Biology subjects

Swift, R. G.

Publications and source records attributed to Swift, R. G..

5 recordsLinked to original sources

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↗

bioRxiv2021

Oxytocin receptor activation does not mediate associative fear deficits in a Williams Syndrome model

Williams Syndrome is caused by a deletion of 26-28 genes on chromosome 7q11.23. Patients with this disorder have distinct behavioral phenotypes including learning deficits, anxiety, increased phobias, and hypersociability. Some studies also suggest elevated blood oxytocin and altered oxytocin receptor expression, and this oxytocin dysregulation is hypothesized to be involved in the underlying mechanisms driving a subset of these phenotypes. A Complete Deletion mouse, modeling the hemizygous critical region deletion in Williams Syndrome, recapitulates many of the phenotypes present in humans. These Complete Deletion mice also exhibited impaired fear responses in the conditioned fear task. Here, we address whether oxytocin dysregulation is responsible for this impaired associative fear memory response. We show direct delivery of an oxytocin receptor antagonist to the central nervous system did not rescue the attenuated contextual or cued fear memory responses in Complete Deletion mice. Thus, increased oxytocin signaling is not acutely responsible for this phenotype. We also evaluated oxytocin receptor and serotonin transporter availability in regions related to fear learning, memory, and sociability using autoradiography in wild type and Complete Deletion mice. While we identified trends in lowered oxytocin receptor expression in the lateral septal nucleus, and trends towards lowered serotonin transporter availability in the striatum and orbitofrontal cortex, we found no significant differences after correction. Together, these data suggest the fear conditioning anomalies in the Williams Syndrome mouse model are independent of any alterations in the oxytocinergic system caused by deletion of the Williams locus.

animal behavior and cognition↗

bioRxiv2020

A MYT1L Syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation

Human genetics have defined a new autism-associated syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes autism, ADHD, intellectual disability, obesity, and brain anomalies is unknown. Here, we develop a mouse model of this syndrome. Physically, Myt1l haploinsufficiency causes obesity, white-matter thinning, and microcephaly in the mice, mimicking clinical phenotypes. During brain development we discovered disrupted gene expression, mediated in part by loss of Myt1l gene target activation, and identified precocious neuronal differentiation as the mechanism for microcephaly. In contrast, in adults we discovered that mutation results in failure of transcriptional and chromatin maturation, echoed in disruptions in baseline physiological properties of neurons. This results in behavioral anomalies including hyperactivity, muscle weakness and fatigue, and social alterations with more severe phenotypes in males. Overall, our findings provide insight into the mechanistic underpinnings of this disorder and enable future preclinical studies.

neuroscience↗