Brain 'Niceness' Protein Required for Social Behavior
14 May, 2007 12:42 pm
The cell surface protein CD38, found on many immune cells such as leukocytes, is also present in neurons and astrocytes in the brain. CD38 is a popular marker for determining the malignancy and stage of chronic leukocytic leukemia in the clinical field. However, CD38?s function in the brain has remained elusive. Higashida and his colleagues have now shown that CD38 is required in mice for the regulation of social behavior, including male?s pair cognition and dam?s nurturing behaviors of pups by regulating oxytocin, originally known as the hormone for female?s uterine contraction during labor and mild ejection in lactation to babies.
Figure : Good mother
Female mice in which CD38 was knocked out (KO) displayed disrupted maternal behavior after separation of a mother and pups. We observed mothers’ behavior with their newborn pups in home cages in which pups were temporarily placed outside the nest. Normal dams retrieved their babies precisely and very quickly to the same small area of the nest.
CD38KO dams took a long time to start to retrieve and behaved as if they were not interested in their babies, alternatively, they ‘neglected’ pups. They often dropped them during retrieving on the way to the nest, as if they did not remember their nest, so that pups were scattered in different places. However, the CD38KO mothers fed the pups sufficiently well for them to grow to the same weight as the control pups. These results show the clear mother’s abnormal nurturing behavior in CD38KO postpartum mice under a stressful condition, such as separation.
Figure : Neglect mother
Next, we examined in young adults of CD38-/- male mice, which experienced repeated pairings with the same female mouse. Normal mice showed a significant decline in the time spent investigating a female upon subsequent presentations of the same female. This phenotype is due to, not because they loose interest to the pair, but have memorized the paired female. So they do no need to further investigate, but they instantaneously recognize the pair. In contrast, CD38KO males showed sustained high levels of investigation at each encounter with the same female and the same level of investigation, in another words, they behave as a ‘stoker’.
Since CD38KO mice did not have deficits in either olfactory-guided foraging or habituation to a non-social olfactory stimulus as tested by the preference ratio of consumption of isovaleric acid solution (sweat-like disgusting smell to us) in their drinking water, the impairment of social memory did not depend on deficits in main olfactory bulb function. Although the function of CD38 in social behavior could be very specific to the particular neural circuitry involved, the data so far do not rule out a more general cognitive dysfunction. Therefore, we examined if the CD38 mutants are able to learn the shock experience in the passive avoidance test. The answer was that yes, they can learn. We concluded that CD38KO males with persistent interest during repeated presentations fail to develop their social memory. The above abnormality resembles a memory deficit found in oxytocin gene or oxytocin receptor knockout mice, in which oxytocin is not produced or even if produced, has no effect. To link between CD38 and oxytocin, we measured plasma and brain oxytocin levels and found that, compared with wild-type animals, CD38 KO mice had reduced oxytocin levels, but elevated levels in the hypothalamus and pituitary in the brain. This indicates, although oxytocin is produced and packaged into vesicles in the hypothalamic neurons and posterior pituitary nerve endings in CD38 KO mice, it was not released into the brain and blood stream. Therefore, oxytocin does not function. Indeed, the behavioral phenotype of CD38 KO mice could be normalized even by a single subcutaneous oxytocin injection. We also tried a genetic approach by infusion of a virus carrying the human CD38 gene into the third ventricle of knockout mice. This procedure resulted in normalization of the plasma and CSF oxytocin level and thereby of normalized social memory, indicating that the mechanisms underlying social behavior require CD38-dependent oxytocin secretion.
In conclusion, our findings shed light on the function of CD38 in the brain and, potentially, in human diseases associated with abnormal social behavior such as pervasive developmental disorder, including autism. Most interestingly, our result gives a theoretical background for one immediately-applicable treatment to one subset of autism patient by oxytocin, but not by gene therapy of expressing CD38, which takes a long way.
Jin, D. et al. CD38 is critical for social behaviour by regulating oxytocin secretion. Nature 446, 41–45 (2007)