Simona Sarafinovska
Program: Neurosciences
Current advisor: Joseph D. Dougherty, PhD
Undergraduate university: Columbia University
Research summary
One great challenge in neuroscience is connecting molecular and cellular phenotypes to behavioral consequences. Research has traditionally been siloed—either focusing on molecular/cellular investigations or behavioral studies, with limited integration between these levels. Throughout my dissertation, I have addressed this fundamental divide by defining the neuronal substrates that drive behavioral differences in social domains through four interconnected studies using mouse models.
My research developed a novel social operant conditioning paradigm that simultaneously quantifies two distinct components of social motivation: effort expended to access a social partner (social reward seeking) and concurrent social orienting. The assay demonstrated that social motivation is a stable individual trait across multiple tests and revealed significant sex differences. Validation with autism-relevant Shank3B mutants showed reduced social orienting and compromised social reward seeking, while manipulating the oxytocin system through receptor antagonism decreased social motivation.
Using cutting-edge single-nucleus RNA-sequencing to profile almost 140,000 nuclei from the tuberal hypothalamus and adjacent thalamus in mice assessed for social motivation, we established that molecular activation patterns predict behavior across individuals. Specifically, activation of paraventricular Agtr1a+ neurons predicted reduced social behavior, with subsequent pharmacological inhibition using FDA-approved telmisartan improving social orienting. We demonstrated that natural variation in neuronal proportions significantly influences adult social behavior even among genetically identical individuals. Chemogenetic inhibition of Nxph4+ neurons in the posterior and lateral hypothalamus suppressed multiple aspects of social motivation.
To address methodological challenges in understanding individual variability in behavioral outcomes, we developed an inducible Calling Cards (iCC) technology. Our observation that social motivation functions as a stable individual trait prompted us to investigate the developmental events that differentiate between highly and lowly socially motivated animals. This investigation required a novel tool capable of recording transcriptional states prior to behavioral assessment. We tested two transcription factor-based strategies by developing two mouse lines: Jun-iCC to capture neural activity-dependent gene expression, and Sp1-iCC to profile actively transcribed regions. Despite limitations, this work establishes important groundwork for future development of temporally controlled molecular recording methods.
Together, these studies form a comprehensive investigation of the developmental, neurobiological, and methodological dimensions of social behavior. By bridging multiple levels of analysis—from single-cell molecular signatures to complex behavioral paradigms—this work provides new insights into the biological underpinnings of social motivation with significant potential implications for understanding conditions characterized by social deficits, including autism spectrum disorder, schizophrenia, social anxiety, and depression.
Graduate publications
Maloney SE, Sarafinovska S, Weichselbaum C, McCullough KB, Swift RG, Liu Y, Dougherty JD. 2023 A comprehensive assay of social motivation reveals sex-specific roles of autism-associated genes and oxytocin. Cell Rep Methods, 3(6):100504.
Yen A, Mateusiak C, Sarafinovska S, Gachechiladze MA, Guo J, Chen X, Moudgil A, Cammack AJ, Hoisington-Lopez J, Crosby M, Brent MR, Mitra RD, Dougherty JD. 2023 Calling Cards: A Customizable Platform to Longitudinally Record Protein-DNA Interactions Over Time in Cells and Tissues. Curr Protoc, 3(9)::e883.
Lagunas T Jr, Plassmeyer SP, Fischer AD, Friedman RZ, Rieger MA, Selmanovic D, Sarafinovska S, Sol YK, Kasper MJ, Fass SB, Aguilar Lucero AF, An JY, Sanders SJ, Cohen BA, Dougherty JD. 2023 A Cre-dependent massively parallel reporter assay allows for cell-type specific assessment of the functional effects of non-coding elements in vivo. Commun Biol, 6(1):1151.
Minakova E, Sarafinovska S, Mikati MO, Barclay KM, McCullough KB, Dougherty JD, Al-Hasani R, Maloney SE. 2021 Ontogenetic Oxycodone Exposure Affects Early Life Communicative Behaviors, Sensorimotor Reflexes, and Weight Trajectory in Mice. Front Behav Neurosci, 15():615798.