1. The effect of natural sensory experience on neural circuit formation
The normal functioning of the brain relies on its intricate and complex circuits. Natural sensory experience is critical to neuronal development and the formation of functional neural circuits. In addition to inducing changes in the target cortex, sensory experience also crossmodally affects other brain regions. Previous works on crossmodal mechanisms have mostly focused on adult individuals,rather than developing organisms. By depriving neonatal mice of somatosensory or visual inputs, respectively using whisker-deprivation or dark-rearing paradigms, we found that these manipulations not only affected the correspondent sensory cortex, but also reduced excitatory synaptic transmission in other sensory cortices. Conversely, increasing sensory stimulation through environmental enrichment significantly accelerated development of excitatory synapses in multiple sensory cortices. This work identified a novel form of experience-dependent crossmodal plasticity in the sensory cortices during early development, in which oxytocin functions as a key mediator, at a much earlier developmental time point than its previously described roles in mediating social emotional behaviors. In ongoing work, we are investigating the circuit basis underlying this form of crossmodal plasticity, as well as the molecular mechanism by which oxytocin regulates synaptic transmission in the sensory cortices. The link between sensory experience and oxytocin signaling may be particularly relevant to autism research, where part of the hotly debated therapeutic role of oxytocin may be mediated through its effect on the sensory cortices, as hypersensitivity or hyposensitivity to sensory input is reported to be prevalent in children with autism spectrum disorders. The potential use of sensory experience to increase oxytocin level in autistic children is a research direction of interest.
2. Molecular mechanism underlying spine pruning
By virtue of their bulbous heads and constricted necks, dendritic spines provide important biochemical andelectrical compartmentalization within neurons, housing thepostsynaptic density of excitatory synapses and associated organelles. During development, the density of dendritic spines is highly dynamic, encompassing a rapid phase of spinogenesis during early development, followed by spine pruning and elimination during adolescence. Spine pruning during neural circuit refinement is critical to efficient information transfer and storage in the brain, but it underlying molecular mechanism is largely unknown. In recent work, we identified a critical role of cadherin/catenin cell adhesion complexes in determining spine fate during the pruning process. By manipulating the level of these complexes at the single spine level using molecular and channelrhodopsin-based tools, we showed that competition between neighboring spines for cadherin/catenin complexes determined their fates: the spine acquiring more complexes enlarged and became more mature, while the loser became smaller or was eliminated.
The competition-based and limited resource mechanism uncovered in this work not only expands our knowledge of neural circuit refinement, but also likely represents a general strategy employed by biological systems. Since defects in spine pruning have been associated with developmental neurological disorders including autism spectrum disorder and schizophrenia, in ongoing work, we are investigating whether changes in the time course of spinogenesis and/or spine pruning contribute to synaptic and behavioral defects in animal models of developmental neurological disorders.