110 — An opening for humor in melancholy

I very much like the sentiment of this overview; that there may yet be a role for the humors, first described by Hippocrates, in neuropsychiatric disease.

Well, not literally. But the concept of bodily fluids altering the way the mind works does make sense in light of the discovery that permeability of the blood-brain barrier can allow circulation of stress-signaling compounds (from the blood) to reach the brain, and in particular reach the nucleus accumbens (NAc).

Peripheral inflammatory molecules, released in response to physical stress, generally cannot interact with the CNS except via intended “ports.” Cldn5 is a protein responsible for the gap-junctions that keep the BBB membrane impermeable to these compounds. In mouse models undergoing stress in their environment, the expression of Cldn5 is dramatically reduced, compared to their healthy peers.

These compounds, once in certain regions of the brain where the blood-brain barrier was found to be most susceptible, appear to lead to depression-like symptoms.

This overview does not answer why the NAc (among select other regions) is selectively affected by the presence of these compounds such as Cldn5. It closes with the humorous observation that blood monocytes, which cluster around NAc after the invasion of these compounds, are of course produced by the spleen, which is where Hippocrates places the origin of Black Bile repsonsible for melacholia.