Verret, L. | bioRxiv Science

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↗