Biology subjects

Kourdougli, N.

Publications and source records attributed to Kourdougli, N..

5 recordsLinked to original sources

bioRxiv2026

Parvalbumin interneuron maturation reorganizes cortical population activity structure during development

During brain development, spontaneous cortical activity undergoes a dramatic transformation from highly synchronous network events to less correlated and sparse neuronal firing that is thought to underlie more flexible neural coding. However, how the structure of population activity changes across this transition, what circuit mechanisms drive this reorganization, and the implications for information encoding have not been fully established. Using longitudinal in vivo calcium imaging in early postnatal mice, we demonstrate that cortical network desynchronization during the second postnatal week is accompanied by a redistribution of fractional variance from dominant, low-dimensional modes into many weaker dimensions, and a growing influence of GABAergic interneurons (INs) on the network. All-optical circuit interrogation revealed that parvalbumin (PV) INs, but not somatostatin (SST) INs, are sufficient to desynchronize the network and shift the distribution of population variance. Through targeted ablation of a fraction of PV INs, we show dimensionality is highly correlated with stimulus decoding accuracy. Furthermore, PV INs undergo a sharp increase in transcriptional maturation between postnatal day (P) 8 and 11, during which they preferentially enrich for synaptic genes. Lastly, a novel, biologically plausible, multi-cell-type computational model reproduced the developmental desynchronization and rise in dimensionality. Strikingly, without being constrained by perturbation data, the model accurately predicted the effects of each IN class on the network that we observed empirically.

neuroscience↗

bioRxiv2025

Translatome profiling reveals opposing alterations in inhibitory and excitatory neurons of Fragile X mice and identifies EPAC2 as a therapeutic target.

Symptoms of Fragile X Syndrome (FXS), the leading monogenic cause of intellectual disability and autism, are thought to arise from an excitation/inhibition (E/I) imbalance. Here, we leverage cell type specific mRNA sequencing to profile molecular alterations of cortical excitatory and inhibitory neurons in Fmr1 knockout (KO) mice, integrating transcriptomic results with circuit and behavioral readouts to prioritize novel therapeutic targets. Differentially expressed genes (DEG) were largely upregulated in Camk2a expressing excitatory neurons but downregulated in Pvalb-expressing inhibitory neurons, and the underlying signaling pathways were often altered in opposite directions. Among the 184 DEGs that were concordantly dysregulated across both cell types, only Rapgef4 (Epac2) was also an FMRP target, an ASD risk gene and brain enriched. EPAC2 has been implicated in synaptic maturation and plasticity. Systemic administration of an EPAC2 antagonist restored cortical circuit function in Fmr1 KO mice and ameliorated sensory behavioral phenotypes. EPAC2 is a potential target for therapy in FXS.

neuroscience↗

bioRxiv2022

Improvement of sensory deficits in Fragile X mice by increasing cortical interneuron activity after the critical period

Changes in the function of inhibitory interneurons (INs) during cortical development could contribute to the pathophysiology of neurodevelopmental disorders. Using all-optical in vivo approaches in postnatal mouse somatosensory cortex (S1), we find that parvalbumin (PV) IN precursors are hypoactive and decoupled from excitatory neurons in Fmr1-/- mice, a model of Fragile X Syndrome (FXS). This leads to a loss of PV-INs in both mice and humans with FXS. Increasing the activity of future PV-INs in neonatal Fmr1-/- mice restores PV density and ameliorates transcriptional dysregulation in S1, but not circuit dysfunction. Critically, administering a novel allosteric modulator of Kv3.1 channels after the S1 critical period does rescue circuit dynamics and tactile defensiveness. Symptoms in FXS and related disorders could be mitigated by targeting PV-INs.

neuroscience↗

bioRxiv2020

EZcalcium: Open Source Toolbox for Analysis of Calcium Imaging Data

Fluorescence calcium imaging using a range of microscopy approaches, such as 2-photon excitation or head-mounted miniscopes, is one of the preferred methods to record neuronal activity and glial signals in various experimental settings, including acute brain slices, brain organoids, and behaving animals. Because changes in the fluorescence intensity of genetically encoded or chemical calcium indicators correlate with action potential firing in neurons, data analysis is based on inferring such spiking from changes in pixel intensity values across time within different regions of interest. However, the algorithms necessary to extract biologically relevant information from these fluorescent signals are complex and require significant expertise in programming to develop robust analysis pipelines. For decades, the only way to perform these analyses was for individual laboratories to write their own custom code. These routines were typically not well annotated and lacked intuitive graphical user interfaces (GUIs), which made it difficult for scientists in other laboratories to adopt them. Although the panorama is changing with recent tools like CaImAn, Suite2P and others, there is still a barrier for many laboratories to adopt these packages, especially for potential users without sophisticated programming skills. As 2-photon microscopes are becoming increasingly affordable, the bottleneck is no longer the hardware, but the software used to analyze the calcium data in an optimal manner and consistently across different groups. We addressed this unmet need by incorporating recent software solutions for motion correction, segmentation, signal extraction and deconvolution of calcium imaging data into an open-source, easy to use, GUI-based, intuitive and automated data analysis software, which we named EZcalcium.

neuroscience↗

bioRxiv2017

Impaired perceptual learning in Fragile X syndrome is mediated by parvalbumin neuron dysfunction in V1 and is reversible.

Atypical sensory processing is a core characteristic in autism spectrum disorders1 that negatively impacts virtually all activities of daily living. Sensory symptoms are predictive of the subsequent appearance of impaired social behavior and other autistic traits2, 3. Thus, a better understanding of the changes in neural circuitry that disrupt perceptual learning in autism could shed light into the mechanistic basis and potential therapeutic avenues for a range of autistic symptoms2. Likewise, the lack of directly comparable behavioral paradigms in both humans and animal models currently limits the translational potential of discoveries in the latter. We adopted a symptom-to-circuit approach to uncover the circuit-level alterations in the Fmr1-/- mouse model of Fragile X syndrome (FXS) that underlie atypical visual discrimination in this disorder4, 5. Using a go/no-go task and in vivo 2-photon calcium imaging in primary visual cortex (V1), we find that impaired discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons, and a decrease in the activity of parvalbumin (PV) interneurons in V1. Restoring visually evoked activity in PV cells in Fmr1-/- mice with a chemogenetic (DREADD) strategy was sufficient to rescue their behavioral performance. Finally, we found that human subjects with FXS exhibit strikingly similar impairments in visual discrimination as Fmr1-/- mice. We conclude that manipulating orientation tuning in autism could improve visually guided behaviors that are critical for playing sports, driving or judging emotions.

neuroscience↗