Angelman Syndrome (AS) is a rare genetic neurodevelopmental disorder characterized by intellectual disabilities, motor and balance deficits, impaired communication, and a happy, excitable demeanor with frequent laughter. We sought to elucidate a preclinical outcome measure in male and female rats that addressed communication abnormalities of AS and other neurodevelopmental disorders in which communication is atypical and/or lack of speech is a core feature. We discovered, and herein report for the first time, excessive laughter-like 50-kHz ultrasonic emissions in the Ube3a mat-/pat+ rat model of AS, which suggests an excitable, playful demeanor and elevated positive affect, similar to the demeanor of individuals with AS. Also in line with the AS phenotype, Ube3a mat-/pat+ rats demonstrated aberrant social interactions with a novel partner, distinctive gait abnormalities, impaired cognition, an underlying long-term potentiation deficit, and profound reductions in brain volume. These unique, robust phenotype...

Many daily choices are based on one’s own knowledge. However, when predicting other people’s behavior, we need to consider the differences between our knowledge and other people’s presumed knowledge. Social agents need a mechanism to use privileged information for their own behavior but exclude it from predictions of others. Using fMRI, we investigated the neural implementation of such social and personal predictions predictions in healthy human volunteers of both sexes by manipulating privileged and shared information. The medial frontal cortex appeared to have an important role in flexibly making decisions using privileged information for oneself or predicting others behavior. Specifically, we show that ventromedial prefrontal cortex tracked the state of the world independent of the type of decision (personal, social), whereas dorsomedial regions adjusted their frame of reference to the use of privileged or shared information. Sampling privileged evidence not available to the confederate also relied on s...

Apolipoprotein E (APOE), one of the primary lipoproteins in the brain has three isoforms in humans – APOE2, APOE3, and APOE4. APOE4 is the most well-established risk factor increasing the pre-disposition for Alzheimer's disease. The presence of the APOE4 allele alone is shown to cause synaptic defects in neurons and recent studies have identified multiple pathways directly influenced by APOE4. However, the mechanisms underlying APOE4 induced synaptic dysfunction remain elusive. Here, we report that the acute exposure of primary cortical neurons or synaptoneurosomes to APOE4 leads to a significant decrease in global protein synthesis. Primary cortical neurons were derived from male and female embryos of Sprague-Dawley rats or C57BL/6J mice. Synaptoneurosomes were prepared from P30 male Sprague-Dawley rats. APOE4 treatment also abrogates the NMDA mediated translation response indicating an alteration of synaptic signaling. Importantly, we demonstrate that both APOE3 and APOE4 generate a distinct translation ...

Mutations in the voltage-gated sodium channel gene SCN1A are associated with human epilepsy disorders, but how most of these mutations alter channel properties and result in seizures is unknown. This study focuses on two different mutations occurring at one position within SCN1A . R1648C is associated with the severe disorder Dravet Syndrome, and R1648H, with the milder disorder GEFS+. To explore how these different mutations contribute to distinct seizure disorders, Drosophila lines with the R-C or R-H mutation, or R-R control substitution in the fly sodium channel gene para were generated by CRISPR-Cas9 gene editing. The R-C and R-H mutations are homozygous lethal. Animals heterozygous for R-C or R-H mutations displayed reduced lifespans and spontaneous and temperature-induced seizures not observed in R-R controls. Electrophysiological recordings from adult GABAergic neurons in R-C and R-H mutants revealed appearance of sustained neuronal depolarizations and altered firing frequency that were exacerbated...

In the mature mouse retina, Otx2 is expressed in both Retinal Pigmented Epithelium (RPE) and photoreceptor (PR) cells, but Otx2 knockout in the RPE alone results in PR degeneration. To study the cell-autonomous function of OTX2 in PRs, we performed PR-specific Otx2 knockout (cKO) in adults. As expected, the protein disappears completely from PR nuclei but is still observed in PR inner and outer segments while its level concomitantly decreases in the RPE, suggesting a transfer of OTX2 from RPE to PRs in response to Otx2 ablation in PRs. The ability of OTX2 to transfer from RPE to PRs was verified by viral expression of tagged-OTX2 in the RPE. Transferred OTX2 distributed across the PR cytoplasm, suggesting functions distinct from nuclear transcription regulation functions. PR-specific Otx2 cKO did not alter the structure of the retina but impaired the translocation of photoreceptor arrestin-1 upon illumination changes, making mice photophobic. RNA-seq analyses following Otx2 knockout revealed down-regulatio...

Hormones regulate behavior either through activational effects that facilitate the acute expression of specific behaviors or through organizational effects that shape the development of the nervous system thereby altering adult behavior. Much research has implicated the neuropeptide oxytocin (OXT) in acute modulation of various aspects of social behaviors across vertebrate species, and OXT signaling is associated with the developmental social deficits observed in autism spectrum disorders, however, little is known about the role of OXT in the neurodevelopment of the social brain. We show that perturbation of OXT neurons during early zebrafish development led to a loss of dopaminergic neurons, associated with visual processing and reward, and blunted the neuronal response to social stimuli in the adult brain. Ultimately, adult fish whose OXT neurons were ablated in early life, displayed altered functional connectivity within social decision-making brain nuclei both in naïve state and in response to social s...

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...

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...