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studies, we propose that this vulnerable state in humans is also transient, and will fade after some time, that is if no major second event occurs within this time domain. During this vulnerable period, CRH neurons and pituitary corticotrophs may show functional changes but these do not lead to altered resting Cortisol levels and readjust by the end of this period of stress sensitization. Although sensitization (Antelman et al., 1989) and increased Cortisol responses may be advantageous in some conditions, they represent a risk factor for the development of pathology (Munck, McGuire, & Holbrook, 1984; De Kloet & Joels, 1996; De Kloet et al., 1997). If during the period of stress sensitization the individual faces another sensitizing stimulus (immune or otherwise), the exaggerated HPA response may be followed by further alterations in CRH neurons and pituitary corticotrophs, further increasing the individual's vulnerability to stressors, as depicted in Fig 4. Therefore, immune activation induced sensitization of the stress response can be considered to represent a premorbid state. By cumulation or kindling like mechanisms, these reversible alterations may be driven into a more persistent mode during which the changes are accompanied by elevated resting Cortisol levels and adrenal hyperactivity. According to this scenario, it can be predicted that the exact timing of stressors relative to the immune activation induced stress vulnerable period is crucial for the development of adrenal hyperplasia and hyperactivity.

We do not imply that this cascade of events is specifically activated by immune stimuli. In fact, major stimuli of other nature (e.g. loss of spouse) can precipitate depression in vulnerable individuals. Nonetheless, we propose that in humans as in rodents, immune stimuli may be particularly powerful triggers to induce long-lasting cross-sensitization to stimuli of a different nature and thereby represent a risk factor for the development of depression. Several observation indicate that immune activation may relate to a specific form of depression.

For instance, multiple sclerosis patients show increased (re)activity of hypothal-

Figure 4. Long-lasting sensitization and its proposed role in the development of psychopathology. Transient activation of the immune system (first arrow) leads to transient activation of the HPA system (thin line), which is followed by a period of adaptive changes in the biological substrate and stress sensitization (bold line). During this period, resting plasma levels of ACTH and Cortisol are not affected but hormone responses to other stimuli (second arrow) are exaggerated. This will result in further alterations in the neuroendocrine substrate and prolonged and/or increased stress vulnerability. When additional stimuli follow within the period of stress sensitization, a pathologic state can be reached during which adrenal Cortisol production becomes chronically activated. For details see text.

Figure 4. Long-lasting sensitization and its proposed role in the development of psychopathology. Transient activation of the immune system (first arrow) leads to transient activation of the HPA system (thin line), which is followed by a period of adaptive changes in the biological substrate and stress sensitization (bold line). During this period, resting plasma levels of ACTH and Cortisol are not affected but hormone responses to other stimuli (second arrow) are exaggerated. This will result in further alterations in the neuroendocrine substrate and prolonged and/or increased stress vulnerability. When additional stimuli follow within the period of stress sensitization, a pathologic state can be reached during which adrenal Cortisol production becomes chronically activated. For details see text.

t t t t amic CRH neurons as indicated by increased numbers of CRH expressing neurons and an increase in the fraction of these neurons that co-express AVP (Erkut, Hofman, Ravid, & Swaab, 1995; Purba, Raadsheer, Hofman, Ravid, Polman, Kamphorst, & Swaab, 1995; Swaab, 1997). Detailed clinical studies revealed subtle HPA dysregula-tions e.g. increased resting Cortisol levels (Grasser, Moller, Backmund, Yassouridis, & Holsboer, 1996; Michelson, Stone, Galliven, Magaikou, Chrousos, Sternberg, & Gold, 1994) and blunted responses to CRH (Michelson et al., 1994) and AVP challenge tests (Wei & Lightman, 1997). These dysregulations in the HPA system show similarities but are not identical with those found in major depression indicating that partly distinct processes underlie these distortions. Accordingly, major depression is not likely to occur more often in multiple sclerosis patients as compared to the average population, but depressive symptoms categorized as depression due to general medical condition are frequently found in these patients (up to 50% lifetime risk, Schubert & Foliart, 1993). In addition, studies on first degree relatives of MS patients show that the genetic basis of depression in these patients is clearly different from that in major depression (Sadovnick, Remick, Allen, Swartz, Yee, Eisen, Farquhar, Hashimoto, Hooge, Kastrukoff, Morrison, Nelson, Oger, & Paty, 1996) supporting the view that other mechanisms, i.e., immune activation induced events, may play a role in MS associated depression.

Another example refers to aging. In elderly populations, a high incidence of minor depression and depressive symptoms has been found and a low prevalence of major depression (Ernst, 1997). Evidence has been reported to show that the onset and remittance of depression is not related with age per se, but rather with physical illness, functional impairment and numbers of infectious and other disease episodes (Beekman, Kriegsman, Deeg, & Van Tilburg, 1995a; Beekman, Deeg, Smit, & Van Tilburg, 1995b). This points to the potential relevance of episodes of immune activation in the development of vulnerability for depression in the elderly. Interestingly, aging is associated with dysregulations of the HPA system (Huizenga, Koper, De Lange, Pols, Stolk, Grobbee, De Jong, & Lamberts, 1998). Studies on post mortem brains showed that aging is associated with indices of increased (re)activity of hypothalamic CRH neurons (increased numbers of CRH expressing neurons, increased fraction of vasopressin coproducing CRH neurons (Raadsheer et al., 1993, 1994b, Raadsheer, Oorschot, Verwer, Tilders, & Swaab, 1994a). Taken together, these findings support the notion that infections or inflammatory episodes that increase with age may induce cumulative long-lasting alterations in hypothalamic CRH neurons that are associated with sensitization to stressors and represent a risk factor for the development of depression.

It should be noted that CRH neurons may play a role in depression by mechanisms other than those mediated by adrenal steroids. Studies with experimental animals show that symptoms resembling those seen in depression can be induced by intra-cerebral administration of CRH and are mediated by CRH receptors in various brainstructures (Chalmers, Lovenberg, Grigoriadis, Behan, & De Souza, 1996). Similarly, transgenic mice overproducing CRH show depression related phenotype (Stenzel-Poore, Heinrichs, Rivest, Koob, & Vale, 1994), whereas CRH deficient and CRH receptor deficient models show suppression of such symptoms (Muglia, Jacobson, & Mazjoub, 1996; Smith, Aubry, Dellu, Contarino, Bilezikjian, Gold, Chen, Marchuk, Hauser, Bentley, Sawchenko, Koob, Vale, & Lee, 1998). Since CRH neurons are known to project to various brain regions including autonomic motor, sensory, and limbic structures, it is conceivable that altered responsiveness of hypothalamic CRH

neurons affect mood, cognition, and behavior. Following this line of reasoning infection, inflammation, surgery, and other immune challenges may induce neuroplastic changes that are associated with increased power and responsiveness of CRH neurons that may play a role in stress sensitization and consequently in the etiology of mood disorders. In this vein, strategies directed to prevent or correct immune activation induced long-lasting sensitization and neuroplasticity may prove beneficial.

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