Stress, stress hormones, and the behavioral neurobiology of brain plasticity

Efforts have long been directed toward studying stress-induced alterations via stress hormones on brain excitability and synaptic plasticity as inferred from combined behavioral, electrophysiological, and immunohistochemical cellular/molecular observations. Kindling of the brain in the rat serves as one model of synaptic plasticity. Kindling in the dorsal hippocampus and the amygdala induces electrical afterdischarges (AD), motor seizures (MS), and postictally, behavioral depression (ED) accompanied by electrical silence in the limbic system. Behaviorally induced changes in the muscarinic cholinoceptive receptor (mAChR) and protein kinase C gamma isomer (PKC gamma) immunoreactivity in different brain regions served as the other measure of plastic changes.

Fragments of the stress hormone opiomelanocortin (OMC) affect kindling-induced electrical and behavioral phenomena in a complex way. The adrenocorticotrophe hormone (ACTH) derivate ACTH 1-16, and melanocyte-stimulating hormone (MSH)-related fragments (alpha- and gamma(2)-MSH) decrease synaptic efficacy. The opioid portion of the molecule (beta-endorphin or related opioid peptides) have opposite effects by increasing excitability and synaptic efficacy in the limbic system as shown by studies using the opioid antagonists naloxone and naltrexone. The stress hormone corticosterone of the adrenal cortex plays a role in plasticity as well: removal of the adrenal causes a temporary, but complex alteration, while corticosterone substitution reinstates brain excitability, and synaptic efficacy.

Social stressors of repeated winners, but not defeat experience, retard the development of AD, MS, and ED in amygdala-kindled rats. Defeat, but not winner stress, reduces synaptic efficacy short term in rats with full-blown expression of kindling-induced seizure behavior. This phase is followed by a longterm increase in the excitability of the neuronal substrate. Immunohistochemical data on mAChR and PKC gamma-ir show that kindling has resulted in permanent changes in the cellular substrate of plasticity. Secondary foci are formed in limbic brain areas like the pyriform and entorhinal cortices that seem to affect the long-term existence of synaptic plasticity.

Behaviorally induced changes in mAChR and PKC-ir are task and substrate dependent. Increased immunoreactivity in the hippocampal pyramidal neurons is specific for spatial learning in mice and rats, and related to reference memory. Alterations in cortical and amygdaloid expression of mAChR in passive and active avoidance tests are related to footshock that serves as unconditioned aversive stimulus to induce conditioning.

The findings of all these experiments have been discussed in terms of stress, adaptation, and normal and pathological plasticities in the brain. In general, one may conclude that social stressors profoundly affect plastic changes of intercellular communication in the brain, but both the brain state and the characteristics of stress are important factors in determining the direction of plastic alterations in brain functions. Stress hormones like opiomelanocortins and corticosteroids are primary candidates as endogenous messengers of stressors.