The dorsomedial hypothalamus and the response to stress: Part renaissance, part revolution

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Abstract

Emotional stress provokes a stereotyped pattern of autonomic and endocrine changes that is highly conserved across diverse mammalian species. Nearly 50 years ago, a specific region of the hypothalamus, the hypothalamic defense area, was defined by the discovery that electrical stimulation in this area evoked changes that replicated this pattern. Attention later shifted to the hypothalamic paraventricular nucleus (PVN) owing to (1) elucidation of its role as the final common pathway mediating activation of the hypothalamic–pituitary–adrenal (HPA) axis, a defining feature of the stress response and (2) the finding that the PVN was the principal location of hypothalamic neurons that project directly to spinal autonomic regions. Consequently, a primary role for the PVN as the hypothalamic center integrating the autonomic and endocrine response to stress was inferred. However, our findings indicate that neurons in the nearby dorsomedial hypothalamus (DMH)—a region originally included in the hypothalamic defense area—and not in the PVN play a key role in the cardiovascular changes associated with emotional or exteroceptive stress. Indeed, excitation of neurons in the parvocellular PVN and consequent recruitment of the HPA axis that occurs in exteroceptive stress is also signaled from the DMH. Thus, the DMH may represent a higher order hypothalamic center responsible for integrating autonomic, endocrine and even behavioral responses to emotional stress.

Introduction

The physiological response to emotional stress consists of an integrated pattern of endocrine and autonomic changes that is highly conserved across mammalian species. Although these changes may be viewed in the context of enhancing the probability of survival in the face of a threatening circumstance, they have also been linked to various disease states in humans, including hypertension Folkow, 1987, Henry et al., 1986, cardiac arrhythmias, sudden cardiac death and myocardial infarction (Meerson, 1994), gastrointestinal motility disorders and gastric or duodenal ulcer formation (Fossey and Lydiard, 1990), and increased susceptibility to infection (Kiecolt-Glaser and Glaser, 1995). In spite of these clinically important consequences, the central pathways and mechanisms responsible for the physiological changes associated with emotional stress remain unclear. However, for two decades, attention in this regard has been focused on the hypothalamic paraventricular nucleus (PVN).

Section snippets

The PVN: anatomic crossroad for endocrine and autonomic function in stress?

Most current thinking regarding the hypothalamus and autonomic cardiovascular control—especially relating to the response to stress—assumes a primary integrative role for the PVN (see Culman and Unger, 1992, Dampney, 1994, Loewy, 1991, Pacak et al., 1995, Swanson, 1991). This assumption rests on two lines of evidence. First, both anatomic and functional evidence support a role for neurons in the PVN as the final common pathway in the CNS mediating the activation of the adrenal cortex that is

The DMH: an effector center for the cardiovascular response to emotional stress

The DMH was considered part of the classical “hypothalamic defense area” based upon the finding that electrical stimulation of this region provoked the defense reaction, a pattern of adjustments characterized by behavioral and autonomic changes typically seen when the organism was confronted with a threatening stimulus (for review, see Hilton, 1979). Our search for central sites where GABAA receptor antagonists might act to increase sympathetic nervous activity first led us to roughly this same

The DMH and stress-induced neuroendocrine changes

Activation of the HPA axis represents a defining feature of the response to stress in mammals. As discussed above, the rationale for the notion that the PVN represents the principal hypothalamic site for integration of the autonomic and endocrine response to stress has its historical origin in the acknowledged role of neurons in this nucleus in the mobilization of adrenal corticosteroids. However, several lines of evidence point to the possibility that neurons in the DMH play a crucial role in

Afferent pathways to the DMH

While evidence exists that points to efferent pathways mediating the increases in plasma ACTH and the tachycardia as described above, much less is known about the afferent pathways to the DMH that might activate the neurons in this region that are relevant to these changes. The DMH receives input from a host of forebrain regions that might play such a role (Thompson and Swanson, 1998). Interestingly, while the PVN represents a major target for efferents from the region, neurons in the most

Summary and conclusion

Our work over the past decade provides compelling evidence that neurons in the region of the DMH, a region included in the “hypothalamic defense area” nearly thirty years ago, are responsible for coordination and integration of multiple physiological and behavioral responses to emotional or exteroceptive stressors. Support for this hypothesis derives from the results of studies that have effectively employed both careful microinjection protocols and complementary functional neuroanatomic

Acknowledgements

This work was supported by USPHS grant NS 19883.

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