Social Isolation Alters Hippocampal miR-30e-5p Expression and Impairs Pattern Separation-Related Behaviour in Adult Mice

Technical Summary: Social Isolation Alters Hippocampal miR-30e-5p Expression and Impairs Pattern Separation-Related Behaviour in Adult Mice

Problem Statement
Social isolation is a well-established model for social stress and a significant risk factor for depression, known to impact hippocampal function and postnatal neurogenesis. While the effects of social isolation during adolescence (juvenile isolation) have been extensively studied, the consequences of prolonged social isolation specifically in adult mice remain less understood. Furthermore, the molecular mechanisms linking social isolation to hippocampal dysfunction, particularly through post-transcriptional regulation by microRNAs (miRNAs), require further elucidation. Previous research has noted altered miRNA and gene expression in the hippocampus of isolated mice, and a specific single-nucleotide polymorphism in human miR-30e has been associated with increased mature miRNA expression, cognitive impairment, and psychiatric conditions such as depression and schizophrenia. This study addresses the gap in understanding how adult social isolation influences hippocampal function via miRNA-mediated gene regulation, with a specific focus on miR-30e-5p.

Methodology
The study utilized adult male BALB/c mice subjected to a 10-week period of social isolation to model prolonged adult isolation. The researchers investigated the molecular and behavioral consequences of this stressor through the following approaches:

• Molecular Analysis: Quantification of miR-30e-5p expression levels in the ventral hippocampus. The study also examined the expression of Neurod1, identified as a target gene of miR-30e-5p.
• Behavioral Assessment: Evaluation of hippocampal-dependent cognition using an object pattern separation task. Additionally, the mice were assessed for anxiety- and depression-like behaviors.
• Stress Response: The study measured the response of isolated mice to acute stress to determine if the isolation induced a blunted physiological reaction.

Key Results
The investigation yielded several specific findings regarding the impact of adult social isolation:

• Molecular Changes: Ten weeks of isolation resulted in a significant increase in miR-30e-5p expression within the ventral hippocampus. Concurrently, the expression of its target gene, Neurod1, was reduced, indicating a functional regulatory relationship.
• Cognitive Impairment: Isolated mice demonstrated impaired performance in object pattern separation, a task dependent on hippocampal function.
• Behavioral Specificity: Despite the cognitive deficits, the study did not observe clear anxiety- or depression-like behaviors in the isolated group.
• Stress Response: The isolated mice exhibited a blunted response to acute stress compared to controls.

Significance and Claims
The paper claims that adult social isolation affects hippocampal function through post-transcriptional gene regulation, specifically implicating the miR-30e-5p pathway. The findings suggest that miR-30e-5p plays a critical role in neurogenesis and cognition in the context of psychological stress. By linking increased miR-30e-5p expression to the downregulation of Neurod1 and subsequent cognitive deficits, the study highlights a specific molecular mechanism through which social stress in adulthood can alter brain function, distinct from the mechanisms observed in adolescent isolation models. The authors emphasize that these alterations occur even in the absence of overt anxiety or depression-like phenotypes, underscoring the specificity of the cognitive and molecular impacts of adult isolation.