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1. Epigenetic tuning of brain signal entropy in emergent human social behavior

   https://doi.org/10.1186/s12916-020-01683-x  

   Puglia, Meghan H. ; Krol, Kathleen M. ; Missana, Manuela ; Williams, Cabell L. ; Lillard, Travis S. ; Morris, James P. ; Connelly, Jessica J. ; Grossmann, Tobias ( December 2020 , BMC Medicine)

   null (Ed.)

   Abstract Background How the brain develops accurate models of the external world and generates appropriate behavioral responses is a vital question of widespread multidisciplinary interest. It is increasingly understood that brain signal variability—posited to enhance perception, facilitate flexible cognitive representations, and improve behavioral outcomes—plays an important role in neural and cognitive development. The ability to perceive, interpret, and respond to complex and dynamic social information is particularly critical for the development of adaptive learning and behavior. Social perception relies on oxytocin-regulated neural networks that emerge early in development. Methods We tested the hypothesis that individual differences in the endogenous oxytocinergic system early in life may influence social behavioral outcomes by regulating variability in brain signaling during social perception. In study 1, 55 infants provided a saliva sample at 5 months of age for analysis of individual differences in the oxytocinergic system and underwent electroencephalography (EEG) while listening to human vocalizations at 8 months of age for the assessment of brain signal variability. Infant behavior was assessed via parental report. In study 2, 60 infants provided a saliva sample and underwent EEG while viewing faces and objects and listening to human speech and water sounds at 4 months of age. Infant behavior was assessed via parental report and eye tracking. Results We show in two independent infant samples that increased brain signal entropy during social perception is in part explained by an epigenetic modification to the oxytocin receptor gene ( OXTR ) and accounts for significant individual differences in social behavior in the first year of life. These results are measure-, context-, and modality-specific: entropy, not standard deviation, links OXTR methylation and infant behavior; entropy evoked during social perception specifically explains social behavior only; and only entropy evoked during social auditory perception predicts infant vocalization behavior. Conclusions Demonstrating these associations in infancy is critical for elucidating the neurobiological mechanisms accounting for individual differences in cognition and behavior relevant to neurodevelopmental disorders. Our results suggest that an epigenetic modification to the oxytocin receptor gene and brain signal entropy are useful indicators of social development and may hold potential diagnostic, therapeutic, and prognostic value. 

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2. Paleogenomic insights into cooperation in the ancient Andes from positive selection on oxytocin pathway genes

   https://doi.org/10.1111/gbb.12877  

   Joseph, Sophie K. ; Wagman, Elizabeth ; Diab, Nabeel ; Ryu, Nicholas ; Lee, Minwoo ; Haas, Randall ; Rilling, James K. ; Aldenderfer, Mark S. ; Lindo, John ( February 2024 , Genes, Brain and Behavior)

   Human societies are characterized by norms that restrict selfish behavior and promote cooperation. The oxytocin system is an important modulator of social behavior that may be involved in the evolution of cooperation. Oxytocin acts in both the nucleus accumbens and the anterior cingulate cortex to promote social bonding and social cohesion. Expression of theCD38andOXTRgenes is known to affect oxytocin secretion and binding, respectively, in these brain areas. The Andean highlands provide an excellent opportunity to evaluate the role of oxytocin in the evolution of cooperation. The rich archeological record spans 13,000 years of population growth and cooperative challenges through periods of highland exploration, hunting economies, agro‐pastoralism, and urbanization. Through allele trajectory modeling using both ancient and contemporary whole genomes, we find evidence for strong positive selection on theOXTRandCD38alleles linked with increased oxytocin signaling. These selection events commenced around 2.5 and 1.25 thousand years ago, placing them in the region's Upper Formative and Tiwanaku periods—a time of population growth, urbanization, and relatively low rates of violence. Along with remarkable and enduring cultural developments, increased oxytocin secretion and receptor binding in these brain areas may have facilitated large‐scale cooperation that promoted early urbanization in the Titicaca Basin of the Andean highlands.

    

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3. The central oxytocinergic system of the prairie vole

   https://doi.org/10.1007/s00429-024-02832-1  

   Ramos, E_N ; Jiron, G_M ; Danoff, J_S ; Anderson, Z. ; Carter, C_S ; Perkeybile, A_M ; Connelly, J_J ; Erisir, A. ( July 2024 , Brain Structure and Function)

   Oxytocin (OXT) is a peptide hormone and a neuropeptide that regulates various peripheral physiological processes and modulates behavioral responses in the central nervous system. While the humoral release occurs from the axons arriving at the median eminence, the neuropeptide is also released from oxytocinergic cell axons in various brain structures that contain its receptor, and from their dendrites in hypothalamic nuclei and potentially into the cerebrospinal fluid (CSF). Understanding oxytocin’s complex functions requires the knowledge on patterns of oxytocinergic projections in relationship to its receptor (OXTR). This study provides the first comprehensive examination of the oxytocinergic system in the prairie vole (Microtus ochrogaster), an animal exhibiting social behaviors that mirror human social behaviors linked to oxytocinergic functioning. Using light and electron microscopy, we characterized the neuroanatomy of the oxytocinergic system in this species. OXT+ cell bodies were found primarily in the hypothalamus, and axons were densest in subcortical regions. Examination of the OXT+ fibers and their relationship to oxytocin receptor transcripts (Oxtr) revealed that except for some subcortical structures, the presence of axons was not correlated with the amount ofOxtracross the brain. Of particular interest, the cerebral cortex that had high expression ofOxtrtranscripts contained little to no fibers. Electron microscopy is used to quantify dense cored vesicles (DCV) in OXT+ axons and to identify potential axonal release sites. The ependymal cells that line the ventricles were frequently permissive of DCV-containing OXT+ dendrites reaching the third ventricle. Our results highlight a mechanism in which oxytocin is released directly into the ventricles and circulates throughout the ventricular system, may serve as the primary source for oxytocin that binds to OXTR in the cerebral cortex.

    

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4. Distribution of vasopressin 1a and oxytocin receptor protein and mRNA in the basal forebrain and midbrain of the spiny mouse (Acomys cahirinus)

   https://doi.org/10.1007/s00429-022-02581-z  

   Powell, Jeanne M. ; Inoue, Kiyoshi ; Wallace, Kelly J. ; Seifert, Ashley W. ; Young, Larry J. ; Kelly, Aubrey M. ( March 2023 , Brain Structure and Function)

   The nonapeptide system modulates numerous social behaviors through oxytocin and vasopressin activation of the oxytocin receptor (OXTR) and vasopressin receptor (AVPR1A) in the brain. OXTRs and AVPR1As are widely distributed throughout the brain and binding densities exhibit substantial variation within and across species. Although OXTR and AVPR1A binding distributions have been mapped for several rodents, this system has yet to be characterized in the spiny mouse (Acomys cahirinus). Here we conducted receptor autoradiography and in situ hybridization to map distributions of OXTR and AVPR1A binding and Oxtr and Avpr1a mRNA expression throughout the basal forebrain and midbrain of male and female spiny mice. We found that nonapeptide receptor mRNA is diffuse throughout the forebrain and midbrain and does not always align with OXTR and AVPR1A binding. Analyses of sex differences in brain regions involved in social behavior and reward revealed that males exhibit higher OXTR binding densities in the lateral septum, bed nucleus of the stria terminalis, and anterior hypothalamus. However, no association with gonadal sex was observed for AVPR1A binding. Hierarchical clustering analysis further revealed that co-expression patterns of OXTR and AVPR1A binding across brain regions involved in social behavior and reward differ between males and females. These findings provide mapping distributions and sex differences in nonapeptide receptors in spiny mice. Spiny mice are an excellent organism for studying grouping behaviors such as cooperation and prosociality, and the nonapeptide receptor mapping here can inform the study of nonapeptide-mediated behavior in a highly social, large group-living rodent. 

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5. Quantification of surface-localized and total oxytocin receptor in myometrial smooth muscle cells

   https://doi.org/10.1016/j.heliyon.2024.e25761  

   Fang, Yingye ; Reinl, Erin L. ; Liu, Audrey ; Prochaska, Trinidi D. ; Malik, Manasi ; Frolova, Antonina I. ; England, Sarah K. ; Imoukhuede, Princess I. ( February 2024 , Heliyon)

   Oxytocin acts through the oxytocin receptor (OXTR) to modulate uterine contractility. We previously identified OXTR genetic variants and showed that, in HEK293T cells, two of the OXTR protein variants localized to the cell surface less than wild-type OXTR. Here, we sought to measure OXTR in the more native human myometrial smooth muscle cell (HMSMC) line on both the cell-surface and across the whole cell, and used CRISPR editing to add an HA tag to the endogenous OXTR gene for anti-HA measurement. Quantitative flow cytometry revealed that these cells possessed 55,000 ± 3200 total OXTRs and 4900 ± 390 cell-surface OXTRs per cell. To identify any differential wild-type versus variant localization, we transiently transfected HMSMCs to exogenously express wild-type or variant OXTR with HA and green fluorescent protein tags. Total protein expression of wild-type OXTR and all tested variants were similar. However, the two variants with lower surface localization in HEK293T cells also presented lower surface localization in HMSMCs. Overall, we confirm the differential surface localization of variant OXTR in a more native cell type, and further demonstrate that the quantitative flow cytometry technique is adaptable to whole-cell measurements. 

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