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Astral Codex Ten Podcast

Feb 22, 2021



Depression probably has something to do with decreased synaptogenesis in the brain, maybe the hippocampus in particular. Neurons are less likely to respond to stimuli by connecting to other neurons. The whole network becomes sparser than usual, and dysfunctional thought-loops that thrive in sparse network conditions start taking over.

We understand parts of the pathways that regulate synaptic growth. When the body wants more synapses, it releases neurotrophic hormones like BDNF (brain-derived neurotrophic factor). These activate various receptors including tropomyosin receptor kinase B (TrkB, affectionately pronounced "track B" because it's one of two related pathways for these signals). TrkB then something Ras mTORC something something synaptogenesis now you're not depressed anymore hooray.

Pictured: BDNF binds to TrkB. The IRS confiscates 1/2 of it as taxes, which radicalizes the receptor and makes it join Gab (see footnote 1), where it tweets out an SOS message to the Ras of Ethiopia. But the left wing of the receptor joins the Palestine Liberation Council and moves to California (see footnotes 2+). California has sunshine and good beaches, so you stop feeling depressed.

This part sort of makes sense. But it coexists uneasily with other puzzle pieces in our knowledge of depression. For example, we give people SSRIs, their serotonin levels go up, and this makes them feel better. Why? Because of BDNF something TrkB something mTORC something? Probably; mice with dysregulated BDNF/TrkB systems don't benefit from antidepressants. But why does more serotonin cause BDNF something TrkB something? I've looked for years for a paper that says something like "by the way, serotonin makes cells release more BDNF". But despite a few suggestive links I don't see anyone strongly asserting that they understand this.