Cognitive control deficits are one of the frequent challenges accompanying autism spectrum disorder (ASD). However, little is known about the link between ASD risk genes and neural circuit mechanisms underlying cognitive control behavior, especially in the prefrontal cortex (PFC).

Recent genetic and transcriptome studies have shown that many ASD risk genes are enriched in fetal and infant deep layer PFC projection neurons. In the current project, Hirofumi Morishita and his team aim to identify specific deep layer PFC projection neurons and associated networks that are convergingly vulnerable to multiple ASD risk gene manipulations and also responsible for cognitive control behavior. Insights from these studies can help to establish pre-clinical strategies for ameliorating cognitive deficits in ASD.

Morishita and his team recently demonstrated that deep layer PFC top-down frontal-sensory projections from the anterior cingulate to the visual cortex play an essential causal role in cognitive control¹. Further, they found that this key top-down cognitive control circuit undergoes an adolescent maturation² driven by the suppression of nicotinic acetylcholine receptor (nAChR) signaling³. Of note, preliminary findings from Morishita’s lab indicate that this maturational process is disrupted in multiple ASD genetic mouse models.

Morishita thus hypothesizes that multiple ASD risk genes disrupt deep layer top-down frontal-sensory projection and associated networks contributing to cognitive control deficit. He plans to test this hypothesis by applying circuit-specific approaches to monitor and modulate neural activity in deep layer frontal-sensory projection neurons during free moving cognitive control tasks with mice in which ASD risk genes (Fmr1 and Shank3) have been deleted. His team also plans to employ circuit selective viral modulation of nAChR signaling to ameliorate cognitive control deficits in ASD mouse models.

Findings from these studies are expected to identify specific PFC circuits that are altered by the loss of ASD risk genes and their effects on cognitive control behavior. They have the potential to identify targets for the amelioration of cognitive deficits in ASD.

1. Norman K.J. et al. Neuron 109, 1202-1213 (2021) PubMed
2. Nabel E.M. et al. Nat. Commun. 11, 3983 (2020) PubMed
3. Falk E.N. et al. Sci. Adv. 7, eabe1527 (2021) PubMed