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...

In everyday life, we have no trouble categorizing objects varying in position, size, and orientation. Previous fMRI research shows that higher-level object processing regions in the human lateral occipital cortex may link object responses from different affine states (i.e., size and viewpoint) through a general linear mapping function capable of predicting responses to novel objects. In this study, we extended this approach to examine the mapping for both Euclidean (e.g., position and size) and non-Euclidean (e.g., image statistics and spatial frequency) transformations across the human ventral visual processing hierarchy, including areas V1, V2, V3, V4, ventral occipitotemporal cortex, and lateral occipitotemporal cortex. The predicted pattern generated from a linear mapping function could capture a significant amount of the changes associated with the transformations throughout the ventral visual stream. The derived linear mapping functions were not category independent as performance was better for the ...

Many patients with chronic pain conditions suffer from depression. The mechanisms underlying pain-induced depression are still unclear. There are critical links of medial prefrontal cortex (mPFC) synaptic function to depression, with signaling through the endocannabinoid (eCB) system as an important contributor. We hypothesized that afferent noxious inputs after injury compromise activity-dependent eCB signaling in the mPFC, resulting in depression. Depression-like behaviors were tested in male and female rats with traumatic neuropathy [spared nerve injury (SNI)], and neuronal activity in the mPFC was monitored using the immediate early gene c- fos and in vivo electrophysiological recordings. mPFC eCB Concentrations were determined using mass spectrometry, and behavioral and electrophysiological experiments were used to evaluate the role of alterations in eCB signaling in depression after pain. SNI-induced pain induced the development of depression phenotypes in both male and female rats. Pyramidal neurons...

Most human movements require coordinated activation of multiple muscles. Although many studies reported associations between arm, leg, and trunk muscles during functional tasks, their neural interaction mechanisms still remain unclear. Therefore, the aim of our study was to investigate arm-trunk or arm-leg neural interactions in the corticospinal tract during different arm muscle contractions. Specifically, we examined corticospinal excitability of the erector spinae (ES; trunk extensor), rectus abdominis (RA; trunk flexor), and tibialis anterior (TA; leg) muscles while participants exerted: (1) wrist flexion and (2) wrist extension isometric contraction at various contraction intensity levels ranging from rest to 50% of maximal voluntary contraction (MVC) effort. Corticospinal excitability was assessed using motor evoked potentials (MEPs) elicited through motor cortex transcranial magnetic stimulation (TMS). Results showed that ES MEPs were facilitated even at low contractions (>5% MVC) during wrist flexi...

Neuroendocrine control of reproduction is disrupted in many individuals with polycystic ovary syndrome (PCOS), who present with increased luteinizing hormone (LH), and presumably gonadotropin-releasing hormone (GnRH), release frequency, and high androgen levels. Prenatal androgenization (PNA) recapitulates these phenotypes in primates and rodents. Female offspring of mice injected with dihydrotestosterone (DHT) on gestational days 16–18 exhibit disrupted estrous cyclicity, increased LH and testosterone, and increased GnRH neuron firing rate as adults. PNA also alters the developmental trajectory of GnRH neuron firing rates, markedly blunting the prepubertal peak in firing that occurs in three-week (3wk)-old controls. GnRH neurons do not express detectable androgen receptors and are thus probably not the direct target of DHT. Rather, PNA likely alters GnRH neuronal activity by modulating upstream neurons, such as hypothalamic arcuate neurons co-expressing kisspeptin, neurokinin B (gene Tac2), and dynorphin,...