Oxytocin Receptor in Sensori-Motor Circuits and Its Association with Hypothalamus Activity

The neurophysiological foundation and anatomical basis of circuits necessary for adult behaviors are established early in development. Numerous perinatal and postnatal variables affect circuit trajectory during developmental sensitive periods. Therefore, to understand adult behaviors, a consideration of the developmental origins of the behavior are important. The infant must attend to relevant sensory stimuli and environmental input predominantly from the caregiver during sensitive periods in development. The caregiver can orient, enhance, and highlight relevant stimuli to the infant. Early postnatal events such as parental care and environmental stimuli are critical factors that influence the oxytocin (OXT) and OXT receptor (OXTR) system. As an effector, OXT can facilitate the acquisition of sensory experiences in a social context and as a target, OXT and OXTR expression can be altered by early life experiences. OXT/OXTR manipulations in newborns have some potent acute and long-term effects. OXTRs are widely expressed in the brain and peripheral tissues both before birth and after birth in mice. Chapter 1 of this dissertation is a review of the dynamic expression patterns of OXTR and the effects of OXT at different developmental stages and across-species. During postnatal development, through activation of OXTR, OXT can shape the maturation of its own system, and other neurotransmitter systems. Chapter 2 describes the effects of congenital loss of OXTR on Oxt gene expression in the hypothalamus across development, and discusses the role of OXTR as potential mediators of sensory experience. These effects may be clinically relevant. Prader-Willi syndrome (PWS) is a genetic disorder with severe hypothalamic dysfunction including impaired OXT system (decreased OXT immunoreactivity in the paraventricular nucleus of the hypothalamus (PVN) and reduced Oxtr gene expression the frontal cortex in postmortem tissue). Further, PWS phenotypes have origins in sensorimotor deficits at infancy with promising therapeutic effects of OXT. Chapter 3 describes a series of experiments conducted to assess the role of peripheral OXTR in PWS, and identifies critical anatomical regions in the periphery where OXT/OXTR can interact with genes in the PWS imprinted domain. Because the production of mature OXT in the neonatal mouse is low and maternal production of OXT is high, the earliest OXT signaling events in the developing mammal may be from maternal sources of OXT and can act on peripheral OXTR in neonatal mice. Chapter 4 describes where the effector sites are located in the periphery, what type of sensory signals they might regulate, the brainstem projections of neurons expressing Oxtr, and describes a useful mouse-line using a Cre-Lox P approach for a further understanding of OXTR in peripheral sensory ganglia. To summarize, as presented in Chapter 5, these data suggest that OXTR is an important candidate to mediate sensory experience and perhaps attune the infant brain to attend to sensory stimuli in a social context. In this way, OXT/OXTR in peripheral sensorimotor systems may set-up a mechanism by which environmental stimuli programs neuropeptide synthesis and release in the brain, and establishes the foundation for neurotypical hypothalamic circuits.