Ralph Porneso

Developmental plasticity, or the capacity of genotypes to produce different phenotypes under varying contexts, is poorly characterized in humans. Here we developed a longitudinal variance and a genotype-by-time model able to disentangle genetic effects from between-subject variability. Applied to early growth (infant length and BMI) and cognitive traits (math and reading) of 45,000 to 65,000 individuals, our models discovered 76 lead putative plasticity loci. Nearly all loci are novel; six replicate signals from independent interaction studies. We found evidence that additive genetic variation captures marginal effects from interactions, challenging the assumption that effect estimates from genome-wide association studies (GWAS) are purely additive. Notably, over 90% of putative plasticity loci are involved in distal intra-chromatin interactions implicating regulatory activity. Our findings provide molecular evidence that non-additive genetic variation contributes to complex traits and highlight the utility of longitudinal models in uncovering the biological underpinnings of trait plasticity.

Detailed characterization of interneuron types in primary visual cortex (V1) has greatly contributed to understanding visual perception, yet the role of chandelier cells (ChCs) in visual processing remains poorly characterized. Using viral tracing we found that V1 ChCs predominantly receive monosynaptic input from local layer 5 pyramidal cells and higher-order cortical regions. Two-photon calcium imaging and convolutional neural network modeling revealed that ChCs are visually responsive but weakly selective for stimulus content. In mice running in a virtual tunnel, ChCs respond strongly to events known to elicit arousal, including locomotion and visuomotor mismatch. Repeated exposure of the mice to the virtual tunnel was accompanied by reduced visual responses of ChCs and structural plasticity of ChC boutons and axon initial segment length. Finally, ChCs only weakly inhibited pyramidal cells. These findings suggest that ChCs provide an arousal-related signal to layer 2/3 pyramidal cells that may modulate their activity and/or gate plasticity of their axon initial segments during behaviorally relevant events.