Biology subjects

Verret, L.

Publications and source records attributed to Verret, L..

5 recordsLinked to original sources

bioRxiv2026

Evolutionary and biological insights into the paternally expressed Snord116-Ipw-Snord115 gene array at the imprinted Prader-Willi syndrome domain

Placental mammal-specific box C/D small nucleolar RNA (SNORD) genes within the imprinted human 15q11q13 domain have garnered increasing attention because their poorly understood roles in the brain and their potential involvement in Prader-Willi syndrome (PWS). Using two novel knockout (KO) mouse models, we demonstrate that combined deletion of Snord116 and Snord115 genes, but not the intervening Ipw ncRNA gene, leads to partially penetrant perinatal lethality (40-50%). Snord116/115-deficient neonates display postnatal growth impairment, hypoglycemia and endocrine dysregulation, including failure of the postnatal leptin surge. Despite showing no overt alterations in feeding behavior, adult Snord116/115-KO mice recapitulate most phenotypes previously reported in Snord116-KO models. RNA-seq analyses of the hypothalamus, prefrontal cortex and cerebellum reveal limited global changes. However, we observed upregulation of two of the most compelling putative RNA targets of Snord116 and Snord115 (Dgkk and Htr2c, respectively) in the postnatal hypothalamus. Nevertheless, no evidence was found to support efficient Snord115-guided ribose methylation of Htr2c mRNA. Finally, comparative analyses across 64 representative placental mammal species reveal that many PWS-associated SNORD genes, including SNORD115, display greater evolutionary changes than previously appreciated, raising questions about the functional relevance and evolutionary selective pressures that have shaped the diversification of certain family members across species. Overall, our study provides an unbiased re-assessment of the evolutionary, molecular and physiological significance of the paternally expressed Snord116-Ipw-Snord115 genomic interval and highlights the early postnatal period as a critical, yet largely underexplored, developmental window during which recently evolved SNORDs likely function as dispensable fine-tuners of gene expression.

genetics↗

bioRxiv2026

Loss of SNORD115 mitigates SNORD116-driven sleep abnormalities in mouse models of Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by the loss of paternally expressed genes within the imprinted 15q11-q13 locus, which includes clusters of box C/D small nucleolar RNAs (SNORDs), notably the SNORD115 and SNORD116 gene families. Although paternally inherited SNORD116 deletions have been associated with sleep disturbances in patients and mouse models, the respective and combined contributions of SNORD115 and SNORD116 to sleep regulation remain unclear. Here, we combined polysomnographic recordings with quantitative analysis of hypothalamic neuronal populations to assess sleep-wake architecture, sleep homeostasis, and underlying circuit alterations in mice carrying paternal deletions of SNORD115, SNORD116, or both clusters. SNORD116 deletion was associated with a selective increase in REM sleep, particularly during the light phase and during recovery following sleep deprivation, without affecting slow-wave sleep or REM-associated theta activity. In contrast, SNORD115 deletion did not alter sleep. Unexpectedly, combined deletion of SNORD115 and SNORD116 did not reproduce the REM sleep phenotype observed in SNORD116-deficient mice, indicating that SNORD115 loss attenuates SNORD116-dependent REM sleep alterations. At the cellular level, melanin-concentrating hormone (MCH) neuron density was reduced in both SNORD116-KO and double SNORD116/115-KO mice, whereas hypocretin (Hcrt) neurons were preserved across genotypes. Notably, REM sleep alterations did not parallel MCH loss, as increased REM sleep was absent in double-KO animals despite comparable reduction in MCH neuron density. Transcriptomic analyses at ZT0 further revealed only limited changes in hypothalamic gene expression across models. Together, these findings reveal an unanticipated interaction between SNORD115 and SNORD116 in the regulation of REM sleep and uncover a dissociation between genetic alterations, neuronal circuit organization, and sleep phenotype. More broadly, they caution against inferring physiological functions or disease-relevant mechanisms from single SNORD deletions within complex imprinted loci, and indicate that current mouse models may not faithfully capture sleep alterations associated with PWS.

neuroscience↗

bioRxiv2024

Enriched environment requires remodeling of hippocampal perineuronal nets to trigger memory improvement in Alzheimer's mouse model

Alzheimers disease (AD) is a major neurodegenerative disorder influenced by both genetic and environmental factors. Engaging in mentally stimulating activities is believed to reduce cognitive decline by establishing a cognitive reserve, though the underlying neurobiological mechanisms remain elusive. In this study, we explore the role of parvalbumin-expressing inhibitory neurons (PV) and their associated perineuronal nets (PNN) in cognitive deficits observed in AD. Using the Tg2576 mouse model, we demonstrate that 10 days of exposure to an enriched environment (EE) significantly restores spatial and social memory, accompanied by an increase in PV and PV/PNN cell populations in the hippocampus. Notably, preventing PV/PNN remodeling in the CA1 region during EE abolishes the spatial memory improvements, whereas localized neuregulin-1 (NRG1) injections induce PV/PNN remodeling and restore memory function. These findings suggest that hippocampal PV/PNN remodeling is essential for the cognitive benefits of EE in AD, highlighting this neuronal population as a critical substrate for cognitive reserve. This study provides new insights into the mechanisms by which environmental factors may mitigate cognitive decline in AD, offering potential avenues for therapeutic interventions. Highlights10-day environmental enrichment increases PV+ and PV+/PNN+ in the hippocampus of Tg2576 mouse model of AD Blocking PV/PNN remodeling during EE prevents memory recovery in Tg2576 mice Enhancing PV/PNN remodeling with NRG1 leads to restored memory in Tg2576 mice PV/PNN remodeling in area CA1 affects spatial memory, while in CA2, it impacts social memory

neuroscience↗

bioRxiv2024

Fine Social Discrimination of Siblings in Mice: Implications for Early Detection of Alzheimer's Disease

The ability to distinguish between individuals is crucial for social species and supports behaviors such as reproduction, hierarchy formation, and cooperation. In rodents, social discrimination relies on memory and the recognition of individual-specific cues, known as "individual signatures". While olfactory signals are central, other sensory cues --such as auditory, visual, and tactile inputs -- also play a role. However, little research has explored the fine discrimination of individuals with overlapping cues, such as siblings or cohabitating mice. This study investigates whether mice can discriminate between two closely related individuals: siblings from the same litter and cage. We tested the hypothesis that it would be more challenging for mice to distinguish between siblings than between unrelated mice due to shared cues. Moreover, social cognitive impairments are common in neurodegenerative diseases like Alzheimers disease (AD), where difficulties in recognizing faces and voices progressively disrupt social interactions in patients. Using a mouse model of AD (Tg2576), known for the progressive onset of cognitive deficits, we assessed whether the ability to discriminate between siblings is preserved in "pre-symptomatic" animals. Thus, we first demonstrated that male and female C57BL6/J mice can discriminate siblings, regardless of sex. Next, we revealed that "pre-symptomatic" 3-month-old Tg2576 mice exhibit impairments in fine social memory, while their general social memory remains unaffected. Thus, we demonstrate that the inability to perform fine social discrimination is an early cognitive impairment that arises before other well-documented memory abnormalities in this AD mouse model. SIGNIFICANCE STATEMENTDiscriminating between individuals is vital for social species, supporting reproduction, hierarchy formation and cooperation. This study examined whether mice can perform fine social discrimination, i.e., distinguish between siblings from the same home cage. We found that both male and female C57BL6/J mice can discriminate siblings, regardless of their sex. Notably, this fine social discrimination ability is impaired in mouse model of Alzheimers disease (AD) at a very early stage of the pathology, i.e., at an age when they can still recognize two unrelated mice from different home cages. This suggests that fine social discrimination deficits occur early in AD, and could serve as an early marker of the pathology.

animal behavior and cognition↗

bioRxiv2022

Ventral Tegmental Area dopamine projections to the hippocampus trigger long term potentiation and contextual learning

In most models, dopamine is not involved in the initiation but only in the long-term maintenance of LTP and memory. Conversely, we discovered that repeatedly stimulating Schaffer collaterals in concomitance with midbrain dopamine afferents to CA1 triggers hippocampal LTP. Moreover, we show that this dopamine pathway is involved in contextual learning. Thus, midbrain dopamine can play the role of a teaching signal triggering non-Hebbian LTP and allowing supervised learning.

neuroscience↗