Investigation of social brain circuits in mouse models of the 16p11.2 locus

  • Awarded: 2011
  • Award Type: Research
  • Award #: 204719

Pavel Osten and his colleagues at Cold Spring Harbor Laboratory in New York study mouse brain circuits mediating social and other innate behaviors, such as aggression and sexual behaviors. The researchers use a novel automated whole-mount microscopy method called serial two-photon tomography and computational whole-brain analysis of the induction of the immediate early gene c‐FOS, a molecular marker of neuronal activation. This method allows them to map brain circuits mediating behaviors in control mice. It also enables them to identify brain circuit deficits that may underlie abnormal behaviors in genetic mouse models of autism.

As part of the current project, focused on the study of autism mouse models with a deficiency in the 16p11.2 chromosomal region, Osten and his group generated the first cellular‐resolution map of whole‐brain activation evoked during a brief social interaction between male and female control mice. They found a network of 43 brain regions organized mainly in three circuits: areas downstream of the accessory olfactory bulb, mediating pheromonal and volatile signaling; the striato‐pallido-thalamo cortical circuit, mediating arousal and reward; and hypothalamic nuclei, mediating reproductive functions. This dataset provides an essential baseline for future comparisons of brain activation patterns in control mice and genetic mouse models of autism, including the 16p11.2 mouse model.

The group also discovered that the 16p11.2 mice have an increased seizure propensity, a finding that may be related to the increased rate of seizures in children with autism who have deletions in this region. They used whole‐brain c‐FOS screening to search for brain regions with abnormally elevated c‐FOS induction, which would suggest an abnormally elevated excitation/inhibition ratio. Osten and his team have identified several areas of the cortex as regions with a particularly abnormal activation response, suggesting that these areas may play significant roles in generating the behavioral phenotype.

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