Mechanisms underlying neural circuit development and plasticity

The normal functioning of the brain relies on its intricate and complex circuits. Natural sensory experience is critical to the neuronal morphogenesis, synaptogenesis and the formation of functional neural circuits. In previous work, we showed the early developing brain exhibits different plasticity rules, as compared to the mature brain. Specifically, we:

1) showed that early sensory experience globally and cross-modally regulates the development of multiple sensory cortices, in a mechanism mediated by the neuropeptide oxytocin;

2）identified a dipeptidergic circuit, involving PAG Tac1 neurons and PVH oxytocin neurons, through which pleasant touch experience promotes social interactions and preference for the touch context;

3) found that during early neuroinflammation, perivascular pericytes rapidly sense the inflammatory signal and release the cytokine CCL2, which in turn, increase excitatory synaptic transmission in multiple brain regions;

4) show that during neural circuit maturation in the adolescent brain, sensory experience coordinately regulates the maturation of “useful” spines and the pruning of “less used” spines, in a mechanism dependent on the limited resource, the cadherin/catenin cell adhesion complex.

Based on these results, we proposed the “early global cross-modal neural circuit development hypothesis”. It is well known that the early developing brain is more plastic, and that some brain regions have critical periods. However, the underlying mechanisms are not well understood. We use a combination of single cell expression profiling, molecular biology, genetics and immunohistochemistry to investigate the molecular mechanisms underlying this type of plasticity. We also use electrophysiology, optical imaging and behavioral assays to identify the cellular and circuit mechanisms through which sensory experience and environmental factors regulates the early development of neurons, glial cells and the neurovascular unit. Understanding early global cross-modal plasticity mechanisms in the developing brain is critical to our understanding of the basic mechanism of brain wiring. Developmental neurological disorders, such as autism spectrum disorders and intellectual disabilities, have devastating impacts on the well-being of affected children. By understanding the operating principles of the young brain, early individualized interventions, through either drug therapies or behavioral training, can be developed, with important clinical and social implications.

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2. Yu H., Miao W., Ji E., Huang S., Jin S., Zhu X., Liu M.Z., Sun Y.G., Xu F., and Yu X.* (2022) Social touch-like tactile stimulation activates a tachykinin 1-oxytocin pathway to promote social interactions. Neuron 110(6):1051-1067. (highlighted by same issue Preview 110(6):909-911)

3. Cao H., Li M., Li G., Wen B., Lu Y., and Yu X.* (2020) Retinoid X receptor α regulates DHA-dependent spinogenesis and functional synapse formation in vivo. Cell Reports 31(7):107649.

4. Wang M., Yu Z., Li G., and Yu X.* (2020) Multiple morphological factors underlie experience-dependent cross-modal plasticity in the developing sensory cortices. Cerebral Cortex, 30(4):2418–2433.

5. Duan L., Zhang X.D., Miao W.Y., Sun Y.J., Xiong G., Wu Q., Li G., Yang P., Yu H., Li H., Wang Y., Zhang M., Hu L.Y., Tong X., Zhou W.H., Yu X.* (2018) PDGFRβ cells rapidly relay inflammatory signal from the circulatory system to neurons via chemokine CCL2. Neuron 100(1):183-200. (highlighted by same issue Preview 100(1):11-13)

6. Hu C.C., Xu X.*, Xiong G.L., Xu Q., Zhou B.R., Li C.Y., Qin Q., Liu C.X., Li H.P., Sun Y.J.*, Yu X.* (2018) Alterations in plasma cytokine levels in Chinese children with autism spectrum disorder. Autism Research 11(7):989-999.

7. Li M.Y., Miao W.Y., Wu Q.Z., He S.J., Yan G., Yang Y., Liu J.J., Taketo M.M. and Yu, X.* (2017) A critical role of presynaptic Cadherin/Catenin/p140cap complexes in stabilizing spines and functional synapses in the neocortex. Neuron 94(6):1155-1172

8. Wang M., Li H., Takumi T., Qiu Z., Xu X.*, Yu X.* and Bian W.J.* (2017) Distinct Defects in Spine Formation or Pruning in Two Gene Duplication Mouse Models of Autism Neurosci. Bull. 33(2):143-152

9. Bian W.J., Miao W.Y., He S.J., Qiu Z. and Yu, X.* (2015) Coordinated spine pruning and maturation mediated by inter-spine competition for cadherin/catenin complexes. Cell 162(4): 808-822 [highlighted by Nat. Rev. Neurosci. 16(10):577; selected as “exceptional” by Faculty 1000]

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