Each year, thousands of publications present functional magnetic resonance imaging (fMRI) data that suggest that a particular brain region is active during a particular cognitive task.  Casual readers of such papers might forget that this technique does not actually measure neural activity, but rather blood oxygenation level-dependent (BOLD) contrasts.  Synaptic transmission requires large energy expenditures, and increased energy metabolism has been hypothesized to act directly on blood vessels to increase blood flow and alter BOLD signals.  This week, however, Devor et al.  Report that this hypothesis is not always correct.  As expected, stimulating the forepaw of rats increased blood oxygenation, vessel diameter, glucose uptake, spiking, and synaptic release in the contralateral primary somatosensory cortex.  In the ipsilateral cortex, however, neural activity and glucose uptake increased, but blood oxygenation and blood flow did not.  These results indicate that blood flow is not directly tied to metabolism, and BOLD signals do not always reflect neural activity.

Construction of the brain’s border fence is supervised by Wnt/b-catenin signaling, report Liebner et al. in The Journal of Cell Biology.

Like many a modern nation, the brain requires tight border security to maintain levels of nutrients and keep out toxic substances. The blood–brain barrier (BBB) is a virtually impermeable network of tight junctions between endothelial cells that prevents paracellular flow of materials. Because Wnt/b-catenin signaling is a major pathway regulating other aspects of brain development, the authors examined its potential role in constructing the BBB.

In brain endothelial cells, Wnt signaling was active during the time of maximum vascular development, but not after the BBB matured. Activation of the Wnt signaling pathway in vivo and in vitro promoted BBB development, and inactivation prevented it. In vitro increasing Wnt signaling also strengthened junctions between non-brain endothelial cells.

This suggests that Wnt signaling might be tweaked to mend the BBBs in patients where it has failed—such as in stroke—or to temporarily open the BBB to deliver drugs that would normally be shut out.

When reaching for an object, the brain prepares neural commands sent to the target muscles to minimize energy expenditure, according to a study published in PLoS Computational Biology by neuroscientists and mathematicians from the INSERM and ENSTA.

How the human brain organizes and controls our actions is a crucial question in life sciences. In recent decades, an important theoretical advance has been the use of computational models and the assumption that the brain behaves like an optimal controller. In most studies, an optimality criterion is chosen a priori and assumed to produce smooth and harmonious movements, as those recorded experimentally. Most existing models, however, fail to explain how our interactions with the external environment are integrated into optimization processes.

In particular, gravity is one of the constraints that permanently act upon the movements of living organisms. The simple observation of vertical arm movements reveals that muscle activity when moving upwards differs from when moving downwards. This led the authors to surmise that the brain takes advantage of gravitational force during movement, trying to optimize energy consumption. The discovery of this biological rule has resulted from the use of a hypothetical-deductive mathematical method which predicted short periods of muscle inactivation and direction-dependent hand kinematics. These predictions have been verified experimentally using human volunteers. Moreover, they have demonstrated a necessary and sufficient condition of optimal control for arm movements which is a novelty in motor control studies.

The authors explain how the brain plans movements by integrating biological and environmental constraints and the method may be of potential value for understanding motor dysfunction and guiding subsequent rehabilitation programs. Moreover, it opens the prospect of studying brain functions by a cooperative interaction of mathematicians and neuroscientists. Interestingly, the paper is a clear demonstration that mathematical principles and theories, formerly used for understanding the non-living world, are now used for understanding how biological organisms integrate these laws.

Scientists at the Gladstone Institute of Neurological Disease (GIND) have identified a new strategy to destroy amyloid-beta (AB) proteins, which are widely believed to cause Alzheimer’s disease (AD). Li Gan, PhD, and her coworkers discovered that the activity of a potent AB-degrading enzyme can be unleashed in mouse models of the disease by reducing its natural inhibitor cystatin C (CysC).

All of us produce AB proteins in the brain. However, in most people, the proteins never build up to dangerous levels because they are cleared away by enzymes that destroy them. Previously Dr. Gan’s laboratory had shown that cathepsin B (CatB) is such an AB-degrading enzyme. In the latest issue of the journal Neuron, the researchers report a highly effective approach to promote CatB-mediated clearance of AB .

“Many groups have developed drugs to block the production of AB, but the efficacy and safety of this approach remains to be demonstrated in clinical trials,” said GIND Director Lennart Mucke, MD “By identifying an effective strategy to enhance the removal of AB, this research provides a very promising alternative or complementary therapeutic avenue.”

High levels of AB in the brain may result from overproduction of AB or from an inability to eliminate it from the brain. While most work has focused on the first option, the latter has been problematic. For example, efforts to develop a vaccine that would trigger the immune system to eliminate AB have shown limited success and resulted in adverse side effects.

“Our strategy to harness the activity of a powerful AB-degrading enzyme takes advantage of the brain’s own defense system to remove the toxic AB build-up,” said Dr. Gan. “In principle, one could boost the activity of CatB by expressing more of it in the brain or by reducing the activity of CysC, its natural inhibitor. We focused on the latter strategy because it has greater long-term therapeutic potential.”

Many enzymes that degrade proteins are kept in check by regulators called protease inhibitors. The activity of CatB is regulated by the protease inhibitor CysC. By reducing CysC activity, the scientists were able to unleash the AB-degrading power of CatB, effectively preventing the build-up of AB in mouse models of AD.

To examine the impact of this manipulation on brain function, Dr. Gan’s team measured brain cell activities that relate closely to learning and memory. Increasing CatB activity by lowering CysC levels prevented AB-induced deficits in those cellular activities. The investigators also tested the modified AD mice for learning and memory in a water maze. Higher levels of CatB activity improved the ability of AD to learn the maze and to retain the new information. Increasing CatB activity also prevented the premature mortality that is typically seen in these Alzheimer models.

“Our results suggest that CysC reduction has major therapeutic potential,” Dr. Gan said. “The next step will be to develop pharmacological approaches to inhibit CysC in the human brain.”

Life exists at the edge of chaos, where small changes can have striking and unanticipated effects, and major stimuli may go unheard. But there is no space for ambiguity when the brain needs to transform head motion into precise eye, head, and body movements that rapidly stabilize our posture and gaze; otherwise, we would stumble helplessly through the world, and our vision would resemble an undecipherable blur.In their latest study, published in the current issue of the journal Neuron, researchers at the Salk Institute for Biological Studies explain how the vestibular-ocular reflex, which keeps us and the world around us stable, achieves the accuracy it is famous for. Unlike most signals in the brain, whose transmission is frequency-dependent, signals from the vestibular system of the inner ear, which detects motion, are relayed in a linear fashion no matter how fast the neurons are firing.

“Most of what we know about signal transmission between neurons comes from studying special cortical or hippocampal neurons, but many vital functions, such as balance and breathing, are controlled by neurons in the brain stem, which, as we discovered, work very differently,” says Howard Hughes Medical Institute investigator Sascha du Lac, Ph.D., an associate professor in the Systems Neurobiology Laboratory. “Pursuing the mechanisms that control neurons in the brain stem is important for developing new classes of biotherapeutic agents.”

Du Lac and her team focus on a simple type of learning: How does the brain learn to stabilize an image on the retina and use eye movement to compensate for a moving head? This so-called vestibular-ocular reflex, or VOR, needs to be fast; for clear vision, head movements must be compensated for almost immediately. To achieve the necessary speed, the VOR-circuit involves only three types of neurons: sensory neurons, which detect head movement; motor neurons, directing eye muscles to relax or contract; and so-called vestibular nucleus neurons in the brainstem that link the two.

While the brevity of this circuit keeps reflex times short, it was less clear what qualities of the circuit ensure that eye velocity is precisely matched to head velocity. Since the VOR operates accurately no matter how fast we move our head, scientists long expected that the signal transmission at the synapses—specialized points of contact between nerve cells—that connect the sensory onto the vestibular nucleus neurons would be linear.

However, transmission at most synapses is non-linear. Brain cells signal by sending electrical impulses along axons, long, hair-like extensions that reach out to neighboring nerve cells. When an electrical signal reaches the end of an axon, the voltage change triggers release of neurotransmitters, the brain’s chemical messengers. These neurotransmitter molecules then travel across the space between neurons at a synapse and trigger an electrical signal in the adjacent cell—or not.

“Most known synapses act as information filters, and both the probability and the extent of neurotransmitter release as well as the efficacy of the postsynaptic response depend heavily on the recent history of the synapse,” says first author Martha W. Bagnall, Ph.D., a former graduate student in du Lac’s lab and now a postdoctoral researcher at the University of California, San Diego. “But no matter whether you go jogging or watch TV on your couch, the VOR needs to accurately match sensory input with motor output,” she adds.

When Bagnall and her colleagues took a closer look at the first synapse in the VOR circuit, they found that no matter how fast the sensory neuron was firing, the same amount of neurotransmitter was released. And instead of vacillating, the post-synaptic neuron took the information and transmitted it faithfully.

A brain isn’t born fully organized. It builds its abilities through experience, making physical connections between neurons and organizing circuits to store and retrieve information in milliseconds for years afterwards.Now that process has been caught in the act for the first time by a Duke University research team that watched a naïve brain organize itself to interpret images of motion.

“This is the first time that anyone has been able to watch as visual experience selectively shapes the functional properties of individual neurons,” said David Fitzpatrick, professor of neurobiology and director of the Duke Institute for Brain Sciences. “These results emphasize just how important experience is for the early development of brain circuits.” The group’s findings appear online Oct. 22 in the journal Nature.

Using an advanced imaging system that can see changes in calcium levels within individual neurons as an indication of electrical activity, the team has been able to see inside the brain of a one-month old ferret as it opened its eyes for the first time and learned how to interpret moving images.

They watched the brain learning how to see. As a ferret learned to discriminate one pattern of motion from another over the course of a few hours, the researchers could see large numbers of individual neurons in the visual cortex develop specific responses and become organized into functional assemblies called cortical columns. Additional experiments confirmed that the changes were dependent on the neurons being activated by the animal’s experience with moving visual images.

The measurements were made using something called “in vivo two-photon laser scanning microscopy,” which allows researchers to focus on a virtual slice of living tissue a few microns thick, and up to 300 microns below the surface of the brain. By scanning at multiple depths, the researchers were able to examine the properties of hundreds of neurons in a single animal. A fluorescent dye sensitive to calcium allowed the scientists to detect changes in the activity of individual neurons as the learning occurred.

Ferrets are born with their eyes closed and remain so for the first 30 days or so, Fitzpatrick explained. What the Duke team saw happening as the animals opened their eyes and watched moving images for the first time was the emergence of columns of neurons sensitive to a particular feature of the visual stimulus: its direction of motion.

In visual areas of the mature brain, individual neurons are programmed to be most responsive to a particular direction of motion. Some are most responsive to left-to-right motion, for example, and others will be most responsive to down-to-up or right-to-left and so on. As signals from a visual stimulus enter these brain centers for interpretation, the entire collection of neurons that has been programmed to detect motion will fire signals to cast their votes, in effect, on which direction the stimulus is moving. Those neurons which are programmed to be most responsive to the direction the stimulus is actually moving cast the loudest votes.

“Before experience with a moving stimulus, individual neurons respond almost equally to opposite directions of motion and there is little order in the way they are arranged,” Fitzpatrick said. “But as a result of experience with moving images, their response to a particular direction of motion strengthens and they begin to act like their neighbors, forming columns of neurons with similar preferences. We have been able to visualize the self-organizing process by which the brain uses experience to guide the construction of circuits that are critical for interpreting moving stimuli.”

The scientists next have to figure out how neurons end up preferring one motion direction over another, and what aspects of the circuit are altered to create the direction-selective responses.

Fitzpatrick is confident that the findings from these experiments can be generalized to other brain regions and will be of value in understanding neurological and psychiatric disorders.

“Many people don’t realize that the vast majority of cortical connections are being formed at a time when experience can influence neural activity,” he said. “Understanding how experience shapes the architecture of developing neural circuits, and identifying the underlying cellular and molecular mechanisms could provide the key to a number of developmental brain disorders.”

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.”

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.

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.”