Harris, E. P. | Search bioRxiv

bioRxiv2024

Fate (or state) of CA2 neurons in a mineralocorticoid receptor knockout.

Hippocampal area CA2 has emerged as a functionally and molecularly distinct part of the hippocampus and is necessary for several types of social behavior, including social aggression. As part of the unique molecular profile of both mouse and human CA2, the mineralocorticoid receptor (MR; Nr3c2) appears to play a critical role in controlling CA2 neuron cellular and synaptic properties. To better understand the fate (or state) of the neurons resulting from MR conditional knockout, we used a spatial transcriptomics approach. We found that without MRs, CA2 neurons acquire a CA1-like molecular phenotype. Additionally, we found that neurons in this area appear to have a cell size and density more like that in CA1. These finding support the idea that MRs control at least CA2s state during development, resulting in a CA1-like fate.

neuroscience↗

bioRxiv2024

A cafeteria diet blunts effects of exercise on adult hippocampal neurogenesis but not neurogenesis-dependent behaviours in adult male rats

Animal studies have shown that a cafeteria (CAF) diet (high in saturated fat and sugar), is associated with memory impairments and increased anxiety, while exercise can enhance antidepressant-like effects and cognitive function. The mechanisms underlying the effects of a CAF diet, exercise, or their convergence on memory, mood and anxiety are not fully understood, but alterations in adult hippocampal neurogenesis (AHN), gut microbial metabolites, or plasma metabolic hormones may play a role. Therefore, this study investigated whether a 7.5-week voluntary running exercise intervention in young adult male rats could alter the effects of a concurrent CAF diet on depression-like, anxiety-like and cognitive behaviours and AHN, and determined associated changes in metabolic hormones and gut microbial metabolites. We found that exercise produced a mild anxiolytic effect, regardless of diet, and increased PYY, a hormone previously shown to reduce anxiety-like behaviour. CAF diet induced differential abundance of caecal metabolites, and exercise attenuated CAF diet-induced decreases in certain metabolites implicated in cognitive function or depression-like behaviour. Although exercise exerted antidepressant-like effects in the FST, induced subtle improvements in spatial learning strategy, and increased plasma metabolic hormones previously implicated in depression-like behaviour in CAF diet-fed animals, CAF diet blunted exercise-induced increases in plasma GLP-1 and AHN, suggesting that exercise should be accompanied by a healthy diet to increase AHN. Together, these findings highlight the importance of exercise and healthy diet for hippocampal health and provide insight into potential metabolite and hormone-mediated mechanisms underlying the effects of CAF diet and exercise on brain and behaviour. Key points- Diets high in saturated fat and sugar are associated with memory impairments and increased anxiety while exercise can exert antidepressant-like effects and enhance cognitive function, but the biological underpinnings of these effects and whether exercise can negate effects of such diets remain to be elucidated. - We found that running exercise modestly reduced anxiety in rats fed either a healthy or a cafeteria-style diet and increased a hormone (peptide YY) previously shown to decrease anxiety. - Running exercise exerted antidepressant-like effects in cafeteria diet-fed rats and attenuated cafeteria diet-induced decreases in gut metabolites previously implicated in cognition or depression-like behaviour. - Cafeteria diet blunted exercise-induced production of new neurons in the hippocampus, a brain region important in mood and memory. - These data highlight the importance of combining exercise with a healthy diet for hippocampal health, while identifying potential targets for intervention or dietary supplementation to prevent a cafeteria diet blunting beneficial effects of exercise

neuroscience↗

bioRxiv2023

Early resource scarcity causes cortical astrocyte enlargement and sex-specific changes in the orbitofrontal cortex transcriptome in adult rats

Astrocyte morphology affects function, including the regulation of glutamatergic signaling. This morphology changes dynamically in response to the environment. However, how early life manipulations alter adult cortical astrocyte morphology is underexplored. Our lab uses brief postnatal resource scarcity, the limited bedding and nesting (LBN) manipulation, in rats. We previously found that LBN promotes later resilience to adult addiction-related behaviors, reducing impulsivity, risky decision-making, and morphine self-administration. These behaviors rely on glutamatergic transmission in the medial orbitofrontal (mOFC) and medial prefrontal (mPFC) cortex. Here we tested whether LBN changed astrocyte morphology in the mOFC and mPFC of adult rats using a novel viral approach that, unlike traditional markers, fully labels astrocytes. Prior exposure to LBN causes an increase in the surface area and volume of astrocytes in the mOFC and mPFC of adult males and females relative to control-raised rats. We next used bulk RNA sequencing of OFC tissue to assess transcriptional changes that could increase astrocyte size in LBN rats. LBN caused mainly sex-specific changes in differentially expressed genes. However, Park7, which encodes for the protein DJ-1 that alters astrocyte morphology, was increased by LBN across sex. Pathway analysis revealed that OFC glutamatergic signaling is altered by LBN in males and females, but the gene changes in that pathway differed across sex. This may represent a convergent sex difference where glutamatergic signaling, which affects astrocyte morphology, is altered by LBN via sex-specific mechanisms. Collectively, these studies highlight that astrocytes may be an important cell type that mediates the effect of early resource scarcity on adult brain function.

neuroscience↗