Stress

Genetics, Gender, Age: Part 2
by National Institute of Health

(Page 5 of 6)

The sensitization appears to depend on the characteristics of the stressors to which the animal had previously been exposed. As indicated earlier, young animals that have been exposed to an acute stressor demonstrate increased activity of NE and DA when they are later exposed to a stressor. As a result, reexposure may result in declining neurotransmitter levels. However, in animals that have been exposed to a chronic stressor regimen, subsequent reexposure to the stressor induces a sensitization with respect to both synthesis and utilization of NE and DA. As a result, the level of the neurotransmitter does not decline readily. In effect, the nature of the previous stressor experiences (and the neurochemical changes engendered) determine an animal's response to stressor reexposure and thus might also influence behavioral responses engendered by subsequent challenges.

When animals are repeatedly exposed to a particular stressor, adaptation may occur and, consequently, neurotransmitter alterations may become progressively less pronounced. However, when animals are subsequently introduced to a stressor not previously encountered, then the adaptation is not evident, and a marked neurochemical change is again elicited. Thus, the adaptation that occurs with sustained exposure to a stressor may be unique to that particular stressful stimulus, and diminished responsivity may not occur in response to a new stimulus. Conversely, a chronic stressor regimen may result in an increased response following exposure to a different type of stressor. In effect, it seems that although repeated exposure to a particular stressor may promote either adaptation with respect to stressor appraisal or some aspects of neuronal functioning (the stressor is appraised as being less aversive, or variations occur with respect to either the receptor sensitivity and/or number present at presynaptic or postsynaptic sites, or with respect to transmitter release), these processes may be affected in a different fashion when a novel stressor is introduced, culminating in augmented neuronal functioning.

Studies by Tilders and colleagues have revealed important processes concerning the sensitization of neuroendocrine functioning that occur in response to both processive and systemic stressors. These investigators have found that stressors may induce prolonged changes of neuroendocrine functioning within certain neurons of the hypothalamus that communicate with the pituitary gland. As discussed in the sidebar, both corticotropin-releasing hormone and arginine vasopressin can stimulate the release of adrenocorticotropic hormone (ACTH) and, hence, corticosterone release from the adrenal glands. Furthermore, AVP may potentiate the effects ordinarily elicited by CRH. With the passage of time following stressor exposure, the CRH neurons may co-produce AVP, thus rendering the HPA axis more sensitive to stressors. Essential features of these findings include the following: 1. changes of AVP and CRH co-production may be long lasting and thus account for some of the protracted effects of stressors that have been reported, and 2. the long-term effects of stressors also could be provoked by the administration of cytokines (substances that act as signaling molecules within the immune system), suggesting that immune activation also may proactively influence the response to subsequently encountered adverse experiences.

Early Life Stimulation. The stimulation or handling of laboratory animals during their first few weeks after birth (which also entailed a brief separation from their mothers) was found to decrease age-related learning disturbances and increased resistance to the effects of later stressors. Animals that had experienced stimulation during the first 21 days of life showed basal concentrations of ACTH and corticosterone comparable to that of nonstimulated animals. However, as adults, when exposed to a stressor, the stimulated animals displayed blunted ACTH and corticosterone responses and a faster return to basal hormone levels. These long-lasting variations may have involved a cascade of neuronal changes, culminating not only in altered regulatory processes associated with HPA functioning but also in variations with respect to the propensity to consume alcohol during later adulthood.

Liu and colleagues conducted studies to determine why brief handling involving separation from the mother (for as little as 15 minutes per day) had such pronounced and persistent effects. After reuniting with their young following the brief separation, mothers exhibited increased licking, grooming, and nursing of their offspring. Moreover, because the high levels of these maternal responses were correlated with altered hormonal responses to stressors, the researchers suggested that maternal behavioral style acted to "program" HPA responses to later environmental stressors. Whether such factors also contribute to alcohol intake remains to be established.

Anisman and colleagues studied two mouse strains that exhibit very different behavioral and neurochemical profiles in response to stressors. The more stress-reactive strain displayed relatively poor maternal behavior, spent less time within the nest, and took longer to retrieve young offspring, which had been placed in different portions of the cage, compared with the less stressreactive strain. Thus, the exaggerated response to stressors in the more reactive mice may be related in part to maternal factors. When young mice of the stress-reactive strain were raised by mothers from the less reactive strain (cross-fostered on the day of birth), some behavioral disturbances and the exaggerated HPA alterations of the more reactive mice were decreased. However, maternal behavior alone is not sufficient for this outcome to emerge. In particular, being raised by a mother from the more reactive strain did not engender behavioral or hormonal disturbances in young mice of the more resilient strain. This finding implies that heightened stress reactivity in these mice results from a combination of genetic factors and inadequate maternal care.

About the Author

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