Brain inflammation dramatically disrupts memory retrieval networks

Brain inflammation can rapidly disrupt our ability to retrieve complex memories of similar but distinct experiences, according to UC Irvine neuroscientists Jennifer Czerniawski and John Guzowski.

Their study – which appears today in The Journal of Neuroscience – specifically identifies how immune system signaling molecules, called cytokines, impair communication among neurons in the hippocampus, an area of the brain critical for discrimination memory. The findings offer insight into why cognitive deficits occurs in people undergoing chemotherapy and those with autoimmune or neurodegenerative diseases.

Moreover, since cytokines are elevated in the brain in each of these conditions, the work suggests potential therapeutic targets to alleviate memory problems in these patients.

“Our research provides the first link among immune system activation, altered neural circuit function and impaired discrimination memory,” said Guzowski, the James L. McGaugh Chair in the Neurobiology of Learning & Memory. “The implications may be beneficial for those who have chronic diseases, such as multiple sclerosis, in which memory loss occurs and even for cancer patients.”

What he found interesting is that increased cytokine levels in the hippocampus only affected complex discrimination memory, the type that lets us differentiate among generally similar experiences – what we did at work or ate at dinner, for example. A simpler form of memory processed by the hippocampus – which would be akin to remembering where you work – was not altered by brain inflammation.

In the study, Czerniawski, a UCI postdoctoral scholar, exposed rats to two similar but discernable environments over several days. They received a mild foot shock daily in one, making them apprehensive about entering that specific site. Once the rodents showed that they had learned the difference between the two environments, some were given a low dose of a bacterial agent to induce a neuroinflammatory response, leading to cytokine release in the brain. Those animals were then no longer able to distinguish between the two environments.

Afterward, the researchers explored the activity patterns of neurons – the primary cell type for information processing – in the rats’ hippocampi using a gene-based cellular imaging method developed in the Guzowski lab. In the rodents that received the bacterial agent (and exhibited memory deterioration), the networks of neurons activated in the two environments were very similar, unlike those in the animals not given the agent (whose memories remained strong). This finding suggests that cytokines impaired recall by disrupting the function of these specific neuron circuits in the hippocampus.

“The cytokines caused the neural network to react as if no learning had taken place,” said Guzowski, associate professor of neurobiology & behavior. “The neural circuit activity was back to the pattern seen before learning.”

The work may also shed light on a chemotherapy-related mental phenomenon known as “chemo brain,” in which cancer patients find it difficult to efficiently process information. UCI neuro-oncologists have found that chemotherapeutic agents destroy stem cells in the brain that would have become neurons for creating and storing memories.

Dr. Daniela Bota, who co-authored that study, is currently collaborating with Guzowski’s research group to see if brain inflammation may be another of the underlying causes of “chemo brain” symptoms.

She said they’re looking for a simple intervention, such as an anti-inflammatory or steroid drug, that could lessen post-chemo inflammation. Bota will test this approach on patients, pending the outcome of animal studies.

“It will be interesting to see if limiting neuroinflammation will give cancer patients fewer or no problems,” she said. “It’s a wonderful idea, and it presents a new method to limit brain cell damage, improving quality of life. This is a great example of basic science and clinical ideas coming together to benefit patients.”

Research Shows How Brain Can Tell Magnitude of Errors

University of Pennsylvania researchers have made another advance in understanding how the brain detects errors caused by unexpected sensory events. This type of error detection is what allows the brain to learn from its mistakes, which is critical for improving fine motor control.  

Their previous work explained how the brain can distinguish true error signals from noise; their new findings show how it can tell the difference between errors of different magnitudes. Fine-tuning a tennis serve, for example, requires that the brain distinguish whether it needs to make a minor correction if the ball barely misses the target or a much bigger correction if it is way off.

The study was led by Javier Medina, an assistant professor in the Department of Psychology in Penn’s School of Arts & Sciences, and Farzaneh Najafi, then a graduate student in the Department of Biology. They collaborated with postdoctoral fellow Andrea Giovannucci and associate professor Samuel S. H. Wang of Princeton University.

It was published in the journal eLife.

Our movements are controlled by neurons known as Purkinje cells. Each muscle receives instructions from a dedicated set of hundreds of these brain cells. The instructions sent by each set of Purkinje cells are constantly fine tuned by climbing fibers, a specialized group of neurons that alert Purkinje cells whenever an unexpected stimulus occurs.

“An unexpected stimulus is often a sign that something has gone wrong,” Medina said, “When this happens, climbing fibers send signals to their related Purkinje cells that an error has occurred. These Purkinje cells can then make changes to avoid the error in the future.”

These error signals are mixed in with random firings of the climbing fibers, however, and researchers were long mystified about how the brain tells the difference between this noise and the useful, error-related information it needs to improve motor control.

Medina and his team showed the mechanism behind this differentiation in a study published earlier this year. By using a non-invasive microscopy technique that could monitor the Purkinje cells of awake and active mice, the researchers could measure the level of calcium within these cells when they received signals from climbing fibers.

The unexpected stimuli in this experiment were random puffs of air to the face, which caused the mice to blink. The researchers located Purkinje cells that control the mice’s eyelids and saw that calcium levels necessary for neuroplasticity, i.e., the brain’s ability to learn, were greater when the mice got an error signal triggered by a puff of air than they were after a random signal.

While being able to make such a distinction is critical to the brain’s ability to improve motor control, more information is needed to fine-tune it.  

“We wanted to see if the Purkinje cells could tell the difference not just between random firings and true errors signals but between smaller and bigger errors,” Medina said.

In their new study, the researchers used the same experimental set-up, with one key difference. They used air puffs of different durations: 15 milliseconds and 30 milliseconds.

What they found was that the eyelid-associated Purkinje cells filled with different amounts of calcium depending on the length of the puff; the longer ones produced larger spikes in calcium levels.        

In addition, the researchers saw that different percentages of eyelid-related Purkinje cells respond depending on the length of the puff.  

“Though there is a large population of climbing fibers that can give error-related information to the relevant Purkinje cells when they encounter something unexpected, not all of them fire each time,” Medina said. “We saw that there is information coded in the number of climbing fibers that fire. The longer puffs corresponded to more climbing fibers sending signals to their Purkinje cells.”

Their study could help explain how practice makes perfect, even when errors are imperceptibly small.

“If you felt a short puff and a long puff, you might not be able to say which one was which, but Purkinje cells can tell the difference,” Medina said. “The difference between a ‘very good’ and an ‘awesome’ tennis serve rests on being able to distinguish errors even as tiny as that.” 

Nerve impulses can collide and continue unaffected

According to the traditional theory of nerves, two nerve impulses sent from opposite ends of a nerve annihilate when they collide. New research from the Niels Bohr Institute now shows that two colliding nerve impulses simply pass through each other and continue unaffected. This supports the theory that nerves function as sound pulses. The results are published in the scientific journal Physical Review X.

Nerve signals control the communication between the billions of cells in an organism and enable them to work together in neural networks. But how do nerve signals work?

Old model

In 1952, Hodgkin and Huxley introduced a model in which nerve signals were described as an electric current along the nerve produced by the flow of ions. The mechanism is produced by layers of electrically charged particles (ions of sodium and potassium) on either side of the nerve membrane that change places when stimulated. This change in charge creates an electric current.

This model has enjoyed general acceptance. For more than 60 years, all medical and biology textbooks have said that nerves function is due to an electric current along the nerve pathway. However, this model cannot explain a number of phenomena that are known about nerve function.

New model

Researchers at the Niels Bohr Institute at the University of Copenhagen have now conducted experiments that raise doubts about this well-established model of electrical impulses along the nerve pathway.

“According to the theory of this ion mechanism, the electrical signal leaves an inactive region in its wake, and the nerve can only support new signals after a short recovery period of inactivity. Therefore, two electrical impulses sent from opposite ends of the nerve should be stopped after colliding and running into these inactive regions,” explains Thomas Heimburg, Professor and head of the Membrane Biophysics Group at the Niels Bohr Institute at the University of Copenhagen.

Thomas Heimburg and his research group conducted experiment in the laboratory using nerves from earthworms and lobsters. The nerves were removed and used in an experiment which allowed the researchers to stimulate the nerve fibres with electrodes on both ends. Then they measured the signals en route. 

“Our study showed that the signals passed through each other completely unhindered and unaltered. That’s how sound waves work. A sound wave doesn’t stop when it meets another sound wave. Both waves continue on unimpeded. The nerve impulse can therefore be explained by the fact that the pulse is a mechanical wave in the form of a sound pulse, a soliton, that moves along the nerve membrane,” explains Thomas Heimburg.

The theory is confirmed

When the sound pulse moves through the nerve pathway, the membrane changes locally from a liquid to a more solid form. The membrane is compressed slightly, and this change leads to an electrical pulse as a consequence of the piezoelectric effect.

“The electrical signal is thus not based on an electric current but is caused by a mechanical force,” points out Thomas Heimburg.

Thomas Heimburg, along with Professor Andrew Jackson, first proposed the theory that nerves function by sound pulses in 2005. Their research has since provided support for this theory, and the new experiments offer additional confirmation for the theory that nerve signals are sound pulses.

Zebrafish Model of a Learning and Memory Disorder Shows Better Way to Target Treatment

Using a zebrafish model of a human genetic disease called neurofibromatosis (NF1), a team from the Perelman School of Medicine at the University of Pennsylvania has found that the learning and memory components of the disorder are distinct features that will likely need different treatment approaches. They published their results this month in Cell Reports.

NF1 is one of the most common inherited neurological disorders, affecting about one in 3,000 people. It is characterized by tumors, attention deficits, and learning problems. Most people with NF1 have symptoms before the age of 10. Therapies target Ras, a protein family that guides cell proliferation. The NF1 gene encodes neurofibromin, a very large protein with a small domain involved in Ras regulation.

Unexpectedly, the Penn team showed that some of the behavioral defects in mutant fish are not related to abnormal Ras, but can be corrected by drugs that affect another signaling pathway controlled by the small molecule cAMP. They used the zebrafish model of NF1 to show that memory defects – such as the recall of a learned task — can be corrected by drugs that target Ras, while learning deficits are corrected by modulation of the cAMP pathway. Overall, the team’s results have implications for potential therapies in people with NF1.

“We now know that learning and memory defects in NF1 are distinct and potentially amenable to drug therapy,” says co-senior author Jon Epstein, MD, chair of the department of Cell and Developmental Biology. “Our data convincingly show that memory defects in mutant fish are due to abnormal Ras activity, but learning defects are completely unaffected by modulation of these pathways. Rather these deficits are corrected with medicines that modulate cAMP.”

Over the last 20 years, zebrafish have become great models for studying development and disease. Like humans, zebrafish are vertebrates, and most of the genes required for normal embryonic development in zebrafish are also present in humans. When incorrectly regulated, these same genes often cause tumor formation and metastatic cancers.

Zebrafish have also become an ideal model for studying vertebrate neuroscience and behavior. In fact, co-senior author Michael Granato, PhD, professor of Cell and Developmental Biology, has developed the first high-throughput behavioral assays that measure learning and memory in fish. For example, Granato explains, “normal fish startle with changes in noise and light level by bending and swimming away from the annoying stimuli and do eventually habituate, that is get used to the alternations in their environment. But, NF1 fish mutants fail to habituate. However, after adding cAMP to their water, they do learn, and then behave like the non-mutant fish.”

This clearly indicates that learning deficits in the NF1 mutant fish are corrected by adding various substances that boost cAMP signaling. “Our data also indicate that learning and memory defects are reversible with acute pharmacologic treatments and are therefore not hard-wired, as might be expected for a defect in the development of nerves,” says Epstein. “This offers great hope for therapeutic intervention for NF1 patients.”

The interactive brain

Neuroscientist explores mechanism that can cause deficit in working memory

Amy Griffin, associate professor of psychological and brain sciences at the University of Delaware, has received a five-year, $1.78 million grant from the National Institute of Mental Health to support her research into the brain mechanisms of working memory.

A neuroscientist, Griffin has been interested for some time in the interaction between the prefrontal cortex, located at the front of the brain, and the hippocampus, a region in the temporal lobe of the brain. When the two areas fail to work together, that failure appears to be correlated with deficits in working memory, a condition that commonly occurs in schizophrenia, general anxiety and other psychiatric disorders.

The hippocampus is the portion of the brain responsible for memory, while the prefrontal cortex controls executive function, a term that includes such cognitive abilities as problem-solving, planning and abstract thinking.

“These are two areas of the brain that are far apart, but their oscillations [rhythmic activities] are synchronized,” Griffin said. “When one area is active, so is the other.”

Working memory, sometimes called short-term memory, is “the kind of memory that fails when you walk into a room and forget why you came there,” she said.

When the oscillations in the hippocampus and prefrontal cortex are out of sync, deficits of working memory occur. In those cases, Griffin said, “both regions are active, but they’re not talking to each other.” The mechanism that causes that lack of communication has not been well explored, and her research will seek to do that.

Griffin and her research team plan to conduct two types of experiments. One will inhibit activity in a brain region called the nucleus reuniens, a region that is hypothesized to synchronize the hippocampus and prefrontal cortex and is expected to cause impairments with working memory. In the other experiment, researchers will activate the nucleus reuniens to increase synchrony, hoping to learn if that improves working memory.

The research will employ a cutting-edge technique called optogenetics, a process that uses proteins to make neurons sensitive to light and then uses light to control them. 

“Optogenetics is becoming a common technique,” Griffin said. “It’s a way to study these processes on a millisecond timescale.” 

A 2013 article in the journal Nature Neuroscience said optogenetics “is transforming the field of neuroscience. For the first time, it is now possible to use light to both trigger and silence activity in genetically defined populations of neurons with millisecond precision.”

Griffin, using a rat model, will inject the light-sensitizing substance — a harmless virus — into the nucleus reuniens and then use a laser to inhibit or activate this brain region. The rats then perform tasks that assess their working memory. Synchronization between the hippocampus and prefrontal cortex will also be recorded, with the prediction that the degree of the working memory impairment will be correlated with reductions in synchrony.

“Our experiments will not be interfering with the activities of the hippocampus or the prefrontal cortex within themselves,” Griffin said. “We want to affect only the ability of the structures to talk to each other.”

Compound protects brain cells after traumatic brain injury

A new class of compounds has now been shown to protect brain cells from the type of damage caused by blast-mediated traumatic brain injury (TBI). Mice that were treated with these compounds 24-36 hours after experiencing TBI from a blast injury were protected from the harmful effects of TBI, including problems with learning, memory, and movement.

Traumatic brain injury caused by blast injury has emerged as a common health problem among U.S. servicemen and women, with an estimated 10 to 20 percent of the more than 2 million U.S. soldiers deployed in Iraq or Afghanistan having experienced TBI. The condition is associated with many neurological complications, including cognitive and motor decline, as well as acquisition of psychiatric symptoms like anxiety and depression, and brain tissue abnormalities that resemble Alzheimer’s disease.

"The lack of neuroprotective treatments for traumatic brain injury is a serious problem in our society," says Andrew Pieper, senior study author and associate professor of psychiatry, neurology, and radiation oncology at the University of Iowa Carver College of Medicine. “Everyone involved in this work is motivated to find a way to offer hope for patients, which today include both military personnel and civilians, by establishing a basis for a new treatment to combat the deleterious neuropsychiatric outcomes after blast injury.”

It is known that TBI, as well as certain neurodegenerative diseases, damages axons—the tendril-like fibers that sprout from brains cells (neurons) and form the connections called synapses. In TBI, axon damage is followed by death of the neuron. The new study, published Sept. 11 in the journal Cell Reports, shows that a group of compounds, called the P7C3 series, blocks axon damage and preserves normal brain function following TBI.

Pieper led the team of scientists that discovered the P7C3 compound several years ago at UT Southwestern Medical Center. Subsequent studies showed that the root compound and its active analogs protect newborn neurons from cell death and also protect mature neurons in animal models of neurodegenerative diseases, including Parkinson’s disease and amyotrophic lateral sclerosis (ALS).

The researchers have also previously shown efficacy of P7C3 molecules in brain injury due to concussion, and plan to investigate whether these compounds might be applicable in stroke as well, given that there appear to be common factors mediating neuronal cell death in these conditions.

By tweaking the structure of the original P7C3 compound, Pieper and his colleagues Joseph Ready and Steven McKnight, at UT Southwestern Medical Center, have further improved its potency and drug-like properties. In the latest study, Pieper’s team at the UI Carver College of Medicine, including co-first authors graduate student Terry Yin, senior technician Jeremy Britt, and graduate student Hector De Jesus-Cortes, tested the neuroprotective effects of the newest version, (-)-P7C3-S243, which can be given orally, in mice with blast-induced TBI.

In the study, blast-induced TBI caused learning, memory, and movement problems in the mice, which resemble the problems experienced by people affected by TBI. The researchers found that (-)-P7C3-S243 prevented acute memory and learning impairment caused by TBI. The compound also prevented TBI-associated balance and coordination problems in mice exposed to blast-injury. By examining the brain tissue at a cellular level, the team also found that the protection afforded to brain functions after injury was matched by preservation of normal neuronal axon structure and synaptic neurotransmission.

Importantly, the compound still produced its protective effects even when treatment was delayed until 24 to 36 hours after the blast injury.

"Seeing protection even when the compound was given this long after injury was important because it represents a liberal window of time within which almost all patients would be expected to be able to access treatment after injury," Pieper says.

The team also found that learning, memory, and coordination problems caused by the TBI persisted in untreated mice at least eight months after the single injury occurred, suggesting that the compound actually prevented these problems rather simply speeding up a normal recovery process.

In a separate study led by Pieper’s colleagues McKnight and Ready at UT Southwestern, and also published on Sept. 11 in the journal Cell, the team has identified the biological mechanism by which P7C3 compounds act in the brain. The compounds activate the molecular pathway that preserves neuronal levels of an energy molecule known as nicotinamide adenine dinucleotide (NAD).

"Based on the well-established role of NAD in axonal degeneration, the ability of (-)-P7C3-S243 to protect mice after blast-mediated traumatic brain injury is likely related to preservation of NAD levels," Pieper explains. "Now that we understand the mechanism of action of the P7C3 class of compounds, we can see why they should have therapeutic utility in an unusually broad spectrum of neurodegenerative conditions, without impeding any of a number of other normal forms of cell death.

"Our ultimate goal is to facilitate development of a new class of neuroprotective drugs with wide applicability to treating patients with TBI and other currently untreatable forms of neurodegeneration," he adds.

Tipping the Balance of Behavior

Humans with autism often show a reduced frequency of social interactions and an increased tendency to engage in repetitive solitary behaviors. Autism has also been linked to dysfunction of the amygdala, a brain structure involved in processing emotions. Now Caltech researchers have discovered antagonistic neuron populations in the mouse amygdala that control whether the animal engages in social behaviors or asocial repetitive self-grooming. This discovery may have implications for understanding neural circuit dysfunctions that underlie autism in humans.

This discovery, which is like a “seesaw circuit,” was led by postdoctoral scholar Weizhe Hong in the laboratory of David J. Anderson, the Seymour Benzer Professor of Biology at Caltech and an investigator with the Howard Hughes Medical Institute. The work was published online on September 11 in the journal Cell. 

"We know that there is some hierarchy of behaviors, and they interact with each other because the animal can’t exhibit both social and asocial behaviors at the same time. In this study, we wanted to figure out how the brain does that," Anderson says.

Anderson and his colleagues discovered two intermingled but distinct populations of neurons in the amygdala, a part of the brain that is involved in innate social behaviors. One population promotes social behaviors, such as mating, fighting, or social grooming, while the other population controls repetitive self-grooming—an asocial behavior.

Interestingly, these two populations are distinguished according to the most fundamental subdivision of neuron subtypes in the brain: the “social neurons” are inhibitory neurons (which release the neurotransmitter GABA, or gamma-aminobutyric acid), while the “self-grooming neurons” are excitatory neurons (which release the neurotransmitter glutamate, an amino acid).

To study the relationship between these two cell types and their associated behaviors, the researchers used a technique called optogenetics. In optogenetics, neurons are genetically altered so that they express light-sensitive proteins from microbial organisms. Then, by shining a light on these modified neurons via a tiny fiber optic cable inserted into the brain, researchers can control the activity of the cells as well as their associated behaviors.

Using this optogenetic approach, Anderson’s team was able to selectively switch on the neurons associated with social behaviors and those linked with asocial behaviors.

With the social neurons, the behavior that was elicited depended upon the intensity of the light signal. That is, when high-intensity light was used, the mice became aggressive in the presence of an intruder mouse. When lower-intensity light was used, the mice no longer attacked, although they were still socially engaged with the intruder—either initiating mating behavior or attempting to engage in social grooming.

When the neurons associated with asocial behavior were turned on, the mouse began self-grooming behaviors such as paw licking and face grooming while completely ignoring all intruders. The self-grooming behavior was repetitive and lasted for minutes even after the light was turned off.

The researchers could also use the light-activated neurons to stop the mice from engaging in particular behaviors. For example, if a lone mouse began spontaneously self-grooming, the researchers could halt this behavior through the optogenetic activation of the social neurons. Once the light was turned off and the activation stopped, the mouse would return to its self-grooming behavior.

Surprisingly, these two groups of neurons appear to interfere with each other’s function: the activation of social neurons inhibits self-grooming behavior, while the activation of self-grooming neurons inhibits social behavior. Thus these two groups of neurons seem to function like a seesaw, one that controls whether mice interact with others or instead focus on themselves. It was completely unexpected that the two groups of neurons could be distinguished by whether they were excitatory or inhibitory. “If there was ever an experiment that ‘carves nature at its joints,’” says Anderson, “this is it.”

This seesaw circuit, Anderson and his colleagues say, may have some relevance to human behavioral disorders such as autism.

"In autism," Anderson says, "there is a decrease in social interactions, and there is often an increase in repetitive, sometimes asocial or self-oriented, behaviors"—a phenomenon known as perseveration. "Here, by stimulating a particular set of neurons, we are both inhibiting social interactions and promoting these perseverative, persistent behaviors."

Studies from other laboratories have shown that disruptions in genes implicated in autism show a similar decrease in social interaction and increase in repetitive self-grooming behavior in mice, Anderson says. However, the current study helps to provide a needed link between gene activity, brain activity, and social behaviors, “and if you don’t understand the circuitry, you are never going to understand how the gene mutation affects the behavior.” Going forward, he says, such a complete understanding will be necessary for the development of future therapies.

But could this concept ever actually be used to modify a human behavior?

"All of this is very far away, but if you found the right population of neurons, it might be possible to override the genetic component of a behavioral disorder like autism, by just changing the activity of the circuits—tipping the balance of the see-saw in the other direction," he says.