(Medical Xpress) -- We don’t see only what meets the eye. The visual system constantly takes in ambiguous stimuli, weighs its options, and decides what it perceives. This normally happens effortlessly. Sometimes, however, an ambiguity is persistent, and the visual system waffles on which perception is right. Such instances interest scientists because they help us understand how the eyes and the brain make sense of what we see.
Most scientists believe rivalry occurs only when there’s “spatial conflict”—two objects striking the same place on the retina at the same time as our eyes move. But the retina isn’t the only filter or organizer of visual information. There’s also the “non-retinal reference frame”—objects such as mountains or chairs that locate things in space and make the world appear stable even when our eyes are moving.
“We asked: what if visual ambiguities are not presented on the same spot on the retina, but on the objects [in the frame] as they move around,” says California Institute of Technology cognitive scientist Jeroen J.A. van Boxtel. Indeed, he and colleague Christof Koch found evidence of rivalry in this reference frame, with surprising effects on the better-understood spatial conflict. The findings, which will appear in an upcoming issue ofPsychological Science, a journal published by the Association of Psychological Science, offer intriguing clues to how the visual system works.
In their experiments, van Boxtel and Koch created spatial conflict with a “motion quartet,” which changes the arrangement of four dots. If the dots are displaced in certain ways, the visual system isn’t sure if the movement is vertical or horizontal. If the dots move to an altogether different space, there’s no rivalry. Then the researchers upped the perceptual ante by creating an object reference frame with three white discs and shifting it, too, along with or in opposition to the smaller dots.
Seven male and female participants viewed the changing arrangements in four conditions. In one, both dots and discs remained stationary (creating spatial rivalry); in each of two, either dots or discs moved right or left; in the fourth, both moved horizontally together (creating ambiguity in the frame). Each time, participants had to press a button indicating whether the dots moved horizontally or vertically. The presses were analyzed for perceived movement “bias” (more horizontal or vertical) and duration—evidence either of rivalry or visual clarity.
The results: Even when the dots moved to another space altogether—so there was no spatial conflict—the moving discs created the effect of perceptual ambiguity. But the researchers also found that visual rivalry disappeared when the dots were stationary and the disks moved (that is, the dots were not linked to the disks). It was as if the brain had bigger fish—object-frame rivalry—to fry.
In subsequent experiments—one changing the vertical relationship of the dots and one placing the dots outside the white discs—the researchers got results similar to those they would have gotten without the frame. Their conclusion: The visual system is working out object-frame rivalry as it would spatial rivalry, probably with the same brain regions and processes.
பெண் என்ன பிள்ளை பெறும் எந்திரமா?” என்று கேட்டார் தந்தை பெரியார்.
‘ஆம்’ என்கிறது இன்றைய நவீன மருத்துவ விஞ்ஞானம். குழந்தை ‘பாக்கியம்’ இல்லாதவர்களுக்கு குழந்தை பெற்றுத் தருவதற்காக, இந்தியாவில் வாடகைத் தாய்மார்கள் உருவாகிவருகிறார்கள்.
இவர்களின் கருப்பையில் ஆணின் உயிர் அணு செலுத்தப்பட்டு, கரு உண்டாக்கப்படுகிறது. அவர்கள் பத்து மாதம் சுமந்து பெற்றுத் தந்தால், ‘கணிசமான பணம்’ தரப்படுகிறது.
ஆம், தாய்மை ஒரு ‘தொழிலாக’ மாற்றப்பட்டிருக்கிறது. வழக்கம்போல் வறுமையைக் காரணம் காட்டி, ஏழைகளைச் சூறையாடுகிற இந்த சமூகம்,..,இந்த முறையும் ஏழைப் பெண்களின் வறுமைக்கு மாற்றாக தாய்மையைச் சூறையாடியிருக்கிறது.
மனித உறவுகளில் உன்னதம் என்று சொல்லப்படுகிற தாய்மையையும் வர்த்தகமாயிருக்கிறது.
வசதியான தம்பதிகளுக்குக் குழந்தை பெற்றுக் கொள்வதில் உள்ள குறைபாடு அல்லது...
குழந்தைப் பெற்றுக் கெள்ளும் ‘பிராசஸ்’ ரொம்ப ‘இம்சை’ என்ற காரணத்தால் குழந்தை பெற்றுக் கொள்ள விருப்பம் அற்ற மனைவி, அதனால் தனது சொத்துக்கு வாரிசு அற்று போய்விடுமே என்ற ‘ஏக்கம்’...
குழந்தை பெற்று கொண்டால் உடல் வனப்பு குறைந்துவிடும் என நினைக்கும் சில பணக்கார பெண்கள்...
இவைகளே வாடகைத் தாய்மார்களை உருவாக்கி வருகிறது.
குழந்தை பெற்றுத்தரும் வரை பத்து மாத காலத்துக்கு இந்தப்பெண்கள் யார் கண்ணிலும் படாமல் தலைமறைவு வாழ்க்கை வாழவேண்டும். குழந்தைப் பெற்றவுடன் தொப்புள் கொடியோடு குழந்தைக்கும் தாய்க்குமான உறவைத் துண்டித்து கொள்ளவேண்டும்.
ஒருவேளை பிறக்கும் குழந்தை ஊனமுற்று இருந்தால், அந்தக் குழந்தையை பெற்ற தாயிடமே விட்டு விட்டுச் சென்று விடுவார்கள்.
கருவுருகிற பெண் தன் உணவை, தன் சுவாசத்தை, தன் உயிரையே ஊட்டித்தான் குழந்தையைச் சுமக்கிறாள்.
எவ்வளவு நெருக்கமான உறவாக இருந்தாலும், தன்னை உடல் ரீதியாக துன்புறுத்துகிறவர்கள் மீது, கட்டுக்கடங்காத அளவுக்கு வெறுப்பு வருவது மனித இயல்பு.
ஆனால் ஒரு பெண் தாய்மை அடைந்து இறுதியில் குழந்தை பெறுவது என்பது ஓய்வு நேரத்தில் மெல்லிய வயலினிசையை கேட்பது போல், இனிமையான அனுபவம் அல்ல.... அது உயிர் வலி. பெண்ணை மறுபிறப்பு அடைய வைப்பது மாதிரி பிறக்கிறது குழந்தை.‘என்னை இம்சைப் படுத்திய குழந்தை எனக்கு வேண்டாம்’ என்று எந்த தாயாவது குழந்தையை தள்ளி வைப்பாளா?
மாறாக, ‘தன்னைவிட குழந்தைதான் முக்கியம்’ என்கிற உணர்வைதான் ஒரு பெண்ணின் மனதில் கர்ப்பகால நாட்களும், பிரசவவலி என்கிற அந்த மரண தரிசனமும் ஏற்படுத்தி இருக்கும். அதுதான் தாய்மை.
வாடகைத் தாய்மார்களை உருவாக்குகிறவர்கள், பெண்களின் இந்த உணர்வுகளை மதிப்பதில்லை.
சொல்லப்போனால்.... பெண்களை உணர்வுள்ள மனுஷியாகவே மதிப்பதில்லை. ஒரு இயந்திரத்தில் மூலப்பொருட்களை உள்ளே தள்ளினால், அது ஒரு முழுப் பொருளை வெளியே தள்ளுவதுபோல், ஒரு பெண்ணின் உடலில் செயற்கையான முறையில் கருமுட்டையை செலுத்தியப் பிறகு, அந்தப் பெண் குழந்தையை வெளியே தள்ளிவிட்டு போய்கொண்டே இருக்க வேண்டும் என்கிறது மோசடியான மருத்தவ வர்த்தகம்
ஏழைப் பெண்களுக்கான இந்தக் கொடுமையை பெண் மருத்துவர்களே தீவிரமாக செய்கிறார்கள். (வர்க்க வேறுபாட்டில் ஆண் என்ன? பெண் என்ன?)
மக்களின் வறுமையை பயன்படுத்தி சிறுநீரகத் திருட்டில் ஈடுபடும் மருத்துவர்கள், அதே வறுமையை பயன்படுத்தி பெண்களை வாடகைத் தாய்களாக மாற்றி கோடிக்கணக்கல் சம்பாதிக்கிறார்கள். மருத்துவம் இன்று அச்சுறுத்துகிற மனிதர்களின் கசாப்புக்கடை வர்த்தகமாக மாறி இருக்கிறது.
இந்த நவீன வடிவமான வாடகைத் தாய்மார்கள் முறையால், அதிக லாபம் அடையப்போவது மருத்துவ வர்த்தகம்தான். சமூக ரீதியாக இந்த முறை பெரிய தீங்கையே ஏற்படுத்தும், அதுவும் இந்தியா போன்ற மூன்றாம் உலக நாடுகளில்தான் இந்த முறை பெருமளவில் பயன்படுத்தப்படும். காரணம், இந்த முறைக்கு பணக்கார நாட்டுப் பெண்கள் உடன் படமாட்டார்கள். மலிவு விலையில் தாய்மார்கள் இந்தியாவில் கிடைப்பார்கள் என்பதால், வெளிநாட்டினரும் இந்தியத் தாய்மார்களின் தாய்மையைச் சூறையாட அதிக வாய்ப்பிருக்கிறது. ஏற்கனவே மாற்றுச்சிறுநீரக அறுவை சிகிச்சைக்கு தங்களின் வறுமையை போக்க, சிறுநீரத்தை விற்றனர் நமது நெசவாளர்களும், விவசாயிகளும் என்பது நமது ஞாபகத்தில் கவலையோடு பதிவாகியிருக்கிறது.
ஆக, இந்த நவீன மருத்துவ விஞ்ஞானம் இந்தியா போன்ற மூன்றாம் உலக நாட்டுப் பெண்களின் உணர்வுகள் மீது, உரிமைகள் மீது தொடுத்து இருக்கிற தாக்குதலாகவே இருக்கிறது.
இப்படி , தாய்மையை வர்த்தகமாக அனுமதித்தால், இன்று எல்லாப் பொருட்களும் பிளாஸ்டிக் கவரில் கிடைப்பது மாதிரி, இன்னும் கொஞ்சநாளில் தாய்ப்பாலும் ‘சாஷே’ யில் (Sache) கிடைக்கும் அவல நிலையும் வந்துவிடும். -
இந்த " வாடகை தாய்" முறை பெண்களுக்கு எதிராகத் திட்டமிட்டு நிகழ்த்தப்படுகிற உடல் மற்றும் உளவியல் சார்ந்த வன்முறையாகவே இருக்கிறது.
Shakespeare was a master at portraying profound emotional upset in the physical symptoms of his characters, and many modern day doctors would do well to study the Bard to better understand the mind-body connection, concludes an analysis of his works, published in Medical Humanities.
Kenneth Heaton, a medical doctor and extensively published author on William Shakespeare's oeuvre, systematically analysed 42 of the author's major works and 46 of those of his contemporaries, looking for evidence of psychosomatic symptoms.
He focused on sensory symptoms other than those relating to sight, taste, the heart, and the gut.
He found that Shakespeare's portrayal of symptoms such as dizziness/faintness, and blunted or heightened sensitivity to touch and pain in characters expressing profound emotions was significantly more common than in works by other authors of the time.
Vertigo/giddiness/dizziness is expressed by five male characters in "Taming of the Shrew", "Romeo and Juliet", "Henry VI" part 1, "Cymbeline" and "Troilus and Cressida". The nearest approximation in contemporaries' works was one incident in John Marston's "The Malcontent".
There are at least 11 instances of breathlessness associated with extreme emotion in "Two Gentlemen of Verona", "The Rape of Lucrece", "Venus and Adonis", and "Troilus and Cressida", compared with just two in the works of other writers.
Fatigue/weariness as a result of grief or distress is a familiar sensation among Shakespeare's characters, most notably in "Hamlet", "The Merchant of Venice", "As You Like It", "Richard II" and "Henry IV" part 2. This crops up twice as frequently as in other contemporaries' works, argues Dr Heaton.
Disturbed hearing at a time of high emotion occurs in "King Lear", "Richard II" and "King John" while blunted/exaggerated senses are portrayed in "Much Ado about Nothing", "Venus and Adonis", "King Lear", "Love's Labour's Lost" and "Coriolanus".
"Shakespeare's perception that numbness and enhanced sensation can have a psychological origin seems not to have been shared by his contemporaries, none of whom included such phenomena in the works examined," writes Dr Heaton.
The Bard also uses coldness - for example, "Romeo and Juliet" - and faintness to convey shock, including in "Titus Andronicus", "Julius Caesar", "Love's Labour's Lost", and "Richard III", significantly more frequently than other writers of the period.
Dr Heaton concludes that his data show that Shakespeare "was an exceptionally body-conscious writer," suggesting that the technique was used to make his characters seem more human and engender greater empathy or raise the emotional temperature of his plays and poems.
And his findings should encourage doctors to remember that physical symptoms can have psychological causes, he suggests.
"Many doctors are reluctant to attribute physical symptoms to emotional disturbance, and this results in delayed diagnosis, overinvestigation, and inappropriate treatment," he writes.
"They could learn to be better doctors by studying Shakespeare. This is important because the so-called functional symptoms are the leading cause of general practitioner visits and of referrals to specialists," he says.
ATHENS, Ohio — She was gone for good, and no amount of meditation could resolve the grief, even out here in the deep quiet of the woods.
Milt Greek pushed to his feet. It was Mother’s Day 2006, not long after his mother’s funeral, and he headed back home knowing that he needed help. A change in the medication for his schizophrenia
, for sure. A change in focus, too; time with his family, to forget himself.
And, oh yes, he had to act on an urge expressed in his psychotic
delusions: to save the world.
So after cleaning the yard around his house — a big job, a gift to his wife — in the coming days he sat down and wrote a letter to the editor of the local newspaper, supporting a noise-pollution ordinance.
Small things, maybe, but Mr. Greek has learned to live with his diagnosis in part by understanding and acting on its underlying messages, and along the way has built something exceptional: a full life, complete with a family and a career.
He is one of a small number of successful people with a severe psychiatric diagnosis who have chosen to tell their story publicly. In doing so, they are contributing to a deeper understanding of mental illness — and setting an example that can help others recover.
“I started feeling better, stronger, the next day,” said Mr. Greek, 49, a computer programmer who for years, before receiving medical treatment, had delusions of meeting God and Jesus.
“I have such anxiety if I’m not organizing or doing some good work. I don’t feel right,” he said. “That’s what the psychosis has given me, and I consider it to be a gift.”
Doctors generally consider the delusional beliefs of schizophrenia to be just that — delusional — and any attempt to indulge them to be an exercise in reckless collusion that could make matters worse. There is no point, they say, in trying to explain the psychological significance of someone’s belief that the C.I.A. is spying through the TV; it has no basis, other than psychosis.
Yet people who have had such experiences often disagree, arguing that delusions have their origin not solely in the illness, but also in fears, longings and psychological wounds that, once understood, can help people sustain recovery after they receive treatment.
Now, these psychiatric veterans are coming together in increasing numbers, at meetings and conferences, and they are writing up their own case histories, developing their own theories of psychosis, with the benefit of far more data than they have ever had before: one another’s stories.
“It’s a thrilling time, because people with lived experience are beginning to collaborate in large numbers,” said Gail A. Hornstein
, a psychologist at Mount Holyoke College and author of “Agnes’s Jacket: A Psychologist’s Search for the Meanings of Madness.” “They are developing their own theories, their own language about what their experiences means from the inside.”
Mr. Greek is one of the most exceptional, having built a successful life and career despite having schizophrenia — and, he says, because of it. He manages the disorder with medication, personal routines, and by minding the messages in his own strange delusions.
is the best thing that ever happened to me,” he said. “I know a lot of people with the diagnosis don’t feel that way, but the experience changed me, for the better. I was so arrogant, so narcissistic, so self-involved, and it humbled me. It gave me a purpose, and that purpose has been very much a part of my recovery.”
The Village Eccentric
Like many idealistic undergraduates, Mr. Greek arrived at Ohio University in Athens on a mission. Only, like many undergrads, he wasn’t completely sure what it was.
“To discover a psychological code that people should live by, to create world peace,” he said. “Something like that.”
The town was ready to listen, regardless. It was the fall of 1981, and Athens still had one sandal planted in the 1960s; communes thrived in the Appalachian foothills to the north, and big ideas were in the air, at least in the streets and bars near campus, where professors and students gathered.
One stood out. “You can’t imagine how intense he was back then,” said June Holley, a friend and business consultant in Athens. “He had this long, very thick, curly chestnut hair and wild eyes; he looked like a lion. He could be loud, and I think a lot of people just didn’t want to deal with it.”
Local residents gave him the sidewalk, avoided eye contact, and generally accepted him as one variety of village lunatic — in a town with a rich history of them.
He knew the role, at some level. The son of a college math professor and a lawyer, progressives both, Milton Thomas Greek grew up in Roanoke, Ill., and neighboring Benson, about two hours southwest of Chicago. He declared himself an atheist
early and often, which in a devout Christian community was one way to stir the air — and the boys who ruled the schoolyard.
“They told me I was damned — damned! — and came after me,” Mr. Greek said. “Now I see that it was just an excuse, like picking on the fat kid for being fat, or the nerd for being a nerd. But at the time I thought it was all about religion.”
He did not discover the secret to world peace and, by senior year, was in a troubled marriage, and began seeing and hearing things others did not. One day he saw a homeless man in the Athens bus station with eyes “like landscapes that went back into the man’s head infinitely far, stretching on for eternity.” God’s eyes; who else?
Later, he was hitchhiking, and a man with long hair and sandals pulled over to offer a ride, his eyes rippling with the same eternal light as the street person’s. Jesus? It had to be (“I’d already met God, so it made sense.”) The man said something about a small town in the woods, and Mr. Greek thought that that town had to be heaven.
His marriage collapsed. His friends stopped calling. He was back at home in Illinois when a doctor finally gave him a diagnosis — schizophrenia — and prescribed medication.
It seemed like a charade, from start to finish. The doctor never asked what he thought his hallucinations
meant, or whether the strange thoughts were linked to experiences in his life. He stopped taking the pills.
“I became very suicidal,” he said. “I had no idea what’s happening to me during this entire time. I had been this big atheist, but here I am thinking that the rapture is about to start and that I’m the Antichrist — all this religious imagery.”
Why?
The answer was obvious and ultimately liberating, but he had to spend a long time wandering in the woods — literally — to find it.
It was 1984, he had begged his way back into Ohio University for graduate studies in sociology, still lost in his own mind, his thoughts turning darker by the day. He was alienating classmates, professors, friends.
About the only exception was Ms. Holley, a graduate student some 15 years his senior who enjoyed his company, and one day he decided to visit the commune where she lived, with her family and several other families. It took him two days to find it, the first spent wandering the misty woods until dark in a waking, delusional dream, and the second stumbling into a clearing just off Hooper Ridge Road, where Ms. Holley and her friends took him in.
Over the next several months they sat with him, accepted him as a member of the tribe, and encouraged his mission to improve the world at face value. And save his life they probably did, in part by suggesting that he seek help.
It was Ms. Holley who delivered the message. “I trusted her completely, so when she said I was hallucinating — when she used the word ‘hallucination’ — I knew it was true,” Mr. Greek said. “I would have to give the medication another try.”
He was lucky. It worked, blunting the psychosis enough that he was able to complete a programming course and find work, first in Illinois and later back in Athens at Ohio University’s Information Technology department. In time he found something more: During a snowstorm in 1996, Mr. Greek knocked on the door of a neighbor he had seen around Athens, a single mother with two teenage children, carrying a full-time job plus graduate classes, who was at that very moment (he would learn later) praying for something to get her through the winter.
The man at the door did not exactly look like a savior, in his beat-up jeans and unruly hair, his soft eyes and half-smile. But he offered to cook dinner — stir fry — on a day when the fridge was nearly empty.
The two neighbors became friendly, then close, and finally fell for each other. Neither can say exactly when it happened, but she remembers looking out her window one day to see Mr. Greek pull up to his apartment across the street, his old Honda coughing white smoke. He popped the hood and backed away from the car in slow motion, staring at the engine, then turned abruptly toward his apartment — and vanished, falling face-first into some bushes. “I thought, ‘Well, O.K., he’s got something,” she said. “I’m not sure what. Absentmindedness, maybe?”
They married in 2003 (Mr. Greek’s wife, an artist, asked that her name not appear in this article, for her own privacy), and she helped him fit his religious delusions, now controlled by medication, into a coherent personal story that has guided his day-do-day life.
The frightening voices and ominous signs saying that he was damned were no more than embodiments of his very real childhood terror of being cast out, as the schoolyard boys threatened. His search for heaven on earth was in part an attempt to escape that fate, to find a secure place. But it also dramatized a longing to put the world right, a mission that may have started as vain fantasy, but in time became an emotional imperative, a need to commit small acts of kindness, like cooking dinner for a snowed-in neighbor.
A Regimen for Coping
“He has this long list of causes that he’s extremely passionate about, and he has strong opinions about almost everything, but he’s also very sensitive to his relations with people and open to other philosophies,” said Melissa Van Meter, who has worked with Mr. Greek at the university and holds very different political views. “It has just impressed me that he could handle so much personally and do so well professionally.”
“When I began to see the delusions in the context of things that were happening in my real life, they finally made some sense,” Mr. Greek said. “And understanding the story of my psychosis helped me see what I needed to stay well.”
Mr. Greek’s regimen combines meditation, work and drug treatment with occasional visits to a therapist and a steady diet of charitable acts. Some of these are meant to improve the community; others are for co-workers and friends, especially those dealing with a psychiatric diagnosis.
To help others experiencing psychotic delusions, he relies on his own theory of what delusions may mean. In an analysis of 20 delusional experiences, all described by sufferers in the first person, Mr. Greek identifies four story lines.
Among them are the rescuer (on a mission to save a particular group); the self-loathing person (lost in a sense of extreme worthlessness); the visionary (on a journey to spiritual realms to bring back truth); and the messianic (out to transform the world through miracles, or contact with deities) — the last of which is his own psychosis story.
Each, in Mr. Greek’s reading, grows out of a specific fear or trauma, whether isolation, abuse or family dysfunction, in the same way his own delusional story symbolized a fear of being a social reject. He is preparing the study for publication in a psychiatric journal and has put much of his thinking into a manual for families dealing with psychosis, called “Schizophrenia: A Blueprint for Recovery
.”
Mr. Greek’s analysis of the story lines in psychosis is certainly not the first of its kind, nor the most comprehensive. Psychiatrists, psychologists
, therapists and brain scientists have spun out hundreds of ideas about what goes on during a delusion.
But until recently patients themselves — that is, nonprofessionals who have lived with hallucinations and delusions — had little more than their own strange story to study, in any detail. Now they have dozens, and Mr. Greek is one of a small number of such “native” theorists who argue that the content of a delusion should not be ignored but engaged, carefully, once a person has his or her hallucinations under control.
Underlying Needs
“By exploring a person’s anomalous beliefs and experiences, we are better able to understand the underlying feeling and needs that give fuel to these experiences,” said Paris Williams, a psychologist who has struggled with psychosis and recently published a doctoral dissertation
analyzing the content of six people’s delusions, which has informed Mr. Greek’s work.
For instance, said Dr. Williams, who is working on a book called “Rethinking Madness,” “we can find ways to make them feel safe when they believe they are being persecuted by malevolent forces, or find ways to help them feel empowered when they experience demanding voices.”
One place Mr. Greek feels safe is in a clearing in the woods behind his house, where on a recent afternoon he disappeared wearing a tie-dyed shirt and old jeans with the knees worn completely through. He practices mindfulness meditation here, tuning in to the rhythms of life that usually pass unnoticed.
Back at home, he runs thoughts and perceptions by his wife. “He says things like, ‘Is that a marching band I’m hearing, or am I just hallucinating?’ ” she said. “I’ll say, ‘Uh no, I don’t hear a band, Milt,’ and he’s fine.”
And he visits a therapist when stress levels are running very high. The therapist has given him diagnoses of schizophrenia and “mood disorder, not otherwise specified,” according to his medical records, and she treats him in sessions and with an antipsychotic drug, adjusting the dosage up or down depending on his mood.
Since his mother’s death, Mr. Greek and his wife have taken several more emotional blows, with other close relatives dying. He has been especially stretched, between his work, various community projects, and traveling to speak, often to police groups about how to understand psychotic thinking when dealing with people on the street.
It was too much, and in August he visited his therapist again, and soon after made a deal with his wife. “She and I signed a contract identifying and limiting volunteer work I will do next year,” he said in an e-mail. “I am being coached on how to say no.”
The world is not yet saved from itself, nor for that matter is Athens. But even a messianic rescuer needs a day off, if only to come back stronger the next.
Meaning in Madness: Milton Greek, who has been diagnosed with schizophrenia, believes that decoding the messages in delusions can help some people recover.
Supersized. Experiments with mice suggest that transplanted neurons (green, inset) can help repair a genetic defect that causes obesity.
Credit: Oak Ridge National Laboratories (mouse); C. Zhou et al., Science (neuron)
Immature neurons transplanted into the brains of obesity-prone mice can prevent the animals from becoming so fat, according to a new study. The researchers caution that their experiment was never intended as a step toward treating obesity in humans, but they say it provides an important proof of principle that transplanted fetal cells can integrate themselves into an abnormal neural circuit and help restore its function. Other researchers say the work highlights both the promise and the challenges of developing cell therapies for complex brain disorders.
The road to fetal or stem cell therapies for the nervous system has been rocky. Despite early promise, recent trials of fetal cell transplants for Parkinson's disease have yielded disappointing results
of a stem cell therapy for spinal injury. It also announced that, for financial reasons, it would abandon further stem cell work.
Yet basic neuroscience research has been more encouraging. In the past decade, scientists overturned century-old dogma by showing that some parts of the human brain produce new neurons throughout life. There is evidence that these new neurons get wired into existing neural circuits
and may help maintain or enhance brain function, suggesting that transplanted cells may be able to do the same.
In the new study, reported online today in Science, Harvard University neuroscientist Jeffrey Macklis and colleagues investigated whether fetal neurons transplanted into a part of the mouse brain that does not normally produce new neurons of its own could repair an abnormal neural circuit. The recipients of the transplant treatment were genetically altered mice lacking the receptor for leptin, a hormone that regulates metabolism and body weight. In normal mice, leptin acts on neurons in a part of the brain called the hypothalamus, which regulates metabolism and other essential functions. But in the mutant mice, these neurons can't respond to leptin, and the mice become obese and diabetic.
, Macklis and colleagues found. The rodents with transplanted cells weighed about 40 to 45 grams on average, compared with 25 grams for normal mice and 55 to 60 grams for mutant mice that received a sham operation but no neurons. Also, they were not diabetic.
The team used several methods to examine how the transplanted neurons fared. The transplanted neurons had a gene for a protein that glows green in certain light, and using this and other markers, the researchers saw under the microscope that the cells had differentiated into several different types of neurons normally found in the hypothalamus and had formed synaptic connections with other neurons. Using electrodes to record the electrical activity of hypothalamic neurons, the researchers confirmed that the transplanted cells responded to leptin as expected and could communicate with the recipient mouse's own neurons. "These newly incorporated neurons were in a sense acting as antennas for leptin and sending those signals into the brain," Macklis says.
Macklis says the lessons learned from these experiments could help researchers trying to develop cell therapies for conditions such as amyotrophic lateral sclerosis, Parkinson's disease, and spinal injury. Using exactly the right cells, either by carefully selecting cells to transplant and precisely guiding their development or by incorporating immature neurons already present in the adult brain, will be crucial, he says.
In the new study, his group transplanted immature cells that were just at the stage of differentiating into several types of hypothalamic neurons. Additional experiments showed that fetal cells taken slightly later in development or from a different part of the brain did not prevent or reduce obesity when transplanted into the mutant mice. "These experiments say that if you get the neurons just right, it's possible for the adult brain to accept them, to wire them in, and have them fully functional."
"The work is obviously very carefully done," says Evan Snyder, a stem cell researcher at the Sanford-Burnham Medical Research Institute in San Diego, California. The findings, he says, add to a growing realization that cell therapies will have to be tailored to the specific neural circuit that's affected. In the optimistic early days of the field, Snyder says, scientists hoped that simply transplanting stem cells or neural progenitors into a brain would repair neural circuits because cues in the cellular environment would tell the new cells what to do. That's turning out not to be the case. "Reconstructing a circuit is going to require knitting together a number of specialized cells and not relying on the environment to do it," he says. "I'm still optimistic, but there's going to be a lot of intellectual heavy lifting."
Contrary to expectations that the neurotransmitter GABA only inhibited neuronal firing in the adult brain, RIKEN-led research has shown that it can also excite interneurons in the hippocampus of the rat brain by changing the conductance of ions across the membranes of these cells.
According to conventional wisdom, activation of the GABAA receptor subtype at the communication junction between neurons—the synapse—strongly increases membrane conductance of ions, triggering a process called shunting, which inhibits neuronal firing. Led by Alexey Semyanov of the RIKEN Brain Science Institute in Wako, Japan, the team demonstrated that activation of these receptors outside of synaptic junctions, so-called ‘extrasynaptic receptors’ can also excite the neurons.
Further activation of these extrasynaptic receptors by application of higher concentrations of GABA turn excitation into inhibition (Fig. 1). “To our knowledge, this is the first demonstration that changes in membrane conductance can switch the action of a neurotransmitter from excitation to inhibition,” Semyanov says.
Semyanov and colleagues treated slices of the mouse hippocampus with low or high concentrations of GABA and compared the effects. They showed that the more GABA they added, the more they could detect an increase in the conductance of the membranes of hippocampus cells called CA1 interneurons. The increased conductance was mediated through extrasynaptic GABAA receptors.
The CA1 interneurons could spontaneously fire action potentials—electrical impulses that transfer signals in the network of interconnected neurons. Adding low concentrations of GABA increased the rate of action potential firing, while high concentrations of GABA reduced action potential firing in the cells. Because the concentration of GABA that slowed neuronal firing had also enhanced membrane conductance, the researchers argue that increasing this conductance by activating extrasynaptic GABAA receptors can result in inhibition via shunting along the membrane, which would cause a decrease in action potential generation in the neurons.
The hippocampus plays a key role in learning and memory, and GABA concentrations are known to increase in this part of the brain during exploratory behavior in rats. The findings therefore raise the intriguing possibility that changes in GABA concentration in the brain during some behavioral tasks could bidirectionally change neuronal excitability; this could be a characteristic of the hippocampal neuronal network that may be required for some behavioral tasks in animals.
“Many clinically used drugs, such as sedatives or anti-epileptics, target GABA receptors,” notes Semyanov. “Our findings could potentially explain their therapeutic action as well as some of their unwanted side effects.”
More information: Song, I., Savtchenko, L. & Semyanov, A. Tonic excitation or inhibition is set by GABAA conductance in hippocampal interneurons. Nature Communications 2, 376 (2011). http://www.nature. … mms1377.html
Supersized. Experiments with mice suggest that transplanted neurons (green, inset) can help repair a genetic defect that causes obesity.