Projects
Early Life Stress (ELS)
Details
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From Adversity to Connectivity: How Early Life Stress Influences the Formation of Frontolimbic Circuits
Early life stress (ELS), through poverty and neglect, disrupts cortical circuit formation, producing lasting neurobehavioural deficits with marked sex differences. GABAergic interneuron dysfunction is strongly implicated in these outcomes, yet its relationship with ELS and sex-specific vulnerabilities remains unclear. This work investigates how ELS-induced alterations in GABAergic maturation drive aberrant frontolimbic activity patterns, using in vivo two-photon microscopy, pharmacogenetics, viral tracing, and computational modelling to establish the principles governing stress-dependent prefrontal circuit development.
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Longitudinal tracking of early interneuron circuit dysfunctions underlying anxiety-related disorders in early life stress
The mechanisms by which early-life stress (ELS) disrupts brain development and contributes to anxiety disorders remain poorly understood. The prefrontal cortex (PFC) is particularly vulnerable to ELS, and altered PFC maturation may partly explain the heightened susceptibility to anxiety observed in females. The contribution of cortical interneurons to this process remains substantially under-investigated. This project employs longitudinal neuroimaging in rodent models to map PFC development from early postnatal stages through to adulthood, aiming to elucidate how stress-induced interneuron changes underpin anxiety-related disorders. Funded by Brain & Behavior Research Foundation.
Neurodevelopmental Disorders
Details
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Circuit-level mechanisms and developmental rescue of tyrosine hydroxylase deficiency
Funded by Jerome Lejeune Foundation
Publications
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A postnatal molecular switch drives activity-dependent maturation of parvalbumin interneurons
Abstract
Monika Moissidis, Leyla Abbasova, Martijn Selten, Rafael Alis, Clémence Bernard, Yaiza Domínguez-Canterla, Fazal Oozeer, Shenyue Qin, Audrey Kelly, Laura Mòdol, Navneet A Vasistha, Benjamin Jones, Pawan Dhami, Konstantin Khodosevich, Fursham Hamid, Paul Lavender, Nuria Flames, Oscar Marín
DOI: 10.1016/j.cell.2025.06.029
Abstract
Cortical neurons are specified during embryonic development but often acquire their mature properties at relatively late stages of postnatal development. This delay in terminal differentiation is particularly prominent for fast-spiking parvalbumin-expressing (PV+) interneurons, which play critical roles in regulating the function of the cerebral cortex. We found that the maturation of PV+ interneurons is triggered by neuronal activity and mediated by the transcriptional cofactor peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α). Developmental loss of PGC-1α prevents PV+ interneurons from acquiring unique structural, electrophysiological, synaptic, and metabolic features and disrupts their diversification into distinct subtypes. PGC-1α functions as a master regulator of the differentiation of PV+ interneurons by directly controlling gene expression through a transcriptional complex that includes ERRγ and Mef2c transcription factors. Our results uncover a molecular switch that translates neural activity into a specific transcriptional program, promoting the maturation of PV+ interneurons at the appropriate developmental stage.
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Somatostatin interneurons control the timing of developmental desynchronization in cortical networks
Abstract
Laura Mòdol, Monika Moissidis, Martijn Selten, Fazal Oozeer, Oscar Marín
DOI: 10.1016/j.neuron.2024.03.014
Abstract
Synchronous neuronal activity is a hallmark of the developing brain. In the mouse cerebral cortex, activity decorrelates during the second week of postnatal development, progressively acquiring the characteristic sparse pattern underlying the integration of sensory information. The maturation of inhibition seems critical for this process, but the interneurons involved in this crucial transition of network activity in the developing cortex remain unknown. Using in vivo longitudinal two-photon calcium imaging during the period that precedes the change from highly synchronous to decorrelated activity, we identify somatostatin-expressing (SST+) interneurons as critical modulators of this switch in mice. Modulation of the activity of SST+ cells accelerates or delays the decorrelation of cortical network activity, a process that involves regulating the maturation of parvalbumin-expressing (PV+) interneurons. SST+ cells critically link sensory inputs with local circuits, controlling the neural dynamics in the developing cortex while modulating the integration of other interneurons into nascent cortical circuits.
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Prominent in vivo influence of single interneurons in the developing barrel cortex
Abstract
Yannick Bollmann, Laura Modol, Thomas Tressard, Artem Vorobyev, Robin Dard, Sophie Brustlein, Ruth Sims, Imane Bendifallah, Erwan Leprince, Vincent de Sars, Emiliano Ronzitti, Agnès Baude, Hillel Adesnik, Michel Aimé Picardo, Jean-Claude Platel, Valentina Emiliani, David Angulo-Garcia, Rosa Cossart
DOI: 10.1038/s41593-023-01405-5
Abstract
Spontaneous synchronous activity is a hallmark of developing brain circuits and promotes their formation. Ex vivo, synchronous activity was shown to be orchestrated by a sparse population of highly connected GABAergic ‘hub’ neurons. The recent development of all-optical methods to record and manipulate neuronal activity in vivo now offers the unprecedented opportunity to probe the existence and function of hub cells in vivo. Using calcium imaging, connectivity analysis and holographic optical stimulation, we show that single GABAergic, but not glutamatergic, neurons influence population dynamics in the barrel cortex of non-anaesthetized mouse pups. Single GABAergic cells mainly exert an inhibitory influence on both spontaneous and sensory-evoked population bursts. Their network influence scales with their functional connectivity, with highly connected hub neurons displaying the strongest impact. We propose that hub neurons function in tailoring intrinsic cortical dynamics to external sensory inputs.
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Assemblies of perisomatic GABAergic neurons in the developing barrel cortex
Abstract
Laura Modol, Yannick Bollmann, Thomas Tressard, Agnès Baude, Alicia Che, Zhe Ran S Duan, Rachel Babij, Natalia V De Marco García, Rosa Cossart
DOI: 10.1016/j.neuron.2019.10.007
Abstract
The developmental journey of cortical interneurons encounters several activity-dependent milestones. During the early postnatal period in developing mice, GABAergic neurons are transient preferential recipients of thalamic inputs and undergo activity-dependent migration arrest, wiring, and programmed cell-death. Despite their importance for the emergence of sensory experience and the role of activity in their integration into cortical networks, the collective dynamics of GABAergic neurons during that neonatal period remain unknown. Here, we study coordinated activity in GABAergic cells of the mouse barrel cortex using in vivo calcium imaging. We uncover a transient structure in GABAergic population dynamics that disappears in a sensory-dependent process. Its building blocks are anatomically clustered GABAergic assemblies mostly composed by prospective parvalbumin-expressing cells. These progressively widen their territories until forming a uniform perisomatic GABAergic network. Such transient patterning of GABAergic activity is a functional scaffold that links the cortex to the external world prior to active exploration.
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GABAergic restriction of network dynamics regulates interneuron survival in the developing cortex
Abstract
Zhe Ran S Duan, Alicia Che, Philip Chu, Laura Modol, Yannick Bollmann, Rachel Babij, Robert N Fetcho, Takumi Otsuka, Marc V Fuccillo, Conor Liston, David J Pisapia, Rosa Cossart, Natalia V De Marco García
DOI: 10.1016/j.neuron.2019.10.008
Abstract
During neonatal development, sensory cortices generate spontaneous activity patterns shaped by both sensory experience and intrinsic influences. How these patterns contribute to the assembly of neuronal circuits is not clearly understood. Using longitudinal in vivo calcium imaging in un-anesthetized mouse pups, we show that spatially segregated functional assemblies composed of interneurons and pyramidal cells are prominent in the somatosensory cortex by postnatal day (P) 7. Both reduction of GABA release and synaptic inputs onto pyramidal cells erode the emergence of functional topography, leading to increased network synchrony. This aberrant pattern effectively blocks interneuron apoptosis, causing increased survival of parvalbumin and somatostatin interneurons. Furthermore, the effect of GABA on apoptosis is mediated by inputs from medial ganglionic eminence (MGE)-derived but not caudal ganglionic eminence (CGE)-derived interneurons. These findings indicate that immature MGE interneurons are fundamental for shaping GABA-driven activity patterns that balance the number of interneurons integrating into maturing cortical networks.
