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After a great deal of time, I decided to get back to posting on this. So thanks everyone for keeping up with the site while I took my hiatus.

Phys Ed: Your Brain on Exercise

I thought this was rather nifty.


Anyways... to sum it up... exercise increases neurogenesis in the brain, which is essentially the formation of new neurons, through the regulation of bone-morphogenetic protein (BMP), which retards the utilization of adult stem cells. Additionally, through the increase of a protein named Noggin, which acts as a BMP antagonist.

Phys Ed: Your Brain on Exercise

Phys Ed: Your Brain on Exercise
By GRETCHEN REYNOLDS
Jim Wehtje/Getty Images

What goes on inside your brain when you exercise? That question has preoccupied a growing number of scientists in recent years, as well as many of us who exercise. In the late 1990s, Dr. Fred Gage and his colleagues at the Laboratory of Genetics at the Salk Institute in San Diego elegantly proved that human and animal brains produce new brain cells (a process called neurogenesis) and that exercise increases neurogenesis. The brains of mice and rats that were allowed to run on wheels pulsed with vigorous, newly born neurons, and those animals then breezed through mazes and other tests of rodent I.Q., showing that neurogenesis improves thinking.
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But how, exactly, exercise affects the staggeringly intricate workings of the brain at a cellular level has remained largely mysterious. A number of new studies, though, including work published this month by Mr. Gage and his colleagues, have begun to tease out the specific mechanisms and, in the process, raised new questions about just how exercise remolds the brain.

Some of the most reverberant recent studies were performed at Northwestern University’s Feinberg School of Medicine in Chicago. There, scientists have been manipulating the levels of bone-morphogenetic protein or BMP in the brains of laboratory mice. BMP, which is found in tissues throughout the body, affects cellular development in various ways, some of them deleterious. In the brain, BMP has been found to contribute to the control of stem cell divisions. Your brain, you will be pleased to learn, is packed with adult stem cells, which, given the right impetus, divide and differentiate into either additional stem cells or baby neurons. As we age, these stem cells tend to become less responsive. They don’t divide as readily and can slump into a kind of cellular sleep. It’s BMP that acts as the soporific, says Dr. Jack Kessler, the chairman of neurology at Northwestern and senior author of many of the recent studies. The more active BMP and its various signals are in your brain, the more inactive your stem cells become and the less neurogenesis you undergo. Your brain grows slower, less nimble, older.
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But exercise countermands some of the numbing effects of BMP, Dr. Kessler says. In work at his lab, mice given access to running wheels had about 50 percent less BMP-related brain activity within a week. They also showed a notable increase in Noggin, a beautifully named brain protein that acts as a BMP antagonist. The more Noggin in your brain, the less BMP activity exists and the more stem cell divisions and neurogenesis you experience. Mice at Northwestern whose brains were infused directly with large doses of Noggin became, Dr. Kessler says, “little mouse geniuses, if there is such a thing.” They aced the mazes and other tests.

Whether exercise directly reduces BMP activity or increases production of Noggin isn’t yet known and may not matter. The results speak for themselves. “If ever exercise enthusiasts wanted a rationale for what they’re doing, this should be it,” Dr. Kessler says. Exercise, he says, through a complex interplay with Noggin and BMP, helps to ensure that neuronal stem cells stay lively and new brain cells are born.

But there are caveats and questions remaining, as the newest experiment from Dr. Gage’s lab makes clear. In that study, published in the most recent issue of Cell Stem Cell, BMP signaling was found to be playing a surprising, protective role for the brain’s stem cells. For the experiment, stem cells from mouse brains were transferred to petri dishes and infused with large doses of Noggin, hindering BMP activity. Without BMP signals to inhibit them, the stem cells began dividing rapidly, producing hordes of new neurons. But over time, they seemed unable to stop, dividing and dividing again until they effectively wore themselves out. The same reaction occurred within the brains of living (unexercised) mice given large doses of Noggin. Neurogenesis ramped way up, then, after several weeks, sputtered and slowed. The “pool of active stem cells was depleted,” a news release accompanying the study reported. An overabundance of Noggin seemed to cause stem cells to wear themselves out, threatening their ability to make additional neurons in the future.

This finding raises the obvious and disturbing question: can you overdose on Noggin by, for instance, running for hours, amping up your production of the protein throughout? The answer, Dr. Gage says, is, almost certainly, no. “Many people have been looking into” that issue, he says. But so far, “there has not been any instance of a negative effect from voluntary running” on the brain health of mice. Instead, he says, it seems that the effects of exercise are constrained and soon plateau, causing enough change in the activity of Noggin and BMP to shake slumbering adult stem cells awake, but not enough to goose them into exhausting themselves.

Still, if there’s not yet any discernible ceiling on brain-healthy exercise, there is a floor. You have to do something. Walk, jog, swim, pedal — the exact amount or intensity of the exercise required has not been determined, although it appears that the minimum is blessedly low. In mice, Mr. Gage says, “even a fairly short period” of exercise “and a short distance seems to produce results.”

CDP-Choline

Description
CDP-Choline is an interesting supplement which has recently been discovered to have various nootropic activities. Having done a bit of research on it, I found some really interesting benefits.

Citicoline (INN), also known as cytidine diphosphate-choline (CDP-Choline) and cytidine 5'-diphosphocholine is a psychostimulant/nootropic. It is an intermediate in the generation of phosphatidylcholine from choline.

Studies suggest that CDP-choline supplements increase dopamine receptor densities, and suggest that CDP-choline supplementation can ameliorate memory impairment caused by environmental conditions. Preliminary research at Harvard found that citicoline supplements help improve focus and mental energy and may possibly be useful in the treatment of attention deficit disorder. Citicoline has also been shown to elevate ACTH independent of CRH levels and to amplify the release of other HPA axis hormones such as LH, FSH, GH and TSH in response to hypothalamic releasing factors. These effects on HPA hormone levels may be beneficial for some individuals but, may have undesirable effects in those with medical conditions featuring ACTH or cortisol hypersecretion including, but not limited to, PCOS, type II diabetes and major depressive disorder.^[3]

Research

1. Spiroperidol binding (dopamine D2 receptors) and quinuclidinyl benzilate binding (muscarinic receptors) in striata of 19-month old mice was analyzed for animals that had received chronic administration of cytidine 5'-diphosphocholine (CDP-choline) incorporated into the chow consumed (100 or 500 mg kg-1 added per day) for the 7 months [before their death]

2. Treated animals displayed an increase in the dopamine receptor densities of 11% for those receiving 100 mg kg-1 and 18% for those receiving 500 mg kg-1 as compared to the control aged animals that had received no CDP-choline. Control animals showed, from 2 months to 19 months of life, a 28% decrease in the receptor density. No change in the affinity of the receptors for spiroperidol was found in the treated or untreated animals.

3. Muscarinic acetylcholine receptor densities were also partially recovered by the same treatment in aged animals that showed a 14% decrease of these receptors in this case. The muscarinic receptor density increased 6% for the animals that received 100 mg kg-1 and 17% for the animals that received 500 mg kg-1 without any change in the affinity of the receptor for quinuclidinyl benzilate.

4. Aged animals displayed a slight increase in brain membrane fluidity as indicated by a decrease in the polarization value of the non-polar fluorophore 1,6-diphenyl-1,3,5-hexatriene. Interestingly, in the treated animals a greater increase in membrane fluidity was determined and found to be very similar for the two doses.^[1]

The dietary supplement CDP-choline, sold as a brain-boosting agent and under study for stroke and traumatic brain injury, may block skull and brain damage that can result from alcohol consumption early in pregnancy, Medical College of Georgia researchers report.

Researchers thought neural crest cells were tough cells whose function could be replaced if they happened to get injured. Instead they found that 25 percent of mouse embryos exposed to alcohol during that critical period had defects in the fibrous joints that connect the skull. "You get a snowball effect: The neural crest is damaged, the meninges doesn't develop properly and tissue like bone and brain that are regulated by the meninges don't develop properly either," Bieberich said.

When they added ceramide-neutralizing CDP-choline to the mouse cells, cell death and ceramide levels were reduced. Alcohol prompts the body to produce more ceramide from the brain lipid sphingomyelin, a major component of cell membranes. They found that CDP-choline pushes back toward producing less ceramide, preventing damage providing the drinking stops.^[5]

Cytidine 5'-diphosphocholine, CDP-choline or citicoline, is an essential intermediate in the biosynthetic pathway of the structural phospholipids of cell membranes, especially in that of phosphatidylcholine. Upon oral or parenteral administration, CDP-choline releases its two principle components, cytidine and choline. When administered orally, it is absorbed almost completely, and its bioavailability is approximately the same as when administered intravenously. Once absorbed, the cytidine and choline disperse widely throughout the organism, cross the blood-brain barrier and reach the central nervous system (CNS), where they are incorporated into the phospholipid fraction of the membrane and microsomes. CDP-choline activates the biosynthesis of structural phospholipids in the neuronal membranes, increases cerebral metabolism and acts on the levels of various neurotransmitters. Thus, it has been experimentally proven that CDP-choline increases noradrenaline and dopamine levels in the CNS. Due to these pharmacological activities, CDP-choline has a neuroprotective effect in situations of hypoxia and ischemia, as well as improved learning and memory performance in animal models of brain aging. Furthermore, it has been demonstrated that CDP-choline restores the activity of mitochondrial ATPase and of membranal Na+/K+ ATPase, inhibits the activation of phospholipase A2 and accelerates the reabsorption of cerebral edema in various experimental models. CDP-choline is a safe drug, as toxicological tests have shown; it has no serious effects on the cholinergic system and it is perfectly tolerated. These pharmacological characteristics, combined with CDP-choline's mechanisms of action, suggest that this drug may be suitable for the treatment of cerebral vascular disease, head trauma of varying severity and cognitive disorders of diverse etiology. In studies carried out on the treatment of patients with head trauma, CDP-choline accelerated the recovery from post-traumatic coma and the recuperation of walking ability, achieved a better final functional result and reduced the hospital stay of these patients, in addition to improving the cognitive and memory disturbances which are observed after a head trauma of lesser severity and which constitute the disorder known as postconcussion syndrome. In the treatment of patients with acute cerebral vascular disease of the ischemic type, CDP-choline accelerated the recovery of consciousness and motor deficit, attaining a better final result and facilitating the rehabilitation of these patients. The other important use for CDP-choline is in the treatment of senile cognitive impairment, which is secondary to degenerative diseases (e.g., Alzheimer's disease) and to chronic cerebral vascular disease. In patients with chronic cerebral ischemia, CDP-choline improves scores on cognitive evaluation scales, while in patients with senile dementia of the Alzheimer's type, it slows the disease's evolution. Beneficial neuroendocrine, neuroimmunomodulatory and neurophysiological effects have been described. CDP-choline has also been shown to be effective as co-therapy for Parkinson's disease. No serious side effects have been found in any of the groups of patients treated with CDP-choline, which demonstrates the safety of the treatment.^[2]

Citicoline supplementation has been used to ameliorate memory disturbances in older people and those with Alzheimer's disease. This study used MRS to characterize the effects of citicoline on high-energy phosphate metabolites and constituents of membrane synthesis in the frontal lobe. Phosphorus ((31)P) metabolite data were acquired using a three-dimensional chemical-shift imaging protocol at 4 T from 16 healthy men and women (mean +/- SD age 47.3 +/- 5.4 years) who orally self-administered 500 mg or 2000 mg Cognizin Citicoline (Kyowa Hakko Kogyo Co., Ltd, Ibaraki, Japan) for 6 weeks. Individual (31)P metabolites were quantified in the frontal lobe (anterior cingulate cortex) and a comparison region (parieto-occipital cortex). Significant increases in phosphocreatine (+7%), beta-nucleoside triphosphates (largely ATP in brain, +14%) and the ratio of phosphocreatine to inorganic phosphate (+32%), as well as significant changes in membrane phospholipids, were observed in the anterior cingulate cortex after 6 weeks of citicoline treatment. These treatment-related alterations in phosphorus metabolites were not only regionally specific, but tended to be of greater magnitude in subjects who received the lower dose. These data show that citicoline improves frontal lobe bioenergetics and alters phospholipid membrane turnover. Citicoline supplementation may therefore help to mitigate cognitive declines associated with aging by increasing energy reserves and utilization, as well as increasing the amount of essential phospholipid membrane components needed to synthesize and maintain cell membranes. Copyright (c) 2008 John Wiley & Sons, Ltd.^[4]

^[1] Changes in brain striatum dopamine and acetylcholine receptors induced by chronic CDP-choline treatment of aging mice.

^[2] CDP-choline: pharmacological and clinical review.

^[3] Wikipedia: CDP-Choline

^[4] Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy.

^[5] CDP-choline may block skull and brain damage that result from alcohol consumption early in pregnancy