BrdU immunohistochemistry is used for studying adult neurogenesis.
What’s neurogenesis? Neurogenesis refers to the creation of new neurons in the hippocampus. The hippocampus is the brain structure implicated in mood, learning, and memory.
For many years, neuroscientists believed the brain was static after adulthood. You had all the neurons you would ever have at the end of adolescence. This view has been overturned with the recognition that neurogenesis (the birth of new neurons) continues into adulthood.
The discovery of post-adolescent neurogenesis is reassuring, because it means the brain is more plastic and resilient than we first thought. You can repopulate your brain with brand, spanking new neurons!
Impaired neurogenesis is implicated in depression and other psychiatric conditions. The idea is that chronic, severe stress suppresses neurogenesis, which negatively impacts mood and cognition. The depression-neurogenesis connection first came to light when it was discovered that the vast majority of antidepressants up-regulate neurogenesis.
So when psychiatrists say that SSRIs “work” by increasing serotonin, or SNRIs work by increasing serotonin and norepinephrine, what they really mean is that these drugs affect neurotransmitters in such a way as to enhance neurogenesis. Neurogenesis is the final common endpoint of antidepressant action (at least, this is the prevailing view at the moment).
In this post, I’ll discuss all the different ways that neurogenesis can be manipulated (increased). I’ll consider the effect of prescription drugs, diet, supplements, and behavior on neurogenesis. I’ll also provide some actionable tips about how you can leverage this knowledge to optimize neurogenesis.
Neurogenesis can be increased by antidepressant drugs (but also other drugs), dietary supplements, lifestyle factors and behavior (like exercise) and other factors.
Historically, corticosteroids were the first factors to be analyzed for their influence on adult neurogenesis 1.
Corticosteroids are released into the bloodstream following the activation of the hypothalamo-pituitary-adrenal (HPA) axis, mainly by anxiety 2.
Corticosterone, the principal corticosteroid in rodents, regulates its own secretion through negative feedback, by associating with two receptors (the mineralocorticoid MR, the glucocorticoid GR), present in the dentate gyrus (DG).
Suppression of corticosterone secretion after bilateral adrenalectomy (adx) increases glial and neuronal births in the dentate gyrus, whereas mitotic activity in the subventricular zone stays unchanged 3, suggesting a site-specific inhibitory influence of corticosteroids. Cell death is also enriched, but the populations of cells undergoing mitosis or apoptosis are distinct: immature cells break up at the interface of the hilus, whereas more mature neurons, found in the interface of the molecular layer, expire (72). The specific functions of MR and GR on adrenalectomy-induced structural changes have recently been examined 4.
Aldosterone, treatment with a low dose of the MR agonist, prevents adrenalectomy -induced increase in cell death, whereas a higher dose is necessary to normalize cell proliferation. Furthermore, treatment with a GR agonist, RU 28362, at doses that will completely take this receptor prevents both adrenalectomy-induced cell death and birth. So the stimulation of both MR and GR mediates the consequences of corticosterone on cell proliferation and shields mature cells from cell death.
The mechanisms by which cell proliferation is hampered by corticosterone are not well known. Yet, it remains to be determined which of those mechanisms is involved in vivo. Because a minority of precursor cells express corticosteroid receptors, corticosterone may not act directly on proliferating precursors. But it cannot be excluded that immature forms of receptors which are not recognized by present antibodies are involved. Corticosterone could act on nearby glial or neuronal cells expressing corticosteroid receptors, which might restrain the cell cycle by releasing growth factors 5. Or, corticosterone could modulate proliferation indirectly by increasing glutamate release in the dentate gyrus as the effects of adx or elevated rates of corticosterone could be blocked by NMDA receptor activation or inactivation, respectively.
Corticosterone may also inhibit cell proliferation by downregulating the generation of insulin-like growth factor I (IGF-I) 6.
Actionable tip: reduce stress and anxiety, which increases circulating corticosterone. If you have depression, consider looking into drugs like NSI-189, which specifically up-regulate neurogenesis by blocking corticosterone.
Selective-serotonin re-uptake inhibitors (SSRIs), but also other classes of antidepressants, are well-known to up-regulate neurogenesis. Tricyclics also have a positive effect on the integration of new neurons in the adult mammalian brain.
Conversely, prolonged, untreated major depressive disorder may itself be ultimately neurotoxic, mediated by the deleterious effects of excess glucocorticoids on hippocampal neuronal morphology.
Almost all antidepressants independent of class, ranging from mirtazepine (Remeron) to SSRIs, seem to enhance hippocampal neurogenesis in animal models, an effect which has been recapitulated in humans in a 2009 Nature paper.
It has been questioned whether there is any evidence that the antidepressant effect of these medications is necessarily related to increased neurogenesis. One canonical study published in Science, demonstrated that neurogenesis is actually required for the behavioral effects of antidepressants. They accomplished this feat by irradiating nascent neurons with x-rays and observing that the antidepressant effect of these drugs was abolished.
Actionable tip: If you’re depressed, seek treatment.
Thyroid hormone (thyroxine) is a potent regulator of neurogenesis.
Thyroid hormone has a big impact on brain function. Even subtle decrements in circulating thyroid hormone in the developing brain can cause profound intellectual disability.
Thyroid hormone determines the metabolic set point of ever cell in the human body. Thyroxine binds to nuclear hormone receptors where it controls the transcription of hundreds of genes. Thyroxine (T4) and its active metabolite triiodothyronine (T3) potently enhance neurogenesis, a result which has been consistently reproduced. Moreover, late life thyroid dysfunction may be linked to cognitive impairment, though this area of research remains contentious.
Actionable tip: you can increase iodine intake by consuming iodine-rich foods, like seaweed. Iodine is needed to synthesize thyroid hormone in the thyroid gland. If you have any of the symptoms of hypothyroidism, get evaluated for hypothyroidism.
Running is a tried and tested method for enhancing neurogenesis in animal models, and apparently swimming works too. Actually, any kind of rigorous exercise has beneficial effects on the brain, including weight lifting (for example).
Unsurprisingly, both sexual experiences and sex hormones themselves promote neurogenesis. Thinking about sex as a kind of environmental novelty is a good framework for understanding this effect, since a stimulating, novel social environment (or any kind of environmental enrichment for that matter) is pro-cognitive. Sex hormones, especially estrogen, are increasingly reported to have neuroprotective and neurotrophic effects in the central nervous system in a wide array of experimental paradigms, though this area of research is not without controversy.
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[^4] Montaron MF, Piazza PV, Aurousseau C, Urani A, Le Moal M, and Abrous DN. Implication of corticosteroid receptors in the regulation of hippocampal structural plasticity. Eur J Neurosci 18: 3105–3111, 2003
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Yu IT, Lee SH, Lee YS, and Son H. Differential effects of corticosterone and dexamethasone on hippocampal neurogenesis in vitro. Biochem Biophys Res Commun 317: 484–490, 2004. ↩