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Stressor controllability and learned helplessness: The roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor

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Abstract

The term ‘learned helplessness’ refers to a constellation of behavioral changes that follow exposure to stressors that are not controllable by means of behavioral responses, but that fail to occur if the stressor is controllable. This paper discusses the nature of learned helplessness, as well as the role of the dorsal raphe nucleus, serotonin, and corticotropin-releasing hormone in mediating the behavioral effects of uncontrollable stressors. Recent research indicates that (a) uncontrollable stressors sensitize serotonergic neurons in the dorsal raphe, and that a corticotropin-releasing factor-related ligand, acting at the Type II receptor, is essential to this sensitization process, and (b) the consequent exaggerated release of serotonin in response to subsequent input is at least in part responsible for the behavioral changes that occur. Finally, implications for the general role of corticotropin-releasing hormone in stress-related phenomena and for the learned helplessness paradigm as an animal model of either depression or anxiety are discussed.

Section snippets

Learned helplessness

In its modern context, the term ‘learned helplessness’ was first used with reference to experiments directed at understanding the serendipitous observation that animals that were first exposed to an aversive Pavlovian conditioning procedure, in which a light and a shock delivered to the footpads via fixed electrodes were repeatedly paired while the animal was restrained in a Pavlovian harness, later failed to learn to escape and avoid footshocks in a shuttlebox (Overmieer, 1968). The light

5-HT and the DRN

Given a manipulation as complex as uncontrollable versus controllable stress, and diverse behavioral consequences (failure to escape, exaggerated fear conditioning, reduced aggression, neophobia), it should be no surprise that numerous neurochemical systems are involved in the mediation of learned helplessness. However, our recent work has focused on 5-HT neurons within the DRN. Indeed, the broad array of behaviors modulated by uncontrollable stress was the starting point for a consideration of

CRH

The DRN is a small midbrain structure, containing perhaps 30,000 neurons in the rat. It is, thus, not likely to be capable of performing the complex information processing necessary to determine whether a stressor is controllable or uncontrollable, and is doubtlessly part of a more extended circuit. In addition, a number of other structures and transmitters have been shown to be important in the production of learned helplessness. It may be that the DRN is on the efferent side of the ‘learned

CRH and 5-HT

It is clear that CRH and other CRH-like ligands are intimately involved in mediating stress-related and emotional/mood phenomena, with CRHR1 generally being regarded as the critical mediator. CRHR2 has generally not been accorded a major role in such processes. Indeed, deletion of the CRHR2(α) gene has been reported to either produce a phenotype characterized by increased anxiety-like behavior (Bale et al., 2000, Kishimoto et al., 2000), or to have no effect on anxiety (Coste et al., 2000).

Acknowledgements

Preparation of this manuscript was supported by National Institutes of Health grant MH50479.

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