienting response by which animals move the head, in concert with the sensors (e.g., eyes, pinna, whiskers), to evaluate the stimulus. The basal ganglia are known to control orienting movements through tonically active GABAergic neurons in the substantia nigra pars reticulata (SNr) that project to the superior colliculus. Using optogenetics, we explored the ability of GABAergic SNr neurons on one side of the brain to generate orienting movements. In a strain of mice that express channelrhodopsin (ChR2) in both SNr GABAergic neurons and afferent fibers, we found that continuous blue light produced a robust sustained excitation of SNr neurons which generated ipsiversive orienting. Conversely, in the same animal, trains of blue light excited afferent fibers more effectively than continuous blue light, producing a robust sustained inhibition of SNr neurons which generated contraversive orienting. When ChR2 expression was restricted t...

Human infants who suffer from intrauterine growth restriction (IUGR), which is a failure to attain their genetically predetermined weight, are at increased risk for postnatal learning and memory deficits. Hippocampal dentate gyrus (DG) granule neurons play an important role in memory formation; however, it is unknown whether IUGR affects embryonic DG neurogenesis, which could provide a potential mechanism underlying abnormal postnatal learning and memory function. Using a mouse model of the most common cause of IUGR, induced by hypertensive disease of pregnancy, we first assessed adult learning and memory function. We quantified the percentages of embryonic hippocampal DG neural stem cells (NSCs) and progenitor cells and developing glutamatergic granule neurons, as well as hippocampal volumes and neuron cell count and morphology 18 and 40 d after delivery. We characterized the differential embryonic hippocampal transcriptomic pathways between appropriately grown and IUGR mouse offspring. We found that IUGR...

Knee joint trauma can cause an osteochondral defect (OD), a risk factor for osteoarthritis (OA) and cause of debilitating pain in patients. Rodent OD models are less translatable because of their smaller joint size and open growth plate. This study proposes sheep as a translationally relevant model to understand the neuronal basis of OD pain. A unilateral 6-mm deep OD was induced in adult female sheep. Two to six weeks after operation, lumbar dorsal root ganglia (DRG) neurons were collected from the contralateral (Ctrl) and OD side of operated sheep. Functional assessment of neuronal excitability and activity of the pain-related ion channels transient receptor potential vanilloid receptor 1 (TRPV1) and P2X3 was conducted using electrophysiology and Ca2+ imaging. Immunohistochemistry was used to verify expression of pain-related proteins. We observed that an increased proportion of OD DRG neurons (sheep, N  = 3; Ctrl neurons, n  = 15, OD neurons, n  = 16) showed spontaneous electrical excitability (Ctrl: 20...

The ability to adapt under significant adversity, defined as psychological resilience, is instrumental in preventing stress-related disorders. An important aspect of resilience is the capacity to endure affective distress when in pursuit of goals, also known as distress tolerance. Evidence that links intrinsic baseline interactions within large-scale functional networks with performance under distress remains missing. We hypothesized that the anterior cingulate cortex (ACC) may engage in distress tolerance because of its involvement in attention and emotion regulation. Accordingly, we tested whether behavioral performance under distress is associated with baseline resting-state ACC functional connectivity (FC). Distress tolerance was measured in 97 participants using the behavioral indicator of resiliency to distress (BIRD) task. Analyses contrasted participants who quit the task before its designated termination ( n  = 51) with those who persisted throughout it ( n  = 46). Seed-based FC analysis indicated...