Hippocampal neuroplasticity induced by early-life stress: functional and molecular aspects.

Whereas genetic factors contribute crucially to brain function, early-life events, including stress, exert long-lasting influence on neuronal function. Here, we focus on the hippocampus as the target of these early-life events because of its crucial role in learning and memory. Using a novel immature-rodent model, we describe the deleterious consequences of chronic early-life 'psychological' stress on hippocampus-dependent cognitive tasks.

Mechanisms of late-onset cognitive decline after early-life stress.

Progressive cognitive deficits that emerge with aging are a result of complex interactions of genetic and environmental factors. Whereas much has been learned about the genetic underpinnings of these disorders, the nature of "acquired" contributing factors, and the mechanisms by which they promote progressive learning and memory dysfunction, remain largely unknown. Here, we demonstrate that a period of early-life "psychological" stress causes late-onset, selective deterioration of both complex behavior and synaptic plasticity: two forms of memory involving the hippocampus, were severely but selectively impaired in middle-aged, but not young adult, rats exposed to fragmented maternal care during the early postnatal period.

Enduring, handling-evoked enhancement of hippocampal memory function and glucocorticoid receptor expression involves activation of the corticotropin-releasing factor type 1 receptor.

Early-life experience, including maternal care, influences hippocampus-dependent learning and memory throughout life. Handling of pups during postnatal d 2-9 (P2-9) stimulates maternal care and leads to improved memory function and stress-coping. The underlying molecular mechanisms may involve early (by P9) and enduring reduction of hypothalamic corticotropin-releasing factor (CRF) expression and subsequent (by P45) increase in hippocampal glucocorticoid receptor (GR) expression.

Endogenous neuropeptide Y prevents recurrence of experimental febrile seizures by increasing seizure threshold.

Febrile seizures (FSs) typically occur at the onset of fever and do not recur within the same febrile episode despite enduring or increased hyperthermia. Recurrent seizures during the same febrile episode are considered "complex," with potentially altered prognosis. A characterized immature rat model of FS was used to test the hypotheses that (1) a first FS influences the threshold temperature for subsequent ones, and (2) the underlying mechanisms involve the release and actions of the endogenous inhibitory hippocampal neuropeptide Y (NPY).

Hippocampal neurogenesis is not enhanced by lifelong reduction of glucocorticoid levels.

Neurogenesis of dentate gyrus granule cells is generally considered to be negatively regulated by glucocorticoids. We tested the hypothesis that exposure to low plasma corticosteroid levels starting in the early postnatal period enhances granule cell proliferation rate during adulthood. Rat pups were adrenalectomized (ADX) on postnatal day 10 and were then "clamped" throughout life at low corticosterone levels via oral supplementation.

Modulation of dendritic differentiation by corticotropin-releasing factor in the developing hippocampus.

The interplay of environmental and genetic factors in the developmental organization of the hippocampus has not been fully elucidated. The neuropeptide corticotropin-releasing factor (CRF) is released from hippocampal interneurons by environmental signals, including stress, to increase synaptic efficacy. In the early postnatal hippocampus, we have previously characterized a transient population of CRF-expressing Cajal-Retzius-like cells.

Region-specific onset of handling-induced changes in corticotropin-releasing factor and glucocorticoid receptor expression.

Early-life experience including maternal care profoundly influences hormonal stress responses during adulthood. Daily handling on postnatal day (P) 2-9, eliciting augmented maternal care upon returning pups to their cage, permanently modifies the expression of the stress neuromodulators corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR). We have previously demonstrated reduced hypothalamic CRF expression already at the end of the handling period, followed by enhanced hippocampal GR mRNA levels (by P45).

Stress and the developing hippocampus: a double-edged sword?

The mechanisms that regulate neuronal function are a sum of genetically determined programs and experience. The effect of experience on neuronal function is particularly important during development, because early-life positive and adverse experience (stress) may influence the still "plastic" nervous system long-term. Specifically, for hippocampal-mediated learning and memory processes, acute stress may enhance synaptic efficacy and overall learning ability, and conversely, chronic or severe stress has been shown to be detrimental.

Involvement of stress-released corticotropin-releasing hormone in the basolateral amygdala in regulating memory consolidation.

It is well established that adrenal stress hormone-induced activation of the basolateral complex of the amygdala (BLA) influences memory consolidation. The present experiments investigated the involvement of corticotropin-releasing hormone (CRH) in the BLA in modulating memory consolidation. Bilateral infusions of the CRH receptor antagonist [9-41]-alpha-helical CRH (0.

Stressed-out, or in (utero)?

The molecular and cellular mechanisms by which plasticity is induced in the mature CNS (and, specifically, in the hippocampus) by environmental input are progressively being elucidated. However, the mechanisms - and even the existence - of functional and structural effects of environmental input (and, particularly, stress) early in life are incompletely understood. Here, we discuss recent evidence that stressful stimuli have a significant impact on neonatal (rat) and prenatal (human) hippocampal function and integrity.

Corticotropin-releasing hormone (CRH) downregulates the function of its receptor (CRF1) and induces CRF1 expression in hippocampal and cortical regions of the immature rat brain.

In addition to regulating the neuroendocrine stress response, corticotropin-releasing hormone (CRH) has been implicated in both normal and pathological behavioral and cognitive responses to stress. CRH-expressing cells and their target neurons possessing CRH receptors (CRF1 and CRF2) are distributed throughout the limbic system, but little is known about the regulation of limbic CRH receptor function and expression, including regulation by the peptide itself. Because CRH is released from limbic neuronal terminals during stress, this regulation might play a crucial role in the mechanisms by which stress contributes to human neuropsychiatric conditions such as depression or posttraumatic stress disorder.