Editorial

This issue of Stress, which closes volume 8, includes papers based on presentations at the World Congress on Stress, which was held in London in 2004. Three of these papers are reviews addressing the theme of the involvement of the amygdala in anxiety- and fear-related behaviours, and the implications for stress-related emotional disorders (Berretta 2005; Lowry et al. 2005; Shekhar et al. 2005). The papers by Ellenbroek et al. (2005) and by Serra et al. (2005) relate to neurodevelopmental effects on the offspring of early maternal deprivation and of prolonged social isolation on adult rats, respectively. The paper by Serra et al. complements the review by Matsumoto et al. (2005; also based on a presentation at the 2004 5th World Congress on Stress) on neurosteroidogenesis during social isolation stress. The following is an overview of the reviews on the amygdala.

The amygdala has a key role in stressor processing, particularly for emotional stressors, and especially in organising the associated anxiety- or fear-related behaviour, and the affective salience of sensory input. It also has a central role in organising memories associated with a stressor. Shekhar et al. (2005) review the case for the proposal that plasticity of circuitry in the amygdala underlies chronic anxiety states that result from stress. The focus of the model is the basolateral complex, recipient of multimodal sensory inputs, the major source of output from the amygdala, and important in emotional learning. Here, dysfunction of corticotropin releasing factor (CRF) or urocortin 1 mechanisms, involving CRF₁ receptors within the amygdala which normally play a major role in vigilance and anxiogenesis, is proposed to underlie pathological emotional states. Shekhar et al. discuss the evidence that the mechanism of this dysfunction is a consequent increased excitatory glutamate-mediated activity relative to inhibitory GABA-mediated activity within the amygdala. Importantly Shekhar et al. explain how this imbalance is usually prevented, and the consequences of imbalance at the level of synaptic plasticity in basolateral neurones, in the context of the modulating inputs to the nucleus. This plasticity can lead to activation of basolateral amygdala circuits by inappropriate stimuli, and hence a pathological anxiety state.

Berretta (2005) reviews the role of the amygdala in both processing sensory information and, through its efferent connections with cortical networks, in the formation of memories related to a stressful experience, as exemplified by a conditioned stress response (specifically Pavlovian fear conditioning) as the paradigm. This raises what may seem to be a semantic point, whether “fear” is separable from “stress”, but the issue has important implications for understanding the processing of responses that accompany fear, and the role of the amygdala. Put simply, surely fear reflects stress. Berretta begins by establishing that the amygdala receives both auditory input (the conditioning stimulus) and nociceptive input (the painful stressor), and that conditioning involves plasticity in the amygdala. The focus is then on the central nucleus and basolateral amygdala. Berretta explains why the central nucleus is regarded as the autonomic centre of the amygdala, reflecting the nature of its distant inputs and outputs, while it also receives one-way traffic from within the amygdala. The central nucleus is evidently also a major site of plasticity in the context of conditioned learning. Berretta further elaborates the connectivity of the basolateral amygdala, and the functional role of this region in associative learning, this being the locus of convergence of the conditioning and unconditioned stimuli in Pavlovian fear-conditioning. The significance of this paradigm is that it points to the role of the basolateral amygdala in guiding adaptive behaviour in response to a stressor, both immediately and in the future. Berretta explains how the coincidence of action of noradrenaline released in the basolateral complex and glucocorticoid underlie the formation of stress-related memories, interacting with local circuitry and in turn involving the hippocampus. Extinction of conditioned responses, or learning to forget, is also important, and Berretta outlines the evidence that the medial prefrontal cortex is important in this process, through interactions with the amygdala. These interactions lead to considering dysfunction of extinction mechanisms as features of several psychiatric disorders, including in the pathogenesis of post-traumatic stress disorder.

Lowry et al. (2005) focus on anxiety, or more specifically anxiety-related behaviour, and the role of serotonin in circuits involving the amygdala, based on animal studies. A premise of these authors is that in relation to anxiety it is important to understand the distribution of the outputs from the sub-regions of the raphe nuclei in the brainstem, the source of serotonin in the brain, and the cellular properties of the raphe neurones that project to the amygdala. In particular, following the focus of Shekhar et al. (2005) and Berretta (2005), discussed above, they address the serotonergic innervation of the basolateral amygdala. Lowry et al. base their review on a necessary operational definition of anxiety as, briefly, an emotional state in which the outcome of emotionally salient events is uncertain, especially when both rewarding and aversive outcomes are possible, causing internal conflict; this state involves increased vigilance and autonomic and neuroendocrine responses. Experimental models therefore assess approach vs avoidance behaviours, and anxiolytics (prototypically benzodiazepines) increase the former and decrease the latter. Lowry et al. give an overview of the neural circuitry in which the amygdala is an integral component that is responsible for such anxiety-related behaviours, detailing evidence for an important role of serotonin, which has long been known to facilitate anxiety-related behaviour. Specifically, basolateral amygdala neurones are well-established as a target for serotonin, and serotonin acts here to alter anxiety-related behaviour. The source of this serotonin is the dorsal raphe nucleus (specifically in the mid-rostrocaudal region), so it seems important to focus on this sub-set of serotonin neurones to understand more about the organisation of anxiety-related behaviour. Indeed, Lowry et al. have found that serotonin neurones in the mid-rostrocaudal dorsal raphe nucleus, shown by retrograde tracing to project to the basolateral amygdala, are selectively activated by urocortin 2 and by several drugs that increase anxiety-related behaviour. These studies provide a basis for a more detailed analysis of the regulation of those serotonin neurones involved in anxiogenesis via the basolateral amygdala, according to the destination of their axons, including collateral projections, and their synaptic inputs.

As well as the mechanisms reviewed by Berretta (2005), Lowry et al. (2005) and Shekhar et al. (2005), vasopressin produced in the brain has been identified as a neuropeptide involved in the generation of anxiety-related behaviour, and in depression (Landgraf and Wigger 2003). A further consequence of disordered vasopressin mechanisms in the brain has been revealed in the research report by Dobruch et al. published in this issue of Stress (2005). Their studies indicate that after experimentally-induced myocardial infarction in rats there is increased sensitivity of cardiovascular control mechanisms to an acute mild emotional stress. This is shown as greater increases in blood pressure and heart rate caused by the stressor, and Dobruch et al. have shown that this results from altered activity of central vasopressin mechanisms. Hence, it seems that the amplified cardiovascular responses after myocardial infarction and anxious behaviour may have a common basis in overactivity of vasopressin signalling. Here, perhaps is potential for a therapeutic approach to reduce the recognised adverse cardiovascular consequences of stress in individuals who have experienced myocardial infarction.

John A Russell

Notes

* Further World Congresses on Stress are being planned by the International Society for the Investigation of Stress for July 2006 (in Chicago), and for 2007 to mark the Hans Selye centennial anniversary. In June 2006, the combined 6th International Congress of Neuroendocrinology and 10th Annual Meeting of the Society for Behavioral Neuroendocrinology (SBN) in Pittsburgh, USA (see the International Neuroendocrine Federation website: http://www.isneuro.org/ for details), and the following Endocrine Brain day of the Endocrine Society meeting in Boston, USA (see www.endo-society.org) will feature symposia and plenary lectures on stress.