Arcuate dopaminergic/GABAergic neurons project within the hypothalamus and to the median eminence.

Cotransmission, meaning the release of multiple neurotransmitters from one synapse, allows for increased diversity of signaling in the brain. Dopamine (DA) and γ-aminobutyric acid (GABA) are known to coexpress in many regions such as the olfactory bulb and the ventral tegmental area. Tuberoinfundibular dopaminergic neurons (TIDA) in the arcuate nucleus of the hypothalamus (Arc) project to the median eminence (ME) and regulate prolactin release from the pituitary, and prior work suggests dopaminergic Arc neurons also cotransmit GABA. However, the extent of cotransmission, and the projection patterns of these neurons have not been fully revealed. Here, we used a genetic intersectional reporter expression approach to selectively label cells that express both tyrosine hydroxylase (TH) and vesicular GABA transporter (VGAT). Through this approach, we identified cells capable of both DA and GABA cotransmission in the Arc, periventricular (Pe), paraventricular (Pa), ventromedial, and the dorsolateral hypothalamic nuclei, in addition to a novel population in the caudate putamen. The highest density of labeled cells was in the Arc, 6.68% of DAPI-labeled cells at Bregma -2.06 mm, and in the Pe, 2.83% of DAPI-labeled cells at Bregma -1.94 mm. Next, we evaluated the projections of these DA/GABA cells by injecting an mCherry virus that fluoresces in DA/GABA cells. We observed a cotransmitting DA/GABA population, with projections within the Arc, and to the Pa and ME. These data suggest DA/GABA Arc neurons are involved in prolactin release as a subset of TIDA neurons. Further investigation will elucidate the interactions of dopamine and GABA in the hypothalamus.NEW & NOTEWORTHY Cotransmitting dopaminergic (DA) and γ-aminobutyric acid (GABA)ergic (DA/GABA) neurons contribute to the complexity of neural circuits. Using a new genetic technique, we characterized the locations, density, and projections of hypothalamic DA/GABA neurons. DA/GABA cells are mostly in the arcuate nucleus (Arc), from which they project locally within the arcuate, to the median eminence (ME), and to the paraventricular (Pa) nucleus. There is also a small and previously unreported group of DA/GABA cells in the caudate putamen.

Cluster Analysis of Short Sensory Profile Data Reveals Sensory-Based Subgroups in Autism Spectrum Disorder.

Autism spectrum disorder is a common, heterogeneous neurodevelopmental disorder lacking targeted treatments. Additional features include restricted, repetitive patterns of behaviors and differences in sensory processing. We hypothesized that detailed sensory features including modality specific hyper- and hypo-sensitivity could be used to identify clinically recognizable subgroups with unique underlying gene variants. Participants included 378 individuals with a clinical diagnosis of autism spectrum disorder who contributed Short Sensory Profile data assessing the frequency of sensory behaviors and whole genome sequencing results to the Autism Speaks' MSSNG database. Sensory phenotypes in this cohort were not randomly distributed with 10 patterns describing 43% (162/378) of participants. Cross comparison of two independent cluster analyses on sensory responses identified six distinct sensory-based subgroups. We then characterized subgroups by calculating the percent of patients in each subgroup who had variants with a Combined Annotation Dependent Depletion (CADD) score of 15 or greater in each of 24,896 genes. Each subgroup exhibited a unique pattern of genes with a high frequency of variants. These results support the use of sensory features to identify autism spectrum disorder subgroups with shared genetic variants.

Student views on the role of self-regulated learning in a surgery clerkship.

BACKGROUND: Self-regulated learning, including student-generated learning goals and flexibility in the learning structure are increasingly being used to enhance medical education. The role of these practices in surgical education of medical students has not been studied. MATERIALS AND METHODS: We administered an 18-question electronic survey to all third-year medical students at Washington University in St. Louis School of Medicine. Of the 126 students invited, 64 responded and 56 were included in the analysis. RESULTS: We found that third-year medical students develop learning goals at the beginning of the surgery clerkship. Although these learning goals theoretically can be a mechanism for enhanced student-faculty engagement, students are not aware of formal mechanisms for sharing these goals with faculty members. Furthermore, students report a lack of flexibility within the surgery clerkship and discomfort with requesting specific learning opportunities. Finally, students report that they believe increased flexibility could improve student engagement, learning, and the overall clerkship experience. CONCLUSIONS: We therefore propose that a mechanism for students to share their learning goals with faculty and an infrastructure in which student learning experiences can be tailored to fit with these individualized goals would enhance student surgical learning.

Sensory Symptoms Across the Lifespan in People With Cerebral Palsy.

BACKGROUND: To estimate the prevalence of sensory symptoms in people with cerebral palsy (CP) across the lifespan. METHODS: In this cross-sectional study, the self-reported Sensory Processing Scale Inventory (SPS-I) was administered via Research Electronic Data Capture (REDCap) between February 1, 2022, and August 15, 2022, to people with CP or their caregivers enrolled in the online MyCP Community Registry. We determined the association between SPS-I scores and age (Pearson correlation) and functional status as assessed using five validated functional classification systems for CP (analysis of variance [ANOVA]). We hypothesized that sensory symptoms would differ between younger and older individuals with CP. RESULTS: Of 155 responses (28% response rate, age one to 76 years, 34% male), 97% reported at least one bothersome sensory symptom. Total sensory symptoms decreased with age (R2 = 0.12, P < 0.0001), driven by decreases in hyposensitivity symptoms (R2 = 0.32, P < 0.0001), primarily tactile hyposensitivity (R2 = 0.29, P < 0.0001). Sensory symptoms increased with greater functional impairment across all functional domains (ANOVA, P < 0.0001). However, the age-specific decrease in hyposensitivities was most pronounced in people with the greatest gross motor functional impairment (R2 = 0.70, P = 0.0004). CONCLUSION: Our findings suggest that hyposensitivity, primarily tactile sensitivity, decreases with age in people with CP. Future work should assess whether decreased hyposensitivity contributes to other age-related changes in CP like increased pain.

Sensory experiences questionnaire unravels differences in sensory profiles between MECP2-related disorders.

The methyl CpG-binding protein-2 (MECP2) gene is located on the Xq28 region. Loss of function mutations or increased copies of MECP2 result in Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), respectively. Individuals with both disorders exhibit overlapping autism symptoms, yet few studies have dissected the differences between these gene dosage sensitive disorders. Further, research examining sensory processing patterns in persons with RTT and MDS is largely absent. Thus, the goal of this study was to analyze and compare sensory processing patterns in persons with RTT and MDS. Towards this goal, caregivers of 50 female individuals with RTT and 122 male individuals with MDS, between 1 and 46 years of age, completed a standardized measure of sensory processing, the Sensory Experiences Questionnaire. Patterns detected in both disorders were compared against each other and against normative values. We found sensory processing abnormalities for both hyper- and hypo-sensitivity in both groups. Interestingly, abnormalities in MDS were more pronounced compared with in RTT, particularly with items concerning hypersensitivity and sensory seeking, but not hyposensitivity. Individuals with MDS also exhibited greater sensory symptoms compared with RTT in the areas of tactile and vestibular sensory processing and for both social and nonsocial stimuli. This study provides a first description of sensory symptoms in individuals with RTT and individuals with MDS. Similar to other neurodevelopmental disorders, a variety of sensory processing abnormalities was found. These findings reveal a first insight into sensory processing abnormalities caused by a dosage sensitive gene and may ultimately help guide therapeutic approaches for these disorders.

The Impact of Cognitive Behavioral Therapy on Sleep Problems in Autistic Children with Co-occurring Anxiety.

PURPOSE: This study seeks to examine the relationship between anxiety-symptom severity and sleep behaviors in autistic children receiving cognitive behavioral therapy (CBT). METHODS: We conducted a secondary-data analysis from a sample of 93 autistic youth, 4 to 14 years, participating in 24 weeks of CBT. Clinicians completed the Pediatric Anxiety Rating Scale (PARS) and parents completed the Children's Sleep Habits Questionnaire, Abbreviated/Short Form (CSHQ-SF) at baseline, mid-treatment, post-treatment and 3 months post-treatment. Mediation analysis evaluated the role of anxiety symptoms in mediating the effect of time in treatment on sleep. RESULTS: There was a negative association between time in treatment and scores on the CSHQ-SF (b = - 3.23, SE = 0.493, t = - 6.553, p < 0.001). Increased time in treatment was associated with decreased anxiety (b = - 4.66, SE = 0.405, t = - 11.507, p < 0.001), and anxiety symptoms decreased with CSHQ-SF scores (b = 0.322, SE = 0.112, t = 2.869, p = 0.005). The indirect effect of time in treatment on CSHQ-SF scores through PARS reduction was negative, but not statistically significant. CONCLUSION: Increased time in CBT was associated with decreased anxiety severity and improved sleep behaviors. Reductions in anxiety symptoms may mediate improvements in sleep problems, but larger sample sizes are necessary to explore this further.

Detection of submillisecond spike timing differences based on delay-line anticoincidence detection.

Detection of submillisecond interaural timing differences is the basis for sound localization in reptiles, birds, and mammals. Although comparative studies reveal that different neural circuits underlie this ability, they also highlight common solutions to an inherent challenge: processing information on timescales shorter than an action potential. Discrimination of small timing differences is also important for species recognition during communication among mormyrid electric fishes. These fishes generate a species-specific electric organ discharge (EOD) that is encoded into submillisecond-to-millisecond timing differences between receptors. Small, adendritic neurons (small cells) in the midbrain are thought to analyze EOD waveform by comparing these differences in spike timing, but direct recordings from small cells have been technically challenging. In the present study we use a fluorescent labeling technique to obtain visually guided extracellular recordings from individual small cell axons. We demonstrate that small cells receive 1-2 excitatory inputs from 1 or more receptive fields with latencies that vary by over 10 ms. This wide range of excitatory latencies is likely due to axonal delay lines, as suggested by a previous anatomic study. We also show that inhibition of small cells from a calyx synapse shapes stimulus responses in two ways: through tonic inhibition that reduces spontaneous activity and through precisely timed, stimulus-driven, feed-forward inhibition. Our results reveal a novel delay-line anticoincidence detection mechanism for processing submillisecond timing differences, in which excitatory delay lines and precisely timed inhibition convert a temporal code into a population code.

Multiplexed temporal coding of electric communication signals in mormyrid fishes.

The coding of stimulus information into patterns of spike times occurs widely in sensory systems. Determining how temporally coded information is decoded by central neurons is essential to understanding how brains process sensory stimuli. Mormyrid weakly electric fishes are experts at time coding, making them an exemplary organism for addressing this question. Mormyrids generate brief, stereotyped electric pulses. Pulse waveform carries information about sender identity, and it is encoded into submillisecond-to-millisecond differences in spike timing between receptors. Mormyrids vary the time between pulses to communicate behavioral state, and these intervals are encoded into the sequence of interspike intervals within receptors. Thus, the responses of peripheral electroreceptors establish a temporally multiplexed code for communication signals, one consisting of spike timing differences between receptors and a second consisting of interspike intervals within receptors. These signals are processed in a dedicated sensory pathway, and recent studies have shed light on the mechanisms by which central circuits can extract behaviorally relevant information from multiplexed temporal codes. Evolutionary change in the anatomy of this pathway is related to differences in electrosensory perception, which appears to have influenced the diversification of electric signals and species. However, it remains unknown how this evolutionary change relates to differences in sensory coding schemes, neuronal circuitry and central sensory processing. The mormyrid electric communication pathway is a powerful model for integrating mechanistic studies of temporal coding with evolutionary studies of correlated differences in brain and behavior to investigate neural mechanisms for processing temporal codes.

Co-transmitting interneurons in the mouse olfactory bulb regulate olfactory detection and discrimination.

Co-transmission of multiple neurotransmitters from a single neuron increases the complexity of signaling information within defined neuronal circuits. Superficial short-axon cells in the olfactory bulb release both dopamine and γ-aminobutyric acid (GABA), yet the specific targets of these neurotransmitters and their respective roles in olfaction have remained unknown. Here, we implement intersectional genetics in mice to selectively block GABA or dopamine release from superficial short-axon cells to identify their distinct cellular targets, impact on circuit function, and behavioral contribution of each neurotransmitter toward olfactory behaviors. We provide functional and anatomical evidence for divergent superficial short-axon cell signaling onto downstream neurons to shape patterns of mitral cell firing that contribute to olfactory-related behaviors.

A diversity of synaptic filters are created by temporal summation of excitation and inhibition.

Temporal filtering is a fundamental operation of nervous systems. In peripheral sensory systems, the temporal pattern of spiking activity can encode various stimulus qualities, and temporal filtering allows postsynaptic neurons to detect behaviorally relevant stimulus features from these spike trains. Intrinsic excitability, short-term synaptic plasticity, and voltage-dependent dendritic conductances have all been identified as mechanisms that can establish temporal filtering behavior in single neurons. Here we show that synaptic integration of temporally summating excitation and inhibition can establish diverse temporal filters of presynaptic input. Mormyrid electric fish communicate by varying the intervals between electric organ discharges. The timing of each discharge is coded by peripheral receptors into precisely timed spikes. Within the midbrain posterior exterolateral nucleus, temporal filtering by individual neurons results in selective responses to a particular range of presynaptic interspike intervals. These neurons are diverse in their temporal filtering properties, reflecting the wide range of intervals that must be detected during natural communication behavior. By manipulating presynaptic spike timing with high temporal resolution, we demonstrate that tuning to behaviorally relevant patterns of presynaptic input is similar in vivo and in vitro. We reveal that GABAergic inhibition plays a critical role in establishing different temporal filtering properties. Further, our results demonstrate that temporal summation of excitation and inhibition establishes selective responses to high and low rates of synaptic input, respectively. Simple models of synaptic integration reveal that variation in these two competing influences provides a basic mechanism for generating diverse temporal filters of synaptic input.

Sensory receptor diversity establishes a peripheral population code for stimulus duration at low intensities.

Peripheral filtering is a fundamental mechanism for establishing frequency tuning in sensory systems. By contrast, detection of temporal features, such as duration, is generally thought to result from temporal coding in the periphery, followed by an analysis of peripheral response times within the central nervous system. We investigated how peripheral filtering properties affect the coding of stimulus duration in the electrosensory system of mormyrid fishes using behavioral and electrophysiological measures of duration tuning. We recorded from individual knollenorgans, the electrosensory receptors that mediate communication, and found correlated variation in frequency tuning and duration tuning, as predicted by a simple circuit model. In response to relatively high intensity stimuli, knollenorgans responded reliably with fixed latency spikes, consistent with a temporal code for stimulus duration. At near-threshold intensities, however, both the reliability and the temporal precision of responses decreased. Evoked potential recordings from the midbrain, as well as behavioral responses to electrosensory stimulation, revealed changes in sensitivity across the range of durations associated with the greatest variability in receptor sensitivity. Further, this range overlapped with the natural range of variation in species-specific communication signals, suggesting that peripheral duration tuning affects the coding of behaviorally relevant stimuli. We measured knollenorgan, midbrain and behavioral responses to natural communication signals and found that each of them were duration dependent. We conclude that at relatively low intensities for which temporal coding is ineffective, diversity among sensory receptors establishes a population code, in which duration is reflected in the population of responding knollenorgans.

Sensory Processing Phenotypes in Phelan-McDermid Syndrome and SYNGAP1-Related Intellectual Disability.

Sensory processing differences are an established feature of both syndromic and non-syndromic Autism Spectrum Disorders (ASDs). Significant work has been carried out to characterize and classify specific sensory profiles in non-syndromic autism. However, it is not known if syndromic autism disorders, such as Phelan-McDermid Syndrome (PMD) or SYNGAP1-related Intellectual Disability (SYNGAP1-ID), have unique sensory phenotypes. Understanding the sensory features of these disorders is important for providing appropriate care and for understanding their underlying mechanisms. Our objective in this work was to determine the sensory processing abnormalities present in two syndromic ASDs: Phelan-McDermid Syndrome and SYNGAP1-related Intellectual Disability. Using a standardized instrument, the Short Sensory Profile-2, we characterized sensory features in 41 patients with PMD and 24 patients with SYNGAP1-ID, and sub-scores were then calculated for seeking, avoiding, sensitivity and registration, as well as overall sensory and behavior scores. We found both patient groups exhibited atypical sensory features, including high scores in the areas of avoiding and seeking. Thus, we discovered significant sensory processing abnormalities are common in these syndromic ASDs. Measurements of sensory processing could serve as useful clinical endpoints for trials of novel therapeutics for these populations.

A systematic-review of olfactory deficits in neurodevelopmental disorders: From mouse to human.

Olfactory impairment is a common clinical motif across neurodevelopmental disorders, suggesting olfactory circuits are particularly vulnerable to disease processes and can provide insight into underlying disease mechanisms. The mouse olfactory bulb is an ideal model system to study mechanisms of neurodevelopmental disease due to its anatomical accessibility, behavioral relevance, ease of measuring circuit input and output, and the feature of adult neurogenesis. Despite the clinical relevance and experimental benefits, olfactory testing across animal models of neurodevelopmental disease has been inconsistent and non-standardized. Here we performed a systematic literature review of olfactory function testing in mouse models of neurodevelopmental disorders, and identified intriguing inconsistencies that include evidence for both increased and decreased acuity in odor detection in various mouse models of Autism Spectrum Disorder (ASD). Based on our identified gaps in the literature, we recommend direct comparison of different mouse models of ASD using standardized tests for odor detection and discrimination. This review provides a framework to guide future olfactory function testing in mouse models of neurodevelopmental diseases.

The Pediatric Neurology 2020 Research Workforce Survey: Optimism in a Time of Challenge.

BACKGROUND: The past decades have seen a transformational shift in the understanding and treatment for neurological diseases affecting infants and children. These advances have been driven in part by the pediatric neurology physician-scientist workforce and its efforts. However, pediatric neurology research faces substantial challenges from internal and external forces including work-life balance demands, COVID-19 pandemic effects, and research funding. Understanding the impact of these challenges on the perceptions, planning, and careers of pediatric neurology physician-scientists is needed to guide the research mission. METHODS: Our objective was to survey the research challenges, goals, and priorities of pediatric neurologists. In 2020 we conducted a cross-sectional, 28-question survey emailed to 1,775 members of the Child Neurology Society. RESULTS: One hundred fifty-one individuals responded to the survey. Most respondents were grant investigators (52%) and conducted clinical research (69%). Research areas included epilepsy (23%), neurodevelopmental and autism (16%), neurocritical care and stroke (11%), neurogenetics and neurometabolics (9%), neonatal neurology (8%), and others. The most common funding source was the National Institutes of Health (37%). Shared major research concerns were funding, utilization of remote technology, overcoming disparities, natural history and multicenter studies, global neurology, and diversification of the research portfolio. Commitment to continuing and increasing research efforts was evident. CONCLUSIONS: Our survey demonstrates obstacles for physician-scientist researchers in pediatric neurology, but it also shows optimism about continued opportunity. Creative approaches to address challenges will benefit the research mission, maximize the current and future pool of researchers, and help improve the lives of children with neurological disorders.

Update on Palliative Care for Pediatric Neurology.

It has long been recognized that patients with neurological conditions, and particularly pediatric neurology patients, are well suited for palliative care because they frequently have a high symptom burden and variable prognoses. In 1996, the American Academy of neurology formally recognized a need for neurologists to "understand and apply the principles of palliative medicine." Subsequently, some reviews have proposed a simultaneous care model in which palliative care is integrated for all neurology patients from the time of diagnosis. This article will review the current status of palliative care in pediatric neurology and discuss barriers to its integration.

A 14-Year-Old Boy With Fevers, Cytopenias, and Neurocognitive Decline.

A 14-year-old boy presented to our institution with a 1-month history of neurocognitive decline and intermittent fevers. His history was significant for fevers, headaches, and a 10-lb weight loss. Previous examinations by multiple medical providers were significant only for bilateral cervical lymphadenopathy. Previous laboratory workup revealed leukopenia, neutropenia, and elevated inflammatory markers. Despite improvement in his laboratory values after his initial presentation, his fevers persisted, and he developed slowed and "jerky" movements, increased sleep, slurred speech, delusions, visual hallucinations, and deterioration in his school performance. A brain MRI performed at an outside hospital before admission at our institution was concerning for patchy, increased T2 and fluid-attenuated inversion recovery signal intensity in multiple areas, including the basal ganglia. After transfer to our institution and admission to the pediatric hospital medicine team, the patient had an acute decompensation. Our subspecialists will discuss the initial evaluation, workup, differential diagnosis, definitive diagnosis, and subsequent management of this patient.

Retrograde fluorescent labeling allows for targeted extracellular single-unit recording from identified neurons in vivo.

The overall goal of this method is to record single-unit responses from an identified population of neurons. In vivo electrophysiological recordings from individual neurons are critical for understanding how neural circuits function under natural conditions. Traditionally, these recordings have been performed 'blind', meaning the identity of the recorded cell is unknown at the start of the recording. Cellular identity can be subsequently determined via intracellular(1), juxtacellular(2) or loose-patch(3) iontophoresis of dye, but these recordings cannot be pre-targeted to specific neurons in regions with functionally heterogeneous cell types. Fluorescent proteins can be expressed in a cell-type specific manner permitting visually-guided single-cell electrophysiology(4-6). However, there are many model systems for which these genetic tools are not available. Even in genetically accessible model systems, the desired promoter may be unknown or genetically homogenous neurons may have varying projection patterns. Similarly, viral vectors have been used to label specific subgroups of projection neurons(7), but use of this method is limited by toxicity and lack of trans-synaptic specificity. Thus, additional techniques that offer specific pre-visualization to record from identified single neurons in vivo are needed. Pre-visualization of the target neuron is particularly useful for challenging recording conditions, for which classical single-cell recordings are often prohibitively difficult(8-11). The novel technique described in this paper uses retrograde transport of a fluorescent dye applied using tungsten needles to rapidly and selectively label a specific subset of cells within a particular brain region based on their unique axonal projections, thereby providing a visual cue to obtain targeted electrophysiological recordings from identified neurons in an intact circuit within a vertebrate CNS. The most significant novel advancement of our method is the use of fluorescent labeling to target specific cell types in a non-genetically accessible model system. Weakly electric fish are an excellent model system for studying neural circuits in awake, behaving animals(12). We utilized this technique to study sensory processing by "small cells" in the anterior exterolateral nucleus (ELa) of weakly electric mormyrid fish. "Small cells" are hypothesized to be time comparator neurons important for detecting submillisecond differences in the arrival times of presynaptic spikes(13). However, anatomical features such as dense myelin, engulfing synapses, and small cell bodies have made it extremely difficult to record from these cells using traditional methods(11, 14). Here we demonstrate that our novel method selectively labels these cells in 28% of preparations, allowing for reliable, robust recordings and characterization of responses to electrosensory stimulation.