A new study reveals how the brain can connect discrete but overlapping experiences to provide a rich integrated history that extends far beyond individually experienced events and may help to direct future choices.  The research, published by Cell Press in the October 23rd issue of the journal Neuron, also explains why some people are good at generalizing from past experience, while others are not.

Decisions are often guided by drawing on past experiences, perhaps by generalizing across discrete events that overlap in content.  However, how such experiences are integrated into a unified representation is not clear, and fundamental questions remain regarding potential underlying brain mechanisms.  It is likely that such mechanisms involve the hippocampus, a brain structure closely linked with learning and memory.  The midbrain may also play a role, as its projections modulate activity in the hippocampus, and activity in both regions has been shown to facilitate encoding of individual episodes.

Dr. Daphna Shohamy from the Department of Psychology at Columbia University was interested in examining how past experiences might be integrated within the brain to create generalizations that guide future decisions.  “We hypothesized that generalization stems from integrative encoding that occurs while experiencing events that partially overlap with previously encoded events and that such integrative encoding depends on both the hippocampus and midbrain dopamine regions.  Further, we anticipated that greater hippocampal-midbrain engagement during integrative encoding enables rapid behavioral generalization in the future,” offers Dr. Shohamy.

Dr. Shohamy and her collaborator, Dr. Anthony Wagner from the Department of Psychology at Stanford University, used functional magnetic resonance imaging to study participants engaged in an associative learning and generalization task.  They found that activity in the hippocampus and midbrain during learning predicted generalization and observed a cooperative interaction between the hippocampus and the midbrain during integrative encoding.

“By forming a thread that connects otherwise separate experiences, integrative encoding permits organisms to generalize across multiple past experience to guide choices in the present,” explains Dr. Shohamy.  “In people who generalize successfully, the brain is constantly building links across separate events, creating an integrated memory of life’s episodes.  For others, although the brain may accurately remember each past event, this integration does not occur, so that when confronted with a new situation, they are unable to flexibly apply what they learned in the past.”

Targeted memory erasure is no longer limited to the realm of science fiction.  A new study describes a method through which a selected set of memories can be rapidly and specifically erased from the mouse brain in a controlled and inducible manner.  The research, published by Cell Press in the October 23 issue of the journal Neuron, may eventually lead to development of strategies amenable to the human brain that would permit selective erasure of traumatic memories or unwanted fear while leaving other memories intact.

Memory is generally separated into four different stages: acquisition, consolidation, storage, and retrieval.  Previous research has identified specific molecules and events that appear to play a role in the various phases of the memory process.  One such “memory molecule,” calcium/calmodulin-dependent protein kinase II (CaMKII), is an enzyme that has been linked to multiple aspects of learning and memory.

A research team led by Dr. Joe Z. Tsien, from the Brain and Behavior Discovery Institute at the Medical College of Georgia, developed a method for rapidly manipulating CaMKII activity in the brains of transgenic mice.  “We recently developed a chemical genetic strategy that combines the molecular specificity of genetics with the high time-resolution of pharmacological inhibition.  Using this technique, we examined the manipulation of transgenic ?CaMKII activity on the retrieval of short-term and long-term fear memories and novel object recognition memory,” explains Dr. Tsien, who is also renowned for his 1999 creation of Doogie, the smart transgenic mouse with enhanced learning and memory abilities.

Dr. Tsien and colleagues found that transient overexpression of ?CaMKII at the time of recall impaired retrieval of newly formed 1 hr novel object recognition memory and fear memories, as well as 1-month-old fear memories.  The researchers went on to show that recall deficits linked to excessive ?CaMKII activity were not caused by a blockade of the recall process but instead seemed to be due to rapid erasure of the stored memories.  Further, the erased memories were limited to those being retrieved while others remained intact.

The results demonstrate a successful genetic method for rapidly and specifically erasing specific memories, such as new and old fear memories, in a controlled and inducible manner without doing harm to the brain cells.  “Given the fact that so many war veterans often suffer from reoccurring traumatic memory replays after returning home, our report of selective erasure of fear memories in an inducible and rapid way suggests the existence of molecular paradigm(s) under which traumatic memories can be erased or degraded while preserving other memories in the brain,” says Dr. Tsien.  However, he goes on to caution, “No one should expect to have a pill do the same in humans any time soon, we are barely at the foot of a very tall mountain.”

Amyloid precursor protein (APP), whose cleavage product, amyloid-b (Ab), builds up into fibrous plaques in the brains of Alzheimer’s disease patients, jumps from one specialized membrane microdomain to another to be cleaved, report Sakurai et al.

Although there is no definitive evidence that Ab plaques are the direct cause of Alzheimer’s disease, there is much circumstantial evidence to support this.  And working on this hypothesis, scientists are investigating just how the plaques form and what might be done to stop or reverse their formation.

APP, a protein of unknown function, is membrane associated and concentrates at the neuronal synapse.  Certain factors such as high cellular cholesterol and increased neuronal or synaptic activity are known to drive APP cleavage, and Sakurai and colleagues’ paper pulls these two modes of Ab regulation together.

APP associates with membrane microdomains high in cholesterols (lipid rafts).  These lipid rafts can also contain the enzyme necessary for APP cleavage, BACE.  Synaptic activity is known to involve a very different type of membrane microdomain high in an excytosis-promoting factor called syntaxin.  Sakurai et al.  Now show that although APP preferentially associates with syntaxin microdomains, upon neuronal stimulation APP instead associates with microdomains that contain BACE.

It’s unclear why APP should be associated with syntaxin, though it might suggest a role for APP in vesicle trafficking and exocytosis.  Also unclear is why neuronal activity should cause APP to jump from syntaxin domains to BACE domains.  What is clear, however, is that the process is an active one, requiring a kinase called cdk5.  Furthermore, treating neurons with a cdk5 inhibitor called roscovitine, which is currently in trials for cancer treatment, reduced APP’s association with BACE microdomains and reduced APP cleavage.

A research team at the Institut de recherches cliniques de Montreal (IRCM), funded by the Foundation Fighting Blindness – Canada and the Canadian Institutes of Health Research (CIHR), discovered a novel mechanism that regulates how neural stem cells of the retina generate the appropriate cell type at the right time during normal development.  These findings, published today in the renowned journal Neuron, could influence the development of future cell replacement therapies for genetic eye diseases that cause blindness.

In their report, the scientists show that a gene called Ikaros is expressed in the most immature retinal stem cells in the mouse, which are “competent” to generate all seven different cell types that compose the retina.  But this gene is not expressed in the “older” stem cells, which are more restricted in their differentiation potential and produce only the late-born neurons.  “By studying the retina of a mouse in which the Ikaros gene was inactivated, we found that the generation of early-born retinal cell types was impaired, whereas the generation of the late-born retinal cell types was not affected,” explained Dr. Michel Cayouette who led the study.  In contrast, forcing the expression of Ikaros in older retinal stem cells, which have normally turned off its expression, was sufficient to give back the competence to these cells to generate early-born neurons.  Overall, these results indicate that the expression of Ikaros in retinal stem cells is both necessary and sufficient to confer the competence to generate early-born retinal neurons.

The identification of adult retinal stem cells in recent years has opened up the possibility that such cells could one day be used to replace damaged or lost cells in various retinal diseases such as glaucoma, macular degeneration or retinitis pigmentosa.  For such approaches to be effective, however, it is crucial that stem cells generate only the appropriate cell type for a particular condition.  This study suggests that it may be possible to manipulate the competence of retinal stem cells so that they only generate retinal cells associated to a particular temporal stage.  “For example, added Dr. Cayouette, inactivating Ikaros could favor the production of later-born neurons such as photoreceptors, which are lost progressively in retinal degenerative diseases.”  Future studies will be required to assess the usefulness of this approach for potential cell replacement therapies.

Once a toddler has mastered the art of walking, it seems to come naturally for the rest of her life. But walking and running require a high degree of coordination between the left and right sides of the body. Now researchers at the Salk Institute for Biological Studies have shown how a class of spinal cord neurons, known as V3 neurons, makes sure that one side of the body doesn’t get ahead of the other.

The findings, published in the Oct. 9 issue of Neuron, mark an important milestone in understanding the neural circuitry that coordinates walking movements, one of the main obstacles in developing new treatments for spinal cord injuries. In addition to establishing a balance between both sides of the body, they found that the V3 neurons ensure that the stepping rhythm is robust and well-organized.

“In the case of cervical spinal cord injuries, the spinal network that drives your limbs and allows you to walk is still there but no longer receives appropriate activating inputs from the brain.” Says Martyn Goulding, Ph.D., a professor in the Molecular Neurobiology Laboratory, who led the study. “The fact that the V3 neurons are important for generating a robust locomotor rhythm makes them good candidates for efforts aimed at therapeutic intervention after spinal cord injury.”

V3 neurons are so called interneurons, which relay signals from the nerve cells in the spinal cord to motor neurons, which cause muscles to contract. Spinal interneurons form complex networks—commonly referred to as CPGs, short for central pattern generators—that function as local control and command centers for rhythmic movements, which lie at the heart of all locomotion.

Although scientists had known about the locomotor CPG for a long time, they were unable to identify the nerve cells that make up these circuits. When Goulding and others began to break the molecular code that makes these different interneuron cell types, they could start to unravel the wiring of the spinal cord to see how it works.

Neurons in the brain and spinal cord come in two flavors, excitatory neurons that transmit and amplify signals and inhibitory neurons that inhibit and refine those signals. Previously, Goulding and his team discovered that a subset of inhibitory interneurons, the V1 neurons, control the speed of motor rhythm and thus set the pace at which animals walk, while a second group of inhibitory neurons, called V0 neurons, govern the left-right alternating pattern of activity that is needed for stepping, as opposed to hopping, movements. In their latest study, they turned their attention to a class of excitatory neurons, the so-called V3 neurons.

“Most models of the CPG include an inhibitory element that switches off motor neuron activity on one side in order to initiate the next step on the other side of the body, which allows you to walk, hop, skip, and run,” says Goulding. “V3 neurons provide an additional level of control, which makes sure that when you walk and run, the intensity of the activity is matched on both sides of the body. If that were not the case, we would be unable to walk or run along a straight line.”

In the study, postdoctoral researchers in the Goulding lab genetically engineered mice to specifically shut off their V3 neurons and reveal their function. The first author, Ying Zhang, Ph.D., then performed electrophysiological experiments on spinal cords isolated from these mice and found that without functioning V3 neurons, the length of individual motor neuron bursts began to fluctuate wildly. “Instead of a stable, alternating pattern, we found irregular oscillations between the left and the right side,” she says.

“A lot of research focused on the left-right coordination, but it has became clear that different levels of control allow for the fine-tuning of these rhythmic locomotor patterns,” says Zhang. “This study will allow us to put together a map of the neurons contributing to the CPG so that we can think about manipulating the CPG for therapeutic purposes.”

Since the activity of the motor neurons determines how much the muscle contracts and for how long, the researchers wanted to know how this irregular activity pattern of motor neurons influences the gait of mice strolling down a walkway. Taking advantage of the so-called AlstR/AL system, which was developed by Salk researcher Edward M. Callaway, Ph.D., a professor in the Systems Neurobiology Laboratories, the researchers temporarily shut off V3 neurons in adult mice and sent them on their way along a narrow Plexiglas walkway. While the mice still alternated steps with their left and right hind limbs, the length of each step varied markedly, making it difficult for them to walk with a smooth cadence.

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.