Publisher Summary This chapter discusses the regulation of function in the adrenocortical system. There are three major characteristics that describe most changes in activity of the system: (1) the circadian rhythm in basal activity, (2) stress-induced activation, and (3) corticosteroid feedback regulation. The first two may occur on very different timescales, and it is probably a consequence of the differing temporal demands that the third, corticosteroid feedback inhibition, is exerted by a variety of mechanisms over time. At any time of the day, the adrenocortical system can be activated by application of stressors. These include alteration of the value of a regulated variable or may be invoked by subjecting an animal to sudden disturbances of its environment, for example, noise, flashing lights, handling, strange environment, mild heat or cold. The adrenocortical system may be activated by traumatic stimuli or by psychological stimuli—in man, examinations, or mental arithmetic, or medical school admissions exams; in rats, unexpected decreases in food rewards.

Regulation of ACTH secretion: variations on a theme of B.

The three major classes of neurons in the paraventricular nucleus (PVH) provide a rich model for studying hormonal and neural influences on multiple neuropeptides expressed in individual cells. A great deal of previous work has examined this problem at the immunohistochemical level, where hormonal and neural influences on peptide levels have been established. In situ hybridization methods were used here to determine whether these effects are accompanied by measurable changes in neuropeptide mRNA levels. In the first series of experiments, the time-course of corticosterone replacement effects on corticotropin-releasing hormone (CRH) mRNA levels in parvicellular neuroendocrine cells of adrenalectomized animals were determined, and a doseresponse curve was established. CRH mRNA hybridization remains maximal with plasma levels of steroid up to about 50 ng/ml, then declines sharply between about 60–130 ng/ml, and is just detectable at higher levels. We confirmed that corticosterone decreases vasopressin mRNA levels in this cell group and showed that levels of preproenkephalin mRNA are also decreased, whereas no significant changes in cholecystokinin, β-preprotachykinin, and angiotensinogen mRNA levels could be detected. Thus, corticosterone decreases some neuropeptide mRNA levels and has no influence on others in this cell group. Tyrosine hydroxylase mRNA hybridization is also unaffected in this part of the nucleus. In a second group of experiments, the cell-type specificity of corticosterone influences was examined. It was found that while the hormone depresses CRH mRNA levels in parvicellular neurons, it increases such levels in PVH neurons with descending projections, in certain magnocellular neurosecretory neurons, and in a part of the central nucleus of the amygdala, whereas no influence was detected in the rostral lateral hypothalamic area. Furthermore, the stimulatory effects of corticosterone have different threshold levels in different cell groups. Thus, in different types of neurons, corticosterone may increase, decrease, or have no influence on CRH mRNA levels. In contrast, while corticosterone depresses vasopressin mRNA levels in parvicellular CRH neurons, it has no obvious effects on vasopressin mRNA levels in magnocellular or descending neurons; as with CRH, the effects of corticosterone on vasopressin mRNA levels are cell-type specific. In a third series of experiments it was shown that glucocorticoid receptor and mineralocorticoid receptor mRNAs are found in all three cell types in the PVH and that corticosterone tends to produce modest increases in mRNA levels for both receptors. Finally, it was shown that unilateral catecholamine-depleting knife cuts do not change mRNA levels for any of the neuropeptides (or steroid hormone receptors) examined here, although dramatic changes in neuropeptide levels themselves have been shown. The results indicate that corticosterone can alter the rations of neuropeptide mRNAs within individual cell type as well as alther the levels of a particular mRNA in the same or different directions in different cell types. The implications of these results for mechanisms underlying the stress response and for the concept of “biochemical switching” in anatomically fixed neural circuitry are discussed.

Differential steroid hormone and neural influences on peptide mRNA levels in CRH cells of the paraventricular nucleus: a hybridization histochemical study in the rat.

The regulation of corticotropin-releasing factor (CRF) mRNA expression in the rat brain by glucocorticoids and stress was examined by Northern blot analysis and in situ hybridization histochemistry. Rats either were exposed to a single electrical footshock session and killed 2, 4, 12, or 24 hr later (acute stress), or were subjected to the same regimen twice daily for 3 or 7 d and killed on the day following the last session (chronic stress). Rats placed in the experimental chamber but not administered shock comprised a “sham-handling” group. Chronic (7 d) intermittent footshock stress resulted in an 84 +/- 26% (P less than 0.05) increase in CRF mRNA levels in the whole hypothalamus as detected by Northern blot analysis and a 97 +/- 29% (P less than 0.05) increase in the paraventricular nucleus (PVN) as detected using in situ hybridization. No significant change in CRF mRNA levels was observed in the hypothalamus at any time up to 24 hr after a single exposure to footshock stress. A different pattern of results was obtained in other CRF-expressing cell groups. In Barrington's nucleus (a pontine micturition center), both acute and chronic stress produced significant increases in CRF mRNA, while in the olfactory bulb, both paradigms resulted in decreased levels. By Northern blot analysis, CRF mRNA in the olfactory bulb declined steadily, beginning at 4 hr after acute stress, and reached significance at 24 hr (69.2 +/- 1.9% of control, P less than 0.05). Levels from chronically (7 d) stressed animals declined to 54.1 +/- 5.1% of control value (P less than 0.05). Analysis of hybridization histochemical material revealed that both the number of positively hybridized cells and the number of silver grains per cell in the mitral and external plexiform layers of the bulb decreased following acute and chronic stress. However, CRF mRNA levels in the olfactory bulb were decreased to a comparable extent in the sham- handling group, suggesting that exposure to a novel environment can effect a decrease in CRF mRNA levels in the olfactory bulb. To provide comparisons with the effects of manipulation of glucocorticoid status, comparable analyses were carried out in separate groups of animals following adrenalectomy (ADX) with and without corticosteroid replacement. After ADX, CRF mRNA levels in the whole hypothalamus increased 60 +/- 5% (P less than 0.05) and were normalized following dexamethasone replacement. In contrast to the hypothalamus, no effects of steroid manipulation on CRF mRNA levels in the olfactory bulb, midbrain, cerebral cortex, or brain stem were detected.(ABSTRACT TRUNCATED AT 400 WORDS)

https://www.jneurosci.org/content/jneuro/11/3/585.full.pdf

Differential regulation of corticotropin-releasing factor mRNA in rat brain regions by glucocorticoids and stress

A paradigm for reliably stimulating ACTH secretion in urethane-anesthetized male rats has been used to examine hypothalamic secretion of corticotropin-releasing factor-like immunoreactivity (CRF-LI) into the hypophysial portal circulation. Hemorrhage of 15% estimated blood volume evoked a maximal 4.6-fold elevation in circulating ACTH levels from an initial level of 178.4 +/- 51.2 (+/-se) to 814.7 +/- 184.6 pg ml-1. The cumulative amount of ACTH secreted in response to hemorrhage was 10-fold greater than the cumulative amount of ACTH secreted by nonhemorrhaged rats (unweighted cumulative effect over all time points). In another experiment from a similarly hemorrhaged group, the hypophysial portal plasma CRF-LI concentration rose 2-fold from an initial level of 429.7 +/- 34.2 to 839.3 +/- 170.4 pg ml-1. Pretreatment with dexamethasone (100 microgram/kg BW, im) had no effect on initial levels of either CRF-LI or ACTH. The hemorrhage-induced elevations of both CRF-LI and ACTH were abolished in dexamethasone-treated rats. The secretory rate of CRF-LI was calculated to be 1.61 +/- 0.7 pg min-1 in nonhemorrhaged animals. Reversible pharmacological hyperpolarization of the paraventricular nuclei by stereotaxically microinjected procaine (15 micrograms/100 nl) reduced portal plasma CRF-LI and peripheral plasma ACTH to undetectable levels. These observations led to the following conclusions: 1) CRF-LI is an important hypothalamic regulator of adenohypophysial ACTH secretion, 2) CRF-LI in the hypophysial portal circulation is derived from CRF-LI-containing neurons within the paraventricular nuclei, and 3) glucocorticoid negative feedback effects can be exerted at the central level.

Hemorrhage-induced secretion of corticotropin-releasing factor-like immunoreactivity into the rat hypophysial portal circulation and its inhibition by glucocorticoids.

Our previous work has demonstrated that weaning at 19 days of age has deleterious effects on mucosal barrier function in piglet intestine that are mediated through peripheral CRF receptor signaling...

https://www.physiology.org/doi/pdf/10.1152/ajpgi.00304.2006

Gastrointestinal dysfunction induced by early weaning is attenuated by delayed weaning and mast cell blockade in pigs

Central and peripheral humoral responses of the adrenocortical system were measured for 2 h after the application of several stimuli. Two min after the onset of the stressesof shamadrenalectomy or laparotomy with intestinal traction there was a 4-6-fold increase inhypothalamic CRF content as compared to control content. This is the usual CRF response to stress. In contrast, after adrenalectomy or manipulation of the pedicles of adrenal glands, CRF content at 2 min was only slightly increased above baseline values. This finding suggests that touching the adrenal vascular and nervous supply results in a direct neural input to the hypothalamus that is qualitatively different from most other stimuli. At times later than 2 min after stress, when plasma corticosterone levels rise in the intact rat, the patterns of CRF and ACTH responses that were observed after adrenalectomy were determined by whether corticosterone replacement therapy was given. Without corticosterone replacement, the CRF and ACTH responses to...

Michiko Sato

Papers

Corticosterone-induced changes in hypothalamic corticotropin-releasing factor (CRF) content after stress.