Biology subjects

Maloney, S. E.

Publications and source records attributed to Maloney, S. E..

At least 19 recordsLinked to original sources

bioRxiv2026

Hyperexcitable but seizure-free: hippocampal network dysfunction in a Wolfram syndrome model

Wolfram syndrome (WS) is a rare, life-limiting progressive neurodegenerative disorder caused by pathogenic variants in the WFS1 gene. It is a prototype endoplasmic reticulum (ER) stress disorder, and the mechanisms underlying neurological phenotypes in WS remain incompletely understood. Although WFS1 protein is abundant in the hippocampus, the role of this region in WS remains relatively understudied. Here we characterize hippocampal function across scales in mice carrying a patient orthologous Wfs1 variant (p.W542*) on both alleles. Male mutants lose excitatory synapses, and dissociated hippocampal neurons are markedly hyperexcitable yet generate no increase in network bursting and no shift in network criticality, indicating that their additional firing is not recruited into coordinated population activity. This finding translates in vivo wherein intracranial electroencephalogram (EEG) recordings show no epileptiform activity or seizures in either sex, with no hippocampal astrogliosis, alongside a male-specific reduction in hippocampal low-gamma power. Additionally, EEG demonstrates a sex-specific disruption of sleep, which parallels a sex-divergent synaptic phenotype. Mutant male mice show impaired hippocampus-dependent fear memory and reduced voluntary motor activity. Taken together, we propose that cellular hyperexcitability in the WS hippocampus does not translate into increased network bursting, potentially due to disproportionate loss of excitatory synapses. This dissociation may provide a functional substrate for the neurological features of WS.

neuroscience↗

bioRxiv2026

Lactational transfer of synthetic oxytocin and sex-specific suppression of neurodevelopmental risk gene networks in the rat prefrontal cortex

Autism spectrum disorder and related neurodevelopmental disorders (NDDs) affect males at two-to-four times the rate of females, yet the environmental contributors to this sex-differentiated vulnerability remain poorly understood. Here, using a clinically translatable postpartum rat model, we show that synthetic oxytocin (OT) administered for postpartum hemorrhage (PPH) prophylaxis ( PPH-OT), a universally administered obstetric medication, undergoes lactational transfer, confirmed by stable isotope-labeled OT and LC-MS/MS, without altering maternal behavior or neonatal cortical OT receptor expression. In offspring, PPH-OT altered ultrasonic vocalizations during dyadic interaction and caused a male-specific reduction in social approach, without affecting other behavioral domains. Sex-stratified RNA-sequencing of the medial prefrontal cortex (mPFC) revealed pronounced transcriptional dimorphism: males showed 1,732 differentially expressed genes versus 693 in females, and a sex-by-treatment interaction contrast identified 1,229 formally sex-differentiated genes. Male mPFC downregulated genes were significantly enriched for high-confidence NDD risk genes across three independent databases -- SFARI score-1 (highest confidence autism genes; OR = 4.56, p = 0.015), DBD autism (OR = 10.34, p = 7.3x10-{superscript 1}{superscript 2}), and SysNDD autosomal dominant (OR = 9.78, p = 8.4x10-) -- including core regulators of cortical circuit assembly (Grin2a, Grin2b, Reln, Tbr1, Mef2c, and Tcf4), an enrichment pattern largely restricted to males. Hypothalamic transcriptional changes were pronounced but showed no enrichment for NDD risk genes, establishing mPFC specificity. These findings identify PPH-OT as a candidate environmental modifier of male neurodevelopmental vulnerability and provide a pressing rationale for prospective investigation of neurodevelopmental outcomes in PPH-OT-exposed children.

neuroscience↗

bioRxiv2026

Sex differences in exploration-exploitation strategies during home-cage decision making

The exploration-exploitation trade-off refers to the conflict between using known strategies that reliably yield reward (exploitation) and sampling uncertain options that might yield better outcomes (exploration). Dysregulation of this balance is implicated in neuropsychiatric disease, and while sex differences in this balance have been described, the biological bases remain unclear. To quantify sex differences in this trade-off, we tested mice (n=74 male, 62 female) on four home-cage based foraging tasks with an operant pellet dispensing device, Feeding Experimentation Device 3 (FED3). Mice completed the tasks continuously over multiple days and the tasks were their only source of food. Across multiple tasks, males showed higher win-stay behaviour than females, indicating greater exploitation of previously rewarded actions, an effect that was modest in size but highly significant. Power analyses revealed that >30 mice per sex were needed to detect these modest but significant sex differences with 80% power. No consistent sex differences were observed in pellet intake, suggesting that differences in exploitation did not reflect differences in hunger drive or demand for pellets. Exploitation is a more efficient strategy when environmental parameters are fixed, while exploration can be more advantageous when parameters such as reward locations are changing and uncertain. We tested this idea by re-running our mice in a probabilistic foraging task, where actions led to uncertain probabilities of reward. While males continued to show higher levels of win-stay behaviour on this task, this no longer led to increases in accuracy. Behavioural modelling also supported this framework, demonstrating that stronger win-stay behaviour was most advantageous in deterministic models, and less advantageous in probabilistic models. Together, our findings demonstrate that male and female mice have small but significant differences in their exploration-exploitation balance, which leads to more accurate foraging in certain, but not uncertain, environments.

neuroscience↗

bioRxiv2025

ACSS2 mediates prenatal alcohol exposure-related morphological and behavioral phenotypes

The metabolic enzyme Acetyl-CoA Synthetase 2 (ACSS2) recently emerged as an unexpected regulator of molecular and behavioral changes associated with alcohol use. Its role during prenatal exposure, however, remains unknown. Here, we use a combination of proteomic, genomic and behavioral approaches to establish ACSS2 as a key mediator of prenatal alcohol exposure-related phenotypes. We define the developmental window during which ACSS2 translocates to nuclei in the mouse brain, and show that alcohol-derived acetate is incorporated into fetal brain histone acetylation in utero. Using genetically engineered mice not expressing ACSS2, we demonstrate that loss of this enzyme attenuates chronic prenatal alcohol exposure-induced craniofacial abnormalities, motor function deficits, cognitive impairments as well as associated chromatin and gene expression changes in the dorsal hippocampus and the cerebellar vermis. Our results outline a previously unknown mechanism underlying prenatal alcohol exposure-related phenotypes regulated by ACSS2, which will inform the development of future therapeutic interventions. HIGHLIGHTSO_LIACSS2 translocates to nuclei during in utero brain development C_LIO_LIAlcohol-derived acetate is incorporated into fetal brain histone acetylation C_LIO_LIPrenatal alcohol exposure results in long-lasting and ACSS2-dependent chromatin and gene expression changes in the hippocampus and cerebellar vermis C_LIO_LILoss of ACSS2 attenuates molecular changes, craniofacial abnormalities and cognitive impairments linked to prenatal alcohol exposure C_LI

neuroscience↗

bioRxiv2025

Persistence of vestibular function in the absence of glutamatergic transmission from hair cells

Quantal synaptic transmission in vestibular end-organs is glutamatergic. Although genetic deletion of Slc17a8 (termed Vglut3) leads to deafness in mice, the dependence of vestibular function on VGLUT3-mediated quantal transmission is unknown. Here, we investigated the vestibular phenotype of Vglut3-/- mice at the cellular, systems, and behavioral levels. The type-II vestibular hair cells (VHCs) in Vglut3+/+mice were strongly immunoreactive for VGLUT3, while type-I VHCs showed poor immunoreactivity. In Vglut3-/- mice quantal synaptic transmission in utricular calyces was reduced in rate and amplitude by > 95%. In vivo recordings of spontaneous activity in the vestibular nerve revealed similar action potential rates and regularity in Vglut3+/+and Vglut3-/- mice, suggesting a divergent underlying mechanism compared to the silent Vglut3-/- auditory nerve. In behavioral studies, Vglut3-/- mice did not exhibit considerable sensorimotor or balance deficits. Collectively, these data support the view that non-quantal transmission is the predominant mode of neurotransmission between type I VHCs and vestibular calyceal afferent neurons. We propose that non-quantal transmission alone underlies the apparently normal vestibular nerve physiology and behavioral function in Vglut3-/- mice.

neuroscience↗

bioRxiv2025

A novel homecage operant task reveals circadian dynamics of social motivation in mice

Deficits in social motivation are a core feature of many neurodevelopmental disorders, including autism spectrum disorders. While a range of tools have been developed to quantify social motivation in rodents, most rely on brief tests in dedicated apparatuses that can introduce stress and novelty, potentially reducing test reliability. Most current approaches are also typically not suited to studying learning across days or circadian rhythms of social motivation. To address these challenges, we developed a social operant task that can run around-the-clock for multiple days in the mouse homecage, continuously monitoring social motivation around the circadian cycle. The task consists of a custom-built automated door that was installed between two rodent homecages and configured so one mouse could trigger the door to open with a nose-poke action from within their cage. When open, the door allows for social interaction with the neighboring mouse through a perforated stainless-steel panel, which did not allow the mice to cross over into the neighboring cage. Mice opened the door multiple times each day, allowing us to quantify their amount and daily rhythms of social motivation. In our first experiment, C57BL/6J mice (both sexes) were individually housed with an empty adjacent cage for five days, after which a same-sex social partner was introduced for another nine days. Mice opened the door at significantly higher rates when the social partner was present vs. absent, confirming that mice were motivated to earn social interaction. This task also revealed a circadian rhythm to social motivation that peaked about 2 hours after the peak in their feeding rhythm. We speculate that mice first addressed their caloric needs each day before changing their priority to social behavior. Given prior literature implicating the dopamine system in social motivation, we also tested whether dopamine antagonists would block social motivation in our task in a new group of 14 mice (both sexes). The dopamine D1 receptor antagonist SCH23390 (delivered systemically at 0.3mg/kg SC) reduced social seeking without affecting locomotor activity or food intake, demonstrating a selective role for dopamine D1 receptors in social motivation. The dopamine D2 receptor antagonist haloperidol (delivered systemically at 0.3mg/kg SC) also reduced social seeking, but reduced locomotor activity and food intake as well, demonstrating a general reduction in behavior that was not specific to social motivation. Overall, our task offers a way for studying social motivation in the rodent homecage, which has advantages for studying disorders that involve both social and circadian disruptions.

animal behavior and cognition↗

bioRxiv2025

A single binge ethanol exposure is apoptotic within hours across neurodevelopment and partially regulated by the Myt1l gene.

Ethanol rapidly produces widespread neuronal apoptosis during early development, but this susceptibility declines as the brain matures. In previous research, we found Myt1l (a proneuronal transcription factor) mutations can cause precocious differentiation, neuronal immaturity, and transcriptomic alterations, including many in apoptotic regulators. Therefore, we used a recently developed Myt1l haploinsufficient mouse model to examine this genes effects on ethanol-induced apoptosis across different developmental stages. We discovered that haploinsufficiency can moderately influence vulnerability to ethanol in a complex, age- and cell type-specific manner: apoptosis was reduced on P7, increased P21, but unaffected on P60. Remarkably, we also discovered the previously unrecognized ability of a single binge of ethanol to rapidly increase apoptosis within six hours in early adolescent and adult wild-type mice occurring in microglia and the newborn granule neurons in the hippocampus. This suggests apoptosis is an underappreciated contributor to ethanols neuropathology at older ages and, translated to human use, occurs far more frequently than previously recognized.

neuroscience↗

bioRxiv2025

Single-Cell Resolution of Individual Variation in Hypothalamic Neurons Allows Targeted Manipulation Affecting Social Motivation

Despite decades of research, connecting molecular and cellular phenotypes to complex behavioral traits remains an elusive goal1. Social motivation exhibits individual trait variation2, which we hypothesize is mediated by molecular and cellular variability across hypothalamic neurons. To test this, we generated single-nucleus RNA-sequencing profiles3,4 of >120,000 neurons from tuberal hypothalamus and adjacent thalamus in 36 mice, balanced across sex and autism-associated mutation5, with all mice assessed for social motivation2. First, we show that molecular activation patterns predict behavior across individuals: specifically, activation of paraventricular Agtr1a+ (angiotensin receptor 1a) neurons predicted reduced social behavior. Subsequent inhibition of AGTR1A with telmisartan--an FDA-approved antihypertensive6--improved social orienting. Second, we show natural variation in neuronal proportions--likely arising from stochastic developmental events7--is sufficient to shape adult behavior even among genetically-identical individuals: we identified multiple neuronal populations whose relative abundance predicted social reward-seeking behavior. Chemogenetic inhibition of one such population, Nxph4+ neurons of the postero-lateral hypothalamus8, suppressed multiple aspects of social motivation. This work establishes proof-of-principle for an approach where single-cell genomics precisely maps neural substrates governing behavior. This approach revealed that stochastic variations in neuronal architecture deterministically influence social motivation, and enabled identification of therapeutically-actionable targets with immediate translational potential for disorders with social deficits.

genetics↗

bioRxiv2025

Maternal separation disrupts noradrenergic control of adult coping behaviors

Early life stress (ELS) in humans and preclinical rodent models profoundly impacts the brain and correlates with negative affective behaviors in adulthood. The locus coeruleus (LC), a stress-responsive brainstem nucleus that supplies most of the brain with norepinephrine (NE), is known to modulate negative affect. Here we used repeated maternal separation stress (MSS) to investigate the impact of ELS on the LC and stress-related behaviors in adulthood. Using ex vivo cell-attached electrophysiology, we recorded spontaneous LC firing across the lifespan from early development, pre-adolescence, adolescence, through adulthood. MSS significantly increased LC firing during early development and adulthood compared to No MSS mice. We next examined potential changes in the expression of genes linked to LC function. MSS decreased mRNA levels for both the alpha-2A adrenergic receptor and dopamine beta-hydroxylase, the enzyme necessary for NE synthesis. At the behavioral level, MSS increased locomotion in approach-avoidance exploratory assays and increased immobility in the forced swim test. Forced swim increased LC cFos expression, a marker for neuronal excitation, in both No MSS and MSS mice. However, MSS mice had significantly less cFos than No MSS controls. We then sought to reverse this MSS-induced increase in immobility by inhibiting the LC during the forced swim test. In No MSS mice, LC inhibition increased immobility time, however, LC inhibition did not affect MSS immobility. Together, this study demonstrates that MSS dysregulates LC-NE activity across the lifespan and disrupts the role of the LC in regulating coping strategies during stressful events.

neuroscience↗

bioRxiv2024

A survey of hypothalamic phenotypes identifies molecular and behavioral consequences of MYT1L haploinsufficiency in male and female mice.

The transcription factor MYT1L supports proper neuronal differentiation and maturation during brain development. MYT1L haploinsufficiency results in a neurodevelopmental disorder characterized by intellectual disability, developmental delay, autism, behavioral disruptions, aggression, obesity and epilepsy. While MYT1L is expressed throughout the brain, how it supports proper neuronal function in distinct regions has not been assessed. Some features of MYT1L Neurodevelopmental Syndrome suggest disruption of hypothalamic function, such as obesity and endocrine issues, and previous research showed changes in hypothalamic neuropeptide expression following knockdown in zebrafish. Here, we leveraged our heterozygous Myt1l mutant, previously shown to recapitulate aspects of the human syndrome such as hyperactivity, social challenges, and obesity, to examine the impact of MYT1L loss on hypothalamic function. Examining the molecular profile of the MYT1L haploinsufficient hypothalamus revealed a similar scale of disruption to previously studied brain regions, yet with region-specific roles for MYT1L, including regulation of neuropeptide systems. Alterations in oxytocin and arginine vasopressin cell numbers were also found. Behaviors studied included maternal care, social group hierarchies, and aggression, all of which were unchanged. Feeding and metabolic markers were also largely unchanged in MYT1L haploinsufficient mice, yet an interaction was observed between diet and MYT1L genotype on weight gain. Our findings here suggest that gross endocrine function was not altered by MYT1L haploinsufficiency, and that key sex-specific behaviors related to proper hypothalamic function remain intact. Further study is needed to understand the functional impact of the altered hypothalamic molecular profile and changes in neuropeptide cell numbers that result from MYT1L haploinsufficiency.

animal behavior and cognition↗

bioRxiv2024

Lifespan in rodents with MYT1L heterozygous mutation

MYT1L syndrome is a newly recognized disorder characterized by intellectual disability, speech and motor delay, neuroendocrine disruptions, ADHD, and autism. In order to study this gene and its association with these phenotypes, our lab recently created a Myt1l heterozygous mutant mouse inspired by a clinically relevant mutation. This model recapitulates several of the physical and neurologic abnormalities seen in humans with MYT1L syndrome, such as weight gain, microcephaly, and behavioral disruptions. The majority of patients with this syndrome are young, and little is known about the impact of age on health and mortality in these patients. Using a Myt1l mutant mouse, we examined the impact of Myt1l mutation on body weights, lifespan, and histopathology findings of mice at the end of life. This cohort of heterozygous mice demonstrated increased body weight across the lifespan, however there was no significant difference in lifespan, apparent cause of death, or end of life histopathological findings between Myt1l heterozygous and wildtype mice. These findings suggest while Myt1l heterozygous mutation may influence overall brain development, it does not strongly impact other organ systems in the body over time.

genetics↗

bioRxiv2024

Chromosomal and gonadal sex have differing effects on social motivation in mice

Plain English SummaryAs our brain develops, many factors influence how we behave later in life. The brain forms differently in males and females, potentially leading to sex variation seen in many behaviors including sociability. In addition, conditions defined by differences in social behaviors, such as autism, are diagnosed more in males than females. However, researchers dont know exactly how distinct sex factors, such as hormones and sex chromosome genes, lead to different behaviors in males and females. In this study, we used mouse models and tests of mouse behavior to explore these differences. Results show that sex hormones primarily contributed to differences in social motivation between sexes. Yet when we repeated these same assays in a mouse model of genetic liability for a human neurodevelopmental syndrome, we found that sex chromosome genes rather than sex hormones played a larger role in the behavioral consequences of impaired neurodevelopment. These insights can inform future research on the biological mechanisms of social behavior in the context of genetic liability for neurodevelopmental disorders. HighlightsO_LIFour-core genotype mouse model crossed with MYT1L heterozygous mouse revealed independent effects of chromosomal and gonadal sex on social motivation. C_LIO_LIMyt1l haploinsufficiency was associated with increased activity in both males and females. C_LIO_LIWhile females are more active, contributions of chromosomes and gonadal hormones to this sex effect are environment dependent. C_LIO_LIPresence of ovaries was associated with increased measures of social seeking and orienting regardless of genotype. C_LIO_LIChromosomal sex interacted with MYT1L genotype, with increased social orienting and seeking specifically in XX MYT1L heterozygous mice. C_LI BackgroundSex differences in brain development are thought to lead to sex variation in social behavior. Sex differences are fundamentally driven by both gonadal (i.e., hormonal) and chromosomal sex, yet little is known about the independent effects of each on social behavior. Further, mouse models of the genetic liability for the neurodevelopmental disorder MYT1L Syndrome have shown sex specific deficits in social motivation. In this study, we aimed to determine if hormonal or chromosomal sex primarily mediate the sex differences seen in mouse social behavior, both at baseline and in the context of Myt1l haploinsufficiency. MethodsFour-core genotype (FCG) mice, which uncouple gonadal and chromosomal sex, were crossed with MYT1L heterozygous mice to create eight different groups with unique combinations of sex factors and MYT1L genotype. A total of 131 mice from all eight groups were assayed for activity and social behavior via the open field and social operant paradigms. Measures of social seeking and orienting were analyzed for main effects of chromosome, gonads, and their interactions with Myt1l mutation. ResultsThe FCGxMYT1L cross revealed independent effects of both gonadal and chromosomal sex on activity and social behavior. Specifically, the presence of ovaries, and by extension the presence of ovarian hormones, increased overall activity, social seeking, and social orienting regardless of genotype. In contrast, sex chromosomes affected social behavior mainly in the MYT1L heterozygous group, with XX sex karyotype when combined with MYT1L genotype contributing to increased social orienting and seeking. ConclusionsGonadal and chromosomal sex have independent mechanisms of driving increased social motivation in females. Additionally, sex chromosomes may interact with neurodevelopmental mutations to influence sex variation in atypical social behavior.

animal behavior and cognition↗

bioRxiv2024

Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties

Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. We recently reported a family with a paternally inherited intragenic ASTN2 duplication with a range of neurodevelopmental disorders, including autism spectrum disorder (ASD), learning difficulties, and speech and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibit strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity and repetitive behaviors, altered social behaviors, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors were also prominent in Astn2 cKO animals. By Golgi staining, Astn2 KO PCs have region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum reveals a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrates a significant increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicate a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents (IPSCs) in the Astn2 KO animals, suggesting that pre- and postsynaptic components of synaptic transmission are altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.

neuroscience↗

bioRxiv2023

Distinct disease mutations in DNMT3A result in a spectrum of behavioral, epigenetic, and transcriptional deficits

Phenotypic heterogeneity is a common feature of monogenic neurodevelopmental disorders that can arise from differential severity of missense variants underlying disease, but how distinct alleles impact molecular mechanisms to drive variable disease presentation is not well understood. Here, we investigate missense mutations in the DNA methyltransferase DNMT3A associated with variable overgrowth, intellectual disability, and autism, to uncover molecular correlates of phenotypic heterogeneity in neurodevelopmental disease. We generate a DNMT3A P900L/+ mouse model mimicking a disease mutation with mild-to-moderate severity and compare phenotypic and epigenomic effects with a severe R878H mutation. We show that the P900L mutation leads to disease-relevant overgrowth, obesity, and social deficits shared across DNMT3A disorder models, while the R878H mutation causes more extensive epigenomic disruption leading to differential dysregulation of enhancers elements. We identify distinct gene sets disrupted in each mutant which may contribute to mild or severe disease, and detect shared transcriptomic disruption that likely drives common phenotypes across affected individuals. Finally, we demonstrate that core gene dysregulation detected in DNMT3A mutant mice overlaps effects in other developmental disorder models, highlighting the importance of DNMT3A-deposited methylation in neurodevelopment. Together, these findings define central drivers of DNMT3A disorders and illustrate how variable disruption of transcriptional mechanisms can drive the spectrum of phenotypes in neurodevelopmental disease.

neuroscience↗

bioRxiv2023

Extensive characterization of a Williams Syndrome murine model shows Gtf2ird1-mediated rescue of select sensorimotor tasks, but no effect on enhanced social behavior

Williams Syndrome is a rare neurodevelopmental disorder exhibiting cognitive and behavioral abnormalities, including increased social motivation, risk of anxiety and specific phobias along with perturbed motor function. Williams Syndrome is caused by a microdeletion of 26-28 genes on chromosome 7, including GTF2IRD1, which encodes a transcription factor suggested to play a role in the behavioral profile of Williams Syndrome. Duplications of the full region also lead to frequent autism diagnosis, social phobias, and language delay. Thus, genes in the region appear to regulate social motivation in a dose-sensitive manner. A Complete Deletion mouse, heterozygously eliminating the syntenic Williams Syndrome region, has been deeply characterized for cardiac phenotypes, but direct measures of social motivation have not been assessed. Furthermore, the role of Gtf2ird1 in these behaviors has not been addressed in a relevant genetic context. Here, we have generated a mouse overexpressing Gtf2ird1, which can be used both to model duplication of this gene alone and to rescue Gtf2ird1 expression in the Complete Deletion mice. Using a comprehensive behavioral pipeline and direct measures of social motivation, we provide evidence that the Williams Syndrome Critical Region regulates social motivation along with motor and anxiety phenotypes, but that Gtf2ird1 complementation is not sufficient to rescue most of these traits, and duplication does not decrease social motivation. However, Gtf2ird1 complementation does rescue light-aversive behavior and performance on select sensorimotor tasks, perhaps indicating a role for this gene in sensory processing or integration.

animal behavior and cognition↗

bioRxiv2022

A comprehensive assay of social motivation reveals sex-differential roles of ASC-associated genes and oxytocin

Social motivation is critical to the development of healthy social functioning. Autism spectrum condition (ASC) is characterized in part by challenges with social communication and social interaction. The root of these challenges is hypothesized to be a deficit in social motivation, specifically in one or more subcomponents (e.g. social reward reward seeking or social orienting). Current social behavior assays lack the ability to quantitatively measure both social reward seeking and social orienting simultaneously. We have developed an automated socially-rewarded operant conditioning task coupled with video tracking, to quantify effort to achieve access to a social partner and concurrent social orienting behavior in mice. We established that adult wildtype mice will work for access to a social partner, that male mice exhibit greater social motivation compared to females, and there is high test-retest reliability in the task across multiple days. We then benchmarked the method with two test-case manipulations. We first tested a mouse model of Phelan-McDermid syndrome, a neurodevelopmental disorder associated with ASC. These Shank3B mutants failed to show social reward seeking and exhibited reduced social orienting. Next, we demonstrated that oxytocin receptor antagonism decreased social motivation in wildtype mice, consistent with its role in social reward circuitry. Intriguingly, only male mice were vulnerable to Shank3B mutation, while females were more vulnerable to oxytocin blockade, a double dissociation suggesting separate circuits for social motivation in male and female brain. Overall, we believe this method provides a valuable addition to the assessment of social phenotypes in rodent models of ASC and the mapping of potentially sex-specific social motivation circuits in the brain.

animal behavior and cognition↗

bioRxiv2022

Perinatal Oxycodone Exposure Causes Long Term Sex-Dependent Changes in Sensory and Reward Processing in Adult Mice

In utero opioid exposure is associated with lower weight and a Neonatal Opioid Withdrawal Syndrome (NOWS) at birth, along with longer-term adverse neurodevelopmental outcomes and mood disorders. While NOWS is sometimes treated with continued opioids, clinical studies have not addressed if long-term neurobehavioral outcomes are worsened with continued postnatal exposure to opioids. In addition, pre-clinical studies comparing in utero only opioid exposure to continued post-natal opioid administration for withdrawal mitigation are lacking. Therefore, we implemented a rodent perinatal opioid exposure model of Oxycodone (Oxy) exposure for comparison of long-term consequences of Oxy exposure until birth (Short Oxy) to the impact of continued postnatal opioid exposure (Long Oxy) spanning gestation through birth and lactation. Short Oxy exposure was associated with a sex-specific increase in weight gain trajectory in adult male mice. Long Oxy exposure caused an increased weight gain trajectory in adult males, sex-dependent changes in morphine conditioned place preference, and alterations in nociceptive processing in females. Importantly, there was no evidence of long-term social behavioral deficits, anxiety, hyperactivity, or memory deficits following Short or Long Oxy exposure. Our findings suggest that offspring with prolonged opioid exposure experienced some long-term sequelae compared to pups with opioid cessation at birth. These results highlight the potential long-term consequences of opioid administration as a mitigation strategy for clinical NOWS symptomology and suggest alternatives should be explored.

neuroscience↗

bioRxiv2021

Mecp2 deletion results in profound alterations of developmental and adult functional connectivity

As a regressive neurodevelopmental disorder with a well-established genetic cause, Rett Syndrome and its Mecp2 loss-of-function mouse model provide an excellent opportunity to define potentially translatable functional signatures of disease progression, as well as offer insight into Mecp2s role in functional circuit development. Thus, we applied optical fluorescence imaging to assess mesoscale calcium functional connectivity (FC) in the Mecp2 cortex prior to symptom onset as well as during decline. We found that FC was profoundly disrupted in Mecp2 males both in juvenile development and early adulthood. Female Mecp2 mice displayed a subtle homotopic contralateral increase in motor cortex as juveniles but not in adulthood, where instead parietal regions were implicated. Additionally, conditional rescue studies indicated FC phenotypes are driven by excitatory neurons. Altogether, the female results identify subtle candidate translatable biomarkers of disease progression, while the male results indicate MeCP2 protein is needed in a circuit-specific manner for FC.

neuroscience↗