Biology subjects

Vignoli, B.

Publications and source records attributed to Vignoli, B..

3 recordsLinked to original sources

bioRxiv2024

Mapping Synaptic Ensembles Through In Vitro Functional Cell Assemblies

In memory circuits, synaptic engrams consist of ensembles of strengthened synapses that form between engram neurons encoding distinct memory traces. As proposed in Hebbs seminal postulate, these potentiated synapses enable the functional cell assembly essential for neuronal wiring. While existing technologies can track potentiated synapses in behaving animals, understanding the in vivo spatial-temporal organization of synaptic engrams remains challenging. We developed an in vitro hybrid system that integrates digital light processing with optogenetics and used optical stimulation to synchronize the firing patterns of two-neuron modules within a network, supporting Hebbs postulate experimentally. After illumination, we observed that synapses predominantly strengthen on dendrites between the two illuminated neurons, reflecting neuron responses to the wiring activity. This observation provides a strong conceptual foundation for our methodology. Our setup also allows for direct illumination and strengthening of synaptic ensembles, granting spatial-temporal control over the synaptic networks. Building on Hebbs theoretical framework, our system offers a solid experimental approach to test the fundamental principles underlying synaptic engrams.

neuroscience↗

bioRxiv2023

Male violence disrupts estrogen receptor β signaling in the female hippocampus

Women are the main target of intimate partner violence (IPV), which is escalating worldwide. Mechanisms subtending IPV-related disorders, such as anxiety, depression and PTSD, remain unclear. We employed a mouse model molded on an IPV scenario (male vs. female prolonged violent interaction) to unearth the neuroendocrine alterations triggered by an aggressive male mouse on the female murine brain. Experimental IPV (EIPV) prompted marked anxiety-like behavior in young female mice, coincident with high circulating/cerebral corticosterone levels. The hippocampus of EIPV-inflicted female animals displayed neuronal loss, reduced BrdU-DCX-positive nuclei, decreased mature DCX-positive cells, and diminished dendritic arborization level in the dentate gyrus (DG), features denoting impaired neurogenesis and neuronal differentiation. These hallmarks were associated with marked down-regulation of estrogen receptor {beta} (ER{beta}) density in the hippocampus, especially in the DG and dependent prosurvival ERK signaling. Conversely, ER expression was unchanged. After EIPV, the DG harbored lowered local BDNF pools, diminished TrkB phosphorylation, and elevated glucocorticoid receptor phosphorylation. In unison, ER{beta} KO mice had heightened anxiety-like behavior and curtailed BDNF levels at baseline, despite enhanced circulating estradiol levels, while dying prematurely during EIPV. Thus, reiterated male-to-female violence jeopardizes hippocampal homeostasis in the female brain, perturbing ER{beta}/BDNF signaling, thus instigating anxiety and chronic stress.

neuroscience↗

bioRxiv2020

PHARMACOLOGICAL PROTEIN INACTIVATION BY TARGETING FOLDING INTERMEDIATES

Recent computational advancements in the simulation of biochemical processes allow investigating the mechanisms involved in protein regulation with realistic physics-based models, at an atomistic level of resolution. Using these techniques to study the negative regulation of the androgen receptor (AR), we discovered a key functional role played by non-native metastable states appearing along the folding pathway of this protein. This unexpected observation inspired us to design a completely novel drug discovery approach, named Pharmacological Protein Inactivation by Folding Intermediate Targeting (PPI-FIT), based on the rationale of negatively regulating protein expression by targeting folding intermediates. Here, PPI-FIT was tested for the first time on the cellular prion protein (PrP), a cell surface glycoprotein playing a key role in fatal and transmissible neurodegenerative pathologies known as prion diseases. We predicted the all-atom structure of an intermediate appearing along the folding pathway of PrP, and identified four different small molecule ligands for this conformer, all capable of selectively lowering the expression of the protein by promoting its degradation. Our data support the notion that the level of target proteins could be modulated by acting on their folding pathways, implying a previously unappreciated role for folding intermediates in the biological regulation of protein expression.

biochemistry↗