Korshunova, I. | Search bioRxiv

bioRxiv2026

Spatial navigation through evolution: a single-cell atlas of the mammalian entorhinal cortex

Spatial navigation is a fundamental mammalian ability, supported by the entorhinal cortex (EC), a structurally conserved yet functionally diverse region across mammalian species. However, how molecular signaling underlies both shared and species-specific navigational strategies remains unclear. Here, we present a cross-species single-cell atlas of the EC from human, Hamadryas baboon, mouse, and Egyptian fruit bat - species spanning distinct evolutionary lineages and navigational demands, including true 3D navigation in bats. Using this resource, we identify conserved principal neuron populations as well as species-specific innovations, including mixed-layer or functional identities and fruit bat-specific subtypes. GABAergic interneurons neurons show strong conservation of somatostatin (SST) and parvalbumin (PV) families, while VIP GABAergic neurons exhibit pronounced species-specific divergence, with an expanded repertoire in primates. Integration with whole-brain diffusion tensor imaging reveals conserved and species-specific connectivity between the EC, hippocampus, and sensory cortices. Major species-specific cellular innovations were further validated using orthogonal histological approaches, confirming their anatomical and laminar organization. Overall, this atlas provides a comparative framework available for the research community to dissect the molecular, cellular, and circuit principles underlying conserved and specialized spatial navigation across mammals.

neuroscience↗

bioRxiv2024

Single-cell profiling of cortical tubers in tuberous sclerosis complex shows molecular structure preservation and massive reorganization of metabolism

Tuberous sclerosis complex (TSC) is a multisystemic genetic disorder associated with loss-of-function mutations in the TSC1 or TSC2 gene, which lead mTOR pathway hyperactivation and epileptogenesis. Cortical tubers are the hallmark of TSC and represent disorganized cortical structure underlying the generation of focal seizures. Here, we report single-nucleus RNA sequencing in resected cortical tubers vs matched pediatric controls. Strikingly, in spite of severe cortical disorganization, we found that cortical tubers preserve all neuronal subtypes, even the rarest ones. Moreover, we showed that principal neurons largely preserve spatial position based on transcriptional signatures. Principal neurons and layer 1-2 GABAergic neurons that modulate upper cortical circuits exhibited the largest gene expression changes. Interestingly, multiple mTOR pathway gene expression changes in TSC counteracted mTOR hyperactivation. TSC neuronal, but not glial, networks exhibited massive metabolic reorganization with a reduction in mitochondrial respiration and a concomitant switch to fatty acid metabolism. Finally, we show that neuron-specific AMPA receptor signaling might underlie epileptogenesis in TSC and could represent a potential candidate for therapeutic targeting.

neuroscience↗