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. Stress promotes secretion of the neuropeptide corticotropin-releasing hormone (CRH) from hippocampal interneurons, activating receptors (CRF 1 ) located on pyramidal cell dendrites. Additionally, chronic CRF 1 occupancy negatively affects dendritic arborization in mouse organotypic slice cultures, similar to the pattern observed in middle-aged, early-stressed (CES) rats. Here we found that CRH expression is augmented in hippocampus of middle-aged CES rats, and then tested whether the morphological defects and poor memory performance in these animals involve excessive activation of CRF 1 receptors. Central or peripheral administration of a CRF 1 blocker following the stress period improved memory performance of CES rats in novel-object recognition tests and in the Morris water maze. Consonant with these effects, the antagonist also prevented dendritic atrophy and LTP attenuation in CA1 Schaffer collateral synapses. Together, these data suggest that persistently elevated hippocampal CRH-CRF 1 interaction contributes importantly to the structural and cognitive impairments associated with early-life stress. Reducing CRF 1 occupancy post hoc normalized hippocampal function during middle age, thus offering potential mechanism-based therapeutic interventions for children affected by chronic stress.

Limiting dams' ability to construct a nest for their pups leads to an abnormal repertoire of nurturing behaviors, possibly as a result of chronic stress and mild anxiety of the dams. Because the fragmented and aberrant maternal behavior provoked chronic stress in the pups, the limited-nesting paradigm provides a useful tool for studying the mechanisms and consequences of such early-life stress experience in the offspring.

Biallelic pathogenic variants in PLPBP (formerly called PROSC) have recently been shown to cause a novel form of vitamin B6-dependent epilepsy, the pathophysiological basis of which is poorly understood. When left untreated, the disease can progress to status epilepticus and death in infancy. Here we present 12 previously undescribed patients and six novel pathogenic variants in PLPBP. Suspected clinical diagnoses prior to identification of PLPBP variants included mitochondrial encephalopathy (two patients), folinic acid-responsive epilepsy (one patient) and a movement disorder compatible with AADC deficiency (one patient). The encoded protein, PLPHP is believed to be crucial for B6 homeostasis. We modelled the pathogenicity of the variants and developed a clinical severity scoring system. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding. To explore the pathophysiology of this disease further, we developed the first zebrafish model of PLPHP deficiency using CRISPR/Cas9. Our model recapitulates the disease, with plpbp À/À larvae showing behavioural, biochemical, and electrophysiological signs of seizure activity by 10 days post-fertilization and early death by 16 days post-fertilization. Treatment with pyridoxine significantly improved the epileptic phenotype and extended lifespan in plpbp À/À animals. Larvae had disruptions in amino acid metabolism as well as GABA and catecholamine biosynthesis, indicating impairment of PLP-dependent enzymatic activities. Using mass spectrometry, we observed significant B6 vitamer level changes in plpbp À/À zebrafish, patient fibroblasts and PLPHP-deficient HEK293 cells. Additional studies in human cells and yeast provide the first empirical evidence that PLPHP is localized in mitochondria and may play a role in mitochondrial metabolism. These models provide new insights into disease mechanisms and can serve as a platform for drug discovery.

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. These methods were complemented by neuroanatomical and functional assessments of hippocampal network integrity during adolescence, adulthood and middle-age. The high-resolution MRI identified selective loss of dorsal hippocampal volume, and intra-hippocampal DTI uncovered disruption of dendritic structure, consistent with disrupted local connectivity, already during late adolescence in adversity-experiencing rats. Memory deteriorated over time, and stunting of hippocampal dendritic trees was apparent on neuroanatomical analyses. Thus, disrupted hippocampal neuronal structure and connectivity, associated with cognitive impairments, are detectable via non-invasive imaging modalities in rats experiencing early-life adversity. These high-resolution imaging approaches may constitute promising tools for prediction and assessment of at-risk individuals in the clinic.

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.Reboxetine treatment led to a rapid (evident at 2 days) enhancement in BDNF transcription in several hippocampal regions. This increase was also observed when reboxetine treatment was combined with voluntary physical activity for 2 weeks. Treatment with citalopram led to an increase in BDNF mRNA in only one hippocampal region (CA2) after short-term (2 days) treatment, and when combined with exercise, increased BDNF mRNA in the CA4 and dentate gyrus after 2 weeks. As reported in previous studies, voluntary physical activity enhanced BDNF transcription in several hippocampal areas, both on its own and in combination with antidepressant treatments. Examination of the levels of individual BDNF transcript variants influenced by each of these antidepressants revealed distinct patterns of expression in response to the various treatments, and showed that exercise-plus-antidepressant produced significant changes where antidepressant alone failed. Overall, treatment with the norephinephrine-selective antidepressant, reboxetine, in combination with exercise, led to both rapid and sustained increases in hippocampal BDNF mRNA expression. The serotonergic agent, citalopram, appeared to require longer treatment intervals in order to influence BDNF expression positively.

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. We discuss how enriched postnatal experience enduringly augments spatial learning, and how chronic early-life stress results in persistent and progressive deficits in the structure and function of hippocampal neurons. The existing and emerging roles of epigenetic mechanisms in these fundamental neuroplasticity phenomena are illustrated. KeywordsCRH; epigenetic; hippocampus; neonatal; early-life experience; maternal care; learning and memory; stress; corticotropin releasing hormone; glucocorticoids; GR; neuroplasticity; programming; resilience The clinical problem: association of early-life experience with learning and memoryNumerous clinical reports demonstrate a strong association between early-life experience and subsequent cognitive functions. Chronic childhood stress (such as extreme poverty, loss of parent, social deprivation or abuse) correlates with learning and memory impairments later in life (Kaplan et al., 2001;Nelson et al., 2007;Wilson et al., 2007). As examples, lower socioeconomic level early in life correlates with cognitive function in adulthood, and post-institutionalized orphans have abnormal neuronal function in limbic areas including the hippocampus, as shown by functional MRI studies (Chugani et al., 2001), and by worse cognitive performance when compared to never-institutionalized children (Nelson et al., 2007). Improving the experience of these institutionalized infants by placing them in families significantly improves learning and memory long-term. Remarkably, the timing of the placement into foster care is crucial, and placement before the age of two years is Corresponding author: Tallie Z. Baram, MD, PhD, tallie@uci.edu, Tel.: +1-949-824-1063; fax: +1-949-824-1106;, Address: Med Sci I; ZOT 4475, University of California at Irvine, Irvine, California 92697-4475, USA. * Equal contributorsPublisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeurobiol Learn Mem. Author manuscript; available in PMC 2012 July 1. (Bos, Zeanah, Smyke, Fox, & Nelson, 2010). These data suggest that critical developmental periods exist for the processes by which early-life experience shapes cognitive function throughout life.The impact of early-life expe...

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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. Diverse models have been created, and have resulted in a wealth of behavioral outcomes. Here we focus on recent findings highlighting early-life stress-induced behavioral disturbances, ranging from hippocampus-dependent memory deficits to problems with experiencing pleasure (anhedonia). The use of naturalistic animal models of chronic early-life stress provides insight into the spectrum of cognitive and emotional outcomes and enables probing the underlying mechanisms using molecular-, cellular-, and network-level approaches.