Locating ground zero: How the brain’s emergency workers find the disaster area
Like emergency workers rushing to a disaster scene, cells called microglia speed to places where the brain has been injured, to contain the damage by ‘eating up’ any cellular debris and dead or dying neurons. Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have now discovered exactly how microglia detect the site of injury, thanks to a relay of molecular signals. Their work, published today in Developmental Cell, paves the way for new medical approaches to conditions where microglia’s ability to locate hazardous cells and material within the brain is compromised
When microglia (green) cannot detect ATP (bottom), they don’t move to the injury site as they usually would (top). Credit: Copyright EMBL/Peri
When an emergency occurs, cries can alert bystanders, who will dial the emergency number. A call will go out over the radio, and ambulances, police or fire engines in the area will respond as needed. In the brain, Peri and colleagues found, injured neurons send out their own distress cry: they release a molecule called glutamate. Neighbouring neurons sense that glutamate and respond by taking up calcium. As glutamate spreads out from the injury site, this creates a wave of calcium swallowing. Along that wave, as neurons take up calcium they release a third molecule, called ATP. When the wave comes within reach, a microglial cell detects that ATP and takes it as a call to action, moving in that direction – essentially tracing the wave backwards until it reaches the injury.
Scientists knew already that microglia can detect ATP, but this molecule doesn’t last long outside of cells, so there were doubts about how ATP alone could be a signal that carried far enough to reach microglia located far from the site of injury. The trick, as Peri and colleagues discovered, is the long-lasting glutamate-driven calcium wave that can travel the length of the brain. Thanks to this wave, the ATP signal is not just emitted by the injured cells, but is repeatedly sent out by the neuronsalong the way, until it reaches microglia.
Dirk Sieger and Christian Moritz in Peri’s lab took advantage of the fact that zebrafish have transparent heads, which allow scientists to peer down a microscope straight into the fish’s brain. They used a laser to injure a few of the fish’s brain cells, and watched fluorescently-labelled microglia move in on the injury. When they genetically engineered zebrafish to make neurons’ calcium levels traceable under the microscope, too, the scientists were able to confirm that when the calcium wave reached microglia, these cells immediately started moving toward the injury.
Knowing all the steps in this process, and how they feed into each other, could help to design treatments to improve microglia’s detection ability, which go awry in conditions such as Alzheimer’s and Parkinson’s diseases.
Folly introduced herself and explained that, despite her bad name, was the only one who could bring joy to both gods and men. Indeed, when she stood up before the crowd in the hall, the attendees’ faces lit up with smiles and cheers broke out in the room. She had the power to transfigure them, much as the sun does when it comes up in the morning or spring brings its freshness to the chill of winter. She asked her listeners to attend to her as if she was a street-performer or a comedian, and stated that she was going to act like a Sophist whose job was to praise gods and men.
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Folly planned to sing her own praises because, after all, who knows her better than she knows herself? There is no need to do what the pundits and patricians do when they hire a sycophantic and servile rhetorician to extol their merits. Amazingly, no one before has sought to sing of Folly’s praises. This is strange because most of mankind has partaken in her bounty. Her treatise was going to be truthful and was not designed to merely show off her wit. Many other orators expounded a number of ridiculous things so it is not inappropriate for her to take herself as subject.
Her strategy is not to provide a definition and then divide up her topic; verbal definitions are unnecessary since she is actually before her listeners. Her Latin name is Stultitia and her Greek name is Moria. This is quite obvious since she does not attempt to hide her identity by manipulating her appearance- “I’m always exactly like myself, so that even those who most aspire to the name and reputation of wisdom cannot hide in my presence…” Folly thought it best to imitate the style of the rhetoricians of the day who delighted in mixing Latina and Greek into their oratories and trying to impress their listeners with their erudition.
Returning to the main point, Folly was determined to set the matter straight on her lineage. She was descended from Plutus, god of riches, and Neotes, a nymph of Youth. She was born on the Fortunate Isles where no one grows old or sick and everything is fecund and fertile and beautiful. She was nursed by Methe (Tipsy) and Apaedia (Ninny), both of whom were in her company today. Her company was also comprised of: Philautia (Self-Love), Kolakia (Flattery), Lethe (Forgetfulness), Misponia (Lieabout), Hedone (Pleasure), Anoia (Imbecility), Tryphe (Fascination), Comus (Festivity), and Negretos Hypnos (Sound Sleep). With their faithful help Folly maintains dominion over all things.
Folly, now having established her patrimony, averred that she was ready to detail the benefits she bestows upon gods and men and how much joy she brings them. First of all, nothing is sweeter than life itself and Folly is a part of that, as it is doubtful that men and women would engage in intercourse without a dose of folly. Men would not enter into matrimony if they knew how inconvenient it was, and women would not want to do so either if they knew how painful and time-consuming childbearing and childrearing were; it takes Folly’s servant Forgetfulness to bring matrimony to pass.
Not only life but every good thing derives from folly. Anything that brings pleasure is from folly, and even the Stoics cannot decry the need for pleasure. Indeed, “what part of life is not gloomy, not sullen, not drab, not dull and dreary, unless you add a dash of pleasure, the condiment of folly?” Even Sophocles wrote that “the happiest life is to know nothing at all.”
All of this can be proved simply by looking at children, whose age makes them the happiest of men. They are cooed over and cuddled, all because they possess the charm of foolishness. This foolishness compensates for the toil of bringing them up. As soon as they grow older their bright and shining faces grow dull and they call folly a liar. The further they depart from folly the less they really live. Only folly allows old age to be pleasurable. It is almost like a second childhood; the old are silly, playful, and have no cares because Folly has mitigated the curse of growing older. These old men and women have more in common with children, “for what is the difference between them, apart from the fact that the elders have more wrinkles and more birthdays?”
None of the other gods can do what Folly does- she can restore men to the best and happiest days of their life even when they are old and gray. All those men who have devoted themselves to their studies or other difficult ad serious business have grown old before their time, but, as Folly explains, “my morons are all plump, with sleek and glistening skins…” Folly is truly the only one that can bestow the fountain of youth upon men.
One of the most interesting components of this section is Folly’s discussion of old age and its concomitant follies. Hard work and deep mental duress as well as the natural progression of life bring old age, but Folly claims that she is a veritable elixir of life that can restore the old to the foolishness and bliss of youth. She explains that “add this to the popular saying very much to the point, that ‘folly is the one and only thing that delays youth in her flight and keeps sour old age at a distance’ ” (15). While this claim is easy to gloss over, a deeper look at popular proverbs of the day reveal no such “popular saying” that suggests folly is the way to prolong youth and keep old age at bay. Literary critic Harry Vredeveld delves into the history of Erasmus’s world to try and ascertain the origins, of any, of that familiar proverb.
It may perhaps seem likely that Folly invented this proverb, but she claims it is authoritative and commonly known. She also gives the impression that she is paraphrasing or interpreting it. Vredeveld’s paper continues with the assumption that “Folly is alluding to a common and authoritative, perhaps biblical, proverb which she is deliberately distorting beyond our present recognitions” and seeks to discover what Erasmus’s audience may have thought of. Folly’s whole discussion of old age is buttressed with medical theory; the work is a reflection of the contemporary thinking about old age and its causes.
Medieval medical theory was situated on the four humors of the body (blood, yellow bile, black bile, phlegm) and their connection to the four elements (air, fire, earth, water), and the four ages of man (adolescence, youth, manhood, old age) correlated with the four seasons of the year (springtime, summer, autumn, winter). As the body ages the hot elements that had predominated cool because the body is losing its vital moisture; therefore, “aging, consequently, was defined as the insensibly slow cooling and drying of the body, the effects which begin to make themselves felt at mid-life.” As the body cools and dries, the outward appearance is affected- wrinkles, grey hair, shriveled skin, weakening body, decay of mental powers proliferate. The key to slowing this process down was to discover the elixir of life, or, rather, what could speed up or slow down the cooling/drying process. It was commonly assumed that lascivious behavior like drinking and sexual activity as well as intense mental perturbation such as scholarly study or excessive worrying could speed up the cooling process. Happiness and mirthfulness are the opposite activities/emotions, so naturally they were assumed to slow down the process. Men were encouraged to be cheerful, indulge in recreation, and cease worrying.
As Vredeveld points out, “Folly -we see it clearly now -must be putting herself here in the place of joy, the quintessence of youth.” The biblical proverb becomes clear when Folly is conceived as joy. Proverbs 17:22 (in the King James Version) says: “A merry heart doeth good like a medicine: but a broken spirit drieth the bones.” Vredeveld concedes it is not one that modern readers might immediately identify, but that is because they have “lost touch with the tradition that interpreted biblical texts such as these in the light of current medical views.” Erasmus specifically cites or alludes to this proverb in many of his other works, and the verse was also utilized by the famous physician Arnald of Villanova in his widely-read commentary. The “popular saying” has become illuminated for modern readers.
One other point to make about this opening of the oration is the fantastic, ironical, light-hearted tone Erasmus uses for his narrator/subject. She is a profoundly enticing speaker and her introduction is beguiling and authoritative. Her claims are bold but uttered with such ease that the listener becomes rapt with attention and delight. She is clear in her desire to avoid the absurdities of oration that contemporary speakers prefer to indulge in. She acknowledges that these men love to sprinkle arcane bits of learning and other languages into their speeches but does not need to do that herself. She does, however, allude to many different literary, historical, political anecdotes, proverbs, vignettes, moral lessons, etc.
The Brain May Disassemble Itself in Sleep
Compared with the hustle and bustle of waking life, sleeplooks dull and unworkmanlike. Except for in its dreams, a sleeping brain doesn’t misbehave or find a job. It also doesn’t love, scheme, aspire or really do much we would be proud to take credit for. Yet during those quiet hours when our mind is on hold, our brain does the essential labor at the heart of all creative acts. It edits itself. And it may throw out a lot.
In a provocative new theory about the purpose of sleep, neuroscientist Giulio Tononi of the University of Wisconsin–Madison has proposed that slumber, to cement what we have learned, must also spur the brain’s undoing. As the conscious mind settles into sleep, the neural connections that create a scaffold for our knowledge must partially unravel, his theory suggests. Although this nightly dismantling might seem like a curious act of cerebral self-sabotage, it may in fact be a mechanism for enhancing the brain’s capacity to encode and store new information.
The benefits of sleep for learning and memory are widely accepted in the scientific community. The prevailing view holds that recently formed memories are replayed during sleep and in the process become more sharply etched in the brain [see “Quiet! Sleeping Brain at Work,” by Robert Stickgold and Jeffrey M. Ellenbogen; Scientific American Mind, August/September 2008]. As Tononi surmised, however, the neural circuits buttressing those memories can be fortified only so many times before reaching their maximum strength. He and his colleagues have gathered evidence that sleep also serves as a reset button, uniformly loosening neural connections throughout the brain to put this organ back in a flexible state in which learning can take place.
The theory is still controversial. Some sleep researchers consider the evidence for it too preliminary, favoring the conventional wisdom of sleep as a time of memory consolidation and reinforcement. Still, if Tononi is right, sleep may not be just for curating memories of the recent past. It may also set aside space for memories of experiences we have not yet had.
Saturated Pixels? Learning occurs when an experience—listening to new music, say, or navigating an unfamiliar city—imposes a pattern of activity on groups of neurons. The pattern alters the cells’ interconnections: ties among co-active neurons grow stronger, and those among out-of-step neurons weaken. In this way, the cells become functionally lassoed together. This coalition becomes dedicated to preserving a specific fragment of experience—a memory. During later offline periods—sleep in particular—the pattern stamped in by experience gets replayed, leading to cellular changes that stabilize the pattern.
A decade or so ago most psychologists conceived of sleep as this recap of daytime learning. Yet Tononi sensed a potential problem: if the junctions among neurons—synapses—were being ratcheted tighter and stronger over consecutive nights and days, they would eventually plateau. As with the saturated pixels of a too-bright image, a set of maxed-out, uniform synapses would provide little information. Equally problematic, such a brain would have no way of storing new experiences.
Tononi also noted some interesting properties of the brain waves he and many other researchers had recorded in sleeping people. Scientists had long known that “slow-wave” sleep—that stage of rest when people are hardest to rouse—was necessary and restorative. Even so, he took note of two more specific phenomena. First, he recognized that when people are deprived of slow-wave sleep, they tend to make up for it with longer and more intense bouts of this type of sleep later on
Slumber may loosen the links that undergird knowledge, restoring the brain daily to a vibrant, flexible state