Cerebral Hemispheres 2
NEUROSCIENTIFICALLY CHALLENGED

NEUROSCIENCE MADE SIMPLER

The Serotonin Hypothesis and Neurogenesis


Depression

Although it has become a commonly accepted explanation for the neurobiology of depression among the general public (mostly due to misleading advertisements by pharmaceutical companies), the idea that depression is caused primarily by a serotonin “imbalance” is a description of the processes underlying the disorder so simplified it renders itself inaccurate. The serotonin hypothesis, proposed decades ago, gained increased support of late due to the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treating depression. SSRIs increase extracellular levels of serotonin by blocking its reabsorption from the synaptic cleft back into the cell. The effectiveness of SSRIs led many to draw a one to one correlation between depression and low serotonin levels.

The truth is, however, that the reason why SSRIs work is not very well understood. Experimental attempts at isolating serotonin as the primary factor in depression have been unsuccessful. Regardless, many drug companies latched on to the serotonin hypothesis in promoting their antidepressants because it was simple for the consumer to understand.

The broader picture of the neurobiology of depression is much more complex. It begins with the proper mixture of genetic predisposition and environmental stressors. When that mixture is unfortunately encountered, higher than normal levels of the stress hormone cortisol may be released. These high cortisol levels are thought to cause neuronal damage, especially in the hippocampus. Glucocorticoid receptors (GR), which are receptors for cortisol (a type of glucocorticoid), may become desensitized, resulting in a persistent stress response, causing further neuroendocrine disruption.

This overactivity of the neuroendocrine system, specifically the hypothalamic-pituitary-adrenal (HPA) axis, can cause the release of cytokines. Cytokines are part of an immune response, but in this case they may end up causing further instability in the neuroendocrine system along with concomitant fatigue, loss of appetite, hypersensitivity to pain, and reduced libido.

Levels of a neurotrophin, called brain-derived neurotrophic factor (BDNF), also appear to be affected by all this upset in the HPA and hippocampus. Neurotrophins are proteins that are dedicated to neural support, and BDNF is integral to neurogenesis, plasticity, cell maintenance, and growth. Reduced levels of BDNF have been found to be strongly correlated with depression in human patients. These diminished BDNF levels may be responsible for the hippocampal damage mentioned above, as BDNF is the primary neurotrophin of the hippocampus.

Now enter serotonin. Serotonin is a type of neurotransmitter known as a monoamine, as are dopamine and norepinephrine. After they are released into the synaptic cleft, monoamines are quickly broken down by an enzyme called monoamine oxidase A (MAO-A). Then their constituents are taken back up into the neuron and recycled for future use.

MAO-A activity appears to be increased during depression. Thus, monoamines are metabolized more quickly, allowing less of them to reach their receptors on the other side of the synaptic cleft. Lower monoamine levels can negatively affect mood, cognition, motivation, and sensation of pain. It is thought that higher levels of cortisol may increase MAO-A levels, intensifying the symptoms of depression, and providing the explanation for why SSRIs can alleviate them.

Even this is a simplified illustration of the processes of depression, making the “chemical imbalance” described in drug commercials more similar to a children’s book than a thorough explanation. And a full understanding of the process has not yet been reached. An article in this week’s Science leads us closer to that understanding, however, by examining the effects of fluoxetine on neuronal plasticity in the visual cortex of the rat.

The neurogenesis and increases in BDNF caused by antidepressants appear to be as closely, if not more so, correlated with their effectiveness as changes in the neurotransmission of monoamines like serotonin. In order to further elucidate exactly how these processes work, and specifically if they cause beneficial modifications of neuronal circuitry in the brain, the authors of the report in Science investigated whether fluoxetine (Prozac) could cause plastic changes in the visual cortex that would improve vision in an impaired rat's eye.

They found that the neurogenesis promoted by fluoxetine was significant enough to restore vision in the rat's eye if the other eye was covered (covering the strong eye causes the cortex to focus on making improvements to the visual system through modifying the connections for the weaker eye). They had set out to investigate antidepressant-induced brain plasticity and neurogenesis, and in the process found that antidepressants may also be effective in the treatment of amblyopia (often referred to as lazy eye). Additionally, they provided further support for the idea that neurogenesis and the regulation of BDNF is just as important in treating depression as monoamine levels—and probably the more essential factor. The serotonin hypothesis is a useful way for drug companies to easily explain depression, but it seems to be far from the whole truth.

Vetencourt, J.F., Sale, A., Viegi, A., Baroncelli, L., De Pasquale, R., F. O'Leary, O., Castren, E., Maffei, L. (2008). The Antidepressant Fluoxetine Restores Plasticity in the Adult Visual Cortex. Science, 320 (5874), 385-388. DOI:10.1126/science.1150516

YOUR BRAIN, EXPLAINED

Sleep. Memory. Pleasure. Fear. Language. We experience these things every day, but how do our brains create them? Your Brain, Explained is a personal tour around your gray matter. Building on neuroscientist Marc Dingman’s popular YouTube series, 2-Minute Neuroscience, this is a friendly, engaging introduction to the human brain and its quirks using real-life examples and Dingman’s own, hand-drawn illustrations.

  • Reading like a collection of detective stories, Your Brain, Explained combines classic cases in the history of neurology with findings stemming from the latest techniques used to probe the brain’s secrets. - Stanley Finger, PhD, Professor Emeritus of Psychological & Brain Sciences, Washington University (St. Louis), author, Origins of Neuroscience

  • ...a highly readable and accessible introduction to the operation of the brain and current issues in neuroscience... a wonderful introduction to the field. - Frank Amthor, PhD, Professor of Psychology, The University of Alabama at Birmingham, author, Neuroscience for Dummies

  • An informative, accessible and engaging book for anyone who has even the slightest interest in how the brain works, but doesn’t know where to begin. - Dean Burnett, PhD, author, Happy Brain and Idiot Brain

  • Dingman weaves classic studies with modern research into easily digestible sections, to provide an excellent primer on the rapidly advancing field of neuroscience. - Moheb Costandi, author, Neuroplasticity and 50 Human Brain Ideas You Really Need to Know

BIZARRE

This book shows a whole other side of how brains work by examining the most unusual behavior to emerge from the human brain. In it, you'll meet a woman who is afraid to take a shower because she fears her body will slip down the drain, a man who is convinced he is a cat, a woman who compulsively snacks on cigarette ashes, and many other unusual cases. As uncommon as they are, each of these cases has something important to teach us about everyday brain function.

  • Bizarre is a collection of stories of how the brain can create zombies, cult members, extra limbs, instant musicians, and overnight accents, to name a few of the mind-scratching cases. After reading this book, you will walk away with a greater appreciation for this bizarre organ. If you are a fan of Oliver Sacks' books, you're certain to be a fan of Dingman's Bizarre. - Allison M. Wilck, PhD, Researcher and Assistant Professor of Psychology, Eastern Mennonite University

  • A unique combination of storytelling and scientific explanation that appeals to the brain novice, the trained neuroscientist, and everyone in between. Dingman explores some of the most fascinating and mysterious expressions of human behavior in a style that is case study, dramatic novel, and introductory textbook all rolled into one. - Alison Kreisler, PhD, Neuroscience Instructor, California State University, San Marcos

  • Through case studies of both exceptional people as well as those with disorders, Bizarre takes us on a fascinating journey in which we learn more about what is going on in our skull. - William J. Ray, PhD, Emeritus Professor of Psychology, The Pennsylvania State University, author, Abnormal Psychology

  • Dingman brings the history of neuroscience back to life and weaves in contemporary ideas seamlessly. Readers will come along for the ride of a really interesting read and accidentally learn some neuroscience along the way. - Erin Kirschmann, PhD, Associate Professor of Psychology & Counseling, Immaculata University