Autoradiogram shows uptake and retention of [3H]corticosterone by principal neurons of Ammon's horn and dentate gyrus of bilaterally adrenalectomized, adult rats. [Modified from Gerlach and McEwen (116).]
Access of glucocorticoids to receptors in hippocampus and other brain regions is regulated by 3 factors: corticosteroid binding globulin (CBG), multiple drug resistance P-glycoprotein (MDRpG), and metabolism by 11-hydroxysteroid dehydrogenase type 1 (11 HSD-1). CBG in the blood binds natural glucocorticoids such as corticosterone, cortisol, and their 11-dehydro-metabolites, but not the synthetic glucocorticoid dexamethasone; only unbound steroid is able to enter the brain. However, MDRpG at the blood-brain barrier actively transports synthetic steroids (such as dexamethasone), and to some extent 17-hydroxylated natural steroids, such as cortisol, out of the brain so that they do not enter very readily and only at high doses. Thus MDRpG retards the entry of cortisol into the brain, especially in the rodent, but does not affect corticosterone, which enters readily. In brain tissue, the enzyme 11 HSD-1 converts 11-dehydro-metabolites of corticosterone and cortisol back to the parent steroid, thus “reactivating” these glucocorticoids. See text for details.
Four peptide/protein hormones, insulin-like growth factor I (IGF-I), insulin, ghrelin, and leptin, are able to enter the brain and affect structural remodeling or other functions in the hippocampus. A transport process is involved, and specific receptors are expressed in hippocampus as well as in other brain regions. See text for details. Molecular sizes are indicated for each hormone along with their molecular size in kiloDaltons (kDa): ghrelin, 3.5 kDa; leptin, 16 kDa; insulin, 5.8 kDa; IGF-I, 7.6 kDa.
Four types of allostatic load. Top panel: illustrates the normal allostatic response, in which a response is initiated by a stressor, sustained for an appropriate interval, and then turned off. The remaining panels illustrate four conditions that lead to allostatic load: top left, repeated “hits” from multiple stressors; top right, lack of adaptation; bottom left, prolonged response due to delayed shut down; bottom right, inadequate response that leads to compensatory hyperactivity of other mediators (e.g., inadequate secretion of glucocorticoid, resulting in increased levels of cytokines that are normally counterregulated by glucocorticoids). [From McEwen (211), copyright 1998 Massachusetts Medical Society.]
Dose-response relationships of the cellular effects of corticosterone in the brain. Dose-response relationships are shown for the CA1 hippocampal area (A), the dentate gyrus (B), the PVN of the hypothalamus (C), and the dorsal raphe nucleus (D). Graphs show hormone responses expressed as a percentage of the maximal response in these brain regions. The concentration of corticosterone is an approximate estimate of the local concentration based on the solutions perfused on in vitro preparations or derived from the plasma concentration when fluctuations in hormone levels were accomplished in vivo. A: in the CA1 area, both the amplitude of depolarization-induced calcium currents (white squares) and the hyperpolarization caused by serotonin 1A receptor activation (black circles) display a U-shaped dose dependency. The descending limb is linked to the activation of mineralocorticoid receptors (MRs), whereas the ascending limb is associated with gradual glucocorticoid receptor (GR) activation in addition to already activated MRs, as occurs after stress. B: dentate gyrus granule neurons show a clear MR-dependent effect on the field potential (black squares) and the single-cell response (black triangles) caused by activation of glutamate AMPA receptors. Although these cells also abundantly express GRs, high doses of corticosterone do not cause additional changes in the signal, except when tested in chronically stressed rats (white triangles). C: neurons in the PVN (C) and the raphe nucleus (D) express GRs primarily. In these cells, a linear dose dependency is seen for the frequency of spontaneous γ-aminobutyric acid (GABA)A-receptor-mediated synaptic events (gray squares) and the inhibition caused by serotonin 1A receptor activation (gray circles). [From Joels (143), with permission from Elsevier.]
Opposing effects of stress on learning depend on the timing of the events. A: stress within the context of a learning situation leads to the release of norepinephrine (NA), corticotropin releasing hormone (CRH), and cortisol (CORT), all of which are active in the brain at the time that the initial phases of learning take place. At this stage, the neurotransmitters and hormones facilitate the ongoing process. Corticosterone, however, also initiates a gene-mediated pathway, which will elevate the threshold for input unrelated to the initial event and restore neuronal activity (normalization), with a delay of more than an hour. B: if an organism has been exposed to a stressor some time before the learning process takes place, the gene-mediated suppression of activity will have developed by the time that acquisition occurs. Under these conditions corticosterone will impair learning processes. [From Joels et al. (144), with permission from Elsevier.]
Structural plasticity in hippocampus involving synaptogenesis (S), neurogenesis (N), and dendritic remodeling (D) involves multiple neurochemical systems, evidence for which is summarized below and in the text. Table 2 summarizes interactions of adrenal steroids with key neurochemical systems involved in structural remodeling. 1) Glutamate release and reuptake: S, N, D, see text; 2) NMDA receptor activation, blockade: S, N, D, see text; 3) circulating glucocorticoids involving both mineralocorticoid (MR) and glucocorticoid (GR) receptors: S, N, D, see text; 4) serotonin: N (136); 5) norepinephrine: N (294); 6) endogenous opioids: N (97); 7) benzodiazepines: N, D (163, 192); 8) brain-derived neurotrophic factor (BDNF): N, D, see text; 9) IGF-I, insulin, ghrelin, and leptin: S, N, see text.
Cover: Paracrine hormones, released from the vascular endothelium in response to shear stress, impact on the subintimal space and vascular smooth muscle cell function. Artwork by Paul Ricketts. See Green, Daniel J., Maria T. E. Hopman, Jaume Padilla, M. Harold Laughlin, and Dick H. J. Thijssen. Physiol Rev 97: 495–527, 2017.