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Keywords:

  • stress;
  • magnocellular;
  • parvocellular;
  • endocannabinoid;
  • paraventricular nucleus;
  • feeding;
  • homeostasis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. PVN and Food Intake/Energy Balance
  5. Hypothalamic–Pituitary–Adrenal Axis
  6. Central Glucocorticoid Feedback
  7. Rapid Glucocorticoid Actions in the Hypothalamus
  8. Rapid Glucocorticoid Modulation of Neuroendocrine Systems
  9. Acknowledgments
  10. References

The hypothalamic paraventricular nucleus (PVN) is a major integrative site for the control of homeostasis, including energy balance, through coordinated regulation of neuroendocrine and autonomic outputs. However, cross-talk regulation of PVN neuroendocrine and preautonomic systems is poorly understood. The stress response invokes the coordinated control of motor, hormonal, and vegetative systems to establish homeostasis after an environmental perturbation. Elevated stress levels of circulating glucocorticoids give rise to multiple, complex physiological effects. The complexity of the glucocorticoid actions is caused by the wide range of glucocorticoid target tissues and to the broad time scale over which the actions occur. Recent studies have revealed rapid glucocorticoid actions in the hypothalamus that may provide an integrative signal linking stress with the regulation of energy and fluid homeostasis. Glucocorticoids inhibit PVN and supraoptic nucleus neurons by stimulating a rapid synthesis and retrograde release of endocannabinoids, which suppress synaptic excitation through presynaptic CB1 receptor activation. The glucocorticoid-induced endocannabinoid synthesis is mediated apparently by a novel membrane-associated glucocorticoid receptor found in multiple subpopulations of hypothalamic neuroendocrine cells. It may, therefore, represent a mechanism for rapid glucocorticoid control of activity among different neuroendocrine systems to coordinate a global response to stress. In support of this, leptin, a circulating adipose signal that regulates food intake and energy expenditure through central actions, blocks the glucocorticoid-mediated endocannabinoid release in the PVN. This represents a means by which the regulation of stress and feeding may interface in the PVN, thus providing a possible mechanism for the integration of multiple homeostatic functions.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. PVN and Food Intake/Energy Balance
  5. Hypothalamic–Pituitary–Adrenal Axis
  6. Central Glucocorticoid Feedback
  7. Rapid Glucocorticoid Actions in the Hypothalamus
  8. Rapid Glucocorticoid Modulation of Neuroendocrine Systems
  9. Acknowledgments
  10. References

Homeostasis refers to the internal balance in physiological systems of an organism required to ensure long-term survival. The hypothalamus is the main center of the central nervous system responsible for the maintenance of homeostasis by means of its integration of ascending and descending neural information and circulating hormonal signals to regulate neuroendocrine, autonomic, and behavioral outputs responsible for maintaining physiological systems in balance around theoretical set-points (1). The paraventricular nucleus of the hypothalamus (PVN)1 is ideally positioned to play a key role in homeostatic control through the diverse mix of neuroendocrine and preautonomic effector systems it comprises (2, 3). Homeostatic regulation by the PVN is under the control of multiple subpopulations of neurons, including hypophysiotropic neurons (parvocellular neuroendocrine cells) and neurohypophysial neurons (magnocellular neuroendocrine cells), that mediate hormone secretion from the anterior and posterior lobes of the pituitary gland, respectively, and preautonomic neurons that project to the brainstem and spinal cord. Major homeostatic functions regulated by the PVN include the stress response, feeding behavior and energy balance, fluid balance, cardiovascular function, body temperature, and reproductive function. Homeostasis requires a concerted control of multiple output systems in parallel to establish and maintain the system balance required for survival, implicating feedforward and/or feedback signals to coordinate activity among the different groups of effector neurons. For example, dehydration engages both neuroendocrine and preautonomic systems of the PVN in parallel to trigger a multipronged, integrated response to the environmental perturbation, characterized by water retention, anorexia and changes in heart rate, vascular tone, and cell metabolism. Whereas we possess a relatively good understanding of the linear neuroendocrine and autonomic outputs of the different systems of the hypothalamus involved in homeostatic regulation, we know very little about how these systems coordinate their outputs in parallel to effect global control of homeostasis. I propose that glucocorticoids, through rapid, endocannabinoid-mediated effects on synaptic excitability in the hypothalamus, represent a signal to the brain that coordinates the response of multiple neuroendocrine systems to stress.

PVN and Food Intake/Energy Balance

  1. Top of page
  2. Abstract
  3. Introduction
  4. PVN and Food Intake/Energy Balance
  5. Hypothalamic–Pituitary–Adrenal Axis
  6. Central Glucocorticoid Feedback
  7. Rapid Glucocorticoid Actions in the Hypothalamus
  8. Rapid Glucocorticoid Modulation of Neuroendocrine Systems
  9. Acknowledgments
  10. References

The regulation of food intake and energy expenditure is central to homeostasis, and the PVN is a key structure in the central nervous system circuits controlling food intake and energy homeostasis by virtue of its role as a neuroendocrine and autonomic effector organ. Circulating signals of the nutritional status of the organism access the PVN, either directly or through activation of arcuate nucleus afferents, where they regulate the neuroendocrine and autonomic outputs that, along with outputs from the lateral hypothalamus, control feeding behavior and/or energy expenditure. The neuroendocrine outputs, including the release of oxytocin, vasopressin, corticotropin-releasing hormone (CRH), and thyrotropin releasing hormone (TRH), modulate peripheral gut hormone secretion, adrenal corticosteroid secretion, and cellular energy metabolism. The descending preautonomic outputs of the PVN include the descending oxytocinergic projections to the dorsal vagal motor complex that regulate gastric motility. These PVN efferents generally play an inhibitory role in the control of food intake, such that the PVN can be considered as a satiety center. Lesions of the PVN or chronic inhibition of PVN neurons causes hyperphagia and obesity in rodents (4, 5).

Hypothalamic–Pituitary–Adrenal Axis

  1. Top of page
  2. Abstract
  3. Introduction
  4. PVN and Food Intake/Energy Balance
  5. Hypothalamic–Pituitary–Adrenal Axis
  6. Central Glucocorticoid Feedback
  7. Rapid Glucocorticoid Actions in the Hypothalamus
  8. Rapid Glucocorticoid Modulation of Neuroendocrine Systems
  9. Acknowledgments
  10. References

Stress triggers a physiological response that involves the coordinated control of multiple motor, hormonal, and vegetative systems that are engaged to re-establish homeostasis in the face of the stress perturbation, either real or perceived, of the internal and/or external environment. The neuroendocrine leg of the stress response is characterized by the activation of the hypothalamic–pituitary–adrenal (HPA) axis, which results in high levels of glucocorticoids in the blood. Stressors generally fall into one of two categories that have been referred to by various names but that can be thought of most simply as physiological, or systemic, and psychological, or processive. Although the two types of stress engage distinct brain circuits and may elicit different physiological and behavioral outputs, they both trigger the activation of the HPA axis, such that the neuroendocrine response is a common denominator of diverse stress inputs with varied behavioral and physiological outcomes (6). This common neuroendocrine response consists primarily of activation of the CRH cells in the PVN, leading to CRH release into the portal circulation of the pituitary and causing the secretion of adrenocorticotropic hormone into the bloodstream; the circulating adrenocorticotropic hormone acts at the level of the cortex of the adrenal glands to stimulate the synthesis and secretion of corticosteroid hormones, including glucocorticoids. The resulting stress levels of circulating glucocorticoids give rise to multiple, complex physiological effects with highly variable kinetics throughout the whole of the organism, including effects on glucose metabolism and mobilization in different tissues, regulation of immune and inflammatory responses, cardiovascular effects, neuroendocrine actions, and effects on cognition. This diverse array of physiological actions that can span time periods of from seconds to hours implies a variable and complex function of stress-induced glucocorticoids. In an attempt to simplify this function, the role of stress-induced glucocorticoids in stress regulation has variably been thought of as either facilitating the stress response and, therefore, contributing to it, or suppressing the response to reset the response apparatus, with the two roles having very different consequences and significance (7). The two roles for glucocorticoids would be expected to operate within different time frames: a facilitatory effect engaged with a relatively short latency to support the stress response as it unfolds and a suppressive role occurring after a longer delay to allow the response to go to completion before suppressing it to reset the system. The two modes of action should also have very different cellular mechanisms. While intermediate- and long-latency glucocorticoid effects are exerted through regulation of gene transcription in target tissues, including the brain, the rapid effects are mediated by transcription-independent mechanisms. Both roles of glucocorticoids are probably operative in stress regulation and allow glucocorticoids to present a range of activities that contribute to different aspects of the stress response and its aftermath (7).

Central Glucocorticoid Feedback

  1. Top of page
  2. Abstract
  3. Introduction
  4. PVN and Food Intake/Energy Balance
  5. Hypothalamic–Pituitary–Adrenal Axis
  6. Central Glucocorticoid Feedback
  7. Rapid Glucocorticoid Actions in the Hypothalamus
  8. Rapid Glucocorticoid Modulation of Neuroendocrine Systems
  9. Acknowledgments
  10. References

Among the actions of stress levels of circulating glucocorticoids are the feedback effects on the brain and pituitary gland. A main feedback effect of glucocorticoids is to suppress the activation of the HPA axis, inhibiting HPA hormone secretion, and precipitating the termination of the neuroendocrine stress response. These inhibitory feedback effects on HPA axis activation are thought to occur in the hippocampus, hypothalamus, and pituitary gland (8, 9) (Figure 1) and also break down into short- and long-latency actions (8). However, glucocorticoid effects on central neuroendocrine function impact more than just the HPA axis, because glucocorticoids have been shown to exert inhibitory actions on different neuroendocrine systems located in the PVN and in other parts of the medial hypothalamus. Our recent findings of a rapid glucocorticoid suppression of synaptic excitation in multiple subtypes of PVN neurons suggest that rapid effects of glucocorticoids may be faster and more important for the modulation of diverse neuroendocrine functions than previously thought. Based on these findings, I propose that glucocorticoids may play a role in regulating the stress response by rapidly coordinating the inhibition of multiple hypothalamic outputs that might otherwise interfere with the physiological stress response designed to increase the chances of surviving a destabilizing stimulus. This hormonally mediated effect would follow closely on the heels of the neurally mediated initiation of the stress response and includes the inhibition of CRH secretion, which is no longer needed after initiation of the response.

image

Figure 1. Schematic of HPA activation and glucocorticoid feedback on the brain and pituitary.

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Rapid Glucocorticoid Actions in the Hypothalamus

  1. Top of page
  2. Abstract
  3. Introduction
  4. PVN and Food Intake/Energy Balance
  5. Hypothalamic–Pituitary–Adrenal Axis
  6. Central Glucocorticoid Feedback
  7. Rapid Glucocorticoid Actions in the Hypothalamus
  8. Rapid Glucocorticoid Modulation of Neuroendocrine Systems
  9. Acknowledgments
  10. References

We have recently reported a rapid modulation by glucocorticoids of excitatory and inhibitory synaptic inputs to multiple subtypes of neuroendocrine cells of the hypothalamic PVN and supraoptic nucleus of the hypothalamus (SON) using whole cell patch-clamp recordings in an in vitro rat brain slice preparation. Dexamethasone, a synthetic glucocorticoid, and corticosterone, the endogenous glucocorticoid found in rodents, both elicited a dose-dependent decrease in excitatory post-synaptic currents mediated by glutamate release, with a half-maximal glucocorticoid response near 500 nM (10, 11). The glucocorticoid effect was rapid in onset, occurring within ∼1 minute, and was mediated by the activation of a membrane receptor, because it was maintained when the steroid was restricted to the extracellular compartment by conjugation to membrane impermeant bovine serum albumin, and it was abolished by the direct intracellular application of the unconjugated steroid through the patch pipette. The effect was inhibited by blocking G protein activity in the cells, suggesting that it may be mediated by the activation of a G protein–coupled receptor in the hypothalamic neuroendocrine cells. Surprisingly, glucocorticoids were found to elicit the synthesis of the endocannabinoids arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, and the glucocorticoid effect on glutamate-dependent excitatory post-synaptic currents was blocked by CB1 cannabinoid receptor antagonists (10, 11). This suggested that the rapid glucocorticoid effect on excitatory synaptic transmission in these cells was mediated by the post-synaptic synthesis and retrograde release of endocannabinoids and the resulting suppression of presynaptic glutamate release (Figure 2).

image

Figure 2. Proposed model of rapid glucocorticoid effects on excitatory and inhibitory synaptic inputs to neuroendocrine cells of the PVN and SON. Glucocorticoid (GC) activation of a membrane glucocorticoid receptor (mbGR) in both parvocellular and magnocellular neuroendocrine cells activates a G protein–coupled signaling pathway that results in the synthesis and release of endocannabinoids (CB). The endocannabinoids are transmitted retrogradely to presynaptic glutamate terminals where they suppress glutamate release (−) through actions at CB1 receptors. Glucocorticoids also cause a rapid facilitation of GABA-mediated inhibitory synaptic inputs to magnocellular neurons through the release of a retrograde messenger, although it is not yet known whether this effect is mediated by endocannabinoids.

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In addition to the suppression of excitatory synaptic transmission, glucocorticoids also elicited a rapid facilitation of γ-aminobutyric acid (GABA)-mediated inhibitory post-synaptic currents in magnocellular neuroendocrine cells (i.e., neurohypophysial neurons) but not in parvocellular neuroendocrine cells (i.e., hypophysiotropic neurons) of the SON and PVN. This, too, was mediated by the membrane receptor-stimulated release of a retrograde messenger and was blocked by a CB1 receptor antagonist, yet it is not clear whether this effect is caused by endocannabinoids (Figure 2) because exogenous cannabinoid agonists suppress GABA release onto these cells (12), an effect that is opposite to the glucocorticoid effect.

Thus, a rapid glucocorticoid effect on synaptic inputs to neuroendocrine cells of the PVN and SON had been revealed, an effect that would be expected to mediate an overall inhibition of these cells by suppressing synaptic excitation and, in some cases, facilitating synaptic inhibition through the release of one or more retrograde signals, including endocannabinoids. This provides a possible mechanism for the rapid feedback inhibition of the HPA axis by glucocorticoid-induced endocannabinoid release in the PVN (Figure 3). Our original hypothesis posited that glucocorticoids exert a rapid inhibitory effect on CRH cells, which could explain, in part, the rapid feedback inhibition of the HPA axis by glucocorticoids. However, we found that the rapid inhibitory effect of glucocorticoids was not restricted to parvocellular CRH-expressing neurons, but was also found in magnocellular neurons of the SON and PVN, as described above, as well as in multiple subtypes of parvocellular neuroendocrine cells of the PVN (10, 11). PVN parvocellular and magnocellular neurons identified as CRH-, TRH-, vasopressin-, and oxytocin-expressing neurons all responded to glucocorticoids in a similar fashion (Figure 4), suggesting that the rapid inhibition by glucocorticoids was a more generalized phenomenon among neuroendocrine systems than expected. Therefore, the rapid inhibitory effect of glucocorticoids should not be restricted to the HPA axis but should also be found in the hypothalamic–pituitary–thyroid axis and the hypothalamic–neurohypophysial systems. This corroborates in vivo studies showing rapid inhibition of the secretion of other pituitary hormones by glucocorticoids (13, 14).

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Figure 3. A model of fast feedback inhibition of the HPA axis through glucocorticoid-induced endocannabinoid synthesis and release in the PVN.

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image

Figure 4. Single-cell reverse transcriptase-polymerase chain reaction identification of the peptide phenotype of parvocellular neuroendocrine cells that responded to glucocorticoids with a rapid suppression of glutamate release. All cells were tested for the expression of CRH, TRH, oxytocin (OT), and vasopressin (VP). Each lane was taken from a separate PVN neuron. All but one cell tested expressed mRNA for only a single peptide. Modified from Reference (10) with permission.

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Rapid Glucocorticoid Modulation of Neuroendocrine Systems

  1. Top of page
  2. Abstract
  3. Introduction
  4. PVN and Food Intake/Energy Balance
  5. Hypothalamic–Pituitary–Adrenal Axis
  6. Central Glucocorticoid Feedback
  7. Rapid Glucocorticoid Actions in the Hypothalamus
  8. Rapid Glucocorticoid Modulation of Neuroendocrine Systems
  9. Acknowledgments
  10. References

These findings reveal the rapid crossover regulation of multiple neuroendocrine systems by stress levels of glucocorticoids and suggest that glucocorticoids may represent a possible interface between the stress response and different neuroendocrine functions. Thus, glucocorticoids released in response to stress activation of the HPA axis could rapidly modulate, at the level of the hypothalamus, the thyroid axis to coordinate cell metabolism and energy expenditure with the demands of the stress response; they could regulate oxytocin secretion to control child-bearing/rearing function according to the immediate prerogatives of the stress stimulus; and they should bring blood osmoregulation by vasopressin in line with the immediate needs of the stress response. Note that these effects would be slower than the neurogenic effects of activation of afferent inputs to these systems and would be delayed, compared with the stimulation of the CRH neurons and other cells activated directly by the stress activation of neural circuits, but that they could be rapid enough to coordinate the activity of the multiple systems after stress onset, theoretically within seconds to minutes.

Interestingly, each of the cell types in the PVN found to respond to glucocorticoids with a rapid release of endocannabinoids has been implicated in the control of food intake and/or energy metabolism, with generally anorexigenic actions. Briefly, CRH has been reported to suppress the hyperphagia caused by fasting when applied directly into the PVN (15), and blocking CRH receptors in the PVN facilitates the orexigenic action of local injections of neuropeptide Y in the PVN (16). Interestingly, peripheral pretreatment with dexamethasone was found to facilitate the orexigenic effect of neuropeptide Y injection into the PVN, an effect attributed to the down-regulation of CRH receptors (16), but also possibly, based on our recent findings, by stimulating endocannabinoid release within the PVN (11). The hypothalamic–pituitary–thyroid axis is under the control of TRH neurons in the PVN to regulate cellular metabolism and energy expenditure, and its activity is down-regulated during fasting to adapt to the reduced supply of nutrients (17). Descending oxytocinergic projections to the dorsal vagal complex by PVN preautonomic neurons and oxytocin secreted into the bloodstream from oxytocinergic neuroendocrine cells of the PVN have been implicated in an anorexigenic regulation of feeding (18, 19, 20, 21). Peripheral oxytocin administration increases cholecystokinin levels in the blood and suppresses gastric emptying through a cholecystokinin-dependent mechanism (22), increases glucagon secretion, and facilitates glucose-activated insulin secretion from the pancreas (23, 24). Similarly, intraperitoneal administration of vasopressin causes a dose-dependent inhibition of gastric emptying and food intake (25).

Glucocorticoids and cannabinoids are well-documented stimulants of food intake and energy metabolism, and their respective mechanisms of regulation of feeding converge in the hypothalamus. Glucocorticoids are often used to treat anorexia in a veterinary setting, and cannabinoids are well known for their effective treatment of anorexia, such as that associated with cancer chemotherapy. Systemic glucocorticoid administration, like cannabinoid consumption, has been shown to specifically stimulate intake of palatable foods [i.e., comfort foods (26)]. The acute orexigenic effect of glucocorticoids seems to be mediated by actions in the hypothalamus, and experiments using focal central glucocorticoid administration implicate the PVN specifically in these actions (27). Cannabinoids also stimulate the intake of highly palatable foods (i.e., triggering the “munchies”), and this effect also seems to be mediated, in part, by actions in the hypothalamus (28), although cannabinoid effects on feeding are thought to involve both central and peripheral actions (29). Fasting is characterized by a rise both in the blood levels of glucocorticoids (30) and in the hypothalamic levels of endocannabinoids (31), and the rise in hypothalamic endocannabinoids is thought to be responsible for the hyperphagic response to fasting (32). Thus, there is a similar impact on feeding of glucocorticoids and cannabinoids and a convergence in the hypothalamus of the mechanisms of both to regulate feeding behavior. Interestingly, leptin, a peptide secreted by adipose tissue and a circulating signal to the brain of the nutritional state of the organism, exerts a satiety effect centrally, in part, by lowering hypothalamic endocannabinoid levels (32). Recent findings from our laboratory show that leptin blocks the glucocorticoid-induced endocannabinoid secretion in the PVN, and the glucocorticoid suppression of excitatory synaptic inputs to PVN neuroendocrine cells (33). This provides evidence, therefore, for a rapid modulatory role of glucocorticoids in the hypothalamic control of feeding regulation and supports the function of glucocorticoids as an integrative signal in the coordinated regulation of multiple parallel homeostatic functions.

Another example of a possible rapid modulation of neuroendocrine function by stress-induced glucocorticoids is found during hemorrhage. Hemorrhage is a robust stressor, leading to stress levels of circulating glucocorticoids and a stimulus of both neurohypophysial vasopressin release and sympathetic norepinephrine release into the bloodstream. The elevated circulating glucocorticoids have been found to exert a restraining influence on the hemorrhage-induced elevation of vasopressin and norepinephrine in the blood (34). This inhibitory effect of glucocorticoids on blood vasopressin and norepinephrine levels is presumably through an acute, central effect of the elevated glucocorticoids, thus invoking the rapid glucocorticoid-induced, endocannabinoid-mediated suppression of synaptic activation of neurohypophysial vasopressin neurons (11) and possibly of descending preautonomic neurons controlling sympathetic norepinephrine release. When adrenalectomy was combined with fasting, the response to hemorrhage was found to be fatal, which was attributed not to the fasting-induced hypoglycemia, because it was not prevented by glucose replacement, but to hepatic failure caused by the vasoconstriction because of the extremely high levels of circulating vasopressin and norepinephrine (35). Thus, the stress level of circulating glucocorticoids would be responsible for restricting the secretion of vasopressin and norepinephrine through a rapid feedback mechanism, thereby preventing an exaggerated vasoconstriction that is potentially fatal to the organism.

Glucocorticoids have a broad spatial and temporal realm of action, leading to a complex array of cellular and physiological effects. The recently revealed rapid, membrane-delimited actions on cellular signaling that regulate neuronal excitability add an additional layer of complexity to these effects and broaden the range of physiological functions potentially impacted by circulating glucocorticoids. The rapid kinetics of these cellular actions along with the widespread accessibility the steroid enjoys to tissues throughout the body, including behind the blood–brain barrier, suggest that glucocorticoids may play a greater role in the integration of physiological functions than previously suspected. Thus, glucocorticoids could serve as homeostatic signals to communicate to multiple neuroendocrine systems on a minute-to-minute time scale a state of stress responsiveness and, therefore, to coordinate neuroendocrine activity so that it is appropriate for the environmental circumstances.

Footnotes
  • 1

    Nonstandard abbreviations: PVN, paraventricular nucleus of the hypothalamus; CRH, corticotropin-releasing hormone; TRH, thyrotropin releasing hormone; HPA, hypothalamic–pituitary–adrenal; SON, supraoptic nucleus of the hypothalamus; GABA, γ-aminobutyric acid.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. PVN and Food Intake/Energy Balance
  5. Hypothalamic–Pituitary–Adrenal Axis
  6. Central Glucocorticoid Feedback
  7. Rapid Glucocorticoid Actions in the Hypothalamus
  8. Rapid Glucocorticoid Modulation of Neuroendocrine Systems
  9. Acknowledgments
  10. References