Biologically grounded on-chip model identifies selective topographic reorganization within hyperexcitable...

Area of Science:

• Neuroscience
• Developmental Biology
• Systems Biology

Background:

• Mammalian cerebral cortex projections to the striatum form precise, hierarchical pathways crucial for various processing functions.
• Functional segregation of corticostriatal projections suggests intrinsic organizing principles, despite the striatum's lack of clear anatomical boundaries.
• Disruptions in corticostriatal connectivity are implicated in neurodevelopmental disorders, but the causal relationship with circuit dysfunction is unclear.

Purpose of the Study:

• To investigate the hypothesis that cortical neuron excitability directly shapes the topographic organization of corticostriatal projections.
• To understand the role of intrinsic, activity-sensitive mechanisms in constraining axonal growth during development.
• To explore how early circuit vulnerabilities contribute to connectivity defects in neurodevelopmental disorders.

Main Methods:

• Development of a biologically faithful in vitro platform inspired by the Tesla valve.
• Modeling adjacent corticostriatal territories under controlled excitability regimes.
• Analysis of axonal growth, stabilization, and projection patterns under varying cortical excitability.

Main Results:

• Cortical hyperexcitability disrupted the developmental transition from axonal growth to stabilization.
• Hyperexcitability led to premature invasion of neighboring territories and formation of ectopic convergence zones.
• Segregation between parallel corticostriatal pathways was lost, while local connectivity remained unaffected.

Conclusions:

• Intrinsic, activity-sensitive mechanisms constrain long-range axonal growth to shape the corticostriatal projectome's wiring diagram.
• Cortical hyperexcitability can cause connectivity defects, potentially underlying neurodevelopmental disorders like autism spectrum disorder and schizophrenia.
• Biologically grounded on-chip models are powerful tools for studying early circuit vulnerabilities and their consequences.