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

Minetti, A.; Montagni, E.; Meneghetti, N.; Macchi, F.; Coulomb, E.; Martello, A.; Tiberi, A.; Capsoni, S.; Mazzoni, A.; Allegra Mascaro, A. L.; Spalletti, C.

doi:10.1101/2025.03.05.641628

bioRxiv · 10.1101/2025.03.05.641628

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

Minetti, A.·Montagni, E.·Meneghetti, N.·Macchi, F.·Coulomb, E.·Martello, A.·Tiberi, A.·Capsoni, S.·Mazzoni, A.·Allegra Mascaro, A. L.·Spalletti, C.

View original source ↗Export metadata ↓

Abstract

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.

Source connections

Published article ↗

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Minetti, A., Montagni, E., Meneghetti, N., Macchi, F., Coulomb, E., Martello, A., Tiberi, A., Capsoni, S., Mazzoni, A., Allegra Mascaro, A. L., Spalletti, C.. 2025-03-10. Altered cortical network in Parkinson's Disease: the central role of PV interneuron and synaptic remodelling. https://doi.org/10.1101/2025.03.05.641628

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Attention Across Scales: From Individual Variation to Social Hierarchies and Brain Networks in Semi-Free-Ranging Macaques

Attention is a fundamental brain function supporting perception, decision-making, and social behavior, and its dysfunction profoundly impairs daily life. It is both dynamic and stable, varying across observations and individuals, changing across the lifespan, and being shaped by social and environmental experience. Yet capturing this complexity remains a central challenge in neuroscience. Here, we integrated longitudinal behavioral assessments of semi-free-ranging macaques living in naturalistic social groups with resting-state fMRI. We quantified performance across days, ages, and social hierarchies and related it to intrinsic brain organization. Distinct attentional phenotypes emerged, including individuals with reduced attentional control. Performance followed an inverted-U lifespan trajectory, improving from childhood to adulthood before declining. Social status modulated attentional performance. Critically, nonlinear lifespan trajectories and associations with individual attentional differences were most clearly expressed in frontoparietal connectivity. Together, these findings reveal how sustained attention is organized across scales, providing a biological framework for its individual diversity, social modulation, and neural basis.

neuroscience↗

bioRxiv2026

Decoding natural scenes from patterned optogenetic responses in mouse visual cortex

A central challenge in developing visual cortical prostheses is to determine how visual stimuli should be transformed into effective patterns of cortical stimulation. Although advances in stimulation technologies, including optogenetics, provide increasingly precise control over cortical activity, it remains unclear whether artificially evoked activity can reproduce the information content of naturally evoked visual representations. Here we establish a quantitative framework for evaluating visual encoding strategies by decoding cortical responses evoked by natural vision and patterned optogenetic stimulation. We developed a novel dual-modal paradigm in awake mice to bridge the gap between endogenous photostimulation and artificial network driving. By co-expressing the high-performance calcium indicator GCaMP6s and the red-shifted, ultra-sensitive opsin rsChRmine-oScarlet in the primary visual cortex (V1), we successfully translated dynamic natural movie frames into patterned, spatiotemporal optogenetic stimulation. Quantitative comparisons of macro-scale dynamics demonstrated that this patterned optogenetic injection evokes cortical states highly comparable and representationally aligned with those driven by actual visual photostimulation. To systematically evaluate the fidelity of these responses, we developed STAR, a deep learning model featuring spatial and temporal attention mechanisms, and successfully reconstructed the frames of natural movies from V1 signals under both experimental modalities. Collectively, our results demonstrate that complex sensory information can be both naturally encoded and synthetically injected into V1 circuits with high decoding fidelity. This work provides an empirical and computational proof-of-concept for intelligent, closed-loop biomimetic encoders, establishing a robust framework for next-generation cortical visual neuroprostheses and bidirectional brain-machine interfaces.

neuroscience↗

bioRxiv2026

Why Is Spontaneous Blink Timing Informative? An Adaptive Scheduling Perspective

Spontaneous eye blinks have long been linked to cognitive processing, yet how task demands shape blink timing and its relationship to behavioral performance remains unclear. We examined spontaneous blink behavior in 576 adults performing two variants of the Continuous Performance Task (CPT). Blink occurrence and timing were most strongly modulated by the experimental condition in the more demanding CPT-AX task, whereas their association with response time was stronger in the CPT-X task, where more consistent blink timing predicted faster responses. This dissociation suggests that task structure changes not only blink behavior but also the behavioral relevance of blink timing. These findings are consistent with an adaptive scheduling account of spontaneous blinking and provide a conceptual framework for understanding when and why blink timing contains chronometric information about ongoing cognition.

neuroscience↗