UNIVERSITY OF ILLINOIS
The general goal of this proposal is to develop an animal model for examining the mechanisms through which social support may be protective against various challenges, especially in aging. We will focus here on the hypothesis that oxytocin (OT) plays a central role in buffering against emotional and autonomic reactivity, including stress and anxiety which may have broad consequences for mental and physical health. To dissect the physiological mechanisms that underlie the connection between stress and sociality, we will use the prairie vole (Microtus ochrogaster), an animal similar to humans (but unique among rodents) in its tendency to form selective, long-lasting social bonds. Prairie voles also have a human-like autonomic nervous system and produce high levels of OT. The proposed integrative experiments will examine behavioral, neuroendocrine and autonomic changes following social separation and isolation, as a function of the presence or absence of OT. Because aging individuals may be especially sensitive to the effects of disruptions of social systems, we propose to study both young and older subjects.
Preliminary data suggest that peripheral OT supplementation for the latter 2 weeks of a 4-week SSI period can protect or restore behavior and autonomic function to non-SSI (i.e. paired-living) levels. However, the mechanisms of this effect are not known, including whether these effects are mediated centrally or peripherally. Our initial experiments will address this question in SSI animals by comparing the dose-dependent effects of central (icv) versus peripheral (sc) OT treatments on dependent variables, including measures of emotional reactivity and autonomic function that have previously been shown to be increased by SSI and reversed by peripheral OT. In conjunction with autonomic measures, we will expose animals to various challenges including the elevated plus maze, a swim test and a resident intruder test. Following behavioral testing, terminal measures will be taken of central and peripheral peptides including OT, the related peptide arginine vasopressin (AVP) and corticotropin releasing factor (CRF), a central component of the HPA axis, using c-Fos co-localization to identify target neuropeptides systems that may be activated during challenge.
We will examine the behavioral, neuroendocrine, and autonomic effects of OT blockade, but using a selective OT antagonist to block access of endogenous OT to the OT receptor. OTA will be given peripherally and also centrally (icv). Animals respond to SSI (and certain other forms of stressors) with heightened release of OT. In the absence of OT, individuals may be less capable of managing stressors . However, whether this is the case during SSI has not yet been examined. Results will determine whether blocking the effect of heightened OT following SSI results in increases or decreases in behavioral reactivity and autonomic function, and possibly produces feedback changes in endogenous OT, AVP or CRF systems. We will also investigate whether these effects are through central or peripheral mechanisms. Based on the outcome of these studies it is will be possible to give OT centrally and use OTA to block peripherally and vice versa.
Using data from the above experiments, we will select one method and dose for administering OT, followed by an OTA treatment (either peripheral or central). This experiment tests the hypothesis that peripheral (or central) OT acts through effects on the OTR (central or peripheral)
We will then determine whether the effects of either OT or OTA are different in animals housed alone (SSI) or in pairs.