Session 2: Cognitive and Social Phenotypes in Autism

Larry J. Young, PhD
Center for Behavioral Neuroscience and Dept. of Psychiatry
Emory University, Atlanta GA 30322

Autism spectrum disorders are characterized by profound social impairments, including a lack of social engagement, deficits in communication, and abnormal neural processing of social stimuli. Research using animal models has implicated a role for oxytocin (OT) in social recognition and attachment, affiliation, and the neural processing of social cues. In addition, one study reported that autistic children have half the plasma concentration of OT compared to that of healthy controls (Modahl et al., 1998). We are using an OT knockout (OTKO) mouse model to investigate the role of OT in developmental and social behaviors that may be relevant to autism. The developmental studies suggest that OTKO pups are less distressed by social isolation and less motivated increase social contact with their mothers than wildtype (WT) pups. First, OTKO emit fewer ultrasonic distress calls when isolated from their mother than do WT pups (Winslow et al., 2000). When tested in a two-chambered testing arena in which the pup is placed in the empty chamber and the mother is restricted to the other chamber, OTKO pups exhibit a longer latency to cross into the mother's chamber than do WT pups. In addition, while WT pups show a strong preference for their mother over a novel lactating female in a preference test, OTKO pups show no preference.

As adults, OTKO pups fail to recognize individuals even after repeated exposures. Social recognition in mice is assessed by measuring the decline in olfactory investigation of a stimulus animal after several brief exposures. WT mice display a reduction in olfactory investigation after re-exposure to the same stimulus female while OTKO mice show no decline. This social amnesia is rescued by a single injection of OT into the brain prior to, but not after, the initial exposure. Using c-Fos immunocytochemistry, we have demonstrated that, unlike WT males, OTKO males fail to show an induction of neural activity in the medial amygdala during a social encounter. Instead, OTKO mice exhibit abnormal induction in several other brain regions, including the somatosensory cortex, and hippocampal structures. This suggests that OTKO mice process socially relevant stimuli via alternative neural pathways, and thus fail to develop a social memory. Microinjections of OT directly into the medial amygdala, but not into the olfactory bulb, restore social recognition in the OTKO mice. Based on these studies, there are a number of interesting parallels between autism spectrum disorders and social deficits in OTKO mice.

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