Biology subjects

Sagona, G.

Publications and source records attributed to Sagona, G..

6 recordsLinked to original sources

bioRxiv2024

Postnatal Sensory Experience and Barrel Cortex Alterations Anticipate Autistic Traits in a Mouse Model of Cdkl5 Deficiency Disorder

Autistic traits may arise from atypical sensory experience during postnatal life, but whether there is a causal link between defects in cortical circuitry in the brain, altered sensory processing and social behavior remains unknown. Here, we studied tactile stimuli processing in the barrel cortex (BC) and social interactions in juvenile male mice lacking Cyclin-dependent kinase-like 5 (CDKL5), a model of a severe neurodevelopmental disease showing autistic traits and sensory impairments. We identified in these mice defects of whisker-dependent postnatal sensorimotor reflexes, NMDA receptors-dependent signaling, and dendritic orientation in thalamic inputs-receiving spiny stellate neurons. We also found that CDKL5 is required for mapping and processing whisker-derived tactile stimuli in the BC. Intriguingly, KO mice show autistic traits at p21 that are rescued by neonatal CDKL5 replacement in the BC. Our data suggest that CDKL5 is required to link tactile processing in the BC to the onset of social interaction abilities.

neuroscience↗

bioRxiv2024

Pupillometry and Whole-Brain c-Fos Mapping Uncover Multimodal Mirror Mechanisms in Emotional Contagion Networks of Mice

Emotional contagion (ECo) represents a fundamental form of empathy. In this study, we used pupillometry to quantify ECo by assessing pupil responses of a mouse watching another mouse receive a tail shock. Pupil dilation effectively measured both direct and vicarious emotional response thresholds at the individual level through psychometric curve analysis. The pupillary ECo response diminished when the observer could not see the demonstrator, suggesting a multisensory process involving vision. Viewing videos of tail-shocked mice was sufficient to elicit a pupil response in the observer. Whole-brain c-Fos mapping revealed a broad network of 88 brain regions activated during ECo, with all areas activated in the demonstrator also engaged in the observer. Additionally, in certain brain regions, correlated activation was detected between each observer-demonstrator pair, indicating that ECo promotes a shared neural state. These findings advance our understanding of the neural basis of empathy, with implications for analyzing neuropsychiatric disorder models.

neuroscience↗

bioRxiv2024

Lipid droplet protein Perilipin 2 is critical for the regulation of insulin secretion through beta cell lipophagy and glucagon expression in pancreatic islets

Knockdown (KD) of lipid droplet (LD) protein perilipin 2 (PLIN2) in beta cells impairs glucose-stimulated insulin secretion (GSIS) and mitochondrial function. Here, we addressed a pathway responsible for compromised mitochondrial integrity in PLIN2 KD beta cells. In PLIN2 KD human islets, mitochondria were fragmented in beta cells but not in alpha cells. Glucagon but not insulin level was elevated. While the formation of early LDs followed by fluorescent fatty acids (FA) analog Bodipy C12 (C12) was preserved, C12 accumulated in mitochondria over time in PLIN2 KD INS-1 cells. A lysosomal acid lipase inhibitor Lali2 prevented C12 transfer to mitochondria, mitochondrial fragmentation, and the impairment of GSIS. Direct interactions between LD-lysosome and lysosome-mitochondria were increased in PLIN2 KD INS-1 cells. Thus, FA released from LDs by microlipophagy cause mitochondrial changes and impair GSIS in PLIN2 KD beta cells. Interestingly, glucolipotoxic condition (GLT) caused C12 accumulation and mitochondrial fragmentation similar to PLIN2 KD in beta cells. Moreover, Lali2 reversed mitochondrial fragmentation and improved GSIS in human islets under GLT. In summary, PLIN2 regulates microlipophagy to prevent excess FA flux to mitochondria in beta cells. This pathway also contributes to GSIS impairment when LD pool expands under nutrient load in beta cells.

molecular biology↗

bioRxiv2022

mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a devastating rare neurodevelopmental disease without a cure, caused by mutations of the serine/threonine kinase CDKL5 highly expressed in the forebrain. CDD is characterized by early-onset seizures, severe intellectual disabilities, autistic-like traits, sensorimotor and cortical visual impairments (CVI). The lack of an effective therapeutic strategy for CDD urgently demands the identification of novel druggable targets potentially relevant for CDD pathophysiology. To this aim, we studied metabotropic glutamate receptors 5 (mGluR5) for their important role in critical mechanisms involved in CDD, i.e.: synaptogenesis, dendritic spines formation/maturation and synaptic plasticity, and because mGluR5 function depends on the postsynaptic protein Homer1bc that is downregulated in the cerebral cortex of CDKL5-/y mice. In this study, we reveal that CDKL5 loss tampers with (i) the strength of Homer1bc-mGluR5 binding, (ii) the synaptic localization of mGluR5 and (iii) the mGluR5-mediated enhancement of NMDA-induced neuronal responses. Importantly, we showed that the stimulation of mGluR5 activity by administering in mice specific positive-allosteric-modulators, i.e.: 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) or RO6807794, corrected the synaptic, functional and behavioural defects shown by CDKL5-/y mice. Notably, the cerebral cortex of 2 CDD patients show similar changes in the synaptic organization to mutant CDKL5 mice, including a reduced mGluR5 expression, suggesting that mGluR5 represent a promising therapeutic target for CDD patients.

neuroscience↗

bioRxiv2021

The gut microbiota of environmentally enriched mice regulates visual cortical plasticity

Exposing animals to an enriched environment (EE) has dramatic effects on brain structure, function and plasticity. The poorly known "EE derived signals" mediating the EE effects are thought to be generated within the central nervous system. Here, we shift the focus to the body periphery, revealing that gut microbiota signals are crucial for EE-driven plasticity. Developmental analysis of intestinal bacteria composition in EE mice revealed striking differences from standard condition (ST) animals and enhanced levels of short-chain fatty acids (SCFA). Depleting the EE mice gut microbiota with an antibiotic cocktail decreased SCFA and prevented EE induction of adult ocular dominance (OD) plasticity, spine dynamics and microglia rearrangement. SCFA treatment in ST mice mimicked the EE induction of adult OD plasticity and morphological microglial rearrangement. Remarkably, transferring the microbiota of EE mice to ST recipients activated adult OD plasticity. Thus, taken together our data suggest that experience-dependent changes in gut microbiota regulate brain plasticity.

neuroscience↗

bioRxiv2021

MEYE: Web-app for translational and real-time pupillometry

Pupil dynamics alterations have been found in patients affected by a variety of neuropsychiatric conditions, including autism. Studies in mouse models have used pupillometry for phenotypic assessment and as a proxy for arousal. Both in mice and humans, pupillometry is non-invasive and allows for longitudinal experiments supporting temporal specificity, however its measure requires dedicated setups. Here, we introduce a Convolutional Neural Network that performs on-line pupillometry in both mice and humans in a web app format. This solution dramatically simplifies the usage of the tool for non-specialist and non-technical operators. Because a modern web browser is the only software requirement, this choice is of great interest given its easy deployment and set-up time reduction. The tested model performances indicate that the tool is sensitive enough to detect both spontaneous and evoked pupillary changes, and its output is comparable with state-of-the-art commercial devices.

neuroscience↗