Stressor controllability and learned helplessness

Maier, S.F. & Watkins, L.R. (2005). Stressor controllability and learned helplessness: The roles of the dorsal raphe nucleus, serotonin, and corticotrophin-releasing factor. Neuroscience and Behavioral Reviews, Vol. 29, 829-841.

This paper discusses the roles of serotonin, the dorsal raphe nucleus (DRN) structure, and corticotropin-release hormone (CRH) in the phenomenon of learned helplessness. It also discusses the implications of such research to models of depression and anxiety.

It has long been observed that animals who are exposed to an inescapable aversive conditioning procedure later fail to learn to escape from avoidable aversive stimuli. And beyond this learning deficit, subjects exposed to inescapable shocks (IS) are likely to suffer from ulcers, reduced appetite, reduced motor activity, reduced aggression and social dominance, reduced social interaction, exaggerated fear and fear conditioning, and neophobia, compared to subjects exposed to escapable shocks (ES). This constellation of behavioral changes following exposure to uncontrollable stressors is known as 'learned helplessness'.

A key feature of learned helplessness is that it alters behavior in circumstances different from the original "shocking" experience. When shocked in new environments, this learning deficit reappears and will even last for 48-72 hours after the original uncontrolled stress experience. Further, if the animal is reintroduced to the original environment, the learning deficit will persist much longer (i.e. the animal will not try to escape the aversive experience).

The behavioral changes that take place in this paradigm can be summarized as reduced fight/flight defensive behaviors and increased fear/anxiety related behaviors. The DRN was quickly implicated here since it is well known that stimulation of serotonin neurons within this structure affect fight/flight via projections to the periaqueductal gray (PAG) and potentiate fear/anxiety via projections to the amygdala. Indeed, inescapable shock produced large increases in extracellular serotonin in the DRN, while escapable shock did not. To account for the lasting effects witnessed, researchers looked for signs of sensitization in the DRN which might result in exaggerated serotonin release under later testing conditions. As expected, evidence shows that inhibitory serotonin autoreceptors may be desensitized following IS, thereby sensitizing these DRN neurons to further inputs. Interestingly, lesioning the DRN prevents exaggeration of fear conditioning produced by IS altogether.

In addition to serotonin, CRH also plays a crucial role in enacting the body's stress response. Oddly, it appears that CRH initially inhibits the serotonergic neurons but as dosage increases actually becomes less inhibitory and more excitatory in effect. At least in certain regions of the DRN, evidence suggests CRHR1 activation inhibits serotonin activity while CRHR2 activation excites serotonin neurons. However, it is believed that CRHR2 may play different roles in different brain regions (and possibly even within different areas of the DRN). Thus, global statements about the roles of serotonin, CRH, and their interaction may be problematic.

All of this evidence provides some help in creating the distinction between 'fear' and 'anxiety'. While fear is a motivational system responsible for enacting defensive behaviors in response to either learned or unlearned signals of danger, anxiety may be better understood to be a state within the organism that leads to the exaggeration of fear when it is threatened. Thus, long duration responses that build and dissipate slowly characterize anxiety, while responses that are closely driven by specific stimuli characterize fear.

Finally, the article discusses the relation between learned helplessness and the disorders of depression and anxiety. It is not quick to propose learned helplessness as a proper model for either one, but it does mention that it will be far easier to relate enhanced serotonin activity to anxiety than to depression based on the current literature available. (The model may shed light on the effectiveness of antidepressants against anxiety disorders, as one example. The acute effect of SSRI treatment, increasing serotonergic activity, is known to lead to increased anxiety. However, chronic administration of SSRIs has been shown to desensitize/downregulate post-synaptic serotonin receptors, reducing the anxiety response.)