Biology subjects

Allegra Mascaro, A. L.

Publications and source records attributed to Allegra Mascaro, A. L..

12 recordsLinked to original sources

bioRxiv2026

Disrupted cortex-wide dynamics impair motor planning in Shank3-mutant mice

Coordinated cortical activity underlies voluntary movement planning, yet its disruption is implicated in neurodevelopmental disorders like autism spectrum disorder (ASD). Mutations in the SHANK3 gene, a key ASD risk factor, affect synaptic integrity and cortical network function, but their impact on preparatory cortical dynamics remains unclear. Here, we employed wide-field calcium imaging combined with motion tracking and computational motif analysis to examine cortex-wide activity in Shank3b+/- mice during spontaneous forepaw movements. We found reduced correlation between cortical activity and behavior preceding movement onset, alongside decreased expression of specific cortical motifs involving associative and motor areas. These changes contributed to global functional hyperconnectivity and impaired motor planning. Our findings reveal that disrupted spatiotemporal cortical dynamics in Shank3b+/- mice impair preparatory motor processes, providing insight into neural mechanisms underlying ASD-related motor deficits.

neuroscience↗

bioRxiv2025

Altered cortical network in Parkinson's Disease: the central role of PV interneuron and synaptic remodelling

Parkinson's disease (PD) is traditionally defined by the progressive degeneration of nigrostriatal dopaminergic neurons; however, accumulating evidence highlights extensive cortical dysfunctions as key contributors to motor and non-motor symptoms. Despite this growing recognition, the precise mechanisms underlying cortical network disruptions and their contribution to PD pathophysiology remain poorly understood, particularly in relation to parvalbumin-positive interneurons (PV-INs) and maladaptive plasticity. Here, we investigate the dysregulation of cortical network homeostasis in PD using a 6-hydroxydopamine (6-OHDA) mouse model, focusing on the progressive disruption of parvalbumin-positive interneuron (PV-IN) connectivity, excitatory/inhibitory balance, and neuroinflammatory responses. Using a multimodal approach integrating longitudinal electrophysiology, wide-field calcium imaging, and histological analyses, we revealed striking alterations in cortical activity and connectivity. Specifically, we observed pathological high-gamma hyperactivity during movement, accompanied by severe disruptions in PV-IN connectivity across motor and somatosensory cortices. Histological analyses further revealed synaptic imbalances and microglial dysregulation, suggesting an extensive cortical response to dopaminergic loss. These findings indicate that PV-IN dysfunction drives cortical maladaptive plasticity, leading to network desynchronization and motor deficits. By reframing PD as a disorder of cortical network homeostasis, this study provides novel mechanistic insights and identifies cortical plasticity as a promising therapeutic target for disease modification.

neuroscience↗

bioRxiv2024

Optogenetic inhibition quenches the integration of sensory input in the cortex

SignificanceWe designed a novel all-optical tool to simultaneously silence neuronal activity at arbitrary sites on the dorsal cortex, and monitor the consequences of the manipulation. Optogenetic inhibition of primary sensory regions determined short and long-term dampening of the sensory response across a distributed cortical network. IntroductionMany fundamental processes of brain computation, such as sensory perception and motor control, heavily rely on the mesoscopic dynamics of activity across the cerebral cortex. Manipulating mesoscale activity and observing its effects across multiple brain regions is crucial for understanding the causal link between cortical dynamics and behavior. ObjectiveThe goal of this study was to develop a novel all-optical system that allows inhibition of excitatory neurons while simultaneously monitoring cortical responses at arbitrary sites across the entire dorsal cortex of mice. MethodsWe combined wide-field imaging and optogenetics to create a mesoscale all-optical approach, enabling simultaneous monitoring and manipulation of cortical activity using light. Intravenous injection of two PHP.eB AAVs enabled the whole-brain co-expression of the red-shifted calcium indicator jRCaMP1b and the inhibitory actuator stGtACR2, with stable expression over several weeks. This system was calibrated, and the effects of inhibition on sensory responses were tested. ResultsIncreasing laser power progressively reduced spontaneous activity at the site of irradiation. A single 5-second pulse on the barrel field cortex significantly decreased the amplitude of sensory-evoked responses, not only in the stimulated region but across the entire stimulated hemisphere. ConclusionsThis novel all-optical system enables targeted inhibition while concurrently monitoring mesoscale cortical activity. It provides insights into the dynamics of cortical circuits and offers a milestone for investigating the causal links between neuronal activity and behavior. Future research can use this tool to address sensory responsiveness impairments in neurological and neuropsychiatric disorders.

neuroscience↗

bioRxiv2024

Combining Gamma Neuromodulation and Robotic Rehabilitation Restores Parvalbimin-mediated Gamma Function and Boosts Motor Recovery in Stroke Mice

Stroke is a leading cause of long-term disability, often characterized by compromised motor function. Gamma band is known to be related to Parvalbumin interneurons (PV-IN) synchronous discharge and it has been found to be affected after stroke in humans and animals. Both Gamma band and PV-IN also play a key role in motor function, thus representing a promising target for post-stroke neurorehabilitation. Non-Invasive neuromodulatory approaches are considered a safe intervention and can be used for this purpose. This study presents a novel, clinically relevant, non-invasive and well-tolerated sub-acute treatment combining robotic rehabilitation with advanced neuromodulation techniques, validated in a mouse model of ischemic injury. In the sub-acute phase after stroke, we scored profound deficits in motor-related Gamma band regulation on the perilesional cortex. Accordingly, both at the perilesional and at the whole-cortex levels, the damage results in impaired PV-IN activity, with reduced firing rate and increased functional connectivity levels. Therefore, we tested the therapeutic potential of coupling robotic rehabilitation with optogenetic PV-driven Gamma band stimulation in a subacute post-stroke phase during motor training to reinforce the efficacy of the treatment. Frequency-specific movement-related Gamma band stimulation, when combined with physical training, significantly improved forelimb motor function. More importantly, by pairing robotic rehabilitation with a clinical-like non-invasive 40 Hz transcranial Alternating Current Stimulation, we achieved similar motor improvements mediated by the effective restoring of movement-related Gamma band power and increased PV-IN connections in premotor cortex. Our research introduces a new understanding of the role of parvalbumin-interneurons in post-stroke impairment and recovery. These results highlight the synergistic potential of combining perilesional Gamma band stimulation with robotic rehabilitation as a promising and realistic therapeutic approach for stroke patients. SummaryStroke-induced motor deficits are accompanied by alteration of Gamma modulation and PV-interneurons activity and restored by a combination of non-invasive Gamma stimulation and robotic therapy.

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bioRxiv2024

Age-dependent cortical overconnectivity revers under anesthesia in Shank3 mice

Growing evidence points to brain network dysfunction as a central neurobiological basis for autism spectrum disorders (ASDs). As a result, studies on Functional Connectivity (FC) have become pivotal for understanding the large-scale network alterations associated with ASD. Despite ASD being a neurodevelopmental disorder, and FC being significantly influenced by the brain state, existing FC studies in mouse models predominantly focus on adult subjects under anesthesia. The differential impact of anesthesia and age on cortical functional networks in ASD subjects remains unexplored. To fill this gap, we conducted a longitudinal evaluation of FC across three brain states and three ages in the Shank3b mouse model of autism. We utilized wide-field calcium imaging to monitor cortical activity in Shank3b+/- and Shank3b+/+ mice fromlate development (P45) through adulthood (P90), and isoflurane anesthesia to manipulate the brain state. Our findings reveal that network hyperconnectivity, emerging from the barrel-field cortices during the juvenile stage, progressively expands to encompass the entire dorsal cortex in adult Shank3b+/- mice. Notably, the severity of FC imbalance is highly dependent on the brain state: network alterations are more pronounced in the awake state and shift towards hypoconnectivity under anesthesia. These results underscore the crucial role of anesthesia in detecting autism-related FC alterations and identify a significant network of early cortical dysfunction associated with autism. This network represents a potential target for non-invasive translational treatments.

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bioRxiv2023

Cortical mapping of the sensory response reveals strong brain-state dependence of the late component

Sensory information must be integrated across a distributed brain network for stimulus processing and perception. Recent studies have revealed specific spatiotemporal patterns of cortical activation for the early and late components of sensory-evoked responses, which are associated with stimulus features and perception, respectively. However, our understanding of how the brain state influences the sensory-evoked activation across the mouse cortex remains limited. In this study, we utilized isoflurane to modulate the brain state and conducted wide-field calcium imaging of Thy1-GCaMP6f mice to monitor the distributed activation evoked by multi-whisker stimulation. Our findings reveal that the level of anesthesia strongly shapes the spatiotemporal features and the functional connectivity of the sensory-activated network. As anesthesia levels decrease, we observe increasingly complex responses, accompanied by the emergence of the late component within the sensory-evoked response. The persistence of the late component under anesthesia raises new questions regarding the potential existence of perception during unconscious states.

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bioRxiv2021

Large-scale all-optical dissection of motor cortex connectivity reveals a segregated functional organization of mouse forelimb representations

In rodent motor cortex, the rostral forelimb area (RFA) and the caudal forelimb area (CFA) are major actors in orchestrating the control of forelimb complex movements. However, their intrinsic connections and reciprocal functional organization are still unclear, limiting our understanding of how the brain coordinates and executes voluntary movements. Here we causally probed cortical connectivity and activation patterns triggered by transcranial optogenetic stimulation of ethologically relevant complex movements exploiting a novel large-scale all-optical method in awake mice. Results show specific activation features for each movement class, providing evidence for a segregated functional organization of CFA and RFA. Importantly, we identified a second discrete lateral grasping representation area, namely lateral forelimb area (LFA), with unique connectivity and activation patterns. Therefore, we propose the LFA as a distinct motor representation in the forelimb somatotopic motor map.

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bioRxiv2020

Experimental and computational study on motor control and recovery after stroke: towards a constructive loop betweenexperimental and virtual embodiedneuroscience

Being able to replicate real experiments with computational simulations is a unique opportunity to refine and validate models with experimental data and redesign the experiments based on simulations. However, since it is technically demanding to model all components of an experiment, traditional approaches to modeling reduce the experimental setups as much as possible. In this study, our goal is to replicate all the relevant features of an experiment on motor control and motor rehabilitation after stroke. To this aim, we propose an approach that allows continuous integration of new experimental data into a computational modeling framework. First, results show that we could reproduce experimental object displacement with high accuracy via the simulated embodiment in the virtual world by feeding a spinal cord model with experimental registration of the cortical activity. Second, by using computational models of multiple granularities, our preliminary results show the possibility of simulating several features of the brain after stroke, from the local alteration in neuronal activity to long-range connectivity remodeling. Finally, strategies are proposed to merge the two pipelines. We further suggest that additional models could be integrated into the framework thanks to the versatility of the proposed approach, thus allowing many researchers to achieve continuously improved experimental design.

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bioRxiv2020

A distributed neocortical action map associated with reach-to-grasp

Reach-to-Grasp (RtG) is known to be dependent upon neocortical circuits and extensive research has provided insights into how selected neocortical areas contribute to control dexterous movements. Surprisingly, little infor-mation is available on the global neocortical computations underlying RtG in the mouse. Here, we characterized, employing fluorescence wide-field cal-cium imaging, the neocortex-wide dynamics from mice engaging in a RtG task. We demonstrate that, beyond canonical motor regions, several areas, such as the visual and the retrosplenial cortices, also increase their activ-ity levels during successful RtGs. Intriguingly, homologous regions across the ipsilateral hemisphere are also involved. Functional connectivity among areas increases transiently from rest to planning, and decreases during move-ment. Two anti-correlated neocortical networks emerged during movement. At variance, neural activity levels scale linearly with kinematics measures of successful RtGs in secondary motor areas. Our findings establish the coex-istence of distributed and localized neocortical dynamics for efficient control of complex movements. SIGNIFICANCE STATEMENTIn mammals, including humans, the cerebral cortex is known to be critical for the correct execution of dexterous movements. Despite the importance of the mouse for elucidating the neural circuitry for motor control, its neocortex-wide dynamics during RtG are largely unexplored. We used in-vivo fluores-cence microscopy to characterize the neural activity across the neocortex as mice performed a reach-to-grasp task. We show that for such complex movements, a large network of neocortical areas gets involved, while movement kinematics correlates with neural activity in secondary motor areas. These findings indicate the coexistence, at the mesoscale level, of distributed and localized neocortical dynamics for the execution of fine movements. This study offers a novel view on the neocortical correlates of motor control, with potential implications for neural repair.

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bioRxiv2019

Rehabilitation promotes the recovery of structural and functional features of healthy neuronal networks after stroke

Rehabilitation is the most effective treatment for promoting the recovery of motor deficits after stroke. One of the most challenging experimental goals is to unambiguously link brain rewiring to motor recovery prompted by rehabilitative therapy. Here, we investigated which aspects of cortical remodeling are induced by rehabilitation by combining optical imaging and manipulation tools in a mouse model of stroke. We revealed that the stabilization of peri-infarct synaptic contacts fostered by rehabilitation goes along with increased vascular density induced by angiogenesis. Furthermore, we showed the progressive formation of a new motor representation in the peri-infarct area where temporal and spatial features of cortical activation recovered towards pre-stroke condition. In the same animals we observed the reinforcement of inter-hemispheric connectivity after rehabilitation. The present work provides the first evidences that rehabilitation promotes the combined recovery of structural and functional features distinctive of healthy neuronal networks.

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bioRxiv2017

Whole-brain vasculature reconstruction at the single capillary level

The distinct organization of the brains vascular network ensures that it is adequately supplied with oxygen and nutrients. However, despite this fundamental role, a detailed reconstruction of the brain-wide vasculature at the capillary level remains elusive, due to insufficient image quality using the best available techniques. Here, we demonstrate a novel approach that improves vascular demarcation by combining CLARITY with a vascular staining approach that can fill the entire blood vessel lumen and imaging with light-sheet fluorescence microscopy. This method significantly improves image contrast, particularly in depth, thereby allowing reliable application of automatic segmentation algorithms, which play an increasingly important role in high-throughput imaging of the terabyte-sized datasets now routinely produced. Furthermore, our novel method is compatible with endogenous fluorescence, thus allowing simultaneous investigations of vasculature and genetically targeted neurons. We believe our new method will be valuable for future brain-wide investigations of the capillary network.

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bioRxiv2017

Rehabilitation Restores Cortical Activation Profiles And Stabilizes Synaptic Contacts After Stroke

Rehabilitation is the most effective treatment for promoting the recovery of motor deficits after stroke. Despite its importance, the processes associated with rehabilitative intervention are poorly understood. One of the most challenging experimental goals is to unambiguously link specific circuit changes induced by rehabilitation to improved behavior. Here, we investigate which facets of cortical remodeling are induced by rehabilitation by combining optical imaging and manipulation tools in a mouse model of stroke. We demonstrate the progressive restoration of cortical motor maps and of cortical activity in parallel with the reinforcement of inter-hemispheric connectivity after rehabilitation. Furthermore, we reveal that the increase in vascular density goes along with the stabilization of peri-infarct neural circuitry at synaptic level. The present work provides the first evidences that rehabilitation is sufficient to promote the combined recovery of distinct structural and functional features distinctive of healthy neuronal networks.

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