Primary cilia and neural computation

Abstract

Ciliopathies frequently involve abnormal brain development and affected individuals often present with varying degrees of cognitive impairment and behavioral alterations. In parallel, genetic studies have linked primary cilia to neurodevelopmental disorders such as autism spectrum disorder (ASD). Together, these observations point to a role for primary cilia in cognition, yet their mechanistic contribution to neural function remains unclear. To address this, we define neural computation as the integration of inputs, dynamic thresholding, and routing of outputs, and propose that primary cilia function not as passive sensory antennae, but as dynamic computational microdomains. Within this framework, cilia integrate extrinsic signals and intrinsic cellular states through modular signaling pathways, including GPCR-cAMP-PKA cascades and tightly regulated trafficking mechanisms. These processes are spatially constrained by ciliary gating and transport systems, enabling selective filtering, amplification, and transformation of inputs into context-dependent outputs. During development, these molecular computations scale to shape neural circuit architecture. Ciliary signaling regulates neurogenesis, specifies neuronal identity, and guides neuronal migration and connectivity, thereby embedding computational parameters into the physical structure of the brain. In the mature brain, ciliary GPCRs modulate neuronal and circuit-level dynamics. Receptors such as 5HT6 and SSTR3 influence neuronal excitability and excitation-inhibition balance, while hypothalamic MC4R functions as a rheostat to stabilize state-dependent signaling. In parallel, dynamic trafficking of DRD1 receptors enables flexible regulation of dopaminergic signaling across subcellular compartments. Disruption of ciliary function has been linked to memory impairments, suggesting a role in regulating the stability and competition of memory engrams. These effects may involve multiple plasticity mechanisms, including synaptic tagging and capture, activity-dependent synchronization, and adult neurogenesis. Together, these findings support a unifying view in which primary cilia perform molecular computations that scale across development and adult brain function to influence neural circuits and behavior. Future integration of cilia-targeted molecular tools with systems-level approaches will be essential for disentangling developmental effects from active computational roles in the mature brain.