Neuroplasticity of the hypothalamic–pituitary–adrenal (HPA) axis early in life requires recurrent recruitment of stress-regulating brain regions

Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, California, United States
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 04/2006; 26(9):2434-42. DOI: 10.1523/JNEUROSCI.4080-05.2006
Source: PubMed


An eloquent example of experience-induced neuroplasticity involves the enduring effects of daily "handling" of rat pups on the expression of genes regulating hormonal and behavioral responses to stress. Handling-evoked augmentation of maternal care of pups induces long-lasting reduction of hypothalamic corticotropin releasing hormone (CRH) expression and upregulates hippocampal glucocorticoid receptor levels. These changes promote a lifelong attenuation of hormonal stress responses. We have found previously that handling-evoked downregulation of CRH expression occurs already by postnatal day 9, implicating it as an early step in this experience-induced neuroplasticity. Here, we investigated the neuronal pathways and cellular mechanisms involved. CRH mRNA expression in hypothalamic paraventricular nucleus (PVN) diminished after daily handling but not after handling once only, indicating that "recurrent" handling was required for this effect. Return of handled pups to their cage provoked a burst of nurturing behavior in dams that, in turn, induced transient, coordinate Fos expression in selected regions of the pups' brains. These included central nucleus of the amygdala (ACe) and bed nucleus of the stria terminals (BnST), regions that are afferent to PVN and influence CRH expression there. Whereas handling once sufficed to evoke Fos expression within ACe and BnST, expression in thalamic paraventricular nucleus, a region involved in storing and processing stress-related experience, required recurrent handling. Fos induction in all three regions elicited reduced transcription factor phosphorylation, followed by attenuated activation of CRH gene transcription within the PVN. These studies provide a neurobiological foundation for the profound neuroplasticity of stress-related genes evoked by early-life experience.

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Available from: Yuncai Chen, Jun 05, 2015
    • "The effects of neonatal handling on the HPA axis and the stress response have been widely described (Pryce & Feldon, 2003; Meerlo et al., 1999; Fenoglio et al., 2006; Panagiotaropoulos et al., 2004; Meaney et al., 1991; Severino et al., 2004). "
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    ABSTRACT: During the postnatal period, the nervous system is modified and shaped by experience, in order to adjust it to the particular environment in which the animal will live. This plasticity, one of the most remarkable characteristics of the nervous system, promotes adaptive changes, but it also makes brain more vulnerable to insults. This chapter will focus on the effects of interventions during the postnatal development in animal models of neonatal handling (usually up to 15 min of handling) and maternal separation (usually at least for 3 h). Sex-specific changes and effects of prepubertal stress such as social isolation later on in life were also considered. These interventions during development induce long-lasting traces in the pups' nervous system, which will be reflected in changes in neuroendocrine functions, including the hypothalamus-pituitary-adrenal and hypothalamus-pituitary-gonadal axes; anxiety and cognitive performance; and feeding, sexual, and social behavior. These enduring changes may be adaptive or maladaptive, depending on the environment in which the animal will live. The challenge researchers facing now is to determine how to reverse the deleterious effects that may result from early-life stress exposure.
    No preview · Article · Jan 2015 · Advances in neurobiology
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    • "It should be noted that, in Experiments 2 and 3, the drug injection procedure may potentially influence maternal behavior and thus the levels of synaptic proteins in the hippocampus . Although we limited the duration of injection to <15 min per litter, brief daily separation of the pups from the mother (early handling) has been shown to stimulate maternal care (Liu et al., 1997; Fenoglio et al., 2006b) and enhance hippocampal function of the offspring (Tang, 2001; Fenoglio et al., 2005). Because maternal behavior was not assessed in this study, the possibility that our manipulations affect maternal behavior, which in turn alters hippocampal synaptic protein levels, cannot be completely excluded. "
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    ABSTRACT: Adult individuals with early stressful experience exhibit impaired hippocampal neuronal morphology, synaptic plasticity and cognitive performance. While our knowledge on the persistent effects of early-life stress on hippocampal structure and function and the underlying mechanisms has advanced over the recent years, the molecular basis of the immediate postnatal stress effects on hippocampal development remains to be investigated. Here, we reported that repeated blockade of corticotropin-releasing hormone receptor 1 (CRHR1) ameliorated postnatal stress-induced hippocampal synaptic abnormalities in neonatal mice. Following the stress exposure, pups with fragmented maternal care showed retarded dendritic outgrowth and spine formation in CA3 pyramidal neurons and reduced hippocampal levels of synapse-related proteins. During the stress exposure, repeated blockade of glucocorticoid receptors (GRs) by daily administration of RU486 (100 µg/g) failed to attenuate postnatal stress-evoked synaptic impairments. Conversely, daily administration of the CRHR1 antagonist antalarmin hydrochloride (20 µg/g) in stressed pups normalized hippocampal protein levels of synaptophysin, postsynaptic density-95, nectin-1, and nectin-3, but not the N-methyl-D-aspartate receptor subunits NR1 and NR2A. Additionally, GR or CRHR1 antagonism attenuated postnatal stress-induced endocrine alterations but not body growth retardation. Our data indicate that the CRH-CRHR1 system modulates the deleterious effects of early-life stress on dendritic development, spinogenesis and synapse formation, and that early interventions of this system may prevent stress-induced hippocampal maldevelopment. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · May 2014 · Hippocampus
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    • "Interestingly, the pPa is not engaged in the regulation of HPA responses to an acute stressor that was not preceded by repeated stress (Bhatnagar and Dallman, 1998; Bhatnagar et al., 2000, 2002). Although these studies were conducted in adult animals, the Pa is activated by recurrent handling but not by acute handling in P9 rat pups (Fenoglio et al., 2006), suggesting that the specific engagement of the Pa in conditions of chronic stress or stimulation may occur throughout the lifespan. "
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    ABSTRACT: The purpose of this review is to describe how the function and connections of the paraventricular thalamic nucleus (Pa) may play a role in the regulation of stress and negative emotional behavior. Located in the dorsal midline thalamus, the Pa is heavily innervated by serotonin, norepinephrine, dopamine (DA), corticotropin-releasing hormone, and orexins (ORX), and is the only thalamic nucleus connected to the group of structures comprising the amygdala, bed nucleus of the stria terminalis (BNST), nucleus accumbens (NAcc), and infralimbic/subgenual anterior cingulate cortex (sgACC). These neurotransmitter systems and structures are involved in regulating motivation and mood, and display abnormal functioning in several psychiatric disorders including anxiety, substance use, and major depressive disorders (MDD). Furthermore, rodent studies show that the Pa is consistently and potently activated following a variety of stressors and has a unique role in regulating responses to chronic stressors. These observations provide a compelling rationale for investigating the Pa in the link between stress and negative emotional behavior, and for including the Pa in the neural pathways of stress-related psychiatric disorders.
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