Cross-species analysis uncovers the mitochondrial stress response in the hippocampus as a shared mechanism in mouse early life stress and human depression.

Depression, or major depressive disorder, poses a significant burden for both individuals and society, affecting approximately 10.8% of the general population. This psychiatric disorder leads to approximately 800,000 deaths per year. A combination of genetic and environmental factors such as early life stress (ELS) increase the risk for development of depression in humans, and a clear role for the hippocampus in the pathophysiology of depression has been shown. Nevertheless, the underlying mechanisms of depression remain poorly understood, resulting in a lack of effective treatments. To better understand the core mechanisms underlying the development of depression, we used a cross-species design to investigate shared hippocampal pathophysiological mechanisms in mouse ELS and human depression. Mice were subjected to ELS by a maternal separation paradigm, followed by RNA sequencing analysis of the adult hippocampal tissue. This identified persistent transcriptional changes linked to mitochondrial stress response pathways, with oxidative phosphorylation and protein folding emerging as the main mechanisms affected by maternal separation. Remarkably, there was a significant overlap between the pathways involved in mitochondrial stress response we observed and publicly available RNAseq data from hippocampal tissue of depressive patients. This cross-species conservation of changes in gene expression of mitochondria-related genes suggests that mitochondrial stress may play a pivotal role in the development of depression. Our findings highlight the potential significance of the hippocampal mitochondrial stress response as a core mechanism underlying the development of depression. Further experimental investigations are required to expand our understanding of these mechanisms.

Aging, sex, metabolic and life experience factors: Contributions to neuro-inflammaging in Alzheimer's disease research.

Alzheimer's disease (AD) is prevalent around the world, yet our understanding of the disease is still very limited. Recent work suggests that the cornerstone of AD may include the inflammation that accompanies it. Failure of a normal pro-inflammatory immune response to resolve may lead to persistent central inflammation that contributes to unsuccessful clearance of amyloid-beta plaques as they form, neuronal death, and ultimately cognitive decline. Individual metabolic, and dietary (lipid) profiles can differentially regulate this inflammatory process with aging, obesity, poor diet, early life stress and other inflammatory factors contributing to a greater risk of developing AD. Here, we integrate evidence for the interface between these factors, and how they contribute to a pro-inflammatory brain milieu. In particular, we discuss the importance of appropriate polyunsaturated fatty acids (PUFA) in the diet for the metabolism of specialised pro-resolving mediators (SPMs); raising the possibility for dietary strategies to improve AD outlook.