Accumulating evidence supports a role for T cells in behavioral stress responsiveness. Our laboratory previously reported that lymphocyte deficient Rag2−/− mice on a BALB/c background display resilience to maladaptive stress responses when compared with immune competent mice in the predator odor exposure (POE) paradigm while exhibiting similar behavior in a cued fear-conditioning (FC) paradigm. In the present study Rag2−/− mice on a C57BL/6 background were assessed in the same behavioral paradigms, as well additional tests of anxiety and depressive-like behavior. Furthermore, the effects of naïve CD4+ T cells were evaluated by adoptive transfer of functional cells from non-stressed, wild-type donors to Rag2−/− mice. Consistent with our prior results, Rag2−/− mice displayed an attenuated startle response after POE. Nevertheless, reconstitution of Rag2−/− mice with CD4+ T cells did not modify startle reactivity. Additionally, in contrast with our previous findings, Rag2−/− mice showed attenuated fear responses in the FC paradigm compared to wild type mice and reconstitution with CD4+ T cells promoted fear learning and memory. Notably, reconstitution with CD4+ T cells had anxiolytic and anti-depressant like effects in Rag2−/− mice that had not been previously stressed, but had no effect after POE. Taken together, our results support a role for CD4+ T cells in emotionality, but also indicate that they may promote fear responses by enhancing learning and memory processes.

Accumulating evidence has shown that lymphocytes modulate behaviour and cognition by direct interactions with the central nervous system. Studies have shown that reconstitution by adoptive transfer of lymphocytes from wild type into immune-deficient mice restores a number of neurobehavioural deficits observed in these models. Moreover, it has been shown that these effects are mostly mediated by T lymphocytes. Studies of adoptive transfer thus far have employed adult mice, but whether lymphocytes may also modulate behaviour during development remains unknown. In this study, neonate lymphocyte-deficient Rag2 mice were reconstituted within 48 hours after birth with lymphoid cells from transgenic donors expressing green fluorescent protein, allowing for their identification in various tissues in recipient mice while retaining all functional aspects. Adolescent Rag2 and reconstituted Rag2 along with C57BL/6J wild-type mice underwent a series of behavioural tests, including open field, social interaction and sucrose preference tests. At 12 weeks, they were evaluated in the Morris water maze (MWM). Reconstituted mice showed changes in almost all aspects of behaviour that were assessed, with a remarkable complete rescue of impaired social behaviour displayed by adolescent Rag2 mice. Consistent with previous reports in adult mice, neonatal reconstitution in Rag2 mice restored spatial memory in the MWM. The presence of donor lymphocytes in the brain of neonatally reconstituted Rag2 mice was confirmed at various developmental points. These findings provide evidence that lymphocytes colonize the brain during post-natal development and modulate behaviour across the lifespan supporting a role for adaptive immunity during brain maturation.

A cross-fostering design was used to assess the relative involvement of genetic variability and early postnatal experiences on differential levels of playfulness in juvenile Fischer 344 (F344) and Lewis (LEW) rats and the extent to which strain differences in anxiety may influence play in these two strains. F344 dams were found to lick and groom their pups less than LEW dams and this was not dependent upon the strain of the pups in the litter. As expected, F344 rats were less playful than LEW rats as demonstrated by fewer playful contacts directed to the nape of a Sprague-Dawley (SD) partner and a decreased likelihood of rotating completely to a supine position when their nape was contacted by the SD partner. These differences could not be readily explained by parallel strain differences in anxiety. The pattern of effects on play as a function of cross-fostering depended on both the genetic background of the pup and the motivational state of the pup prior to testing. Whereas in-fostered LEW pups solicited more play as isolation prior to testing increased from 4 to 24 hours, cross-fostered pups of both strains as well as in-fostered F344 pups were relatively insensitive to the motivational modulation of play solicitation. Responsiveness to play solicitations in pups of both strains reared by F344 dams was insensitive to prior isolation whereas pups reared by LEW dams were less likely to respond with a complete rotation to a supine position when solicited as isolation increased from 4 to 24 hours prior to testing. These data suggest that the overall level of playfulness in a particular strain of rat is fairly resistant to cross-fostering and may be particularly sensitive to genetic variation whereas how this urge is titrated and modified by motivational factors may be influenced more by epigenetic factors.

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