Molecular and circuit mechanisms underlying interhemispheric communication in the mammalian brain

Abstract

Interhemispheric communication is a fundamental feature of the mammalian brain, supporting the bilateral integration of sensory, motor, cognitive, and emotional processes. While the corpus callosum has long been recognized as the principal commissural pathway, recent advances have illuminated a far more complex molecular and circuit‑level architecture. This review synthesizes evidence from neuroanatomy, electrophysiology, molecular neuroscience, and neuroimaging to outline how interhemispheric signaling is organized and dynamically regulated. Fast excitatory and inhibitory neurotransmission provides the scaffold for callosal transfer, while neuromodulatory systems, including dopaminergic, cholinergic, serotonergic, and noradrenergic pathways, introduce a chemical layer of regulation that tunes excitability, synchrony, and hemispheric dominance. Developmental processes involving axon guidance molecules and neurotrophins shape the establishment of commissural networks, whereas activity‑dependent plasticity refines functional architecture of these networks across the lifespan. Importantly, interhemispheric interactions are not static but fluctuate dynamically according to behavioral demands, as demonstrated by recent models of dynamic laterality. Disruption of these lateralized processes is implicated in a broad spectrum of conditions, including stroke, dyslexia, autism spectrum disorder, schizophrenia, and mood disorders. By bridging cellular, molecular, and systems‑level insights, this review highlights interhemispheric communication as a key organizing principle of brain function and a promising target for therapeutic interventions aimed at restoring interhemispheric balance.