Jaegeon Lee1,2, Seung Ha Kim1,2, Yong-Seok Lee1,2,3, Yu Kyeong Kim3,4, Sang Jeong Kim1,2,3

Bergmann glia (BG) are radial glial cells in the cerebellar cortex that have multiple functions. They have been shown to interact with Purkinje cells in several ways: they modulate synaptic inputs to Purkinje cells, regulate excitability through external potassium concentration, and directly affect Purkinje cells through neurotransmitter release. In this study, we genetically expressed hM3Dq in BG through GFAP-promoter-contained AAV virus. We showed that this BG-PC regulation is mediated by the NMDA receptor and GABA_A receptor. Furthermore, using calcium imaging, we confirmed that BG activation induces MLI activation. Taken together, we concluded that glutamate released from BG induces GABA release from MLI, which in turn inhibits PC activity. Our findings provide a cellular mechanism for understanding the role of BG in the modulation of neuronal activity in the cerebellum.

1Department of Physiology, 2Department of Biomedical Sciences, 3Memory Network Medical Research Center, Neuroscience Research Institute, Wide River Institute of Immunology, Seoul National University College of Medicine, Seoul, Korea, 4 Department of Nuclear Medicine, Seoul National University Boramae Medical Center.

Britahny M. Baskin^1,2, Grace L. Whitney¹, Emma J. Sandago¹, Kelly K. Wingfield¹, Caroline Topping¹, Camily Hidalgo-Goncalves^1,3, Nina Garbarino^1,4, Mengyuan Liu^1,5, Camron D. Bryant^1,2

Accompanying the opioid epidemic is an increase in neonatal opioid withdrawal syndrome (NOWS), defined by a set of withdrawal symptoms in infants born to mothers who are dependent on opioids, including weight loss, agitation, excessive crying, and hyperalgesia. Despite having a heritable component, the genetic basis of NOWS remains largely unknown. We used a third trimester-approximate model for NOWS in mice comprising twice daily morphine (10 mg/kg, s.c.) from P1-P14 and assessment of opioid withdrawal signs on P7 and P14 (hypothermia, weight loss, locomotor agitation, ultrasonic vocalizations (USVs), and hyperalgesia and developmental milestones (self-righting, negative geotaxis, forlimb grasp, eye opening, pinnae attachment, fur cover, pivot extinction, cliff aversion, and vertical screen test). Ongoing studies implicate strain differences depending on morphine treatment, including blunted developmental weight gain and hypothermia in DBA/2J. There is also a trending Strain x Treatment interaction in thermal hyperalgesia on in the tail withdrawal on P7 (p=0.07) and a Strain x Sex interaction on P14 in the tail withdrawal (p=0.02). For USVs, spectrotemporal analysis of syllable types using supervised and unsupervised machine learning is ongoing. There is a trending Strain x Treatment x Sex interaction on P7 for total USVs (p=0.055) and a significant interaction for percentage of emitted “downward” syllables (p<0.01). Regarding milestones, we observed strain effects on self-righting and pivot extinction and treatment effects on pivot extinction, negative geotaxis, cliff aversion, and forelimb grasp. The Strain x Treatment interactions across NOWS model traits indicate that the BXD-RI panel will be effective for quantitative genetic analysis.

1. Laboratory of Addiction Genetics, Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University
2. NIH/NIDA T32 Training Program on Development and Medications for Substance Use Disorder
3. Williams College Alumni Sponsored Internship Program (ASIP)
4. Peak Awardee, Northeastern University
5. Master’s Program in Biomedical Sciences, Department of Pharmaceutical Sciences, Northeastern University

Paul J. Meyer¹, Christopher P. King^1,2, Thiago M. Sanches³, Apurva S. Chitre³, Nana K. Amissah¹, Karissa T. Reyes¹, Connor Martin², Oksana Polesskaya³, Keita Ishiwari², Hao Chen⁵, Leah C. Solberg Woods⁶, Craig C. Colder¹, David M. Dietz⁴ Abraham A. Palmer^3,7

Individual differences in behavioral regulation, including sensation seeking, attentional control, impulsivity, and cue reactivity, are linked to psychological disorders including substance use disorder (SUD). To examine the phenotypic and genetic relationships in animal models of these traits, we analyzed behavioral and genomic data from a large sample of heterogeneous stock (HS) rats (n ≈ 1600). Seven behavioral tasks assessed key measures, including locomotor response to novelty, social and light reinforcement, reaction time, delay discounting, Pavlovian cue-reactivity, and cocaine-conditioned cue preference. Significant individual variation and sex differences were seen, with females generally displaying higher locomotion, social and light reinforcement, reaction time, cue-reactivity, and cocaine cue preference, while males exhibited greater delay discounting and goal-directed approach. Factor analysis showed most measures clustered within individual tasks, though cocaine cue preference was linked to impulsivity-related traits, including delay discounting and false alarms in the reaction time task. Genome-wide association (GWA) analysis revealed heritabilities ranging from (0.12–0.30) for these traits, with several traits being genetically correlated to drug self-administration traits measured in other HS cohorts. Despite power limitations, preliminary sex-specific GWA for cue-reactivity revealed loci not identified in the pooled analysis. GWA using principal components derived from this test’s measures did not identify additional loci. Across all tasks, several candidate genes were identified; examples include Tenm4 on chromosome 1 (cue-reactivity), Abcfl on chromosome 20 (reaction time) and Otx2 on chromosome 15 (delay discounting). Many loci overlap with human GWA studies for SUD, underscoring the translational relevance of these results.

¹Department of Psychology, University at Buffalo, Buffalo, USA.

²Clinical and Research Institute on Addictions, Buffalo, USA.

³Department of Psychiatry, University of California San Diego, La Jolla, USA.

⁴Department of Pharmacology and Toxicology, University at Buffalo, Buffalo USA.

⁵Department of Pharmacology, Addiction Science and Toxicology, University of Tennessee Health Science Center, Memphis, USA.

⁶Department of Internal Medicine, Molecular Medicine, Center on Diabetes, Obesity and Metabolism, Wake Forest School of Medicine, Winston-Salem, USA.

⁷Institute for Genomic Medicine, University of California San Diego, La Jolla, USA.

Funding Support: DA037844, DA060810