Early-life exercise primes the murine neural epigenome to facilitate gene expression and hippocampal memory consolidation.

Aerobic exercise is well known to promote neuroplasticity and hippocampal memory. In the developing brain, early-life exercise (ELE) can lead to persistent improvements in hippocampal function, yet molecular mechanisms underlying this phenomenon have not been fully explored. In this study, transgenic mice harboring the "NuTRAP" (Nuclear tagging and Translating Ribosome Affinity Purification) cassette in Emx1 expressing neurons ("Emx1-NuTRAP" mice) undergo ELE during adolescence.

"SIT" with Emx1-NuTRAP Mice: Simultaneous INTACT and TRAP for Paired Transcriptomic and Epigenetic Sequencing.

Epigenetic regulation of transcription is gaining increasing importance in the study of neurobiology. The advent of sequencing technology has enabled the study of this regulation across the entire genome and transcriptome. However, modern methods that allow the correlation of transcriptomic data with epigenomic regulation have had several key limitations, including use of separate tissue sources and detection of low-expression genes.

An Improved Method for Individual Tracking of Voluntary Wheel Running in Pair-housed Juvenile Mice.

Rodent cages equipped with access to a voluntary running wheel are commonly used to study the effects of aerobic physical activity on physiology and behavior. Notable discoveries in exercise neurobiology, including the key role of brain-derived neurotrophic factor (BDNF) in neural plasticity and cognition, have been made using rodents housed with voluntary running wheels. A major advantage of using home-cage running wheels over treadmills is the elimination of stress potentially associated with forced running.

Rett Syndrome: A Timely Review From Recognition to Current Clinical Approaches and Clinical Study Updates.

Since the discovery of the genetic basis of Rett syndrome in 1999, our understanding has grown considerably both in the scientific and the clinical realms. In the last two decades, we have learned about the far-reaching effects of the aberrant MeCP2 protein, the growing list of involved genetic factors, and the genotype-phenotype clinical expression of common MECP2 mutations. This knowledge has led to several basic science research and clinical trials, focusing specifically on emerging treatments of Rett syndrome.

A Unique Mouse Model of Early Life Exercise Enables Hippocampal Memory and Synaptic Plasticity.

Physical exercise is a powerful modulator of learning and memory. Mechanisms underlying the cognitive benefits of exercise are well documented in adult rodents. Exercise studies targeting postnatal periods of hippocampal maturation (specifically targeting periods of synaptic reorganization and plasticity) are lacking.

Blocking CRH receptors in adults mitigates age-related memory impairments provoked by early-life adversity.

In humans, early-life adversity is associated with impairments in learning and memory that may emerge later in life. In rodent models, early-life adversity directly impacts hippocampal neuron structure and connectivity with progressive deficits in long-term potentiation and spatial memory function. Previous work has demonstrated that augmented release and actions of the stress-activated neuropeptide, CRH, contribute to the deleterious effects of early-life adversity on hippocampal dendritic arborization, synapse number and memory-function.

New insights into early-life stress and behavioral outcomes.

Adverse early-life experiences, including various forms of early-life stress, have consistently been linked with vulnerability to cognitive and emotional disorders later in life. Understanding the mechanisms underlying the enduring consequences of early-life stress is an active area of research, because this knowledge is critical for developing potential interventions. Animal models of early-life stress typically rely on manipulating maternal/parental presence and care, because these are the major source of early-life experiences in humans.

Improving the Identification of Neonatal Encephalopathy: Utility of a Web-Based Video Tool.

 This study tested the effectiveness of a video teaching tool in improving identification and classification of encephalopathy in infants.  We developed an innovative video teaching tool to help clinicians improve their skills in interpreting the neonatal neurological examination for grading encephalopathy. Pediatric residents were shown 1-minute video clips demonstrating exam findings in normal neonates and neonates with various degrees of encephalopathy.

MRI uncovers disrupted hippocampal microstructure that underlies memory impairments after early-life adversity.

Memory and related cognitive functions are progressively impaired in a subgroup of individuals experiencing childhood adversity and stress. However, it is not possible to identify vulnerable individuals early, a crucial step for intervention. In this study, high-resolution magnetic resonance imaging (MRI) and intra-hippocampal diffusion tensor imaging (DTI) were employed to examine for structural signatures of cognitive adolescent vulnerabilities in a rodent model of early-life adversity.

Hyper-excitability and epilepsy generated by chronic early-life stress.

Epilepsy is more prevalent in populations with high measures of stress, but the neurobiological mechanisms are unclear. Stress is a common precipitant of seizures in individuals with epilepsy, and may provoke seizures by several mechanisms including changes in neurotransmitter and hormone levels within the brain. Importantly, stress during sensitive periods early in life contributes to 'brain programming', influencing neuronal function and brain networks.

Emerging roles of epigenetic mechanisms in the enduring effects of early-life stress and experience on learning and memory.

Epigenetic mechanisms are involved in programming gene expression throughout development. In addition, they are key contributors to the processes by which early-life experience fine-tunes the expression levels of key neuronal genes, governing learning and memory throughout life. Here we describe the long-lasting, bi-directional effects of early-life experience on learning and memory.

Hippocampal dysfunction and cognitive impairments provoked by chronic early-life stress involve excessive activation of CRH receptors.

Chronic stress impairs learning and memory in humans and rodents and disrupts long-term potentiation (LTP) in animal models. These effects are associated with structural changes in hippocampal neurons, including reduced dendritic arborization. Unlike the generally reversible effects of chronic stress on adult rat hippocampus, we have previously found that the effects of early-life stress endure and worsen during adulthood, yet the mechanisms for these clinically important sequelae are poorly understood.

Nitric oxide synthesis is required for exercise-induced increases in hippocampal BDNF and phosphatidylinositol 3' kinase expression.

Previous studies have shown that running exercise, either alone or in combination with antidepressant treatment, results in increased hippocampal BDNF levels. Nitric oxide (NO) is an important signaling molecule that has neuronal survival-promoting properties and has been shown to play an important role in plasticity associated with activating interventions. Herein, we administered the NO synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester (L-NAME), in conjunction with the monoamine oxidase inhibitor (MAOI) antidepressant, tranylcypromine, and voluntary wheel-running exercise to determine whether the enhancement in full-length BDNF mRNA occurring with these interventions is dependent upon NO synthesis.

Hippocampal brain-derived neurotrophic factor expression following treatment with reboxetine, citalopram, and physical exercise.

The antidepressants, reboxetine and citalopram, were used in conjunction with voluntary physical exercise (wheel running) in order to assess the contribution of noradrenergic and serotonergic activation to enhancements in hippocampal brain-derived neurotrophic factor (BDNF) expression resulting from antidepressant treatment and exercise. Reboxetine (40 mg/kg/day), citalopram (10 mg/kg/day), voluntary physical activity, and the combination of antidepressants with exercise were applied to rats for a range of treatment intervals (2 to 14 days). Hippocampal BDNF transcription levels (full-length BDNF, as well as exons I-IV) were then assessed via in situ hybridization.