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Symposium

Neuroscience through the lens of single cell genomics

05/10 – 10:30 <br>
Aula 5 – Entresuelo PABELLON 2 (Room 5, Mezzanine, Building 2)

Chairs:
Daniela Di Bella(Google Scholar Profile)
Harvard University, Boston,  USA / Instituto Leloir, Buenos Aires, Argentina

Micaela Sartoretti (Publications; Affiliations)
The Francis Cricks Institute, United Kingdom

Over the last decade, single-cell genomics has emerged as a powerful tool to study cellular complexity and dynamics across all life sciences, including neuroscience. From disease modeling to neuron-glia interaction, and from embryonic development to adult neurogenesis, it has expanded our understanding of molecular dynamics, cellular landscapes, and transcriptional regulation in the most complex organ found in animals. This symposium brings together speakers who will showcase how the use of this tool can aid in understanding the central nervous system in developmental processes and disease modeling.

SPEAKERS

Daniela Di Bella (C.V.)
Harvard University, Boston, USA / Instituto Leloir, Buenos Aires 
Tittle: “Functional Screen of Identity Determinants in the Developing Mouse Cerebral Cortex”

The generation of diverse and specified cell types rely in the concerted action of intrinsic and extrinsic factors. The mammalian cerebral cortex, with its unparalleled neuronal diversity, serves as an excellent model to study the acquisition of cellular identity. The molecular logic that governs the establishment and topographic organization of cortical cell types remains elusive, with the exception of few characterized transcription factors. Transcription factors play a central role in the interconnected mechanisms controlling cell identity during development, as they instruct the expression of concerted gene programs and gene regulatory networks.
In order to uncover the genes controlling the identity acquisition of the main excitatory neurons in the cortex, we first built a molecular atlas of the developing cortex using single cell RNA-sequencing, sampled every day through the duration of embryonic corticogenesis. From this we infered developmental trajectories unveiling gene regulatory programs that accompany fate specification and diversification. By exploring differentially expressed genes, we proposed candidate transcription factors that promote the two main classes of excitatory neuronal fates -corticofugal versus callosal. We next use multiplexed in vivo perturbations to assess the ability of these transcription factors to alter the identity of the progeny produced. With our work, we aim to identify new identity controllers in the cerebral cortex and to uncover novel mechanisms underlying neuronal specification.

Micaela Sartoretti (C.V.)
Cricks Institute, United Kingdom
Tittle: “Molecular and cellular landscape of the Down syndrome mouse brain”

Down syndrome (DS) is caused by an extra copy of chromosome 21 (Hsa21), leading to overexpression of approximately 230 protein-coding genes. It is the most common genetic cause of intellectual disability, yet the molecular mechanisms underlying cognitive impairment remain unclear. Our lab generated the Dp1Tyb mouse strain, which carries a duplication of 145 genes from mouse chromosome 16 orthologous to Hsa21. These mice display deficits in hippocampal-dependent memory tasks. Using single-nucleus RNA sequencing, I analysed the hippocampal cellular landscape to determine how gene dosage alters neuronal and glial populations. I identified the main neuronal classes, including eleven interneuron clusters, and glial clusters. Interestingly, the frequency of neuroblasts, cells that will differentiate into adult-born neurons during adult hippocampal neurogenesis, was decreased in the Dp1Tyb hippocampus. To explore the mechanism underlying this difference, I subclustered astrocytes and neuroblasts, revealing radial glia-like (RGL) cells and neural progenitor cells (NPCs). Pseudotime trajectory analysis showed an increased frequency of RGL stem cells and a reduction of neuroblasts and immature neurons across the neurogenic lineage in the Dp1Tyb hippocampus. In Dp1Tyb, microglial subclustering revealed an imbalance between populations, with the expanded group displaying reduced homeostatic gene expression. Pathways related to translation and oxidative phosphorylation were also upregulated in Dp1Tyb microglia compared with wild type. Although interneuron proportions were largely unchanged, ligand–receptor network analysis suggested enhanced cadherin-mediated adhesive communication between microglia and specific interneuron clusters, indicating that altered microglia–interneuron interactions may contribute to the DS phenotype.

Damiana Giacomini (C.V.)
Instituto Leloir, Buenos Aires, Argentina.
Title: “Transcriptional dynamics across the development and integration of adult-born hippocampal neurons”

The dentate gyrus, the main entry point of entorhinal input into the hippocampus, continuously generates adult-born granule cells (aGCs) that confer unique forms of plasticity to preexisting circuits. Adult hippocampal neurogenesis is a conserved, multi-stage process that supports memory formation, context discrimination, and cognitive flexibility. In the mouse, the maturation of aGCs extends over several weeks and can be divided into discrete phases based on electrophysiological and morphological properties. Yet, the molecular programs governing their progression remain poorly understood. Using lineage tracing and single-nucleus RNA sequencing, we isolated nuclei from aGCs at defined ages and reconstructed their transcriptional trajectory from radial glia-like cells to fully mature neurons. This analysis uncovered previously uncharacterized intermediate maturation states and revealed sequential gene expression programs underlying stage-to-stage transitions. Building on this framework, we next examined how aging impacts the same developmental sequence. As expected, aging reduced the rate of neurogenesis and slowed neuronal maturation. Our transcriptomic profiling showed that this delay does not reflect a uniform slowing of development but rather the accumulation of aGCs at a discrete postmitotic neuroblast stage. Notably, this state was highly plastic, as voluntary running prevented neuroblast accumulation and promoted progression toward more advanced transcriptional states. These findings highlight postmitotic neuroblasts as a pivotal regulatory node in aging neurogenesis, where activity-dependent cues can re-engage stalled maturation. Together, these studies provide a high-resolution transcriptional roadmap of adult neurogenesis, from early neuroblasts to fully integrated neurons, and identify stage-specific vulnerabilities to aging, offering potential targets to restore hippocampal plasticity.

Piero Rigo (C.V.)
The Francis Crick Institute

Title: “Investigating human hippocampal neurogenesis using single-cell spatial transcriptomics”

Hippocampal neurogenesis is essential in mice, contributing to the rapid growth of neural tissues during development and supporting learning, memory and mood regulation in adults. However, human hippocampal neurogenesis remains poorly characterised during development, while its persistence in adults is still debated. We used single-cell spatial transcriptomics to characterise human hippocampal neurogenesis and its source, i.e. neural stem cells (NSCs), in the developing brain. We observed a large fraction of NSCs in a non-proliferative state at mid-gestation, after the peak of neurogenesis at gestation week 14, suggesting, by analogy with mouse hippocampal neurogenesis, the formation of a reservoir of quiescent NSCs that could support long-term postnatal neurogenesis. Harnessing the acquired knowledge about human developmental neurogenesis, we examined published single-cell RNA sequencing datasets of the adult human hippocampus, where we found many cells displaying transcriptomic profiles similar to those of embryonic NSCs and immature neurons, suggesting abundant neurogenesis may occur in the adult human hippocampus.