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How Adult Neurogenesis Can Help Fight Depression

Michelle hopes to spread awareness of stigmatized health topics by presenting relevant medical findings in her short articles.

Depression, a common mental disorder, has been recorded since the second millennium BCE, termed “melancholia” in ancient Mesopotamian tablets. Throughout history, depression has showcased itself as somewhat of a mystery, often deemed as a result of “demonic possession” or other supernatural means and treated with irrational acts of bloodletting, starvation, and shackling. However, with the advent of new medical technologies in the 20th century, scientists have seen significant progress in understanding the biochemical inner workings of the human brain. Furthermore, scientists have discovered a fascinating neurological process, known as adult neurogenesis, which is now believed to be linked to depression. Resulting from this new knowledge, newer antidepressant drugs have been developed. Moving forward, scientists are continuing to explore new means to enhance this neurogenic process to, ultimately, better treat depression.

An Early Explanation for Depression: Monoamine Hypothesis

Prior conception holds that an inadequate level of neurotransmitters, such as serotonin, dopamine, and norepinephrine, is the underlying cause of depression (Delgado, 2000). However, this monoamine hypothesis alone cannot fully explain the delayed effect of SSRI antidepressant medication, which takes 2-4 weeks to work.

According to this hypothesis, one would expect an immediate improvement of mood shorty after the increase of neurotransmitters in the brain. Furthermore, when scientists tested the effects of monoamine depletion, results did not show an increase in clinical depression in healthy patients nor in depressed individuals who were currently off medication (Heninger, et al., 1996). These studies therefore pointed to the need for an additional hypothesis to better explain the aforementioned discrepancies.

The Discovery of Neurogenesis

The process of neurogenesis illustrated: from neurogenic signals to neurons

The process of neurogenesis illustrated: from neurogenic signals to neurons

Then, in the 1990s, the discovery of stem cells in the human brain allowed scientists to acknowledge the possibility of adult neurogenesis: adult neural stem cell differentiation into various specific neuron cells (“What is Neurogenesis?”, 2017). Different studies have provided support for this notion, including one by Frisén, who utilized carbon dating of radioactive tissue exposed to carbon-14 in the Cold War.

A short video explaining carbon dating and its discoveries

Frisén concluded from the data that the adult hippocampus created approximately 700 new neurons every day (Spalding, et al., 2015). Thus, the neurogenic hypothesis was born, suggesting that depression may be caused by a reduction in the amount of new neurons being formed in the adult hippocampus. Studies abounded over the last decade providing more support for this new hypothesis, including the fact that depressed individuals had notably smaller hippocampi than did the healthy population (Kempton, et al., 2011). These findings are significant as medical scientists can now devise treatment plans that effectively target the neurogenic potential of depressed patients.

Increasing Neurogenesis

Deleting Pro-Apoptotic Genes

Similarities between the adult human brain and rodent brain

Similarities between the adult human brain and rodent brain

Recently, scientists have discovered methods to enhance neurogenesis in mammalian species, which could potentially be applied to human brains. One study experimented on a group of mice that was treated with corticosterone, a steroid acting as a stress marker. Through gene deletion, specifically of the pro-apoptotic gene BAX, which would impel neurogenesis, the scientists found that the mice’s depressive behavior reduced significantly (Hill, et al., 2015). As a result, the scientists concluded that inhibition of BAX in the adult hippocampus could similarly treat depression in humans as well (Hill, et al., 2015).

Using P7C3 Chemical Compounds

P7C3 compound chemical structure

P7C3 compound chemical structure

Yet another study, with a different approach, corroborated this finding. This time, scientists introduced P7C3 compounds to growth hormone secretagogue receptor (GHSR)-null mice. By removing GHSR from the mice, the scientists aimed to prevent the ghrelin hormone from binding and thereby from regulating stress in the central nervous system. As a result, when the mice were exposed to chronic social defeat stress (CSDS), their depressive state became extremely apparent. When the mice were administered the P7C3 drug, results astonishingly revealed that the P7C3 decreased the amount of dentate gyrus (DG) cell deaths, and henceforth allowed an increased number of these DG cells to survive the differentiation processes to become their specific nerve cells (Walker, et al., 2014). Furthermore, the GHSR-null mice experienced mitigated depressive symptoms (measured by the amount of time they spent in the corners of the confined room) from this antidepressant-like drug. The study concluded the significance of this pro-neurogenic chemical in notable applications to human patients with depression (Walker, et al., 2014).

In conclusion, over thousands of years, scholars have documented the harsh realities of depression, proposing numerous hypotheses in order to explain the causes of this mental disorder. Recently, with new advancements in technology, scientists have developed a new theory, the neurogenic hypothesis, suggesting the influence of adult neurogenesis on depression. Many studies on various animal species testing neurogenic activity have demonstrated the positive effect of increasing neurogenesis: the subsequent decrease of the depressive symptoms of those subjects. Ultimately, these strategies can be applied in the future to develop more effective treatment plans for depression in humans.

References

Delgado, P L. “Depression: the Case for a Monoamine Deficiency.” National Center for Biotechnology Information, U.S. National Library of Medicine, 2000, www.ncbi.nlm.nih.gov/pubmed/10775018.

Heninger, G., et al. “The Revised Monoamine Theory of Depression: A Modulatory Role for Monoamines, Based on New Findings From Monoamine Depletion Experiments in Humans.” Pharmacopsychiatry, vol. 29, no. 01, 1996, pp. 2–11., doi:10.1055/s-2007-979535.

Hill, Alexis S, et al. “Increasing Adult Hippocampal Neurogenesis Is Sufficient to Reduce Anxiety and Depression-Like Behaviors.” Nature News, Nature Publishing Group, 2 Apr. 2015, www.nature.com/articles/npp201585.

Kempton, Matthew J. “Structural Neuroimaging Studies in Major Depressive Disorder.” Archives of General Psychiatry, vol. 68, no. 7, 1 July 2011, p. 675., doi:10.1001/archgenpsychiatry.2011.60.

Spalding, Kirsty L. et al. “Dynamics of Hippocampal Neurogenesis in Adult Humans.” Cell 153.6 (2013): 1219–1227. PMC. Web. 12 June 2018.

Walker, AK et al. “The P7C3 Class of Neuroprotective Compounds Exerts Antidepressant Efficacy in Mice by Increasing Hippocampal Neurogenesis.” Molecular psychiatry 20.4 (2015): 500–508. PMC. Web. 12 June 2018.

“What Is Neurogenesis?” Queensland Brain Institute, 18 May 2017, qbi.uq.edu.au/brain-basics/brain-physiology/what-neurogenesis.

This content is accurate and true to the best of the author’s knowledge and does not substitute for diagnosis, prognosis, treatment, prescription, and/or dietary advice from a licensed health professional. Drugs, supplements, and natural remedies may have dangerous side effects. If pregnant or nursing, consult with a qualified provider on an individual basis. Seek immediate help if you are experiencing a medical emergency.

© 2018 Michelle Tram