If the current financial climate has taught us anything, it’s that a system where over-borrowing goes unchecked eventually ends in disaster.  It turns out this rule applies as much to our bodies as it does to economics.  Instead of cash, our body deals in energy borrowed from muscle and given to the brain.

Unlike freewheeling financial markets, the lending process in the body is under strict regulation to ensure that more isn’t lent than can be afforded.  New research by scientists at the Salk Institute for Biological Studies reveals just how this process is implemented.

“We have all seen the sub-prime mortgage crisis,” says Marc Montminy, M.D., Ph.D., a professor in the Clayton Foundation Laboratories for Peptide Biology who led the current study.  “If you take out a loan, sooner or later you’ve got to pay your debt, and the same is true in fasting metabolism.”

The Salk researchers’ findings, which are published ahead of print in the Oct. 5 edition of the journal Nature, may pave the way for novel therapies for sufferers of metabolic diseases in whom such regulation can spiral out of control.

Most tissues in our bodies respond to fasting by switching from their usual high-octane energy source—glucose—to burning a low-octane, cheaper alternative-fat.  For our brains, however, only the high-performance fuel will do.  If no food-derived glucose is available, the body must manufacture its own supply to maintain the brain in the manner to which it is accustomed.  It does so by taking energy from muscle in the form of protein and converting it to glucose in the liver, a process known as gluconeogenesis.  The sugar is then shipped via the bloodstream to the brain to keep it running smoothly.

Gluconeogenesis needs to be turned on rapidly in response to fasting, but shutting it off again is just as crucial.  “You don’t want gluconeogenesis to be prolonged,” says postdoctoral researcher and co-first author Yi Liu, Ph.D. “Because it uses muscle as a protein source, it will eventually lead to muscle wastage.”  Adds Montminy, “The question has always been how is the production of glucose turned on, and how is shut off again?”

Previous work by the Montminy lab and others has shown that two key proteins, CRTC2 and FOXO1, are needed to turn on glucose-making genes during fasting.  CRTC2 is activated by glucagon, a hormone whose levels go up when we stop eating.  FOXO1, on the other hand, is activated when levels of the food-stimulated hormone insulin drop below a certain threshold.  CRTC2’s and FOXO1’s activity needs to be tightly regulated, since producing too much glucose would result in over-borrowing of energy from muscle tissue.

To uncover the mechanism that ensures that this doesn’t happen, the Salk researchers created mice containing the gene for luciferase, a light-emitting enzyme usually found in fireflies, engineered in such a way that it was only turned on when CRTC2 was active.  Using imaging equipment, they could then detect CRTC2 activity in the livers of live mice simply by measuring how much they glowed.

When the mice were fasted, CRTC2 was rapidly activated, and the livers lit up, but to the scientists’ surprise, after six hours the light went out.  Experimentally decreasing the levels of CRTC2 or FOXO1 confirmed there was a two-stage fasting-response.  Lowering CRTC2 reduced gluconeogenesis only early on, while less FOXO1 only affected late glucose production.  As in a relay race, during fasting the baton for glucose production appeared to be passed from CRTC2 in stage one to FOXO1 in stage two.

The crucial switch from CRTC2 to FOXO1 comes in the form of SIRT1, a nutrient sensor that accumulates in the late fasting stage.  Yi discovered that SIRT1 has opposite effects on CRTC2 and FOXO1: it sends the former to the recycling bin, while it activates the latter, and thus the baton is safely transferred from CRTC2 to the FOXO1.

Why does the body want to change between these two regulators of glucose production?  Again, it comes down to body economics.  CRTC2 acts as a rapid response unit to quickly produce high levels of glucose when it detects glucagon.  Switching to FOXO1 later on slows down this production to more sustainable levels, while at the same time helping to produce ketone bodies, an alternative fuel the brain can use that does not require taking protein from muscle.  “It is just like paying your loan back,” says Montminy.  “Later on you produce blood sugar at a different rate than you did at the beginning.”

Knowledge of how this nutrient switch is working may help design new drugs to regulate sugar levels in diabetes patients.  In, particular, chemical activators of the SIRT1 switch may be key.  “This way we could provide control for patients with insulin resistance,” says Montminy, “as typically their blood sugars are elevated after overnight fasting because the switches that regulate the glucose-producing enzymes are too active.”  Perhaps, then, a pharmacological rescue package for patients whose lending systems have been left unregulated may be on the horizon.

Images of the brain’s fastest signals reveal an electromagnetic marker that predicts a patient’s response to a fast-acting antidepressant, researchers have discovered.

“Such biomarkers that identify who will benefit from a new class of antidepressants could someday minimize trial-and-error prescribing and speed delivery of care for what can be a life-threatening illness,” said Carlos Zarate, M.D., of the National Institute of Mental Health (NIMH), Mood and Anxiety Disorders Program.

In the new study at the National Institutes of Health in Bethesda, MD, depressed patients showed increasing activity in a mood-regulating hub near the front of the brain while viewing flashing frightful faces – the more the increase, the better their response to an experimental fast-acting medication called ketamine.  By contrast, healthy controls showed decreasing activity in this brain area under the same conditions.

Zarate, Giacomo Salvadore, M.D., Brian Cornwell, Ph.D., and NIMH colleagues report on their discovery online in Biological Psychiatry September 24, 2008.

Two years ago, Zarate and colleagues reported that ketamine, which targets the brain chemical glutamate, can lift depressions in just hours, instead of the weeks it takes conventional antidepressants, which work through the brain chemical serotonin.  Evidence suggests that glutamate likely acts closer to the source of the depression than serotonin, and is not dependant on slower mechanisms, such as the synthesis of new neurons.

Earlier imaging studies with conventional antidepressants had hinted that increased activity of the mood-regulating hub, called the anterior cingulate cortex (ACC), signals a better response.

To find out if ACC activity might also forecast response to glutamate-targeting medications, the NIMH researchers imaged the brain activity of 11 depressed patients and 11 healthy participants, using magnetoencephalography (MEG).  This imaging technology can non-invasively detect brain electromagnetic activity lasting only milliseconds – the speed of communications in neural circuits – whereas other functional brain imaging techniques can only capture activity that last seconds or minutes, and some involve radiation exposure.

This precise timing enabled the MEG scanner to capture the brain’s split-second responses to rapidly flashing pictures of fearful faces, a task known to activate the ACC.  While healthy participants’ ACC activity dropped off as they quickly habituated to the faces, patients’ ACC activity showed an opposite trend.  The more robust this increase, the more symptoms improved just four hours after a patient received a single infusion of ketamine.

“The ACC may be slow to respond, but not completely impaired, in patients who respond to ketamine,” explained Cornwell.

The lag in ACC activity could be a window into the dysfunctional workings of the glutamate-related circuitry targeted by the medication, the researchers suggest.  Ketamine’s side effects make it a poor candidate for becoming a practical antidepressant, but the new findings are helping to focus the search for new treatments that work through the same mechanism, they say.

The melodious singing of birds has been long appreciated by humans, and has often been thought to reflect a particularly positive emotional state of the singer.  In a new study published in the online, open-access journal PloS ONE on October 1, researchers at the RIKEN Brain Science Institute in Japan have demonstrated that this can be true.  When male birds sang to attract females, specific “reward” areas of their brain were strongly activated.  Such strong brain activation resulted in a similar change in brain reward function to that which is caused by addictive drugs.

The brain of humans and other animals is programmed to have a positive emotional response to rewarding stimuli, such as food or sex.  A critical part of this reward signal is thought to be provided by increased activity of neurons containing dopamine in the brain ventral tegmental area, VTA.  Along with natural rewards, the same brain circuits can also be strongly activated by artificial rewards such as addictive drugs.  Previous studies in mammals have found that after animals are given drugs such as cocaine or amphetamine, the strength of synaptic connections onto dopamine neurons in VTA is strongly increased, or potentiated.  Such potentiation has been suggested to be an important long-lasting adaptation of brain function caused by drug use, and involved in maintenance of addictive behavior.

Whether such potentiation can also be caused by more natural rewards has been less studied.  Social interactions with others are critical for normal healthy life, and therefore should be rewarding for humans and also for other animals.  In the new study in PloS ONE, Ya-Chun Huang and Neal Hessler of the Vocal Behavior Mechanisms Lab examined one specific social behavior, courtship singing of songbirds.  In the zebra finch, an Australian songbird, males sing in two different situations.  Most importantly, males sing “directed song” during courtship of females.  When males are alone, they produce “undirected song”, possibly for practice or to communicate with birds they can’t see.  A previous study by this research group showed that only when males sang to attract a female, but not when they sang while alone, many unidentified neurons in the VTA were strongly activated.

Huang and Hessler now show, in the current study, that such a natural social interaction, singing to a female, can cause the same kind of synaptic potentiation of VTA dopamine neurons as use of addictive drugs, while singing solo did not affect these neurons.  Further study of this system should give insight into how both natural and artificial rewards interact with each other, and specifically how damage to brain reward systems during addiction can disrupt processing of natural rewards such as social interaction.

This study also provides the clearest evidence so far that singing to a female is rewarding for male birds.  This may not be surprising, as such courtship is a necessary step in producing offspring, and so should be a positive experience.  Other studies have provided some evidence that in mammals, including humans, sexual behavior and attachment (as well as rewarding aspects of video games and chocolate) also depend on the same brain reward areas and dopamine.  So, despite the distant evolutionary relationship between birds and humans, it may be that during such intense social interactions as courtship, both share some similar emotional state.

Reported in the Oct. 3, 2008 issue of Cell, the findings–from a study in mice–point to a completely new approach to treating and preventing obesity in humans.  The discovery also offers hope for new ways to treat related disorders, such as type 2 diabetes and cardiovascular diseases–the most prevalent health problems in the United States and the rest of the developed world.

Led by Dongsheng Cai, an assistant professor of physiology at the UW School of Medicine and Public Health, the researchers looked specifically at the hypothalamus–the brain structure responsible for maintaining a steady state in the body–and for the first time found that a cell-signaling pathway primarily associated with inflammation also influences the regulation of food intake.  Stimulating the pathway led the animals to increase their energy consumption, while suppressing it helped them maintain normal food intake and body weight.

The research stems from recent explorations into the problem called metabolic inflammation, a by-product of too much food or energy consumption.  Unlike the classical inflammation typically observed in infections, injuries and diseases such as cancer, the metabolic inflammation seen in obesity-related diseases is much milder, doesn’t lead to overt symptoms or cause tissues damage.

“Metabolic inflammation is a chronic, low-grade condition consisting of inflammatory-like responses at the molecular level.  It has many downstream consequences,” says Cai.  “It causes cellular dysfunction, which can decrease the regulation of several physiological processes, including metabolism.”

Scientists believe that metabolic inflammation may be at the core of many chronic, obesity-related metabolic disorders that are so common today, he adds.

Cai and his team zeroed in on NF-kappaB, a protein complex that can be activated specifically by IKKbeta to induce inflammatory reactions in many cell systems.

In earlier studies at Harvard, Cai and colleagues found that the pathway interrupted sugar, fat or protein metabolism in tissues where metabolism typically takes place–liver, fat and skeletal muscle.  Feeding mice high-sugar and high-fat diets activated the pathway in these tissues.

Once he arrived at the SMPH three years ago, Cai began to consider whether metabolic inflammation might affect “higher-up” players in the central nervous system, particularly the hypothalamus.  This brain structure is a critical master regulator of appetite and energy balance, and also controls metabolism in the peripheral tissues he had studied before.  But nobody knew how the hypothalamus might contribute to the development of metabolic diseases such as obesity and diabetes.

“We wanted to learn whether the pathway or pathways underlying metabolic inflamm ation could affect metabolism regulators in the central nervous system,” he says.

In the current study, Cai and his team found first that IKKbeta/NF-kappaB does indeed exist in specific neurons in the hypothalamus.  The pathway is much more abundant in the hypothalamus than in peripheral tissue, and it normally remains inactive in the brain.

The researchers next showed that over-nutrition through high-fat diet feeding activates IKKbeta/NF-kappaB, specifically in neurons in the hypothalamus.

“When we knocked out the IKKbeta gene to suppress NF-kappaB activity in these neurons, the animals were significantly protected from energy over-consumption and obesity development,” Cai says.

The researchers also examined a cell component called the endoplasmic reticulum (ER), shown recently to be involved in metabolic diseases involving over-nutrition, to see if it might play a role in linking over-nutrition to activate IKKbeta/NF-kappaB in the hypothalamus.

“At the intracellular level, when the ER is challenged with over-nutrition, this leads to ER stress, which can push the IKKbeta/NF-kappaB pathway to an active state, although the involved reactions could be quite complicated,” Cai says.

In several experiments, the researchers found that ER stress caused by over-nutrition activated IKKbeta/NF-kappaB in the hypothalamus.  Suppressing ER stress in the central nervous system significantly preserved normal regulation of food intake and prevented obesity.

Cai says there’s still a lot of work to be done.  His group has begun studying IKKbeta/NF-kappaB’s connections to other pathways and regulations in the hypothalamus.

“The ultimate goal will certainly be to identify a selective and effective suppressor of the pathway to target related neurons,” he says.

But Cai continues to look at the big picture, seeking answers to questions such as: “How does the environment connect to the genetics that seem to underlie the obesity epidemic?  What are the key steps that have led to the dramatic rise of diabetes in the past three decades?  And Why can’t the body adjust to changes that have occurred in the way people eat and what they eat?”

An overload of calories throws critical portions of the brain out of whack, reveals a study in the October 3rd issue of the journal Cell, a Cell Press publication.  That response in the brain’s hypothalamus—the “headquarters” for maintaining energy balance—can happen even in the absence of any weight gain, according to the new studies in mice.

The brain response involves a molecular player, called IKKß/NF-?B, which is known to drive metabolic inflammation in other body tissues.  The discovery suggests that treatments designed to block this pathway in the brain might fight the ever-increasing spread of obesity and related diseases, including diabetes and heart disease.

“This pathway is usually present but inactive in the brain,” said Dongsheng Cai of the University of Wisconsin-Madison.  Cai said he isn’t sure exactly why IKKß/NF-?B is there and ready to spring into action in the brain.  He speculates it may have been an important element for innate immunity, the body’s first line of defense against pathogenic invaders, at some time in the distant past.

” In today’s society, this pathway is mobilized by a different environmental challenge—overnutrition,” he said.  Once activated, “the pathway leads to a number of dysfunctions, including resistance to insulin and leptin,” both important metabolic hormones.

Earlier studies showed that overnutrition can spark inflammatory responses in the peripheral metabolic tissues, including the muscles and liver, and therefore cause various metabolic defects in those tissues that underlie type 2 diabetes.  As a result, scientists identified IKKß as a target for an anti-inflammatory therapy that was effective against obesity-associated diabetes.

Yet whether metabolic inflammation and its mediators played a role in the central nervous system remained uncertain.  Now, the researchers show that a chronic high-fat diet doubles the activity of this inflammatory pathway in the brains of mice.  Its activity is also much higher in the brains of mice who are genetically predisposed to obesity, they found.

The researchers report that that increased activity of the IKKß/NF-?B pathway can be divorced from obesity itself -infusions of either glucose or fat into the brains of mice alone led to this inflammatory brain reaction.

Further studies revealed that this activity in the brain leads to insulin and leptin resistance.  Insulin lowers blood sugar by causing cells of the body to take it up from the bloodstream.  Leptin is a fat hormone important for appetite control.

Moreover, the researchers found that treatments preventing the activity of IKKß/NF-?B in the animals’ brains protected them from obesity.

While chronic inflammation is generally considered a consequence of obesity, the new results suggest the inflammatory reaction might also be a cause of the imbalance that leads to obesity and associated diseases, including diabetes.  As Cai says, it appears that inflammation and obesity are “quite intertwined.”  An abundance of calories itself promotes inflammation, while obesity also feeds back to the neurons to further promote inflammation in a kind of vicious cycle.

The findings could lead to treatments that might stop this cycle before it gets started.

“Our work marks an initial attempt to study whether inhibiting an innate immune pathway in the hypothalamus could help to calibrate the set point of nutritional balance and therefore aid in counteracting energy imbalance and diseases induced by overnutrition,” the researchers said.  “We recognize that the significance of this strategy has yet to be realized in clinical practice; currently, most anti-inflammatory therapies have limited direct effects on IKKß/NF-?B and limited capacity to be concentrated in the central nervous system.  Nonetheless, our discoveries offer potential for treating these serious diseases.”

If realized, such a strategy would likely offer a safe approach given that the critical pathway appears to be unnecessary in the hypothalamus under normal circumstances, they noted.

A new study finds that following minor spinal cord injury, rats that had to use impaired limbs showed full recovery due to increased growth of healthy nerve fibers and the formation of new nerve cell connections. Published in the September 17 issue of The Journal of Neuroscience, these findings help explain how physical therapy advances recovery, and support the use of rehabilitation therapies that specifically target impaired limbs in people with brain and spinal cord injuries.

“After brain and spinal cord injuries, exercise-based physical therapy is the primary rehabilitative strategy in use today,” said Stephen Strittmatter, MD, PhD, at Yale University School of Medicine, an expert unaffiliated with the study. “These therapies are so beneficial to patients, but the anatomical and molecular bases of improvement have not been clear,” Strittmatter said.

The researchers, led by Irin Maier and senior researcher Martin Schwab, PhD at the University of Zurich and the Swiss Federal Institute of Technology, tested rats with minor surgical injuries to the spinal cord that impaired the use of one forelimb. Slings were placed on the rats that restricted the use of either the injured or uninjured limb. After three weeks, researchers removed the slings and tested the rats on an elevated horizontal ladder.

Rats that relied on their impaired limb because use of their unimpaired limb was restricted showed complete functional recovery: they negotiated the ladder as well as rats that had not been injured. In contrast, rats that had not worn slings and those that wore slings restricting the use of the injured limb performed poorly, showing difficulty grasping and negotiating the horizontal rungs of the ladder.

In all of the rats, healthy nerve fibers, or axons, grew into injured regions of the spinal cord. However, rats that relied on their injured limb showed the most extensive nerve growth. “The study shows that when the axons that remain after a spinal cord injury are more active — because the animal is forced to use them — they grow more. This seems to help the animal recover more control of their movements,” said John Martin, PhD, at Columbia University, an expert unaffiliated with the study.

These nerve fibers formed more connections, or synapses, in rats relying on their injured limb compared with those relying on their uninjured limb. This finding suggests that forced limb use encourages healthy nerve cells to form new synapses with cells affected by spinal cord injury, perhaps rerouting and rewiring damaged spinal cord circuits that are important for movement.

Using gene chip technology, the researchers found that forced limb use turned on or turned off genes known to be involved in nerve fiber growth and synapse formation in the spinal cord. Knowing which genes are involved in recovery from spinal cord injury may help researchers develop new drug treatments.

“This study shows that a behavioral approach is remarkably effective in promoting both axon growth and recovery after injury,” said Martin. “We know that physical therapy is effective after brain and spinal injuries. But these new results suggest that a more aggressive therapy, in which the unimpaired limb is prevented from use and the impaired limb is forced to be used, might lead to new neural connections,” he said.

A new study suggests that although humans may have developed complex thought processes that can help to regulate their emotions, these processes are linked with evolutionarily older mechanisms that are common across species.  The research, published by Cell Press in the September 11th issue of the journal Neuron, provides new insight into way the brain manages fear and may guide exploration of novel pharmacological and therapeutic treatments for anxiety disorders.

“The ability to eliminate, control or diminish negative emotional responses is important for adaptive function and critical in the treatment of psychopathology,” says study author, Dr. Mauricio Delgado from Rutgers University.  “Recent research examining the neural mechanisms for diminishing fears has focused on two techniques: extinction, which has been explored across species, and cognitive emotion regulation strategies, which are unique to humans.”  Previous work in rodents and humans has implicated activity in the amygdala and ventral medial prefrontal cortex (vmPFC) in extinction.  In contrast, neural circuits underlying cognitive strategies to regulate emotions are not as well understood.

Dr. Delgado, Dr. Elizabeth A. Phelps from New York University, and their colleagues were interested in examining the similarities and differences of diminishing fear through both techniques.  They used similar experimental paradigms with different means of controlling fear to directly compare the neural mechanisms that mediate extinction and emotional regulation.  A typical fear conditioning method was paired with a measurement of physiological arousal to examine extinction, while a cognitive emotion regulation strategy was also implemented.  Functional magnetic resonance imaging (fMRI) was used to compare the neural activation patterns of extinction and emotional regulation.

The researchers observed that the lateral prefrontal cortex regions engaged by cognitive emotion regulation strategies influenced the amygdala and diminished fear through similar vmPFC connections that are thought to inhibit the amygdala during extinction.  Taken together, the findings indicate that there is overlap in the neural circuitry of diminishing learned fears through emotion regulation and extinction and that vmPFC may play a general regulatory role in diminishing fear across a range of paradigms.

“Our results suggest that even though humans may have developed unique capabilities for using complex cognitive strategies to control emotion, these strategies may influence the amygdala through phylogenetically shared mechanisms of extinction,” explains Dr. Phelps.  “Extinction and cognitive emotion regulation may be, in part, complementary in that they rely on a common neural circuitry and, perhaps, similar neurophysiological and neurochemical mechanisms.”

A typical symptom of Parkinson’s disease is tremor in patients. A group of scientists, including Professor Peter Tass from Forschungszentrum Jülich have succeeded in demonstrating the mechanisms which cause the so-called tremor: neuron clusters in the depths of the brain drive the tremor. This discovery supports Tass’ research activities aiming at developing a therapy for Parkinson’s disease. A new deep brain pacemaker is to bring cells out of the diseased mode for good.

Today’s article in the high-impact journal “Europhysics Letters” shows that the scientists from Forschungszentrum Jülich, a member of the Helmholtz Association, are on the right track. Their new deep brain pacemaker is to help Parkinson’s patients on a large scale for the first time in 2009. Communication between the networks of neurons is disturbed in people suffering from Parkinson’s disease. These “fire” their stimuli at the same time thus causing the typical tremor. The frequency measured here is 5 hertz (Hz), i.e. five oscillations per second. In Germany, there are officially around 150,000 Parkinson’s patients, although it is estimated that up to 450,000 people are affected.

To date, scientists have assumed that the 5-Hz rhythm deep in the brain resulted from nerve signals, which are transmitted from muscles in the limbs back to the brain. The scientific term for this response is “proprioceptive feedback”. The prevailing opinion of many scientists to date, however, is that the “cross fire” is not emitted by the brain. The reason for this assumption was that the measured frequency of the “proprioceptive feedback” and the frequency in a specific core region of the brain, in the thalamus and the basal ganglia, were not completely synchronous.

With a combination of several state-of-the-art analytical processes, the team has now succeeded in demonstrating that it is not only nerve signals from the muscles as feedback that drive the diseased 5-Hz rhythm in the brain. Headed by Prof. Volker Sturm, neurosurgeons in Cologne implanted electrodes in patients for the measurements, and scientists in Saratov, Russia, recalculated the obtained data together with scientists from Jülich. “Signals in the frequency domain of 5 Hz from the core region of the brain also drive the tremor”, explained Peter Tass. “The difference: the feedback from the limbs is a fast and easy stimulus transmission. The signals from the thalamus and the basal ganglia are, however, transmitted to certain loop-like neuron pathways of the brain and spinal cord. Therefore, the dynamics are more complicated and the pathway is longer.”

The Jülich medical scientist, mathematician and physicist believes that these new findings reinforce the theoretical basis of “his” deep brain pacemaker. This device influences the disturbed neurons in the core region of the brain and effectively removes their compulsion to “fire” at the same time. Tass’ new development disturbs this compulsory diseased mode by using very mild, targeted and desynchronized stimuli in different places. In this way, the rhythm becomes irregular and breaks down. Compared to conventional devices of this type, the Jülich deep brain pacemaker puts less strain on the patient and needs less energy. Moreover, the nerve tissue is stimulated in such a way that the neurons abandon their diseased strong synaptic networks and thus forget their compulsion to develop diseased rhythms.

The pacemaker consists of two electrodes that are carefully located at the dysregulated parts of the brain. The so-called stimulator provides the electrodes with energy and signals to stimulate the neurons in the brain. This device is implanted below the collarbone under the skin and thin wires also connect it with the electrodes under the skin.

Research involving large Middle Eastern families, sophisticated genetic analysis and groundbreaking neuroscience has implicated a half-dozen new genes in autism.  More importantly, it strongly supports the emerging idea that autism stems from disruptions in the brain’s ability to form new connections in response to experience – consistent with autism’s onset during the first year of life, when many of these connections are normally made.

Interestingly, not all the affected genes were actually deleted, but only prevented from turning on – offering hope that therapies could be developed to reactivate the genes.  The study, led by researchers at Children’s Hospital Boston and members of the Boston-based Autism Consortium, is the cover article in the July 11 issue of Science.

Autism genes have been difficult to identify because the disorder is complex, with a variety of causes stemming from many possible genes or combinations of genes.  In addition, since people with autism tend not to have children, most of the genes identified thus far aren’t inherited from a parent, but instead are mutated during embryonic development, making them hard to track through traditional linkage studies in families.

Christopher Walsh, MD, PhD, chief of genetics at Children’s Hospital Boston, approached the problem by studying Middle Eastern families.  In traditional Arab societies, it is common for cousins to marry, increasing the likelihood that offspring will inherit rare mutations.  Middle Eastern families also tend to have many children, making them ideal for mapping genes.

“To map a gene for autism in American families, averaging two to three kids per family, you would need to pool many families,” says Walsh, who is also a Howard Hughes Medical Institute investigator at Beth Israel Deaconess Medical Center (BIDMC).  “In larger families, one family alone may be enough to definitively localize a gene.”

The Homozygosity Mapping Collaborative for Autism (HMCA) recruited 104 families with a high incidence of autism from the Arabic Middle East, Turkey and Pakistan; 88 of these families have cousin marriages.  Local clinicians were rigorously trained in administering standardized autism research assessments.  Walsh’s team later flew to sites in Turkey, Dubai, Kuwait and Saudi Arabia to confirm the diagnoses.

Using a technique called homozygosity mapping Walsh and colleagues compared the DNA of family members with and without autism, searching for recessive mutations—those that cause disease only when a child inherits two copies.

“We check each set of chromosomes from beginning to end, looking for one place where the child has two identical pieces of DNA on both chromosomes,” Walsh explains.  “Eventually we find a spot where all affected children have two identical chunks of DNA, and where unaffected children have something different.”

Just over 6 percent of the 88 families showed rare, inherited deletions within DNA regions linked to autism.  These affected DNA regions varied among families, further indication of autism’s large variety of genetic causes.  In all, the technique identified five chromosome deletions affecting at least six identifiable genes (C3orf58, NHE9, PCDH10, contactin-3 [CNTN3], RNF8, and genes encoding a cluster of cellular sodium channels).

One of the genes, NHE9, was also found to be mutated in European and American children with autism (particularly those with both autism and seizures).

Experience-dependent learning: A common thread

The genes discovered are diverse in function, but all seem to be part of a fundamental molecular network that orchestrates the refinement and maturation of brain connections, or synapses, in response to input from the outside world.  It is the refinement of these synaptic connections that is the basis of learning and memory, suggesting that autism at its heart may represent molecular defects of learning.

“This network can be disrupted in a myriad of ways, and may be one mechanism that people with a variety of autism-linked mutations share,” says Michael Greenberg, PhD, a coauthor on the paper and director of the Neurobiology Program at Children’s Hospital Boston.

Normally, as a neuron (brain cell) receives an incoming message at the synapse, a network of reactions is sparked that extends all the way to its nucleus.  Greenberg and his colleagues had long been mapping this network, and had previously found that it activates at least 300 genes.  These genes then communicate back to the neuron’s surface, telling the cell to make a new synapse, strengthen the synapse that’s already there, eliminate a synapse, or make a different kind of synapse.  This give-and-take system is how the brain builds its circuitry; neuroscientists call it “experience-dependent learning.”

Working independently of Walsh, Greenberg and his colleagues had already identified three of the same genes found in the Middle Eastern patients (c3orf58, NHE9, and PCDH10) while looking for genes that turn on or off in neurons as part of this network – either in response to synaptic activity or through so-called transcription factors that are activated by synaptic activity.

The work bolsters a growing body of evidence that autism may represent a disruption of the brain’s ability to modify its synaptic connections in response to experience.

“Taken together, our findings suggest that experience-dependent learning could be relevant to autism, and that autism might result from the deregulation of any one of a number of genes that are part of the same signaling pathway,” Greenberg says.

Can normal function be revived?

Interestingly, only one chromosome deletion found in the Middle Eastern families actually removed a gene – in most cases, what was lost was a region adjacent to the gene that contains its “on/off” switches.  This has important implications for therapy, because it suggests that autism mutations don’t always remove a gene altogether, but only inhibit its activity in certain contexts, says Eric Morrow, MD, PhD, of Massachusetts General Hospital, who is co-first author of the paper with Seung-Yun Yoo, PhD.  “This means that we would not need to replace the gene, if we could only figure out how to reactivate it, perhaps with medications,” says Morrow, who also holds appointments at BIDMC and Children’s.

The findings also support the use of behavioral therapies in autism, which expose children to a rich environment and highly repetitive activities that may help turn on the genes and strengthen synaptic connections, Morrow adds.

“This publication a big event in the world of autism research,” says Clarence Schutt, PhD, Scientific Advisor to the Nancy Lurie Marks Family Foundation, which funded work by both the Walsh and Greenberg labs.  “To have discovered a connection between autism and activity-related gene expression at the synapse will put this field at the center of neuroscience.”

One of the characteristics of type 2 diabetes is insulin resistance, which refers to the inability of cells in the body to respond appropriately to the hormone insulin.  Among the cells in the body that normally respond to insulin are nerves in a region of the brain known as the hypothalamus.  New data, generated in rats, by Hiraku Ono and colleagues, at Albert Einstein College of Medicine, New York, has provided insight into a molecular pathway in the hypothalamus that contributes to the development of insulin resistance.

Insulin plays a key role in controlling the amount of glucose in the body through its ability to make cells, such as liver and fat cells, take up glucose from the blood and store it for future use.  Insulin also prevents liver cells from releasing stored glucose, partly through its effects in the hypothalamus.  In the study, if rats were fed a high-fat diet for a short period of time the ability of insulin to prevent liver cells releasing stored glucose was reduced.  This was associated with both a decrease in insulin-induced signaling and an increase in activation of a protein known as SK6 in the hypothalamus.  The importance of SK6 activation in the hypothalamus in suppressing the ability of insulin to prevent glucose release from liver cells was confirmed by two sets of experiments.  First, it was shown that enforced SK6 activation in the hypothalamus had the same effects as feeding rats a high-fat diet; second, blocking the effects of SK6 activation restored the ability of insulin to prevent glucose release from liver cells, even when rats were fed a high-fat diet.  These data lead the authors to speculate that the earliest stages of diet-induced insulin resistance might be prevented by inhibition of S6K in the hypothalamus.

Neuroscientists at Georgetown University Medical Center have solved a mystery that lies at the heart of human learning, and they say the solution may help explain some forms of mental retardation as well as provide clues to overall brain functioning.

Researchers have long puzzled over why a gene known as brain-derived neurotrophic factor (BDNF), which is crucial to the ability of neurons in the hippocampus to grow and connect to each other – forming the basis of memory and learning – produces two different transcripts, which then each fabricate identical proteins.

In the July 11 issue of Cell, the scientists report the answer, and it has to do with transportation.  They found that the longer of the two transcripts (messenger RNAs, or mRNAs) include extra sequences that “motor” molecules attach to, in order to move the information far away from the nucleus of the cell and toward the long, tree-like branches of the nerve cell known as dendrites.  There, protein-synthesizing machines use that mRNA to produce protein that helps small protrusions (called dendritic spines) on these dendrites grow.

The shorter of the mRNAs are also moved from the nucleus into the cytoplasm of the neuron, but they do not need to be transported to dendrites.  These transcripts produce an identical protein, but in this case, investigators believe they help the axon, the long cable-like body of a neuron, grow.

Learning occurs when both axons and dendritic spines grow and touch each other, forming connections, and existing connections are strengthened.  The scientists’ findings provide a critical understanding of how dendritic spines grow and mature, but this understanding may be more broadly applied.

That’s because as exciting as the findings are for understanding the function – and dysfunction of BDNF as it relates to human learning, they also are relevant for other genes and proteins, says the study’s lead investigator, Baoji Xu, Ph.D., an assistant professor in the Department of Pharmacology at Georgetown.

“The fascinating thing is that many genes produce multiple transcripts for the same protein – and no one has known why,” he says.  “So what we found here is likely very applicable to other genes.  It reveals a mechanism for differential regulation of subcellular functions of proteins.”

In this study, Xu and his research team, which included investigators from the National Institute of Child Health and Human Development (NICHHD), Emory University, and the University of Colorado, looked at why a neuron needs two “species” of BDNF mRNAs.

The gene produces a growth factor that makes neurons grow, and is vital to initial development of the brain; mice born without BDNF have developmental deficits and soon die.  BDNF is also secreted by neurons in adult brains when needed, and that is usually when synaptic junctions between neurons require strengthening, a condition known as “synaptic plasticity” that underlies memory and learning.  “If BDNF is deleted in an adult animal’s brain, the animal will struggle to learn new tasks,” Xu says.

Scientists had found that protein translation occurs in dendrites, and they believed that this protein production was important for synaptic plasticity, “but it has been difficult to study local protein synthesis only in dendrites,” Xu says.  “When you change protein synthesis in dendrites, you also affect protein production in other parts of the neuron.”

To solve that problem, Xu and the scientists managed to create mouse mutants in which the long BDNF mRNA variant is converted to the shorter mRNA form.  They found that in these mice, dendritic spines form normally, but do not mature properly and aren’t “pruned” as they need to be.  “This process is important for the normal function of the brain.  Without it, the mice can’t refine neuronal connections in response to learning,” he says.

Some people diagnosed with mental retardation suffer from the same problem, Xu adds.  “At a certain stage of development, maturation of dendritic spines is frozen.  For example, in Fragile X Syndrome, there are too many immature dendritic spines.

“What we see in our mutant mouse and in Fragile X is similar,” he says.  “If we could find a way to increase BDNF synthesis in dendrites, it may be helpful to people with mental retardation.

“That, of course, is just a theory, but now that we understand the function of these two different mRNAs, we can begin to explore what issues their dysfunction causes in humans,” Xu says.

Individuals who are obese are at increased risk of many diseases, including type 2 diabetes and heart disease.  As 75%-95% of previously obese individuals regain their lost weight, many researchers are interested in developing treatments to help individuals maintain their weight loss.  A new study, by Michael Rosenbaum and colleagues, at Columbia University Medical Center, New York, has provided new insight into the critical interaction between the hormone leptin and the brain’s response to weight loss.

Leptin levels fall as obese individuals lose weight.  So, the authors set out to see whether changes in leptin levels altered activity in the regions of the brain known to have a role in regulating food intake.  They observed that activity in these regions of the brain in response to visual food-related cues changed after an obese individual successfully lost weight.  However, these changes in brain activity were not observed if the obese individual who had successfully lost weight was treated with leptin.  These data are consistent with the idea that the decrease in leptin levels that occurs when an individual loses weight serves to protect the body against the loss of body fat.  Further, both the authors and, in an accompanying commentary, Rexford Ahima, at the University of Pennsylvania School of Medicine, Philadelphia, suggest that leptin therapy after weight loss might improve weight maintenance by overriding this fat-loss defense.

Researchers have determined that there are hundreds of biological differences between the sexes when it comes to gene expression in the cerebral cortex of humans and other primates.  These findings, published June 20th in the open-access journal PloS Genetics, indicate that some of these differences arose a very long time ago and have been preserved through evolution.  These conserved differences constitute a signature of sex differences in the brain.

Many more obvious gender differences have been preserved throughout primate evolution; examples include average body size and weight, and genitalia design.  This study, believed to be the first of its kind, focuses on gene expression within the cerebral cortex.  The cerebral cortex is involved in many of the more complex functions in both humans and other primates, including memory, attentiveness, thought processes and language.

The researchers measured gene expression in the brains of male and female primates from three species: humans, macaques, and marmosets.  To measure activity of specific genes, the products of genes (RNA) obtained from the brain of each animal were hybridized to microarrays containing thousands of DNA clones coding for thousands of genes.  The authors also investigated DNA sequence differences among primates for genes showing different levels of expression between the sexes.

“Knowledge about gender differences is important for many reasons.  For example, this information may be used in the future to calculate medical dosages, as well as for other treatments of diseases or damage to the brain,” says team leader Professor Elena Jazin, at Uppsala University, Sweden.

In addition to the results mentioned above, the researchers also report on evolutionary speeds in genes that have been identified as male or female-oriented.  This could provide clues about the power of natural selection processes during the evolution of primates.

Lead author Björn Reinius notes that the study does not determine whether these differences in gene expression are in any way functionally significant.  Such questions remain to be answered by future studies.

Soon after an individual becomes infected with HIV the virus infects cells in the brain and spinal cord (the central nervous system [CNS]).  Although this causes no immediate problems, during the late-stages of disease it can cause dementia and encephalitis (acute inflammation of the brain that can cause death).  Monkeys infected with a relative of HIV (SIV) also sometimes develop CNS damage and provide a good model of CNS disease in individuals infected with HIV.  Insight into the mechanisms of CNS damage in SIV-infected monkeys has now been provided by a team of researchers at The Scripps Research Institute, La Jolla, who developed an approach to identify molecular changes in the fluid bathing the CNS (the CSF).  The researchers, who were led by Howard Fox and Gary Siuzdak, hope that similar approaches could be used to provide new information about other neurodegenerative and neuropsychiatric disorders.

In the study, an approach known as global metabolomics was used to assess the levels of molecules known as metabolites in the CSF before and after SIV-induced encephalitis was manifest.  The level of a number of metabolites, including some known as fatty acids and phospholipids, was observed to increase during infection.  Consistent with this, a protein known to be important in the generation of fatty acids was found to be increased in the brain of monkeys with SIV-induced encephalitis.  Further studies will be required to determine the precise role of the increased level of each metabolite, but it should be noted that many of them are known to induce receptor signaling and thereby might be able to further modulate CNS function.

A study by Indiana University researchers found a strong connection between the cognitive function of their elderly study participants and their postural stability — or balance. The study, which is in line with recent findings by other researchers involving the brain and balance, also found a brief questionnaire designed to probe cognitive function effective at identifying people with poorer balance. Falls are one of the most common causes of injury and death among the elderly. Motor control experts at Indiana University’s School of Health, Physical Education and Recreation are searching for a way to alert the elderly to when they become more at risk for falls before the falls occur — ideally developing a screening technique that can be conducted by physicians or other health care providers. Koichi Kitano, a doctoral student in the School of HPER’s Department of Kinesiology and lead author of the study, said the questionnaire used for their study could be conducted and scored by physicians and possibly other health care professionals. Patients could complete the questionnaire in around 15 minutes. “It’s an accessible, easy tool to identify people with risk,” he said. Kitano said IU researchers want to continue their research with larger numbers of people and more diverse populations — the current study involved 28 residents ranging in age from 80 to 90. Researchers at the School of HPER are also looking into stretches and exercises that could help the elderly improve their balance. Kitano said, however, that cognitive exercises might be even more effective.