Reviews on stress neuroendocrinology from the 7th International Congress of Neuroendocrinology

The 7th International Congress of Neuroendocrinology (ICN) was held under the auspices of the International Neuroendocrine Federation in Rouen, France from 11 July to 15 July 2010. The Chair of the Local Organising Committee, Hubert Vaudry, and the Chair of the International Scientific Programme Committee, Gareth Leng, focused the meeting on four major themes, one of which was the neuroendocrinology of stress. The rationale for this was that research on neuroendocrine mechanisms of responses to stressors is fundamental to continuing improvement in understanding good and bad consequences of stress and how such knowledge may be turned to improve health, as the major and most prolonged responses to stress are through the hypothalamic–pituitary–adrenal (HPA) axis. This system is regulated by extensive neural networks in the brain that use many transmitters and neuromodulators to process information about a wide range of threats, and eventually shut down the HPA system after a threat has passed. However, the dynamics of individual neuroendocrine responses to stress are determined by experience, including early in life, and are shaped by gender. Insights into new understanding of these different components of stress responses and their regulation were revealed by talks from leading experts.

This issue of Stress includes review papers on this theme from invited lecturers who presented their work at the 7th ICN on aspects of stress neuroendocrinology that represent recent major advances in the field. The topics that they cover are mechanisms of early life, prenatal, programming of stress systems and the important role of sex (Bale 2011); the mechanisms of corticotropin-releasing factor (CRF) gene regulation and signalling (Kageyama et al. 2011); the importance of pituitary adenylate cyclase-activating peptide (PACAP) signalling in organising HPA responses to emotional stress (Tsukiyama et al. 2011); a critical assessment of the importance of urocortin 1 in the brain (Kozicz et al. 2011); and comprehensive accounts of endocannabinoid mechanisms in the brain in feedback regulation of the HPA axis, in the context of both acute and chronic stress (Riebe and Wotjak 2011; Tasker and Herman 2011).

To begin at the beginning, the plenary lecture by Bale (2011) showed how very early prenatal development disturbance of the mother's internal environment, especially arising from maternal stress, can programme abnormal responses of the offspring to stress in later, adult life. Such programming affects not only HPA axis responses but also behavioural and emotional state reactions to stress, in ways that differ between males and females, with males being more vulnerable. There are important implications for the early life origins of mental disorders. Bale (2011) has taken studies on the mechanisms involved back to very early stages of intrauterine development in a mouse model, and has identified sex-dependent epigenetic changes in specific genes that alter their expression and hence function in the placenta as well as in the brain of the conceptus. Hence, altered placental function, especially for males, as a result of maternal stress may be of primary importance in prenatal programming of stress responsiveness in later life.

In response to stress, the CRF neurones in the paraventricular nuclei (PVN) of the hypothalamus have the major role in transducing the activity in stress processing circuitry in the brain into adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary gland, and hence secretion of glucocorticoid from the adrenal cortex. A feature of the CRF neurones in the PVN is that as they are stimulated to secrete, they are also stimulated to transcribe more CRH mRNA with resulting increased CRH synthesis to replace the peptide that has been secreted from the limited store that the neurones hold. Clearly, this is important in ensuring that the neurones can continue to respond. Kageyama et al. (2011) have examined the mechanisms that up- and down-regulate the CRH gene in these neurones in vitro. A primary stimulatory pathway involves activation of adenylate cyclase (e.g. by PACAP), with cAMP acting via a response element in the CRF gene. Glucocorticoid counteracts this, as does suppressor of cytokine-signalling 3, whereas oestrogen and cytokines promote expression. Kageyama et al. (2011) also consider evidence that implicates CRF action on the proliferation of ACTH producing cells and on the formation of ACTH from its precursor, with clinical implications for situations with deficient or excessive CRF production. Tsukiyama et al. (2011) take forward the finding that PACAP is a stimulator of CRF neurones to examine its role in mediating HPA axis activation in response to emotional but not physical stressors in mice. They report that in transgenic PACAP knockout mice, the HPA axis responses to typical emotional stressors were attenuated, but responses to physical stressors were not. The attenuated responses to emotional stress were not explained by altered pituitary or adrenal responses to CRF or ACTH, respectively. Instead, CRF neurones in the PVN were not activated by emotional stress in PACAP knockout mice, while neurones in emotional stress processing circuitry show near normal activation. These authors suggest that abnormalities of PACAP control of the HPA axis may underlie some psychiatric disorders.

The urocortins (1, 2 and 3) are neuropeptides related to CRF, but produced in different neurones in discrete brain regions; urocortin 1 acts on the same receptors as CRF (CRFR1 and R2), while urocortin 3 acts on CRFR2, with actions that seem to oppose those of CRF. Kozicz et al. (2011) have focused on understanding roles of urocortin 1 in the brain; urocortin 1 is produced in centrally projecting neurones in the Edinger–Westphal nucleus in the brainstem, and Kozicz et al. (2011) have identified a range of stimuli and neuropeptides that alter activity of these neurones. A diurnal rhythm in urocortin 1 production indicates a possible role in the circadian rhythm of the HPA axis, while oestrogen is evidently responsible for greater urocortin 1 production in females. A role in metabolic regulation is indicated by anorexic actions of urocortin 1, and by expression of leptin and ghrelin receptors in urocortin 1 neurones, with leptin as a signal of adequate energy stores inhibiting their activity, and fasting having the opposite effect. However, these neurones respond to acute emotional stressors, and to pain, and sustain activation during chronic stressors. These findings have led Kozicz et al. (2011) to propose that the urocortin 1 neurones may be involved in eventual termination of stress responses. Roles in modulating anxiety under stress are indicated by actions on serotonin neurones. However, dissecting out functions of urocortin 1 is complicated by its actions on the same receptors that CRF acts on. Kozicz et al. (2011) consider ways through this difficulty.

The discovery some 6 years ago of the modulating actions of endocannabinoids on HPA axis function during stress has had a dramatic impact on understanding how rapid negative feedback inhibition of the HPA axis during acute stress is effected. These recent discoveries are reviewed by Tasker and Herman (2011) and by Riebe and Wotjak (2011). Tasker and Herman (2011) focus on studies at the level of synapses onto PVN CRF neurones and on synapses in other brain regions that include major stress processing networks. By contrast with feedback by glucocorticoid that involves modulation of gene transcription through intracellular glucocorticoid receptors (GR), rapid feedback acts via GR in the neuronal cell membrane. Tasker and Herman (2011) describe the experimental evidence, from intracellular electrophysiological studies on brain slices, which shows that rapid negative feedback inhibition of CRF neurones is mediated by retrograde inhibitory actions of endocannabinoid on excitatory glutamatergic presynaptic terminals. Importantly, the endocannabinoid is produced by the CRF neurones as a result of the membrane glucocorticoid actions, although the identity of the membrane GR is not yet clear. Matching the wide distribution of cannabinoid receptors in the brain, extension of these studies has shown similar cannabinoid-mediated rapid actions of glucocorticoid in stress processing networks, including the amygdala and hippocampus, which are major regulators of the HPA axis. Hippocampal neurones show excitatory glucocorticoid actions mediated by endocannabinoids, which may be important in stress-related memory formation as well as HPA axis restraint. Notably, in the amygdala, the retrograde cannabinoid action is on input to post-synaptic glutamate neurones that excite the PVN CRF neurones, hence these neurones are inhibited. Interestingly, prior exposure to stress or glucocorticoid modulates the cannabinoid effects, indicating cellular mechanisms underpinning adaptation to stress. Riebe and Wotjak (2011) pursue the role of endocannabinoids in habituation of neuroendocrine systems and behavioural responses and cognitive and emotional changes with chronic stressor exposure. They consider the issue of whether changes in endocannabinoid signalling mechanisms in the amygdala and hippocampus that have been reported during chronic stress underlie habituation or detrimental effects. Riebe and Wotjak (2011) conclude with a discussion of the challenges to be overcome in future studies of the clearly complex actions and roles of endocannabinoids in modulating the central processing of stressors and in assessing their importance in habituation and allostasis. In particular, they provide a conceptual framework to evaluate roles of endocannabinoids in recovery from allostasis, with a view to identifying new therapeutic approaches to disorders related to chronic stress. Hopefully, this framework will help to clear the smoke from the fire of excitement lit by the discovery of stress-related endocannabinoid actions in the brain. More will be revealed at the 8th ICN in Sydney, Australia in 2014.

Declaration of interest: The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper.