The interplay between glutamatergic circuits and oxytocin neurons in the hypothalamus and its relevance to neurodevelopmental disorders.

Oxytocin (OXT) neurons of the hypothalamus are at the center of several physiological functions, including milk ejection, uterus contraction, and maternal and social behavior. In lactating females, OXT neurons show a pattern of burst firing and inter-neuron synchronization during suckling that leads to pulsatile release of surges of OXT into the bloodstream to stimulate milk ejection. This pattern of firing and population synchronization may be facilitated in part by hypothalamic glutamatergic circuits, as has been observed in vitro using brain slices obtained from male rats and neonates. However, it remains unknown how hypothalamic glutamatergic circuits influence OXT cell activity outside the context of lactation. In this review, we summarize the in vivo and in vitro studies that describe the synchronized burst firing pattern of OXT neurons and the implication of hypothalamic glutamate in this pattern of firing. We also make note of the few studies that have traced glutamatergic afferents to the hypothalamic paraventricular and supraoptic nuclei. Finally, we discuss the genetic findings implicating several glutamatergic genes in neurodevelopmental disorders, including autism spectrum disorder, thus underscoring the need for future studies to investigate the impact of these mutations on hypothalamic glutamatergic circuits and the OXT system.

Efficiency of cell-type specific and generic promoters in transducing oxytocin neurons and monitoring their neural activity during lactation.

Hypothalamic oxytocin (OXT) and arginine-vasopressin (AVP) neurons have been at the center of several physiological and behavioral studies. Advances in viral vector biology and the development of transgenic rodent models have allowed for targeted gene expression to study the functions of specific cell populations and brain circuits. In this study, we compared the efficiency of various adeno-associated viral vectors in these cell populations and demonstrated that none of the widely used promoters were, on their own, effective at driving expression of a down-stream fluorescent protein in OXT or AVP neurons. As anticipated, the OXT promoter could efficiently drive gene expression in OXT neurons and this efficiency is solely attributed to the promoter and not the viral serotype. We also report that a dual virus approach using an OXT promoter driven Cre recombinase significantly improved the efficiency of viral transduction in OXT neurons. Finally, we demonstrate the utility of the OXT promoter for conducting functional studies on OXT neurons by using an OXT specific viral system to record neural activity of OXT neurons in lactating female rats across time. We conclude that extreme caution is needed when employing non-neuron-specific viral approaches/promoters to study neural populations within the paraventricular nucleus of the hypothalamus.

Transmission of paternal retrieval behavior from fathers to sons in a biparental rodent.

Transmission of maternal behavior across generations occurs, but less is known about paternal behavior. In biparental species like the California mouse (Peromyscus californicus), paternal care contributes to the well-being of offspring with lasting consequences on the brain and behavior. Paternal huddling/grooming behavior can be passed on to future generations, but whether paternal retrieval, which removes young from potential harm, is transmitted independently is unclear. We manipulated paternal retrieval experience through pup displacement manipulations, then examined whether males exposed to higher levels of paternal retrieval in development altered their adult retrieval behavior with their offspring. Males exposed to heightened paternal retrievals, as compared to reduced retrievals, retrieved their offspring more often but huddled/groomed offspring less during undisturbed natural observations. No differences were observed following a pup displacement challenge. The high paternal retrieval group also exhibited more physical activity and stereotypy. Our results are consistent with the hypothesis that paternal retrieval levels are transmitted across generations and may function via mechanisms separate from huddling/grooming. One modifying factor may be anxiety because increased activity and stereotypy occurred in the high retrieval group. We speculate how the transmission of paternal retrievals may inform a protective parenting style.

Paternal Care Impacts Oxytocin Expression in California Mouse Offspring and Basal Testosterone in Female, but Not Male Pups.

Natural variations in parenting are associated with differences in expression of several hormones and neuropeptides which may mediate lasting effects on offspring development, like regulation of stress reactivity and social behavior. Using the bi-parental California mouse, we have demonstrated that parenting and aggression are programmed, at least in part, by paternal behavior as adult offspring model the degree of parental behavior received in development and are more territorial following high as compared to low levels of care. Development of these behaviors may be driven by transient increases in testosterone following paternal retrievals and increased adult arginine vasopressin (AVP) immunoreactivity within the bed nucleus of the stria terminalis (BNST) among high-care (HC) offspring. It remains unclear, however, whether other neuropeptides, such as oxytocin (OT), which is sensitive to gonadal steroids, are similarly impacted by father-offspring interactions. To test this question, we manipulated paternal care (high and low care) and examined differences in adult offspring OT-immunoreactive (OT-ir) within social brain areas as well as basal T and corticosterone (Cort) levels. HC offspring had more OT-ir within the paraventricular nucleus (PVN) and supraoptic nucleus (SON) than low-care (LC) offspring. Additionally, T levels were higher among HC than LC females, but no differences were found in males. There were no differences in Cort indicating that our brief father-pup separations likely had no consequences on stress reactivity. Together with our previous work, our data suggest that social behavior may be programmed by paternal care through lasting influences on the neuroendocrine system.

Increased vasopressin expression in the BNST accompanies paternally induced territoriality in male and female California mouse offspring.

While developmental consequences of parental investment on species-typical social behaviors has been extensively characterized in same-sex parent-offspring interactions, the impact of opposite-sex relationships is less clear. In the bi-parental California mouse (Peromyscus californicus), paternal retrieval behavior induces territorial aggression and the expression of arginine vasopressin (AVP) in adult male offspring. Although similar patterns of territorially emerge among females, the sexually dimorphic AVP system has not been considered since it is generally thought to regulate male-typical behavior. However, we recently demonstrated that male and female P. californicus offspring experience increases in plasma testosterone following paternal retrieval. Since AVP expression is androgen-dependent during development, we postulate that increases in AVP expression may accompany territoriality in female, as well as male offspring. To explore this aim, adult P. californicus offspring that received either high or low levels of paternal care (retrievals) during early development were tested for territoriality and immunohistochemical analysis of AVP within the bed nucleus of the stria terminalis (BNST), paraventricular nucleus (PVN), and supraoptic nucleus (SON). Consistent with previous studies, high care offspring were more aggressive than low care offspring. Moreover, high care offspring had significantly more AVP immunoreactive (AVP-ir) cells within the BNST than low care offspring. This pattern was observed within female as well as male offspring, suggesting an equally salient role for paternal care on female offspring physiology. Regardless of early social experience, sex differences in AVP persisted in the BNST, with males having greater expression than females.