Eric Kandel is 80 years old, was present at the first Society for Neuroscience meeting in 1969, is 9 years removed from winning the Nobel Prize for physiology and medicine. He’s also so well known at the Neuroscience meeting, he can go by one name, “like Bono,” said SfN president Tom Carew in his introduction to tonight’s Presidental Lecture. So you might have expected Kandel’s talk to be a history lesson, a retelling of how he uncovered the cellular chain of events that underlie learning and memory in sea slugs, fruit flies, mice and, by extension, you and me.
But Kandel, looking like The Sopranos’ Uncle Junior and speaking with Woody Allen’s Brooklyn accent, had very little interest in looking back. After 75 minutes of him excitedly flashing through graphs and figures explaining recent findings in his laboratory at Columbia University, he could only narrow his talk down to four conclusions. My thesis adviser, who was sitting next to me, leaning over and whispered in amazement, “these aren’t conclusions at all, he’s still forging ahead.”
That relentless drive in someone so late in his career was infectious. Kandel said the goal of his talk was to explain how a person remembers his first love for the rest of his life, as if that was a simple quest, but his lecture portrayed science as it should be: a never-ending story, with each answer giving birth to several more questions. While some researchers settle on a single technique and pass the torch to younger researchers when the limits of that technique are reached, Kandel proved that he has stayed on the cutting edge of science, bringing fresh talent into his lab to apply new tools to his endless questions about how neurons encode memory.
As a result, almost a decade after his Nobel victory, Kandel was excitedly telling 10,000 of his colleagues about a new cellular signal, called CRB-3 in mice, which he humbly described as “a new class of functional proteins” and “an entirely new model of synaptic plasticity.” The work was backed up with the latest in genetic, cellular biology and imaging evidence, testimony to both Kandel’s ability to keep up with the fast-moving world of science as well as the sprawling world of neuroscience itself.
“One of the wonderful things that has happened in my forty years in the society, is that neuroscience, which really was quite fragmented when I entered the field…has become a unified organism,” Kandel said.
4:00 PM – Reversing the Remodeling of Drug Addiction
We’ve talked a lot these past three days about ways that drugs and food change the brain, altering a person’s response and desire for rewarding substances and producing addictive behavior. After years of research along these lines, I don’t think anyone is skeptical any more that drugs do change the brain, meaning the question is now what can we do about it? Thus far, the answers to that question have been unsatisfying, but at a news conference focused on addiction research at the Neuroscience meeting, Khaled Moussawi of the Medical University of South Carolina described a promising solution with a cumbersome name: N-acetylcysteine.
A drug that’s already on the market for reducing mucus and reversing the effects of acetaminophen overdose, N-acetylcysteine (let’s call it NAC) has been put to use in the Moussawi’s experiments to reverse the changes that cocaine induces in the brain. As we heard yesterday from Nora Volkow, repeated cocaine removes the brakes that the prefrontal cortex provide for the reward pathway, eliminating the brain’s ability to control a person’s impulses for drug taking. Moussawi treated rats with cocaine and saw all the usual signs of an addicted brain – neurons in the reward pathway that grow extra branches and increased excitability that has reached its ceiling.
But treating his rats with NAC for two weeks was able to reverse these effects, pruning the neurons back to a less-branched form and restoring their ability to be modulated. This could have the effect of restoring the prefrontal cortex control of the reward pathway, reinstating the little voice inside your head that says “Just Say No.” That hypothesis was supported by experiments where Moussawi’s rats were given access to cocaine after their NAC treatment, and were far less interested in pressing the lever to get the drug.
NAC has already been tested in humans, and shown to decrease cigarette smoking, drug craving, pathological gambling and even compulsive behaviors like hair pulling. Encouraging results, and an indicator that damage that drug abusers do to their own brains is reversible, not a permanent, self-imposed sentence.
As many as 60% of women diagnosed with breast cancer are co-diagnosed with a mood disorder such as depression at some point during their fight with the disease. One might think that depression in a cancer patient might stem from the mental stress of having a deadly disease, or from the difficult experience of chemotherapy. But Leah Pyter, a postdoctoral researcher at the University of Chicago’s Institute for Mind and Biology, has performed experiments that suggest the tumor itself, even though it is located in the breast and not the brain, could be producing psychiatric symptoms from a long distance.
Pyter presented those results as part of a symposium on behavioral neuroimmunology, the idea that peripheral disease such as cancer or bacterial infection can influence brain function and thus, behavior. Pyter’s studies used rats dosed with a carcinogen to develop breast tumors and subsequently run through a number of behavioral tests to assess their mood. Presumably, running these tests in animals eliminates the influence of realizing you have a serious disease or going through intensive therapy. And sure enough, Pyter found signs of depression – a reduced willingness to swim, lowered preference for sugar water – and inhibited learning in rats with breast tumors, the first evidence that a tumor in the body could impact brain function.
How does that happen? The immune response to a cancer tumor produces signals called cytokines, which attack the site of the tumor but are also distributed throughout the blood. Reaching the brain, these cytokines may affect brain regions such as the hippocampus, an area associated with learning and memory. Unfortunately, Pyter said, this could throw a patient into a dangerous spiral, with poor mood reducing the effect of treatment, and poor treatment outcome causing further depression, and so on. But research like Pyter’s could also identify sensitive parts of that spiral, where the application of a drug that blocks immune signals from reaching the brain could pull a patient out of the dumps as their body fights off disease.
Inspired by Sadaf Farooqi’s brief talk (I’ll cover her longer lecture tomorrow morning), I went looking for posters on leptin, the reward system and obesity. And I found one with a familiar face presenting: Cristi Frazier, a colleague of mine from my graduate student days who does her research in Xiaoxi Zhuang’s laboratory at the University of Chicago. Frazier’s study looked at the leptin-deficient mouse, an animal model of obesity. As you might expect, these mice are rather roly-poly, and researchers have found that the mice also have abnormal dopamine release and a “reward deficiency,” causing them to east more food to get the same amount of reward.
Frazier put her obese mice and regular mice in a box where they could press a lever for food, and found that both strains happily worked for their supper when it only took 5 or 10 or 15 presses to produce food, but obese mice pressed the lever more and ate more. But when the “cost” of food – how many presses were required to produce a pellet – grew very high (200-250 presses per pellet), obese mice gave up faster, pressing the lever far less than regular mice. Frazier thought this might be related to the dopamine imbalances of the obese mice, and so treated them with L-dopa, the drug used to elevate dopamine in Parkinson’s patients. This treatment, while not affecting regular mice, restored the obese mouse’s motivation to work hard for his food when it required hundreds of lever presses, implicating that changes in dopamine seen in mice (and perhaps people) deficient in leptin could underlie the appetitive changes in obesity.
Two other University of Chicago posters showed the search for mechanisms of drugs that are already in use in the clinic, despite remaining mysteries about how they actually work. That’s more common than you’d think – as long as drugs pass the appropriate clinical trials, doctors try not to worry too much about how the drug produces its beneficial effect. But theories about how such drugs work are often proved wrong, and more information can lead to more effective application of those drugs. Pamela Bergson ran a series of experiments on the blood pressure medication Verapamil, which acts upon channels that allow calcium to enter cells. Researchers have long thought that the drug cannot pass through the small pore of the channel to get inside the cell, but Bergson’s experiments showed that assumption was wrong, and that other, even larger drugs could also get through the channel’s gates. Understanding how that drug accomplishes a feat previously thought impossible could aid in designing drugs specific for one particular type of calcium channel that could create better control of blood pressure.
My friend Bruce Herring also came up with a story about a mysterious drug, and this one is a little better known of late: the anesthetic propofol, which is thought to have contributed to the death of Michael Jackson. Scientists previously thought that propofol may disrupt the receptors of neurotransmitters, sort of the keyhole to the neurotransmitter’s key. But Herring’s experiments, which made up his recently-defended thesis, found that propofol (and two similar anesthetics) effect the release of neurotransmitters, binding to the intricate machinery that pushes those neuronal signals out of the cells and towards nearby neurons. Like Bergson’s work, this new knowledge about already-existing anesthetics could help people design even better drugs that are perhaps more directly effective without causing dangerous side effects.
11:15 AM – The Brain Is What the Brain Eats
I don’t know if it’s a good idea or a bad idea to hear about obesity research right before lunch – listening to this morning’s press conference on the neurobiology of obesity, I started to overly sympathize with the fasting animals sometimes employed in the described experiments. This quick-fire research roundup was meant to drive home the point that obesity, the scourge of public health in developed countries, has it’s origins in the brain, despite the rumblings you feel in your stomach. Though the presentations were brief, they seemed to all agree on one point – obesity is looking more and more like an addiction to food, and what’s worse, it’s an inheritable addiction.
Tracy Bale, from the University of Pennsylvania, presented research that said we should consider blaming our grandparents for our metabolism. When rats were fed a high-fat diet, their offspring tended to be heavier as well when they grew to adulthood, a phenomenon that was first observed long ago. But surprisingly, even the offspring of that offspring exhibited different characteristics, including longer bodies and insensitivity to insulin. Bale suggested that result is evidence that obesity is not just heritable due to genetics, but also epigenetics – changes not in the sequence of DNA, but in the control of DNA. Bale’s colleague at Penn Teresa Reyes studied the offspring of obese mothers and found changes to the reward system chemistry not unlike those seen in abusers of drugs like cocaine and heroin, changes that could drive such children to pursue sweet-tasting, unhealthy foods.
Once again (perhaps today’s unintentional theme), the human data backed up then animal models. Sadaf Farooqi, from the University of Cambridge, did brain imaging studies on people deficient in a hormone called leptin, which is normally secreted by fat cells and tells humans they are full and should stop eating. These leptin-deficient subjects, who are obese, showed elevated responses in the reward systems of their brain to pictures of food, whether it was a cheeseburger or broccoli. Non-obese subjects do not show this activation, and when you give the obese subjects a dose of leptin, their excited reward system settles down. Hence, leptin “regulates how much you like food,” Farooqi said, including her own drool response to the seductive wares of The Cheesecake Factory in Chicago, she laughed.
10:00 AM – The Flexibility of the Growing Brain
If there’s one take-home message from Neuroscience every year, it’s that the brain is a dynamic organ, always changing throughout life. In the microscopically thin sliver of research I’ve been able to present here on the blog, I’ve already described current thinking about how addictive drugs change the brain or how fluctuations in hormones can have dramatic effects upon behavior through their action on neural pathways. Indeed, the brain’s ability to change is what makes it such a remarkable organ, capable of retaining massive amounts of information and controlling complex behaviors in ways that even the most advanced computers remain incapable of doing.
Science has shown repeatedly that the brains of young people are particularly sensitive to change, as they rapidly learn to deal with the environment that surrounds them. Neuroscientists are adding detail to that story by looking at what specific parts of the brain are changed and what genes mediate those changes. But there’s a dark side to neurological changes during early childhood in how stress experienced early in life can cause the brain to develop abnormally; child abuse is often linked with higher incidence of psychiatric disease and criminal behavior in adulthood. That was the focus of this morning’s symposium on early life stress, which featured a group of researchers studying rats, monkeys and humans to find out what switches are erroneously flipped when a brain goes through extreme stress early in life.
The changes across species suggest there is a critical period where stress is especially detrimental to a brain’s development. Regina Sullivan from New York University presented research showing how the stress hormones of baby rats are increased when their mother is taken away, an elevation that makes the young rats more susceptible to fear conditioning and more likely to be anxious or depressed later in life. Judy Cameron found that monkeys separated from their mothers also show anxious behaviors as they age, though the timing is important – when the mother is taken away from a 1-week-old infant, the monkey grows to become anti-social, while monkeys separated from their mothers at three weeks are actually overly social.
And those animal models are relevant to the human experience, as Megan Gunnar from the University of Minnesota explained. Studying children that were adopted from Romanian orphanages into upper middle class Canadian homes, Gunnar found that the children also displayed a critical period. When adopted before the age of 6-8 months, the children were indistinguishable from children born into comfortable situations on measures like IQ and attention. But after that point, when the time in the orphanage was longer than 8 months, the brain’s stress system was found to be overactive in the children, and deficits of intelligence and attention could be measured. Such studies show that the brain may be flexible, and nothing is pre-set, but you’ll be better off if you get through the early years unscathed.