Stressed-out, or in (<em>utero</em>)?

Sarit Avishai-Eliner, Dept of Anatomy and Neurobiology, University of California at Irvine, Irvine, CA 92697, USA and Hebrew University, Jerusalem, and Kaplan Medical Center, Rehovoth, Israel 76100;

Contributor Information.

ude.icu@eillat

Abstract

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. Stressful signals provoke expression and release of neuromodulators, including the peptide corticotropin-releasing hormone (CRH), leading to activation of CRH receptors on principal hippocampal neurons. Although physiological activation of these receptors promotes synaptic efficacy, pathological levels of CRH at hippocampal synapses contribute to neuronal death. Thus, early-life stress could constitute a ‘double-edged sword’: mild stress might promote hippocampal-dependent cognitive function, whereas severe stress might impair neuronal function and survival, both immediately and in the long-term. Importantly, these CRH-mediated processes could be targets of preventive and interventional strategies.

Abstract

The ability of an organism to adapt to its environment is integral to its survival [1]. Daily life involves confrontation with changing situations that can be physiologically or psychologically challenging. To cope with these ‘physical or perceived threats to homeostasis’ (an operational definition of ‘stress’) [2], the ability to alter function and expression of neuronal genes has been developed in the form of molecular and behavioral stress responses. This is advantageous because it allows rapid behavioral, autonomic and cognitive CNS responses to stressful circumstances, followed by prompt re-establishment of the functional steady state. Therefore, upon sensing stress, our brain not only initiates rapid secretion of effector molecules (noradrenaline and adrenal glucocorticoids), but also responds to the inciting signal with patterned and coordinated changes in programmed gene expression [1,3,4].

These responses to stress are a ‘double-edged sword’ [5]. While enhancing neuronal communication and promoting survival, they can impact upon neuronal function and integrity, both immediately and in the long-term. Consequences of stress, such as its negative influences on cognition and emotional stability, are an issue of major relevance to human health: chronic and/or severe activation of the stress response early in life has been shown to be potentially injurious in both humans (reviewed in Refs [3,6,7]) and experimental animals [3,4,5,8]. Indeed, via complex interactions with genetic factors [3], early-life events could be a major determinant of the smaller brain volume and long-term cognitive dysfunction in pre-term infants [9,10], and might play a role in certain affective and dementia disorders in the adult and aging human [1,3,4]. Not surprisingly, mechanisms protecting the immature brain from potentially injurious effects of early stress have been delineated [11].

The mechanisms by which early-life stress provokes these long-term effects remain unresolved but evidence for persistent organizational changes (‘programming’) in CNS stress responses has been building [3,7]. Gaining insight into the biological underpinnings of the consequences of early-life stress requires understanding of the age-specific processes activated by stressful stimuli at the molecular, cellular and circuit levels. Here we focus on novel and evolving concepts regarding the potential mechanisms underlying the short and long-term effects of early-life stress on hippocampal function (e.g. learning and memory) and integrity. Molecular events triggered by stress are highlighted, with emphasis on corticotropin-releasing hormone (CRH), a key stress-activated modulator of limbic neuronal function. We describe recent data showing that administration of CRH to the brains of immature rats reproduces the consequences of severe early-life stress, leading to progressive loss of neurons from the CA3 region of the hippocampus and impaired memory functions throughout life [4]. We also describe the effects of stress-induced CRH, derived from the maternal placenta, on learning functions in the human fetus [12] and discuss their implications for the adverse outcomes observed in many pre-term human infants [7,9,10].

Contributor Information

Sarit Avishai-Eliner, Dept of Anatomy and Neurobiology, University of California at Irvine, Irvine, CA 92697, USA and Hebrew University, Jerusalem, and Kaplan Medical Center, Rehovoth, Israel 76100.

Kristen L. Brunson, Dept of Anatomy and Neurobiology and Dept of Pediatrics, University of California at Irvine, Irvine, CA 92697-4475, USA.

Curt A. Sandman, Dept of Psychiatry, University of California at Irvine, Irvine, CA 92697, USA.

Tallie Z. Baram, Dept of Anatomy and Neurobiology and Dept of Pediatrics, University of California at Irvine, Irvine, CA 92697-4475, USA.

Contributor Information

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