Glucocorticoids and Hippocampal Neurodegeneration

:: Chronic Cortisol Damages The Hippocampus
Stress increases glucocorticoids in the brain (cortisol in humans, corticosterone in rodents). Long exposure neurodegenerative effects include mitochondrial dysfunction, cell atrophy & death, and hyperphosphorylation of cytoskeletal Tau protein (which is important for dendrite remodeling). No, I don't know what those words mean either. So chronic levels of cortisol in the brain can cause cellular damage, and they are known to do particular damage to cells in the hippocampus. Where does cortisol come from? When is it produced?

:: Serotonin Increases Cortisol Via The PVN
When there is an elevated level of serotonin in the cerebrospinal fluid around the hypothalamus (a midbrain structure) and in particular, the paraventricular nucleus of the hypothalamus, somehow that causes the production of glucocorticoids (cortisol) in the adrenal cortex by the kidneys. Weird right? That's super far away from the hypothalamus. But that's the pathway. Where did that elevated serotonin come from? In the brain, serotonin is mostly produced in the Raphe Nuclei in the brain stem, and no one really knows why or when. Maybe serotonin production is increased in response to stress, like threats or physical over-exertion or starvation or I don't know what else. It's as good an answer as any. Regardless of what starts the chain, the rest of the chain goes Serotonin -> PVN of Thalamus -> Adrenal Cortex -> Cortisol. It's a dynamically simple pathway as I've sketched it: more of this, more of that. Let's talk about the root of the pathway - serotonin - and how serotonin-selective reuptake inhibitors (SSRIS) alter serotonin levels.

:: Acute use of SSRIs Increases Serotonin while Chronic use of SSRIs Decreases Serotonin
Elevated serotonin, not underproduction, seems to be the bigger problem of mood disorders, although we're really bad at measuring it in the CNS. Acute (=short term) administration of SSRIs makes serotonin levels higher and worse. If elevated serotonin is associated with mood disorders, and short term administration of antidepressant SSRIs increases serotonin, shouldn't SSRIs make mood disorders worse when you first start taking them? They don't, so far as I know: the usual short-term response to SSRI antidepressants is no change for a few weeks, and then things start to improve. We imagine that after chronic (=long term) administration of SSRIs, some compensatory mechanisms in the brain must reduce serotonin levels. That is the predominant theory. I don't know what compensatory mechanism that might be. I should read up on it. There's another thing that gets worse during short term administration of SSRIs: short term administration of SSRIs interferes with the production of neural growth factors (little hormones which are especially important for healing cell damage in the hippocampus). Let's talk about them.

:: BDNF Counteracts Cortisol's Damage on The Hippocampus
BDNF is a peptide hormone which acts as a growth factor for neurons. Acute (= short term) administration of SSRIs like fluoxetine reduces BDNF. That's bad: it means that the brain can't heal as well when there's cell damage to the hippocampus following sustained exposure to cortisol. And what about long term use of SSRIs? Apparently, based on this, chronic (=long term) SSRI administration increases BDNF transcription. Nice! Biphasic differential transcription, huh? I don't fully know what those words mean in context, but that sounds cool.

:: All Together Now
Supposedly astrocytes synthesize BDNF, GDNF, and NGF. Maybe damage to astrocytes from cortisol is enough to explain the reduction in BDNF following acute administration of SSRIs. So the pathway would be acute (= short term) SSRIs -> higher serotonin -> PVN thalamus activation -> more cortisol production -> cell damage to astrocytes -> less synthesis of BDNF and other growth factors. And how might chronic (= long term) administration of SSRIs counteract hippocampal neurodegeneration? Well, perhaps chronic administration of SSRIs reduces hippocampal neurodegeneration by triggering the mysterious compensatory mechanism that eventually reduces serotonin, which eventually leads to less cortisol, which means astrocytes can produce growth factors and repair cell damage. In this model, it's like there's a threshold concentration of cerebrospinal serotonin required before the compensatory mechanisms trigger, and SSRIs cross that level. It's a guess anyway. Alternatively, that biphasic differential transcription thing in the link. Maybe that's the mechanism. I don't know. I just thought you might like to know what I read about tonight: glucocorticoids and hippocampal neurodegeneration.