Early adversity is an important risk factor that influences brain aging. Diverse animal models of early adversity, including gestational stress and postnatal paradigms disrupting dam-pup interactions evoke not only persistent neuroendocrine dysfunction and anxio-depressive behaviors, but also perturb the trajectory of healthy brain aging. The process of brain aging is thought to involve hallmark features such as mitochondrial dysfunction and oxidative stress, evoking impairments in neuronal bioenergetics. Furthermore, brain aging is associated with disrupted proteostasis, progressively defective epigenetic and DNA repair mechanisms, the build-up of neuroinflammatory states, thus cumulatively driving cellular senescence, neuronal and cognitive decline. Early adversity is hypothesized to evoke an \"allostatic load\" via an influence on several of the key physiological processes that define the trajectory of healthy brain aging. In this review we discuss the evidence that animal models of early adversity impinge on fundamental mechanisms of brain aging, setting up a substratum that can accelerate and compromise the time-line and nature of brain aging, and increase risk for aging-associated neuropathologies.

The brain has traditionally been considered to be a target site of peripheral steroid hormones. On the other hand, extensive studies over the past thirty years have demonstrated that the brain is a site of biosynthesis of several steroids. Such steroids synthesized de novo from cholesterol in the brain are called neurosteroids. To investigate the biosynthesis and biological actions of neurosteroids in the brain, data on the regio- and temporal-specific synthesis of neurosteroids are needed. In the mid 1990s, the Purkinje cell, an important cerebellar neuron, was discovered as a major cell producing neurosteroids in the brain of vertebrates. It was the first demonstration of de novo neuronal biosynthesis of neurosteroids in the brain. Subsequently, neuronal biosynthesis of neurosteroids and biological actions of neurosteroids have become clear by the follow-up studies using the Purkinje cell as an excellent cellular model. Progesterone and estradiol, which are known as sex steroid hormones, are actively synthesized de novo from cholesterol in the Purkinje cell during development, when cerebellar neuronal circuit formation occurs. Importantly, progesterone and estradiol synthesized in the Purkinje cell promote dendritic growth, spinogenesis and synaptogenesis via their cognate nuclear receptors in the Purkinje cell. Neurotrophic factors may mediate these neurosteroid actions. Futhermore, allopregnanolone (3α,5α-tetrahydroprogesterone), a progesterone metabolite, is also synthesized in the cerebellum and acts on the survival of Purkinje cells. On the other hand, at the beginning of 2010s, the pineal gland, an endocrine organ located close to the cerebellum, was discovered as an important site of the biosynthesis of neurosteroids. Allopregnanolone, a major pineal neurosteroid, acts on the Purkinje cell for the survival of Purkinje cells by suppressing the expression of caspase-3, a crucial mediator of apoptosis. I as a recipient of Kobayashi Award from the Japan Society for Comparative Endocrinology in 2016 summarize the discovery of cerebellar and pineal neurosteroids and their biological actions on the growth and survival of Purkinje cells during development.

Each year, more than 790 000 people in the United States suffer from a stroke. Although progress has been made in diagnosis and treatment of ischemic stroke (IS), new therapeutic interventions to protect the brain during an ischemic insult is highly needed. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression post-transcriptionally. Growing evidence suggests that miRNAs have a profound impact on ischemic stroke progression and are potential targets of novel treatments. Notably, inflammatory pathways play an important role in the pathogenesis of ischemic stroke and its pathophysiologic progression. Experimental and clinical studies have illustrated that inflammatory molecular events collaboratively contribute to neuronal and glial cell survival, edema formation and regression, and vascular integrity. In the present review, we examine recent discoveries regarding miRNAs and their roles in post-ischemic stroke neuropathogenesis.