Prenatal ß-catenin/Brn2/Tbr2 transcriptional cascade regulates adult social and stereotypic behaviors.

Social interaction is a fundamental behavior in all animal species, but the developmental timing of the social neural circuit formation and the cellular and molecular mechanisms governing its formation are poorly understood. We generated a mouse model with mutations in two Disheveled genes, Dvl1 and Dvl3, that displays adult social and repetitive behavioral abnormalities associated with transient embryonic brain enlargement during deep layer cortical neuron formation. These phenotypes were mediated by the embryonic expansion of basal neural progenitor cells (NPCs) via deregulation of a ß-catenin/Brn2/Tbr2 transcriptional cascade. Transient pharmacological activation of the canonical Wnt pathway during this period of early corticogenesis rescued the ß-catenin/Brn2/Tbr2 transcriptional cascade and the embryonic brain phenotypes. Remarkably, this embryonic treatment prevented adult behavioral deficits and partially rescued abnormal brain structure in Dvl mutant mice. Our findings define a mechanism that links fetal brain development and adult behavior, demonstrating a fetal origin for social and repetitive behavior deficits seen in disorders such as autism.

Clustering autism: using neuroanatomical differences in 26 mouse models to gain insight into the heterogeneity.

Autism is a heritable disorder, with over 250 associated genes identified to date, yet no single gene accounts for >1-2% of cases. The clinical presentation, behavioural symptoms, imaging and histopathology findings are strikingly heterogeneous. A more complete understanding of autism can be obtained by examining multiple genetic or behavioural mouse models of autism using magnetic resonance imaging (MRI)-based neuroanatomical phenotyping. Twenty-six different mouse models were examined and the consistently found abnormal brain regions across models were parieto-temporal lobe, cerebellar cortex, frontal lobe, hypothalamus and striatum. These models separated into three distinct clusters, two of which can be linked to the under and over-connectivity found in autism. These clusters also identified previously unknown connections between Nrxn1α, En2 and Fmr1; Nlgn3, BTBR and Slc6A4; and also between X monosomy and Mecp2. With no single treatment for autism found, clustering autism using neuroanatomy and identifying these strong connections may prove to be a crucial step in predicting treatment response.

Context-specific social behavior is altered by orbitofrontal cortex lesions in adult rhesus macaques.

Although the orbitofrontal cortex has been implicated in important aspects of social behavior, few studies have evaluated semi-naturalistic social behavior in nonhuman primates after discrete lesions of this cortical area. In the present report, we evaluated the behavior of adult rhesus monkeys during dyadic social interactions with novel animals following discrete lesions of the orbitofrontal cortex. In a constrained condition, in which animals could engage in only restricted social behaviors, there were no significant differences in social behavior between the lesion group and the sham-operated control group. When the experimental animals could freely interact with partner animals, however, lesioned animals differed from control animals in terms of social interest and fear-related behaviors. These alterations were contingent on the partner with which they interacted. The lesioned animals, when compared to the control animals, had a significantly greater propensity to approach some but not all of their social partners. They also grimaced more towards the partner animal that they did not approach. Behavioral alterations were more apparent during the initial interactions between animals. We discuss these findings in relation to the role of the orbitofrontal cortex in context dependent modulation of social behavior.

Emergence of stereotypies in juvenile monkeys (Macaca mulatta) with neonatal amygdala or hippocampus lesions.

The emergence of stereotypies was examined in juvenile rhesus monkeys (Macaca mulatta) who, at 2 weeks of postnatal age, received selective bilateral ibotenic acid lesions of the amygdala (N = 8) or hippocampus (N = 8). The lesion groups were compared to age-matched control subjects that received a sham surgical procedure (N = 8). All subjects were maternally reared for the first 6 months and provided access to social groups throughout development. Pronounced stereotypies were not observed in any of the experimental groups during the first year of life. However, between 1 to 2 years of age, both amygdala- and hippocampus-lesioned subjects began to exhibit stereotypies. When observed as juveniles, both amygdala- and hippocampus-lesioned subjects consistently produced more stereotypies than the control subjects in a variety of contexts. More interesting, neonatal lesions of either the amygdala or hippocampus resulted in unique repertoires of repetitive behaviors. Amygdala-lesioned subjects exhibited more self-directed stereotypies and the hippocampus-lesioned subjects displayed more head-twisting. We discuss these results in relation to the neurobiological basis of repetitive stereotypies in neurodevelopmental disorders, such as autism.