Biology subjects

Papale, A.

Publications and source records attributed to Papale, A..

9 recordsLinked to original sources

bioRxiv2025

Prefrontal and Subcortical Value Representation during Explore-Exploit Decision-Making and Suicide Attempts

BackgroundThis study aims to understand learning and decision-making in suicidal behavior by investigating temporal dynamics of reward value encoding in individuals with late-life depression and a history of suicide attempts. MethodsIn a retrospective case-control study, 134 older adults (33 with depression and history of suicide attempts, 29 with depression and suicidal ideation but no past attempts, 32 with depression and no suicidal ideation/past attempts, and 40 psychiatrically healthy controls) completed an explore-exploit decision-making task during functional MRI (fMRI). Multilevel models of deconvolved fMRI time series, time-locked to trial events, interrogated whether temporal patterns of reward value encoding was associated with suicidal behavior. ResultsSuicidal behavior in general was associated with blunted ventral PFC (vPFC) value signals, but profiles varied as a function of attempt lethality. Specifically, low-lethality suicide attempts and excessive behavioral shifts were associated with abolished phasic responses to value updates in the default network vPFC and its connected regions, including the striatum, amygdala, and hippocampus. Additionally, an unexpected pattern of sustained negative value responses was observed in vPFC and striatal control subregions, and hippocampus of high-lethality suicide attempters. ConclusionsDiverging patterns of decision-related responses may reflect different paths toward suicidal behavior. Impaired value updating in individuals with low-lethality suicide attempts suggests a failure to integrate recent outcomes alongside prior experience, potentially relating to over-reactivity to stressors and a lower threshold for suicide attempts. In contrast, increased control network responses to difficult choices in high-lethality attempters may underlie cognitive constriction and consideration of a narrow set of potential solutions.

neuroscience↗

bioRxiv2024

Insulation between adjacent TADs is controlled by the width of their boundaries through distinct mechanisms

Topologically Associating Domains (TADs) are sub-Megabase regions in vertebrate genomes with enriched intra-domain interactions that restrict enhancer-promoter contacts across their boundaries. However, the mechanisms that separate TADs remain incompletely understood. Most boundaries between TADs contain CTCF binding sites (CBSs), which individually contribute to the blocking of Cohesin-mediated loop extrusion. Using genome-wide classification, we show here that TAD boundary width forms a continuum from narrow to highly extended and correlates with CBS distribution, chromatin features, and gene regulatory elements. To investigate how these boundary widths emerge, we modified the Random Cross-Linker (RCL) polymer model to incorporate specific boundary configurations, enabling us to evaluate the differential impact of boundary composition on TAD insulation. Our analysis identifies three generic boundary categories, each influencing TAD insulation differently, with varying local and distal effects on neighboring domains. Notably, we find that increasing boundary width reduces long-range inter-TAD contacts, as confirmed by Hi-C data. While blocking loop extrusion at boundaries indirectly promotes spurious intermingling of neighboring TADs, extended boundaries counteract this effect, emphasizing their role in maintaining genome structure. In conclusion, TAD boundary width not only enhances the efficiency of loop extrusion blocking but may also modulate enhancer-promoter contacts over long distances across TADs boundaries, providing a mechanism for transcriptional regulation. Significance statementTopologically Associating Domains (TADs) compartmentalize vertebrate genomes to limit cross-domain enhancer-promoter loops. Our study reveals that boundaries between TADs are diverse genomic entities that range from narrow to highly extended. Using an interdisciplinary approach that combines genome-wide data analysis with biophysical polymer modeling, we find that wider TAD boundaries reduce spurious long-range interactions between neighboring domains. Moreover, we reveal how different boundary components can create this difference in insulating capacity. Our identification and characterization of TAD boundary width and composition suggests they have the potential to regulate the formation of enhancer-promoter loops across TAD boundaries at close and long distance.

genomics↗

bioRxiv2023

High changing curvature regions detect chromatin enrichment in single cell data

Chromatin organization is nowadays accessible from population and single cell Hi-C data in the form of large contact matrices. Yet reconstructing the three-dimensional chromatin structure remains challenging and relies on polymer models and numerical simulations to account for these Hi-C data. Here we propose a novel optimization algorithm to identify cross-linker ensemble reproducing the experimental contact matrix. Furthermore, based on the polymer configurations extracted from the optimization procedure, we identify high changing curvature (HCC) regions in the chromatin, detected both in population and in single cell Hi-C, that we also compare to Topological Associated Domains (TADs). We report here that the HCC regions correlate with gene expression and CTCF high density distribution. Interestingly, the HCC region locations are heterogeneous across one cell repeats, revealing cell-to-cell variability. To conclude, HCC regions appear both in single and population Hi-C polymer reconstruction and can provide a possible unit for gene regulation.

genomics↗

bioRxiv2022

Chromatin phase separated nanoregions regulated by cross-linkers and explored by single particle trajectories

Phase separated domains (PSDs) are ubiquitous in cell biology, representing nanoregions of high molecular concentration. PSDs appear at diverse cellular domains, such as neuronal synapses but also in eukaryotic cell nucleus, limiting the access of transcription factors and thus preventing gene expression. We study here the properties of PSDs and in particular how they can be generated by polymers. We show that increasing the number of cross-linkers generate a polymer condensation, preventing the access of diffusing molecules. To investigate how the PSDs restrict the motion of diffusing molecules, we estimate the mean residence and first escaping times. Finally, by computing the mean square displacement of single particle trajectories, we can reconstruct the properties of PSDs in term of a continuum range of anomalous exponents. To conclude, PSDs can result from a condensed chromatin, where the number of cross-linkers control the molecular access.

genetics↗

bioRxiv2021

A complex CTCF binding code defines TAD boundary structure and function

Topologically Associating Domains (TADs) compartmentalize vertebrate genomes into sub-Megabase functional neighbourhoods for gene regulation, DNA replication, recombination and repair1-10. TADs are formed by Cohesin-mediated loop extrusion, which compacts the DNA within the domain, followed by blocking of loop extrusion by the CTCF insulator protein at their boundaries11-20. CTCF blocks loop extrusion in an orientation dependent manner, with both experimental and in-silico studies assuming that a single site of static CTCF binding is sufficient to create a stable TAD boundary21-24. Here, we report that most TAD boundaries in mouse cells are modular entities where CTCF binding clusters within extended genomic intervals. Optimized ChIP-seq analysis reveals that this clustering of CTCF binding does not only occur among peaks but also frequently within those peaks. Using a newly developed multi-contact Nano-C assay, we confirm that individual CTCF binding sites additively contribute to TAD separation. This clustering of CTCF binding may counter against the dynamic DNA-binding kinetics of CTCF25-27, which urges a re-evaluation of current models for the blocking of loop extrusion21-23. Our work thus reveals an unanticipatedly complex code of CTCF binding at TAD boundaries that expands the regulatory potential for TAD structure and function and can help to explain how distant non-coding structural variation influences gene regulation, DNA replication, recombination and repair5,28-34.

genetics↗

bioRxiv2020

Lateralized decrease of parvalbumin+ cells in the somatosensory cortex of ASD models is correlatedwith unilateral tactile hypersensitivity

Inhibitory control of excitatory networks contributes to cortical functions. Increasing evidence indicates that parvalbumin expressing (PV+) basket cells (BC) are a major player in maintaining the balance between excitation (E) and inhibition (I) in the cortex. Disruption of E/I balance in cortical networks is believed to be a hallmark of autism spectrum disorders (ASD) and may contribute to sensory alterations seen in ASD. Here, we report a lateralized decrease in the number of PV+ BCs in L2/3 of the somatosensory cortex in the dominant hemisphere of adult Shank3-/- and Cntnap2-/- mouse models of ASD. The dominant hemisphere was identified during a reaching task to establish each animals dominant forepaw. Double labeling with anti-PV antibody and a biotinylated lectin (i.e., VVA) showed that the number of BCs was not different but rather, some BCs did not express detectable levels of PV (PV-), resulting in an elevated number of PV- VVA+ basket cells. This lateralized reduction was not observed in the number of interneurons from the other two major groups that express somatostatin or the serotonergic receptor 5HT3a. Finally, we showed that dominant hind paws had higher mechanical sensitivity (i.e., lower mechanical thresholds measured with von Frey test) but no difference in thermal sensitivity (measured with Hargreaves test) when compared to the other hind paw. This mechanical hypersensitivity in the dominant paw correlated with the decrease in the number of PV+ interneurons and reduced PV expression in the corresponding cortex. Together, these results suggest that the sensory hypersensitivity in ASD could be due to decreased inhibitory inputs to the dominant somatosensory cortex.

neuroscience↗

bioRxiv2020

Chromatin memory generated by cohesin-like interaction at looping sites

Chromatin loops inside the nucleus can be stable for a very long time, which remains poorly understood. Such a time is crucial for chromatin organization maintenance and stability. We explore here several physical scenarios, where loop maintenance is due to diffusing cross-linkers such as cohesin and CTCF that can bind and unbind at the base of chromatin loops. Using a Markov chain approach to coarse-grain the binding and unbinding, we consider that a stable loop disappears when the last cross-linker (CTCF or cohesin molecule) is unbound. We derive expressions for this last passage times that we use to quantify the loop stability for various value parameters, such as the chemical rate constant or the number of cross-linkers. The present analysis suggests that this binding and unbinding mechanism is sufficient to guarantee that there are always cross-linkers in place because they generate a positive feed-back mechanism that stabilizes the loop over long-time. To conclude, we propose that tens to hundreds cross-linkers per loop are sufficient to guarantee the loop stability in the genome over a cell cycle.

genetics↗

bioRxiv2019

Mouse navigation strategies for odor source localization

Navigating an odor landscape is a critical behavior for the survival of many species, including mice. One ethologically relevant mouse behavior is locating food using odor concentration gradients. To model this behavior, we use a naturalistic open field odor-based spot-finding task, examining navigation strategies as mice search for and approach an odor source. Mice were trained to navigate to odor sources paired with food reward. We detected behavioral changes consistent with localization of the odor source when mice were [~]10cm away from the source. These behaviors included both orientation towards the source and increased exploration time. We found that the amplitude of casting, lateral back and forth head movement, increased exponentially with proximity to the source. We then created concentration-dependent models to simulate mouse behavior, which provided evidence for a serial-sniffing strategy (sampling concentration, moving in space, then sampling again) and a stereo-sniffing strategy (inter-nostril comparison of concentration in a single sniff). Together, these results elucidate key components of behavioral strategies for odor-based navigation. SUMMARY STATEMENTUse of a naturalistic odor-source localizing task uncovers key strategies underlying successful mouse navigation. Concentration-dependent models successfully recapitulate mouse behavior and reveal important behavioral components.

neuroscience↗

bioRxiv2018

Modulation of ERK1/MAPK3 potentiates ERK nuclear signalling, facilitates neuronal cell survival and improves memory in mouse models of neurodegenerative disorders

Cell signalling mechanisms are central to neuronal activity and their dysregulation may lead to neurodegenerative processes and associated cognitive decline. So far, a major effort has been directed toward the dissection of disease specific pathways with the still unmet promise to develop precision medicine strategies. With a different approach, here we show that a selective genetic potentiation of neuronal ERK signalling prevents cell death in vitro and in vivo in the mouse brain while ERK attenuation does the opposite. This neuroprotective effect can also be induced pharmacologically by a cell permeable peptide mimicking the loss of ERK1 MAP kinase, leading to a selective enhancement of ERK2 mediated nuclear cell signalling. The drug treatment prevents neurodegeneration in mouse models of Huntingtons (HD), Alzheimers (AD), and Parkinsons disease (PD). Importantly, the selective potentiation of ERK2 signalling facilitates both structural and synaptic plasticity, enhances cognition in healthy mice and rescues mild cognitive impairments in both models of AD and HD. Altogether, our observation truly represents a remarkable example of a shared molecular mechanism across multiple neurodegenerative disorders and a potentially valuable therapeutic target for neuro-enhancement.

neuroscience↗