Sculpting the hippocampus from within: stress, spines, and CRH

Abstract

Learning and memory processes carried out within the hippocampus are influenced by stress in a complex manner, and the mechanisms by which stress modulates the physiology of the hippocampus are not fully understood. This review addresses how the production and release of the neuropeptide corticotropin-releasing hormone (CRH) within the hippocampus during stress influences neuronal structure and hippocampal function. CRH functions in the contexts of acute and chronic stresses taking place during development, adulthood and aging. Current challenges are to uncover how the dynamic actions of CRH integrate with the well-established roles of adrenal-derived steroid stress hormones to shape the cognitive functions of the hippocampus in response to stress.

Figure 1. Multiple stress mediators enable precise and coordinated functions in both time and space

Each of the stress mediators generally acts within a given timeframe (horizontal vector). Neurotransmitters can function within milliseconds; steroid hormones employ genomic mechanisms that can persist for months and years; neuropeptides typically act within minutes to hours. Clearly, many exceptions to these general rules exist [6]. The vertical axis delineates spatial domains, which are primarily governed by the location of the released stress-mediator and by receptor distribution. Neurotransmitters generally function at discrete synapses; CRH seems to influence populations of neurons [36,54]; although steroid hormones permeate the entire brain, their actions are constrained by the distribution of glucocorticoid and mineralocorticoid receptors. The orchestration and integration of the effects of multiple stress mediators are achieved through overlap in these spatial and temporal domains and potentially through direct molecular interactions [6,14].

Figure 2. Localization of CRH and CRHR₁ within the rodent hippocampus

(a) The peptide CRH labeled using immunohistochemistry (brown), is expressed within the pyramidal cell layer of CA1 (and CA3, not shown). (b) The majority of CRH-producing cells within adult hippocampus are GABAergic interneurons: co-expression of glutamic acid decarboxylase-65 (GAD₆₇) mRNA (a marker for GABAergic cells) in virtually all CRH neurons is apparent using immunohistochemistry for CRH (brown) combined with in situ hybridization for GAD₆₇ (blue). (c) The CRH receptor CRHR₁ (indicated in red) resides on dendritic spine heads (and also on somata, not shown), as shown by confocal microscopy of dendrites from yellow fluorescent protein (YFP)-expressing mice (indicated in green). (d) Boxed area in c; arrows denote CRHR₁ located on spine heads. (e) The receptor co-localizes with postsynaptic density protein 95 (PSD-95), a marker for mature spines: confocal microscopic images obtained after dual immunohistochemistry for CRHR₁ (green) and PSD-95 (red) illustrate co-labeling of the receptor and spine-head marker (arrowheads). Reproduced, with permission, from [36] (a, b) and [50] (c, d, e). Abbreviations: so, stratum oriens; sp, stratum pyramidale; sr, stratum radiatum; slm, stratum lacunosum-moleculare.

Figure 3. Chronic early-life stress shapes hippocampal dendritic structure: a role for CRH signaling

(a) Dendritic impoverishment in pyramidal cells of adult rats that experienced chronic early-life stress (produced using a limited nesting paradigm [74]). Photomicrographs of biocytin-labeled CA1 pyramidal cells illustrate the reductions in total dendritic length and dendritic arborization in the early-stress group (right) compared to controls (left). Scale bar, 80 µm. (b) In the absence of CRHR₁, the dendritic trees of CA1 (and CA3, not shown) pyramidal neurons are exuberant. Photomicrographs of Golgi-impregnated CA1 pyramidal cells from postnatal day 6–7 mice illustrate increased dendritic length and branching in CRHR₁ knockout mice (right), compared to wild type mice (left). Whereas these mice lacked both hippocampal and pituitary CRH receptors, similar findings were also found when growing hippocampi from wild-type and null mice in organotypic slice cultures, suggesting that the dendritic exuberance is a result of a lack of hippocampal CRH signaling [68]. Scale bar, 40 µm. (c) CRH application onto hippocampal organotypic slice cultures reduces dendritic complexity. Cultures were prepared from postnatal day 1 yellow fluorescent protein (YFP)-expressing mice and grown either in control media (left) or in the presence of CRH (100 nM; right) for 2 weeks. Scale bar, 70 µm. The circles in a–c illustrate the similar distribution of dendritic changes induced by stress and altered CRH signaling. (d) A potential mechanism by which CRH may attenuate dendritic length and arborization is through an initial loss of dendritic spines: infusion of CRH (100 nM) onto hippocampal organotypic slice cultures leads to a rapid and reversible loss of spines. High-magnification imaging reveals accelerated spine disappearance that is apparent already by 5 min after the onset of CRH exposure; CRH-induced spine elimination is partially reversed by a 30 min washout. Red arrowheads denote newly formed spines, and the yellow ones show eliminated spines. Scale bar, 6.6 µm. Reproduced, with permission, from [74] (a), [68] (b), [76] (c), and [22] (d)

Box 1. Figure I. Distribution of stress mediators impacting the hippocampus

The simplified diagram illustrates the sources of signaling molecules that influence hippocampal neurons during stress. Circles indicate releasable molecules, and triangles indicate their cognate receptors. Abbreviations: DG, dentate gyrus; CRH, corticotropin releasing hormone; CRHR₁, CRH receptor type 1; Cort, corticosterone; GR, glucocorticoid receptor; MR, mineralocorticoid receptor; NA, noradrenaline; β1R adrenergic receptor; 5HT, serotonin; 5HT-R, serotonin receptor.