Molecule of happiness

NEUROSCIENCE

Just when you thought that serotonin was passe, come discoveries that sweep the small, evolutionarily ancient and slyly powerful signaling molecule back onto centre-stage. Researchers have learned that serotonin plays many critical roles throughout the body, both below the neck and above it, and from the earliest days of prenatal pre-sentience. One team has found that serotonin starts seeping into the embryonic forebrain during the first trimester of pregnancy, helping to shape the basic neural circuitry that later in life will be applied to learning, emoting and consulting a psychiatrist.

Pat Levitt of the Zilkha Neurogenetic Institute at the University of Southern California and his colleagues reported in the journal Nature, the creator of all that architectonic prenatal serotonin turns out to be an organ long dismissed as a passive, sieve: the placenta. Other researchers say serotonin in the gut helps orchestrate the remodeling of bone, the lifelong buildup and breakdown of osteoclasts and osteoblasts that make the human skeleton an exciting organ system.

The latest findings may never lead to a satisfying pharmacologic fix for what the psychiatrist Kay Redfield Jamison has called “ordinary existential angst” and others “terminal you-ness,” but they may help stiffen the spine, and remind us that it’s worth listening to serotonin.

“If I didn’t admit to being surprised by the scope of serotonin function, and how important it is to tissues like bone,” said Patricia Ducy, who studies the effect of serotonin on bone biology at Columbia University Medical Center, “I would be lying.”

Detected in blood serum

Serotonin is a tiny molecule, a bibelot built of 10 carbon atoms, a dozen hydrogens, two nitrogens and a single oxygen. The molecule was first detected in 1948, in blood serum, and it was shown be a vascular toning agent that causes blood vessels to constrict – hence its name, a conjoinment of “serum” and “tone.” Five years later, scientists found serotonin in brain extracts as well. Serotonin and serotonin-like molecules have also been found throughout the animal, plant and fungal communities.

Much effort has been devoted to studying how serotonin operates in the brain, where it serves as a neurotransmitter, activating brain cells to fire messages at each other through their impulsive Morse code. In the adult brain, all serotonin is supplied by a handful of cells located in the hindbrain, atop the spinal cord, but those neurons share their bounty widely through filamentous projections.
Scientists have identified at least 15 distinct serotonin receptors, proteins that clasp onto serotonin and react accordingly. In addition, there is the serotonin transporter, a janitorial protein that removes the serotonin from the little cleft between nerve cells once the molecule’s transmission task is through.

Tells you to keep going

Serotonin in the brain has a basic personality. “It’s a molecule involved in helping people cope with adversity, to not lose it, to keep going and try to sort everything out,” said Philip J Cowen, a serotonin expert at Oxford University and the Medical Research Council. In the fine phrase of his Manchester University colleague, Bill Deakin, “it’s the ‘Don’t panic yet’ neurotransmitter,” said Cowen.

Cowen emphasises that serotonin disruption alone does not directly cause depression. Experiments show that if you shut down serotonin production in normal people by subjecting them to an extreme tryptophan-free diet, they may not notice the difference; those with a history of depression, however, may well fall back into their gloom. Prozac, Zoloft and other so-called serotonin-specific reuptake inhibitors seek to enhance serotonin trafficking by blocking the serotonin transporter, thus allowing the neurotransmitter to linger longer in neuronal vestibules and keep supplying its stimulus package to any shovel-ready receptor that will have it.

A shaper of tissues

A newer class of antidepressants aims not only at the transporter, but also at one or more of the 15 different serotonin receptors, which may heighten the effectiveness of the drug while limiting the spillover side-effects. Much of the new serotonin research focuses on the molecule acting not as a neurotransmitter, a conveyor of information, but as a hormone, a shaper of tissues. In the new Nature paper, Levitt and his co-workers described their studies of early neural development in mice, where, starting at around day 10 of gestation – the equivalent of roughly the eighth week in humans – the mouse forebrain was flooded with serotonin. No other part of the brain was exposed to serotonin – just the forebrain.

The researchers had previously gathered evidence that serotonin served to stimulate the growth of new neural connections rather than incite synaptic activity in existing neurons; after all, the infrastructure of the forebrain was still too rudimentary to start making calls. But what was the source of the anabolic serotonin? Through a series of experiments, researchers ruled out other parts of the embryo, including the hindbrain, and they ruled out the mother. They finally traced it back to the embryo’s silent, headless genetic “twin,” the placenta, which synthesises serotonin and ships it to the forebrain.

“It makes sense that those circuits involved with mood, emotions, confronting challenges in the environment,” said Levitt, “were themselves shaped by the environment early on” – a placental tutorial, written in serotonin and ultimately courtesy of Mom. The vast bulk of the body’s serotonin supply, better than 95 per cent, is synthesised outside the brain, mostly by the gut. The two serotonin stocks are kept segregated by the blood-brain barrier, and are able to perform on entirely independent pathways.

Research suggests that our bones take advantage of both serotonin circuits, to manage the delicate dance between its two cellular castes: the constructive osteoblasts that build up the skeleton, patch the holes and repair cracks, and the destructive osteoclasts devoted to chipping rickety old bone tissue down.

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