Volume 28 Issue 5, May 2025

The cerebral cortex of the human brain is crucial and complex, and includes different subtypes of neuron that need to be specified during development. How this process is regulated is unclear. In this issue of Nature Neuroscience, Nano et al. curate and mine a compendium cell atlas of human cortical development to identify gene programs that drive neuron subtype specification and validate a mechanism using brain organoid models.

We modeled how the hippocampus can construct new cognitive maps from reusable building blocks (structural elements) represented in cortex. This composition supported latent learning and rapid generalization, and predicted the emergence of place responses in replay, which we discovered empirically in an existing dataset.

Lewy body disease (LBD) pathology can first spread from the brain or the body. A study of two large postmortem datasets reveals that there are not one but two possible trajectories originating in the body for LBD progression at its earliest stages, spreading via either sympathetic or parasympathetic nerve pathways to reach the brain.

This postmortem study identifies brain-first and two body-first subtypes in prediagnostic cases of Lewy body disease. It highlights sympathetic and parasympathetic pathways in body-first disease, advancing insights on disease onset and progression.

This study uses single-cell sequencing to investigate the diversification of cortical cell types during evolution. Comparisons across brain regions and species identify molecular signatures of ancestral cell types in the mammalian olfactory cortex.

Nano et al. introduce a pipeline to generate meta-atlases of the human brain from existing single-cell datasets and extract gene modules linked to cell fate specification. Perturbing these programs in human cortical chimeroids validated their roles in cell type specification.

In this work, the authors performed a single-cell genotyping and transcriptomics analysis, revealing cell-type-specific and nonautonomous effects of mTOR pathway mutations in mosaic focal cortical dysplasia.

Targeting the endothelium across ages and neurodegenerative diseases in 92 donors with single-cell inCITE-seq reveals similar alterations in ~40% of capillaries in AD, ALS and FTD. Endothelial TDP-43 loss coincides with increased nuclear p65/NF-κB activity and reduced Wnt/β-catenin.

The authors describe a susceptibility of the peripheral nervous system to neuronal senescence with age or injury relevant for sensory dysfunction, such as chronic pain.

The developmental origin of behavioral individuality is unclear. The authors show that a temporal sequence of genetically encoded stochastic mechanisms explains variation in stereotyped neuronal circuits.

Zhang et al. identify unimodal neural representations in the spinal cord of cutaneous mechanical and heat stimuli gated by a shared feed-forward local inhibitory neuron type and a neural transition during neuropathy, with increased excitatory drive.

The authors uncover slow, facilitating inhibitory connections between serotonin neurons in the dorsal raphe, refuting autoinhibition theories. This recurrence drives winner-take-all effects and nonlinear processing of threat-related inputs.

Using two-photon imaging in awake bats, the authors show that the inferior colliculus encodes vocalization categories as categorical primitives—spatially clustered, category-selective neurons that enable early, efficient and structured processing that may support adaptive behavior.

Inactivation of the ventral subiculum does not change existing schema cells in the orbitofrontal cortex (OFC) but aids their formation during new learning. This challenges the idea that the OFC relies on the hippocampus and suggests that these regions work in parallel to process different aspects of cognitive maps.

A model of compositional state spaces in the hippocampus shows latent learning and rapid generalization. Bakermans et al. show that this model predicts the emergence of place responses in replay.

This study maps the single-axon projections of 7,180 hypothalamic peptidergic neurons in male mice and uncovers extensive collateralization, topographic target innervation and modular intra-hypothalamic organization.

Researchers developed DELTA, a method for brain-wide measurement of synaptic protein turnover with single-synapse resolution, providing a powerful tool to localize and study mechanisms underlying synaptic plasticity and learning.

Kim and coworkers describe a technique, EPSILON, to map AMPA receptor exocytosis, a proxy for synaptic plasticity, in mice. The authors demonstrated a correlation between AMPA receptor exocytosis and cFos expression during a fear conditioning experiment.