Biology subjects

Portera-Cailliau, C.

Publications and source records attributed to Portera-Cailliau, C..

11 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↗

bioRxiv2026

Cortical circuit implementation of signed deviant detection with positive and negative prediction error neurons

Predicting future events is fundamental for animals to adaptively interact with their environment, but whether and how the cerebral cortex processes predictive information remains an unresolved question. We combined in vivo two-photon calcium imaging in mouse somatosensory cortex with an oddball paradigm that decouples sensory stimulus properties from predictability context. We recorded neuronal responses in layer (L)2/3, bottom-up sensory inputs, and top-down prefrontal feedback. We find that L2/3 pyramidal neurons concurrently encode stimulus features and statistical context. We identify coexisting positive prediction error (PE) neurons that subtract predictions from incoming sensory inputs and negative PE neurons that do the opposite. This architecture represents a unified computational principle where error signals scale proportionally with the magnitude of mismatch across distinct stimulus features tested (amplitude, direction, omission). Furthermore, bottom-up pathways operate as unsigned novelty detectors, L2/3 circuit computes signed PE, and top-down projections signal a precision-weighted signed error, demonstrating hierarchical predictive processing.

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↗

bioRxiv2024

A failure to discriminate social from non-social touch at the circuit level may underlie social avoidance in autism

Social touch is critical for communication and to impart emotions and intentions. However, certain autistic individuals experience aversion to social touch, especially when it is unwanted. We used a novel social touch assay and Neuropixels probes to compare neural responses to social vs. non-social interactions in three relevant brain regions: vibrissal somatosensory cortex, tail of striatum, and basolateral amygdala. We find that wild type (WT) mice showed aversion to repeated presentations of an inanimate object but not of another mouse. Cortical neurons cared most about touch context (social vs. object) and showed a preference for social interactions, while striatal neurons changed their preference depending on whether mice could choose or not to interact. Amygdalar and striatal neurons were preferentially modulated by forced object touch, which was the most aversive. In contrast, the Fmr1 knockout (KO) model of autism found social and non-social interactions equally aversive and displayed more aversive facial expressions to social touch when it invaded their personal space. Importantly, when Fmr1 KO mice could choose to interact, neurons in all three regions did not discriminate social valence. Thus, a failure to differentially encode social from non-social stimuli at the circuit level may underlie social avoidance in autism.

neuroscience↗

bioRxiv2023

A novel head-fixed assay for social touch in mice uncovers aversive responses in two autism models.

Social touch, an important aspect of social interaction and communication, is essential to kinship across animal species. How animals experience and respond to social touch has not been thoroughly investigated, in part due to the lack of appropriate assays. Previous studies that examined social touch in freely moving rodents lacked the necessary temporal and spatial control over individual touch interactions. We designed a novel head-fixed assay for social touch in mice, in which the experimenter has complete control to elicit highly stereotyped bouts of social touch between two animals. The user determines the number, duration, context, and type of social touch interactions, while monitoring with high frame rate cameras an array of complex behavioral responses. We focused on social touch to the face because of their high translational relevance to humans. We validated this assay in two different models of autism spectrum disorder (ASD), the Fmr1 knockout model of Fragile X Syndrome and maternal immune activation mice. We observed increased avoidance, hyperarousal, and more aversive facial expressions to social touch, but not to object touch, in both ASD models compared to controls. Because this new social touch assay for head-fixed mice can be used to record neural activity during repeated bouts of social touch it should be of interest to neuroscientists interested in uncovering the underlying circuits.

neuroscience↗

bioRxiv2023

Hypersensitivity to distractors in Fragile X syndrome from loss of modulation of cortical VIP interneurons.

Attention deficit is one of the most prominent and disabling symptoms in Fragile X Syndrome (FXS). Hypersensitivity to sensory stimuli contributes to attention difficulties by overwhelming and/or distracting affected individuals, which disrupts activities of daily living at home and learning at school. We find that auditory or visual distractors selectively impair visual discrimination performance in both humans and mice with FXS, but not their typically developing controls. Vasoactive intestinal polypeptide (VIP) neurons were significantly modulated by incorrect responses in the post-stimulus period during early distractor trials in WT mice, consistent with their known role as error signals. Strikingly, however, VIP cells from Fmr1-/- mice showed little modulation in error trials, and this correlated with their poor performance on the distractor task. Thus, VIP interneurons and their reduced modulatory influence on pyramidal cells, could be a potential therapeutic target for attentional difficulties 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

Plasticity after cortical stroke involves potentiating responses of pre-existing circuits but not functional remapping to new circuits

Functional recovery after stroke is thought to be mediated by adaptive circuit plasticity, whereby surviving neurons assume the roles of those that died. This "remapping" hypothesis is based on human brain mapping studies showing apparent reorganization of cortical sensorimotor maps and animal studies documenting molecular and structural changes that could support circuit rewiring. However, definitive evidence of remapping is lacking, and other studies have suggested that maladaptive plasticity mechanisms, such as enhanced inhibition in peri-infarct cortex, might actually limit plasticity after stroke. Here we sought to directly test whether neurons can change their response selectivity after a stroke that destroys a single barrel (C1) within mouse primary somatosensory cortex. Using multimodal in vivo imaging approaches, including two-photon calcium imaging to longitudinally record sensory-evoked activity in peri-infarct cortex before and after stroke, we found no evidence to support the remapping hypothesis. In an attempt to promote plasticity via rehabilitation, we also tested the effects of forced use therapy by plucking all whiskers except the C1 whisker. Again, we failed to detect an increase in the number of C1 whisker-responsive neurons in surrounding barrels even 2 months after stroke. Instead, we found that forced use therapy potentiated sensory-evoked responses in a pool of surviving neurons that were already C1 whisker responsive by significantly increasing the reliability of their responses. Together, our results argue against the long-held theory of functional remapping after stroke, but support a plausible circuit-based mechanism for how rehabilitation may improve recovery of function.

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↗

bioRxiv2016

Multidimensional imbalances in cortical circuit activity in Fragile-X Syndrome mice

A leading theory for multiple brain disorders, such as schizophrenia and autism, is that they arise from developmental imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this simple 1-dimensional model is sufficiently rich to capture the set of key alterations of neural circuit processing in brain disorders. Here we used a combination of computational modeling and large-scale analysis of in vivo 2-photon Ca2+ imaging data from somatosensory cortex of wild-type and Fmr1 knock-out (KO) mice, a model of Fragile X syndrome, to test the E/I imbalance model. Our main findings were: 1) the E/I imbalance model was not rich enough to capture the alterations in neural activity statistics in Fmr1 KO mice; 2) in a computational model we found greatly varying magnitudes and directions of effects of synaptic and cellular properties on network activity; 3) evidence for opposite changes in circuit properties of Fmr1 KO mice at different stages of development; 4) a reduction in the entropy of circuit activity in young Fmr1 KO mice compared to wild-type, but an opposite increase in adult Fmr1 KO mice. These findings suggest qualitatively new strategies for developing treatments for Fragile-X Syndrome and related disorders.

neuroscience↗