Social Motivation

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

Social motivation, defined as the internal processes that drive these social interactions, has been conceptualized in terms of several interrelated components including social orienting (attending to social stimuli) and social reward seeking (incentive value of social interactions), with each potentially mediated by distinct brain circuits, A focus of my lab is understanding the circuits that drive social motivation, the role of biological sex, and its regulation by genes associated with human conditions like autism spectrum condition (ASC). We developed a novel task to measure social motivation in the mouse leveraging the operant conditioning paradigm. Using this assay, we discovered a more robust level of social motivation in males compared to females, male-biased social motivation changes in models of ASC likelihood, and a female-biased role for the oxytocin system.


MYT1L

Pathogenic variants in the gene MYT1L have been associated with intellectual disability, and autism spectrum condition in exome studies. To study the function of MYT1L and its influence on clinically-relevant behavioral circuits, in collaboration with the Dougherty lab we generated a haploinsufficient mouse model that mirrors a patient-specific mutation (Chen et al., Neuron, 2021). Using this model, the Dougherty lab identified disrupted gene expression, precocious neuronal differentiation as a mechanism for microcephaly, and failure of transcriptional and chromatin maturation in adults. The Maloney lab found this model recapitulated many clinical phenotypes including hypotonia, ASD-related social challenges, ADHD-related hyperactivity, motor coordination issues, and obesity-related weight gain. We are now using a newly validated MYT1L conditional model to temporally and spatially restrict MYT1L loss to understand more directly how this transcription factor influences behavioral circuits.

Spectrum News report

Understanding Gait in IDD

We are interesting in understanding the influence of genetic IDD likelihood on motor functions across development, which we feel is an under-researched symptom domain of IDD, especially given the prevalence of motor disruptions, including gait irregularities, in individuals with IDDs like autism spectrum condition and Williams Syndrome. We used the advanced gait analysis system DigiGait to developed a protocol to measure the trajectory of gait components across development (Akula et al., Brain and Behavior, 2020) and identified components of mouse gait that mirror that in human gait. Specifically, developing mice exhibit a trajectory of gait development that establishes ratios of stride components similar to that observed in humans, which can be leveraged to identify sensitive markers of motor impairment. We then applied this protocol to models of IDD likelihood, Nf1 haploinsufficiency and complete deletion of the Williams Syndrome critical region, and found markedly similar spatial, temporal, and postural gait abnormalities during development across the two models (Rahn et al., JNDD, 2021). We are currently working to characterize gait across other models of IDD likelihood to These data will be used to understand how these distinct variants influence the development of gait to provide the foundation for interrogation of convergent neural circuitry pathology. In addition, we want to understand how gait and other motor deficits track with phenotypes representing the core features of specific IDDs to offer a new perspective on NDDs by demonstrating how motor deficits are linked with social and cognitive issues and that they may share common brain underpinnings.


Williams Syndrome Critical Region

Williams Syndrome (WS) is a neurogenetic developmental disorder that results from a loss of a 26 gene locus called the Williams Syndrome Critical Region (WSCR) and is characterized by cardiovascular problems, dysmorphia, cognitive deficits particularly in the visuospatial domain, and other behavioral phenotypes including anxiety and a hypersocial personality. We are interested in understanding the genetic underpinnings of the cognitive and behavioral features of WS, specifically, which genes within the WSCR drive these different features with a focus on the social behaviors. Using a mouse model that is hemizygous for the mouse homologue of the WSCR, called the Complete Deletion Mouse (CD mouse), which recapitulates many WS features observed in humans, we examined how this locus and individual genes therein (i.e. Gtf2i, Gtf2ird1) drove clinically-relevant phenotypes. We identified social communication, motor function including gait, and conditioning deficits in this model, and the roles of Gtf2i and Gtf2ird1 expression (a,b,c), and oxytocin signaling (d) on these phenotypes. Our most recent work revealed enhanced social motivation along with anxiety-like phenotypes, allowing for future genotype-phenotype explorations of the role of individual WSCR genes in these circuits.

  • a. Kopp ND, McCullough K, Maloney SE, Dougherty JD. Gtf2i and Gtf2ird1 mutation are not sufficient to reproduce mouse phenotypes caused by the Williams Syndrome critical region. Human Molecular Genetics. 2019 Oct; 28(20):3443-3465, PMID: 31418010
  • b. Kopp ND, Nygaard KR, Liu Y, McCullough KB, Maloney SE, Gabel HW, Dougherty JD. Functions of Gtf2i and Gtf2ird1 in the developing brain: transcription, DNA binding and long-term behavioral consequences. Hum Mol Genet. 2020 Jun 3;29(9):1498-1519. doi: 10.1093/hmg/ddaa070. PubMed PMID: 32313931; PubMed Central PMCID: PMC7526791
  • c. Rahn RM, Weichselbaum CT, Gutmann DH, Dougherty JD, Maloney SE. (2021) Shared developmental gait disruptions across two mouse models of neurodevelopmental disorders. J Neurodev Disord. 2021 Mar 20;13(1):10. doi: 10.1186/s11689-021-09359-0. PubMed PMID: 33743598; PubMed Central PMCID: PMC7980331.
  • d. Nygaard KR, Swift RG, Glick RM, Wagner RE, Maloney SE, Gould GG, and Dougherty JD. (2021). Oxytocin receptor activation does not mediate associative fear deficits in a Williams Syndrome model. Genes, Brain and Behavior. 2021 May 12;:e12750. doi: 10.1111/gbb.12750. [Epub ahead of print] PubMed PMID: 33978321.

Modeling clinically-relevant environmental exposures

A significant portion of my work has focused on clinically relevant investigations into the influence of environmental agents on the developing brain and long-term behavioral consequences. Modeling repeated exposures to glucocorticoids as treatment for chronic lung dysfunctions in human infants, we administered dexamethasone to neonatal mouse pups and found decreased cerebellar neuronal density and chronic deficits in fine motor coordination. My thesis research also modeled the risk of learning disabilities following multiple exposures to anesthesia. I investigated histological and behavioral outcomes of repeated exposures to isoflurane in the developing mouse pup and found robust increases in acute neurodegenerations, yet subtle, sex-specific persistent behavioral disruptions (a). During my postdoc research, my interest grew in the role of the serotonin system in the behavioral deficits we observed that are related to IDDs. I led an extensive project to examine the impact of maternal exposure to an SSRI during pregnancy and lactation on offspring developmental and long-term functioning. I identified disruptions to a range of behaviors, including early social communication, perseveration, social dominance, and tactile responsiveness, which are partially rescued by later SSRI exposure, as well as dendritic morphological anomalies in pyramidal cells in areas related to these functions (b). We have now taken the strategies developed to understand SSRI exposure and applied them to understand the influence of opioid exposure on the developing brain. Thus far, we have shown that ontogenetic exposure to oxycodone disrupts weight trajectories, early communicative behavior and early somatosensory reflexes in offspring (c). Mostly recently, we identified intact social behavior and learning and memory circuits yet sex-specific changes in sensory and reward processing following early opioid exposures (d).

  • a. Maloney SE, Yuede CM, Creeley CE, Williams SL, Huffman JN, Taylor GT, Noguchi KN, Wozniak DF. Repeated neonatal isoflurane exposures in the mouse induce apoptotic degenerative changes in the brain and relatively mild long-term behavioral deficits. Scientific Reports. 2019;9:2779.
  • b. Maloney SE, Akula S, Rieger MA, McCullough KB, Chandler, K, Corbett AM et al. Examining the reversibility of long-term behavioral disruptions in progeny of maternal SSRI exposure. eNeuro. 2018 Jul doi:10.1523/ENEURO.0120-18.2018
  • c. Minakova E, Sarafinovska S. Mikati MO, Barclay K, McCullough KB, Dougherty JD, Al-Hasani R, Maloney SE. Ontogenetic Oxycodone Exposure Affects Early-Life Communicative Behaviors, Sensorimotor Reflexes, and Weight Trajectory in Mice. (2021) Front. Behav. Neurosci. 15:615798 Authors contributed equally. d. Minakova E, Mikati MO, Madasu MK, Conway SM, Baldwin JW, Swift RG, McCullough KB, Dougherty JD, Maloney SE, Al-Hasani R*. Perinatal Oxycodone Exposure Causes Long Term Sex-Dependent Changes in Sensory and Reward Processing in Adult Mice. BioRxiv 480568 [Preprint]. February 17, 2022 [cited September 6, 2022]. *dual senior authorship Available from: https://www.biorxiv.org/content/10.1101/2022.02.15.480568v1