A wealth of neuropharmacological data demonstrates that oxytocin (OT) actions in the mammalian forebrain support a wide variety of affiliative behaviors and repress aggressive behaviors. Based on that literature, it was expected that reproductive and affiliative behaviors would be vastly decreased and aggression markedly increased in OT gene knockout (OTKO) mice. The initial publications reporting the behaviors of these mice did not include such phenotypes. Here, we compared single-unit activities recorded from the ventromedial hypothalamus in tissue slices of male and female OTKO mice and their wild-type littermate to test two hypotheses about OT functional genomics. First, we proposed that in OTKO mice, a very similar 9-amino-acid neuropeptide, arginine vasopressin (a likely gene duplication product), can ‘cross over’ and compensate for the lack of OT. This hypothesis was confirmed in both males and females. Further, we proposed that because of the lifelong absence of OT in OTKO, OT receptors would be more sensitive to OT in the knockout animals. We tested this idea in males and found that it was correct. Thus, an answer to the ‘OTKO paradox’ is put forth, with implications for OT-sensitive behaviors in a variety of species.

The expression of the immediate early gene c-fos has been used extensively as a marker for neural activation in response to acute and chronic stressful stimuli in brain and spinal cord. The present study examined the expression of Fos protein in the brainstem nuclei of male and female gonadectomized mice in response to cold stress. Free-floating sections were processed immunohistochemically for Fos protein using standard avidin-biotin complex methods. The number of Fos-positive neurons in each nucleus was determined. Although the experiment was designed to look for gender differences, results were equivalent between females and males. After mice were exposed to a cold ambient temperature (4 degrees C) for 2 h, elevated numbers of Fos-positive neurons were counted in the medullary gigantocellular reticular nucleus, medullary raphe nucleus, nucleus of the solitary tract and in locus coeruleus. However, no elevated expression was found in nucleus ambiguus, nor in neurons of the A1 group, nor the C2 or C3 group. Similar to rats, these results with mice reveal a widespread arousal system in the lower brainstem activated by cold stress in both genders. These findings in gonadectomized mice have set the stage for investigations following hormonal and genetic manipulations.