A new animal model has provided insight into the cellular and molecular mechanisms associated with behavioral therapy for depression.  The study, published by Cell Press in the October 9th issue of Neuron, may provide a good model system for testing cellular and molecular interactions between antidepressive medications and behavioral treatments for depression.

Organisms ranging from simple invertebrates to mammals have evolved mechanisms for instinctive and learned fear that are critical for survival.  However, in humans, pathological forms of learned fear can contribute to anxiety disorders, posttraumatic stress, and depression.  “The fact that learned fear can be associated with psychopathologies in humans suggests that this form of learning is not always appropriate and that effective inhibitory constraints are likely to exist,” explains Eric Kandel from Columbia University.

Previous research investigating how learned fear is processed in the brain has made use of a conditioned inhibition learning paradigm wherein an animal is conditioned to associate a target signal with protection from an impending aversive event, resulting in a reduction of conditioned fear.  This process, where an animal learns to take advantage of sources of security in the environment, is thought to represent a form of “learned safety.”

Daniela Pollak in the Kandel lab was interested in attempting to characterize some of the behavioral consequences of learned safety as well as exploring the phenomenon at the molecular level.  She observed that learned safety reduced depression-like behavior in mice in a manner that was comparable to that seen with pharmacological antidepressants.  Consistent with the behavioral antidepressant effects, learned safety also shared neurobiological hallmarks associated with other antidepressant therapies.  Specifically, learned safety promotes the survival of newborn nerve cells and expression of critical growth factors in the hippocampus.

The researchers went on to search for differentially regulated genes in the amygdala of safetyand fear-conditioned mice.  The amygdala is a brain region associated with emotional symptoms that are a hallmark of depression.  Learned safety led to decreased expression of genes involved in dopamine and substance P signaling, but not serotonin signaling.  This is significant because serotonin receptors are a major target of popular antidepressant medications.

“We propose a model in which the stress-reducing and antidepressant effects of learned safety are mediated through the interaction of (at least) two different neurotransmitter systems.  Our findings suggest that learned safety is an animal model of a behavioral antidepressant that shares some of the neuronal modifications typical of pharmacological antidepressant, but is mediated by different molecular pathways,” offers Kandel.

New research findings suggest that structural abnormalities in the brains of cocaine addicts are related in part to drug use and in part to a predisposition toward addiction.  The research, published by Cell Press in the October 9th issue of the journal Neuron, maps the topography of the addicted brain and provides new insight into the effect of cocaine on neural systems mediating cognition and motivation.

“Human studies have shown differences in how addicts make judgments and decisions, but it is not well understood how these differences relate to alterations in the structure of the brains of addicts.  Claims have been made that cocaine, potentially in connection with alcohol or other drugs, may be toxic to brain cells.  We sought evidence supporting a hypothesis that brain thickness is reduced in some brain regions in addicts, is related to altered decision-making and cognition, and might to some limited degree, be connected to their exposure to cocaine,” explains senior study author Dr. Hans Breiter from Massachusetts General Hospital.

Dr. Breiter and colleagues found that brain regions involved with regulation of attention and reward, specifically the dorsolateral prefrontal cortex (DLPFC) and insular cortices, were significantly thinner in cocaine addicts when compared with matched controls.  Behavioral tests revealed that the thinner cortex was associated with restrictions in preference-based judgment and decision-making, and with less accurate effortful attention.  A general reduction in the level of preference and in the range of decisions reflecting these preferences can be considered an example of a fundamental feature of addiction—the loss of interest in many things outside of drug use.

Some cortical thickness differences were associated with years of drug use, but the researchers also observed differences in the symmetry of DLPFC thickness between control subjects and cocaine addicts that suggested predisposition to drug abuse.  “In human and animal studies, differences in the structure of the right and left sides of the brain are important for many behaviors, and when these normal differences in brain structure are altered, there may be a genetic basis for the change.  We found an altered right/left relationship in a part of the frontal cortex that was also associated with altered judgment and decision-making in addicts.  We further found that the overall brain thickness in the cocaine addicts was more uniform across the brain, which is quite different from what is observed in non-drug users.  These differences did not correlate with any drug use measure.  Together, this set of findings point to predisposing factors being a potential contributing factor to the addiction,” explains Dr. Breiter.

In total, these observations provide evidence that cortical thickness abnormalities associated with cocaine addiction may be a reflection of both drug use and a preexisting inclination to drug abuse.  “A fundamental component of addiction may involve adaptations and/or developmental predispositions involving brain regions necessary for judgment and decision-making regarding complex rewards and attention towards goal-objects.  Addiction thus may represent a complex phenotype with multiple effects necessary for compulsive drug use, and the resulting restriction in the range of behaviors they show,” concludes Dr. Breiter.

New research provides support for the use of St. John’s wort extracts in treating major depression.  A Cochrane Systematic Review backs up previous research that showed the plant extract is effective in treating mild to moderate depressive disorders.

“Overall, we found that the St. John’s wort extracts tested in the trials were superior to placebos and as effective as standard antidepressants, with fewer side effects,” says lead researcher, Klaus Linde of the Centre for Complementary Medicine in Munich, Germany.

Extracts of the plant Hypericum perforatum, commonly known as St. John’s wort, have long been used in folk medicine to treat depression and sleep disorders.  The plant produces a number of different substances that may have anti-depressive properties, but the whole extract is considered to be more effective.

Cochrane Researchers reviewed 29 trials which together included 5,489 patients with symptoms of major depression.  All trials employed the commonly used Hamilton Rating Scale for Depression to assess the severity of depression.  In trials comparing St. John’s wort to other remedies, not only were the plant extracts considered to be equally effective, but fewer patients dropped out of trials due to adverse effects.  The overall picture is complicated, however, by the fact that the results were more favourable in trials conducted in German speaking countries, where St. John’s extracts have a long tradition and are often prescribed by doctors.

Despite the favourable findings for St. John’s wort, researchers are anxious not to make generalisations about the plant’s use as an anti-depressant and recommend consulting a doctor in the first instance, especially as the extracts can sometimes affect the actions of other beneficial drugs.

“Using a St. Johns wort extract might be justified, but products on the market vary considerably, so these results only apply to the preparations tested,” says Linde.

Large synapses with many active zones are expected to produce large EPSCs and reliably produce action potentials in postsynaptic cells.  Therefore, Mc Laughlin et al.  Were surprised at a recent report that at one of the largest synapses in the mammalian brain—the auditory calyx of Held—presynaptic potentials evoked by auditory stimuli did not reliably produce postsynaptic spikes.  The presynaptic calyx has hundreds of active zones, and the synapse is so large that presynaptic and postsynaptic responses can be measured with a single extracellular electrode.  McLaughlin et al.  Suspected that prepotentials not associated with a postsynaptic response were actually spikes from nearby axons that did not synapse on the postsynaptic cell.  They showed that this was the case by measuring interspike intervals at cat calices.  They found that prepotentials associated with a postsynaptic response sometimes occurred within the refractory period of a prepotential that did not produce a response, indicating that they were produced by different neurons.

The differential distribution of specific proteins in axons or dendrites underlies the specialized functions of these neurites.  At least two mechanisms can create a polarized distribution of centrally produced transmembrane proteins: (1) segregation of proteins into distinct vesicles that are specifically targeted to the appropriate domain, and (2) unsorted transport followed by specific endocytosis of inappropriately expressed proteins.  This week, Bushlin et al.  Suggest that the latter mechanism can be regulated by proteins that associate with endocytic vesicles and determine their cargoes.  Knockdown of proteins involved in endocytic vesicle formation, AP180 or clathrin assembly lymphoid myeloid protein (CALM), inhibited axon or dendrite formation, respectively.  Knockdown of either protein caused VAMP2—an axonal synaptic vesicle protein that is normally endocytosed from dendrites—to be expressed in all processes, supporting a role in the establishment of polarity.  CALM knockdown also reduced surface expression of a secreted protein, suggesting that it may be involved in secretory as well as endocytic pathways.

Last week we learned that blocking expression of the AMPA receptor GluR1 subunit in motor neurons reduces dendrite growth, leading to impaired motor function.  This week, Zhou et al.  Begin to unravel the molecular mechanisms tying GluR1 to activity-dependent dendritic growth.  Intracellularly, glutamate receptors interact with membrane-associated guanylate kinases (MAGUKs)—scaffolding proteins that form the postsynaptic density and anchor signaling and other effector molecules near receptors.  GluR1 interacts with the MAGUK synapse-associated protein 97 (SAP97).  Overexpression of SAP97 increased dendritic branching, whereas SAP97 knockdown decreased branching in motor neurons.  This effect was blocked by an AMPA receptor antagonist.  Interaction between GluR1 and SAP97 was required for either to enhance dendritic branching, but only because the interaction localizes SAP97 to the plasma membrane.  If SAP97 was targeted to the membrane by the addition of a palmitoylation sequence, its effects on dendritic branching were restored in the absence of direct interaction with GluR1.

A potentially blinding neurological disorder, often confused with multiple sclerosis (MS), has now become a little less mysterious.  A new study by researchers at the Mayo Clinic in Rochester, Minnesota, may have uncovered the cause of Devic’s disease.  Their new study, which will appear online on October 6th in the Journal of Experimental Medicine, could result in new treatment options for this devastating disease.

Devic’s disease, also known as neuromyelitis optica (NMO), results in MS-like demyelinating lesions along the optic nerves and spine.  Affected individuals often experience rapid visual loss, paralysis, and loss of leg, bladder, and bowel sensation.  Some lose their sight permanently.  Unlike MS, Devic’s disease can be diagnosed by the presence of a specific self-attacking immune protein—an autoantibody referred to as NMO-IgG—in the blood.  Until now, however, clinicians didn’t know how that protein damaged nerves and contributed to disease symptoms.

The Mayo team, lead by Dr. Vanda Lennon, now show that NMO-IgG sets off a chain of events that leads to a toxic build-up of a neurotransmitter called glutamate.  NMO-IgG binds to a protein that normally sops up excess glutamate from the space between brain cells.  When NMO-IgG is around, this sponge-like action is blocked, allowing glutamate to accumulate.  And too much glutamate can kill the cells that produce myelin—the protein that coats and protects neurons.  The authors suggest that glutamate-induced damage to nerve cells and their insulating myelin coats might account for the neurological symptoms associated with Devic’s disease.

If the groups’ results—generated using nerve cell cultures—are confirmed in vivo, drug development could be very straightforward.  Therapeutic trials for glutamate blockers, created to treat other neurodegenerative diseases like Lou Gehrig’s disease (or ALS), are already underway.

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.

A UC Riverside-led team of biomedical scientists has found that a readily available drug called minocycline, used widely to treat acne and skin infections, can be used to treat Fragile X syndrome, the most common inherited cause of mental impairment and the most common cause of autism.

The study’s findings have already impacted future therapies, with the approval of a new clinical trial in Toronto, Canada, that will test minocycline in patients with Fragile X.

Neurons in the brain communicate with each other at specialized contact sites called synapses, with many of these synapses occurring on small mushroom-shaped structures called dendritic spines.

During early development dendritic spines have immature finger-like shapes.  But learning stabilizes the synapses and dendritic spines take on a mature mushroom shape, which make them more efficient.

The brains of patients with Fragile X syndrome have an overabundance of immature dendritic spines.

In their report, the researchers, led by Iryna Ethell and Douglas Ethell, faculty members in UCR’s Division of Biomedical Sciences, describe how dendritic spine development in mice with Fragile X is delayed by enzymes called matrix metalloproteinases (MMPs), which are involved in normal brain development and physiological processes.  They report that high levels of certain MMPs keep the synapses immature and inefficient.

But minocycline, they found, reduces these MMP levels in the mice, allowing the synapses to mature and make more efficient contacts between neurons in the brain.  The outcome: corrected brain abnormalities in dendritic spines, reduced anxiety and improved cognitive function.

Study results appear online, ahead of print, in the Journal of Medical Genetics.

In their experiments, the Ethells found that young Fragile X mice treated with minocycline showed an increase of dendritic spine maturation in the hippocampus, a brain area that is critical for learning and memory.  Besides less anxiety, minocycline-treated mice showed better exploration skills as compared to untreated mice.

The Ethells are enthusiastic about how their discovery already is leading to a clinical trial.

“Clinical studies often quickly follow such basic science because once there is a solid understanding of how problems arise, it is much easier to come up with solutions,” said Iryna Ethell, an associate professor of biomedical sciences.

The study was funded by a grant from the FRAXA Research Foundation.  FRAXA was founded in 1994 by three parents of children with Fragile X to support scientific research aimed at finding a treatment and a cure for Fragile X.

Dr. Michael Tranfaglia, FRAXA’s chief scientific officer, said of the UCR researchers, “This group has done something unique and incredibly valuable: They have identified an off-the-shelf treatment for Fragile X through their basic research.  By bringing their unique perspective to Fragile X research, they have helped us to understand why neurons are malformed in this disorder, and more importantly, how we can treat it.

“We were so impressed with their work that we just awarded Dr. Iryna Ethell the FRAXA Breakthrough Award for 2008.  This is easily the most important scientific breakthrough in the Fragile X field in many years.”

According to Dr. Carl Paribello, president of Fragile X Research Foundation of Canada and the director of the clinical trial (scheduled for early 2009) at Surrey Place Centre Fragile X Clinic in Toronto, Canada, the UCR-led study “will go a long way towards dispelling the idea that mental impairment cannot be treated.”

“The work could lead to the first treatment that actually targets the underlying defect in Fragile X syndrome and not just the symptoms,” Dr. Paribello said.

UCR’s Douglas Ethell, an assistant professor of biomedical sciences, noted that effective therapies for Fragile X syndrome are few and far between.  “This is a good time for identifying highly effective therapeutic strategies that might work in Fragile X patients,” he said.  “We are excited that our research has the potential to affect many lives.”

Fragile X affects 1 in 4000 males and 1 in 6000 females of all races and ethnic groups.  About 1 in 259 women carry Fragile X and could pass it to their children.  About 1 in 800 men carry Fragile X; their daughters will also be carriers.

Minocycline belongs to a group of antibiotics that has been used in people for more than fifty years to treat Lyme disease, acne, and other skin infections.

Minocycline may have beneficial effects in other disorders where higher-than-normal brain levels of MMP-9 are found.  It is currently under study for treating rheumatoid arthritis, multiple sclerosis (MS), Parkinson’s disease, and several other neurodegenerative conditions.

“In the future, new compounds that more specifically target MMP-9 can be developed and tested,” Douglas Ethell said.

Next in their research, the Ethells and their colleagues plan to refine the therapeutic strategy in Fragile X mice to determine the optimal age, if any, to administer minocycline.  They will also explore other MMP inhibitors that may be more effective than minocycline.

“We will investigate whether a combination of MMP inhibitors with other drugs, such as fenobam, can help mature the synapses in Fragile X mice,” Iryna Ethell said.

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.

Hypoglycemic seizures occur in several diseases, particularly diabetes. In rats (and humans) seizures are induced by excess insulin, which stimulates glucose uptake throughout the body, reducing the amount available to neurons. The substantia nigra pars reticulata (SNR) has been implicated in seizure control: hyperpolarization of SNR neurons is anticonvulsant, whereas increased firing in SNR is proconvulsant. To further investigate the mechanism of hypoglycemic seizures, Velíšek et al. injected insulin into rats that had fasted overnight. Fasting doubled the probability that insulin would induce a seizure and decreased the latency to seizure. But differences in blood glucose levels did not explain the difference. Instead, the proconvulsant effect of fasting was associated with decreased expression of K_ATP channels specifically in the SNR. These channels normally open (causing hyperpolarization) only when ATP levels are low (e.g., during hypoglycemia). Decreased K_ATP expression prevents hyperpolarization of SNR neurons during hypoglycemia, and thus is proconvulsant.

In contrast to Barrette et al., Horn al. report that macrophages may hinder regeneration in the spinal cord of rats by promoting axonal retraction. Central nervous system axons normally retract from a site of injury. To examine the role of macrophages in this process, Horn et al. specifically targeted phagocytic cells with toxin enclosed in liposomes. Depleting macrophages after a spinal cord crush did not affect the initial retraction of injured axons, but prevented later retraction that normally occurs after macrophages invade the spinal cord. In vitro studies on dorsal root ganglion neurons revealed that when an activated macrophage contacts a dystrophic axon, the macrophage adheres to and tugs on the axon, pulling it from the substrate and causing retraction. Together, these two studies suggest that whether myeloid cells help or hinder axon regeneration may depend on what type of myeloid cells are present (i.e., what subtypes of macrophages and granulocytes) and where and how macrophages are activated (e.g., by peripheral or CNS cues). Many macrophages (green) but few astrocytes (blue) were present at a lesion site 7 d after nerve crush (left). Treatment with toxic liposomes greatly reduced the number of macrophages, but astrocytes remained.