Biology subjects

Mele, A.

Publications and source records attributed to Mele, A..

6 recordsLinked to original sources

bioRxiv2026

The D2-mdx mouse as a preclinical model for Duchenne muscular dystrophy: a natural history study across two independent sites

IntroductionThe quality of preclinical studies for rare diseases, such as Duchenne muscular dystrophy (DMD), relies on the availability of comprehensive natural disease history data. In addition to the classic BL10-mdx mouse, in recent years, the D2-mdx model has increasingly been used as an alternative model due to its reportedly more severely impaired phenotype. To improve our understanding of disease progression in these two DMD models, we conducted a comprehensive natural history study. Materials and MethodsThis involved a cross-sectional analysis of key in vivo and ex vivo outcome measures performed in two independent laboratories, using the same study setup in compliance with TREAT-NMD Standard Operating Procedures (SOPs), while also taking advantage of site-specific expertise. Globally, largely comparable results were obtained across the two study sites. ResultsBody composition showed pronounced differences between the strains, with BL10-mdx mice displaying a hypertrophic and D2-mdx mice displaying an atrophic phenotype. Dystrophic mice of each strain exhibited significant alterations of disease-relevant indices related to muscle functionality and integrity, mostly worsening with age, in comparison to their wildtypes. Cardiac function was affected earlier and more severely in D2-mdx mice. DiscussionNotably, for some parameters, genetic-background related differences were observed, emphasizing the need to include control groups with matching genetic backgrounds in experimental designs. ConclusionsCollectively, our natural history study provides benchmark data for these two mdx mouse strains to guide model selection for preclinical DMD studies, allowing accurate data interpretation. HighlightsO_LIDistinct body composition phenotypes: BL10-mdx mice exhibit pseudohypertrophy while D2-mdx mice display pronounced atrophy. C_LIO_LIEarlier cardiac dysfunction in D2-mdx: D2-mdx mice develop reduced ejection fraction and stroke volume from 28 weeks, while BL10-mdx only at 52 weeks. C_LIO_LIGenetic background-dependent variations: Intrinsic deficits in wildtype D2 mice demonstrate that genetic background influences outcome measures independent of dystrophic pathology. C_LIO_LIComparable ex vivo muscle physiology: Despite divergent in vivo phenotypes, isolated muscle contractile parameters show similar impairment in both dystrophic models. C_LIO_LIMulti-site standardized validation: Cross-sectional study at two independent laboratories following harmonized TREAT-NMD Standard Operating Procedures. C_LI

pharmacology and toxicology↗

bioRxiv2026

TRAINING SESSION INTERVALS SHAPE FUNCTIONAL CONNECTIVITY IN SPATIAL LEARNING: A BRAIN-WIDE ANALYSIS

A substantial body of research indicates that spaced training, characterized by longer inter-trial intervals between training epochs, consistently outperforms massed training in promoting durable memory. To investigate the neural mechanisms underlying this difference, we quantified c-Fos expression across 126 brain regions and mapped network activity following both spatial and cue-based learning under massed and spaced training protocols. While both training regimens (spaced and massed) and memory types (spatial and cue-based) produced small-world networks with similar overall topology, they differed in the functional organization of specific circuits. Massed spatial training preferentially activated hippocampal-thalamic and claustrum-basal ganglia-thalamic pathways. In contrast, spaced spatial training promoted stronger cortico-thalamic interactions and enhanced communication between the hippocampus and basal ganglia, indicating a shift toward a more integrated, cortically mediated network. These findings suggest that temporal spacing of training reorganizes memory-related brain networks, enhancing cortical-thalamic dynamics to support more efficient spatial memory. Finally, spaced networks were more sensitive to targeted disruptions of key connector hubs--identified through betweenness centrality analysis--than massed networks, pointing to a potential systems-level trade-off.

neuroscience↗

bioRxiv2024

Distinct roles of medial prefrontal cortex subregions in the consolidation and recall of remote spatial memories

It is a common believe that memories with time become progressively independent of the hippocampus and are gradually stored in cortical areas. This view is mainly based on evidence demonstrating an impairing effect of prefrontal cortex (PFC) manipulations in the retrieval of remote memories paralleled by a lack of effect of hippocampal inhibition. What is more controversial is whether activity in the mPFC is required immediately after learning to initiate the consolidation process. Further question are possible functional differences among the subregions of the PFC in the formation and storage of remote memories. To address these issues, we directly contrasted the effects of loss-of-function manipulations of the the anterior cingulate cortex (aCC) and the ventro-medial prefrontal cortex (vmPFC), that includes the infralimbic and the prelimbic cortices, before testing, and immediately after training, on the ability of CD1 mice to recall the location of the hidden platform in the Morris water maze. To this aim we injected in the vmPFC or in the aCC an AAV carrying the hM4Di receptor. Interestingly, pre-test administrations of clozapine-N-oxide (CNO) revealed that the aCC, but not the vmPFC, is necessary to recall remote spatial information. Furthermore, systemic post-training administration of CNO (3mg/kg) impaired memory recall at remote time points but not recent time points in both experimental groups. Overall, these findings revealed a functional dissociation between the two prefrontal areas, demonstrating that they are both involved in the early consolidation of remote spatial memories, but that only the aCC is engaged in their recall. Significant statementThe PFC constitute an heterogeneous brain region from both a neuroanatomical and a functional point of view in which at least two main component can be distinguished: the vmPFC, with extensive connections with the limbic system and the HPC and the aCC characterized by its reciprocal connections with the sensorimotor cortex (Heidbreder and Groenewegen, 2003; Uylings et al., 2003; Le Merre et al., 2021). Contrasting the two components of the PFC, the aim of this study was twofold: investigate their relative contribution to the recall of remote spatial memory and in the consolidation of both recent and remote memories. The results demonstrated an interesting dissociation between the two components. Loss-of-function manipulation of the aCC but not the vmPFC impaired recall of remote spatial memory, however, both subdivisions contributed to its consolidation.

neuroscience↗

bioRxiv2023

Specific patterns of neural activity in the hippocampus after massed or distributed spatial training

Training with long inter-session intervals, termed distributed training, has long been known to be superior to training with short intervals, termed massed training. In the present study we compared c-Fos expression after massed and distributed training protocols in the Morris water maze to outline possible differences in the learning-induced pattern of neural activation in the dorsalCA1 in the two training conditions. The results demonstrate that training and time lags between learning opportunities had an impact on the pattern of neuronal activity in the dorsalCA1. Mice trained with the distributed protocol showed sustained neuronal activity in the postero-septal component of the dorsalCA1. In parallel, in trained mice we found more active cells that tended to constitute spatially restricted clusters, whose degree increased with the increase in the time lags between learning trials. Moreover, activated cell assemblies demonstrated increased stability in their spatial organization after distributed as compared to massed training or control condition. Finally, using a machine learning algorithm we found that differences in the number of c-Fos positive cells and their location in the dorsalCA1 could be predictive of the training protocol used. These results suggest that the topographic organization and the spatial location of learning activated cell assemblies might be critical to promote the increased stability of the memory trace induced by distributed training.

neuroscience↗

bioRxiv2021

EFFICACY OF DISTRIBUTED TRAINING DEPENDS ON THE DORSO-LATERAL STRIATUM

Distributed training has long been known to lead to more robust memory formation as compared to massed training. Here we demonstrate that distributed and massed training differentially engage the dorsolateral and dorsomedial striatum and optogenetic priming of dorsolateral striatum can artificially increase the robustness of massed training to the level of distributed training, identifying a novel therapeutic avenue for memory enhancement.

neuroscience↗

bioRxiv2018

A master regulatory network restoring brain glutamate homeostasis is coordinately activated in stroke

Post-transcriptional regulation by miRNAs is essential for complex molecular responses to physiological insult and disease. Although many disease-associated miRNAs are known, their global targets and culminating network effects on pathophysiology remain poorly understood. We applied AGO CLIP to systematically elucidate altered miRNA-target interactions in brain following ischemia/reperfusion (I/R) injury. Among 1,190 identified, most prominent was the cumulative loss of target regulation by miR-29 family members. Integration of translational and time-course RNA profiles revealed a dynamic mode of miR-29 target de-regulation, led by acute translational activation and later increase in RNA levels, allowing rapid proteomic changes to take effect. These functional regulatory events rely on canonical and non-canonical miR-29 binding and engage glutamate reuptake signals to control local glutamate levels. These results uncover a miRNA target network that acts acutely to maintain brain homeostasis after ischemic stroke.

neuroscience↗