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.”

Why HIV patients develop dementia

Immune cells in the brain under suspicion

“HIV-associated neurocognitive disorders” (HAND) include disorders of the cognitive functions, motor capacities as well as behavioural changes. How exactly HAND occur has not, as yet, been fully understood. “Scientists assume that HIV is harmful to cells directly and that it also triggers indirect mechanisms that lead to nerve cell damage,” explains Dr Simon Faissner (RUB clinic for neurology, St. Josef-Hospital). The researchers strongly suspect that, once activated in the brain and the spinal cord, immune cells keep up a chronic inflammation level which then results in the destruction of nerve cells. An immune activation in peripheral tissue as well as therapeutic consequences may likewise contribute to nerve cell damage in the brain.

First steps of HIV infection are sufficient

The HI virus overcomes the blood-brain barrier hitchhiking on infected immune cells, the monocytes and probably the T cells. The researchers from Bochum tested the hypothesis that HIV-infected monocytes activate specific immune cells in the brain, the so-called microglial cells. These cells, in turn, respond by releasing harmful substances, such as reactive oxygen metabolites and inflammatory signalling molecules, i.e. cytokines. To test this hypothesis, the researchers developed a cell culture system in which they initially examined the effect of HIV-infected monocytes on microglial cells. The researchers simulated the individual steps of HIV infection and measured the concentration of the cytokines released at each stage. Thus, they were able to demonstrate that releasing the viral RNA in the monocytes was a sufficient trigger for maximal microglial activation. Subsequent infection phases – reverse transcription into DNA and the resulting formation of HIV proteins – did not augment activation any further.

Released substances result in neuronal cell death

In the second step, they analysed nerve cells from rat brains to determine if the substances released by the microglial cells could lead to cell death. Compared with the control group, the amount of cell death was indeed twice as high. Studies of liquor cerebrospinalis received from HIV-infected patients have shown a positive correlation with marker of neuronal degeneration in patients who did not as yet present any neurocognitive disorders.

Detailed understanding necessary for therapeutic strategies

“Thanks to our research, we have gained a better understanding of the mechanisms of HIV-associated neurodegeneration,” concludes Prof Dr Andrew Chan. “These results are likely to contribute to HAND biomarkers becoming established. In the long term, these data may be used to develop therapeutic strategies aiming at retarding HAND progression in HIV-infected patients.” Starting points may include activation of microglial cells – a method that is applied in other autoimmune diseases of the central nervous system, for example in multiple sclerosis.

Start-up through FoRUM funds

The research, which was initiated following a collaboration between clinics for neurology and dermatology, St. Josef Hospital, as well as the Department for Molecular and Medical Virology, has been made possible through start-up funding provided by the Faculty of Medicine at Ruhr-Universität (FoRUM). The collaboration has evolved into an international consortium of clinics and basic research organisations in Bochum, Langen, Strasbourg and Mailand. One objective of the follow-up study, for which an application for EU funds is pending, is going to be an in-depth analysis of inflammatory processes in the central nervous system. The researchers will attempt to inhibit inflammatory processes with different drugs. They are, moreover, planning to study direct cell-cell interaction by means of state-of-the-art microscopy, in collaboration with the University of Strasbourg.

(Image credit: Mehau Kulyk/Science Photo Library)

How Aging Can Intensify Damage of Spinal Cord Injury

In the complex environment of a spinal cord injury, researchers have found that immune cells in the central nervous system of elderly mice fail to activate an important signaling pathway, dramatically lowering chances for repair after injury.

These studies were the first to show that spinal cord injuries are more severe in elderly mice than in young adults, corroborating previous anecdotal findings from clinical settings. They also revealed a previously unknown player in the repair of spinal cord injuries in young adults.

A key messenger in that pathway is a receptor on the surface of microglia, immune system cells in the central nervous system that are called into action by the trauma of the spinal cord injury.

In young adult mice, this receptor is activated by microglia to recognize and make use of an inflammation-related signaling chemical that is found in the central nervous system after a spinal cord injury. The microglia in the elderly mice, however, do not activate the receptor at all.

The study showed that the difference in receptor activation has consequences later in the recovery process. The kinds of cells recruited to the injury site in young adult mice appear to have more value in the repair process than do the cells that show up in elderly mice. A host of experiments traced those differing effects back to whether or not microglia activated the receptor.

“The microglia are regulated by several different cell types and different signals, and it appears a lot of those systems change with age,” said Jonathan Godbout, associate professor of neuroscience at The Ohio State University and senior author of the study.

“We’ve shown evidence that this more severe injury occurs in an aging animal, and that the difference in recovery is related to the ability to express the receptor. The consequence is we have a different profile of cells at the injury site, and in aging mice, that environment is less reparative.”

These differences at the cellular level were associated with vast differences in the characteristics of injury and recovery. The lesions on the injured spinal cord were 38 percent longer, on average, in elderly mice than in young adult mice. In addition, the older mice were unable to gain movement of their hind limbs by the time most younger mice had regained that mobility.

The research is published in the Journal of Neuroscience.

The receptor in question is called the IL-4 alpha receptor, and its job is to “see” the infusion of interleukin-4, or IL-4, in the central nervous system after the spinal injury. IL-4 is a cytokine, a type of protein connected to immune system function. Many cytokines promote inflammation, but IL-4 is associated with curbing inflammation.

Godbout and colleagues observed that IL-4 in the central nervous systems in both young adult and aging mice sent signals to recruit additional repair cells to the injury site – cells called macrophages and monocytes. These are types of white blood cells that originate in the bone marrow and circulate in what is known as the “periphery,” via blood and outside the central nervous system. But only in young adult mice were these types of cells contributors to wound healing and clearing of debris, necessary inflammatory functions that help rather than harm.

“This was surprising to us because aging is typically associated with increased inflammation so we’d expect to see higher levels of inflammatory cytokines in the aged mice,” said first author Ashley Fenn, who just received her Ph.D. in neuroscience from Ohio State. “But in the aged mice with a spinal cord injury, we saw reduced levels of some inflammatory signals associated with a failure to reprogram the microglia with IL-4 toward a reparative profile. That’s how we figured out the IL-4 is unique in the spinal cord injury paradigm, that it induces an inflammatory response that appears to be beneficial.”

The IL-4 in the young adult mice also led to production of arginase, a protein that serves as a biomarker of the injury repair response. Significantly less arginase was detected in the injured elderly mice, another signal that the disabled receptor interfered with IL-4’s assistance in injury repair.

The communication among systems has long been a focus of Godbout’s research. He is an investigator in Ohio State’s Institute for Behavioral Medicine Research (IBMR) and Center for Brain and Spinal Cord Repair.

“There is some level of communication going on between the central nervous system microglia and the peripheral immune system’s macrophages. In our model, differences in that communication affected the ability to bring in cells to the site of the injury. Maybe the aging microenvironment brings in cells that are less beneficial,” he said.

About 200,000 people are currently living with a spinal cord injury in the United States, and an estimated 12,000 to 20,000 new injuries occur each year, according to the Centers for Disease Control and Prevention.

Though any therapy based on this research would take many years to develop, Godbout and Fenn said that finding a drug that could stimulate expression of the IL-4 alpha receptor in elderly spinal cord injury patients might have potential to improve their outcomes.

Study finds stem cell combination therapy improves traumatic brain injury outcomes

Traumatic brain injuries (TBI), sustained by close to 2 million Americans annually, including military personnel, are debilitating and devastating for patients and their families. Regardless of severity, those with TBI can suffer a range of motor, behavioral, intellectual and cognitive disabilities over the short or long term. Sadly, clinical treatments for TBI are few and largely ineffective.

In an effort to find an effective therapy, neuroscientists at the Center of Excellence for Aging and Brain Repair, Department of Neurosurgery in the USF Health Morsani College of Medicine, University of South Florida, have conducted several preclinical studies aimed at finding combination therapies to improve TBI outcomes.

In their study of several different therapies—alone and in combination—applied to laboratory rats modeled with TBI, USF researchers found that a combination of human umbilical cord blood cells (hUBCs) and granulocyte colony stimulating factor (G-CSF), a growth factor, was more therapeutic than either administered alone, or each with saline, or saline alone.

The study appeared in a recent issue of PLoS ONE.

“Chronic TBI is typically associated with major secondary molecular injuries, including chronic neuroinflammation, which not only contribute to the death of neuronal cells in the central nervous system, but also impede any natural repair mechanism,” said study lead author Cesar V. Borlongan, PhD, professor of neurosurgery and director of USF’s Center of Excellence for Aging and Brain Repair. “In our study, we used hUBCs and G-CSF alone and in combination. In previous studies, hUBCs have been shown to suppress inflammation, and G-CSF is currently being investigated as a potential therapeutic agent for patients with stroke or Alzheimer’s disease.”

Their stand-alone effects have a therapeutic potential for TBI, based on results from previous studies. For example, G-CSF has shown an ability to mobilize stem cells from bone marrow and then infiltrate injured tissues, promoting self-repair of neural cells, while hUBCs have been shown to suppress inflammation and promote cell growth.

The involvement of the immune system in the central nervous system to either stimulate repair or enhance molecular damage has been recognized as key to the progression of many neurological disorders, including TBI, as well as in neurodegenerative diseases such as Parkinson’s disease, multiple sclerosis and some autoimmune diseases, the researchers report. Increased expression of MHCII positive cells—cell members that secrete a family of molecules mediating interactions between the immune system’s white blood cells—has been directly linked to neurodegeneration and cognitive decline in TBI.

“Our results showed that the combined therapy of hUBCs and G-CSF significantly reduced the TBI-induced loss of neuronal cells in the hippocampus,” said Borlongan. “Therapy with hUBCs and G-CSF alone or in combination produced beneficial results in animals with experimental TBI. G-CSF alone produced only short-lived benefits, while hUBCs alone afforded more robust and stable improvements. However, their combination offered the best motor improvement in the laboratory animals.”

“This outcome may indicate that the stem cells had more widespread biological action than the drug therapy,” said Paul R. Sanberg, distinguished professor at USF and principal investigator of the Department of Defense funded project. “Regardless, their combination had an apparent synergistic effect and resulted in the most effective amelioration of TBI-induced behavioral deficits.”

The researchers concluded that additional studies of this combination therapy are warranted in order to better understand their modes of action. While this research focused on motor improvements, they suggested that future combination therapy research should also include analysis of cognitive improvement in the laboratory animals modeled with TBI.

Uncovering a Healthier Remedy for Chronic Pain

Physicians and patients who are wary of addiction to pain medication and opioids may soon have a healthier and more natural alternative.

A Duke University study revealed that a derivative of DHA (docosahexaenoic acid), a main ingredient of over-the-counter fish oil supplements, can sooth and prevent neuropathic pain caused by injuries to the sensory system. The results appear online in the Annals of Neurology.

The research focused on a compound called neuroprotectin D1=protectin D1 (NPD1=PD1),  a bioactive lipid produced by cells in response to external stimuli. NPD1=PD1 is present in human white blood cells, and was first identified based on its ability to resolve abdominal and brain inflammation. 

"These compounds are derived from omega-3 fatty acids found in fish oil, but are 1,000 times more potent than their precursors in reducing inflammation," said Ru-Rong Ji, professor of anesthesiology and neurobiology at Duke University Medical Center and principal investigator of the study.  

The team used laboratory mouse models of nerve injuries to simulate pain symptoms commonly associated with post-surgical nerve trauma. They treated these animals with chemically synthesized NPD1=PD1, either through local administration or injection, to investigate whether the lipid compound could relieve these symptoms. 

Their findings revealed that NPD1=PD1 not only alleviated the pain, but also reduced nerve swelling following the injuries. Its analgesic effect stems from the compound’s ability to inhibit the production of cytokines and chemokines, which are small signaling molecules that attract inflammatory macrophages to the nerve cells. By preventing cytokine and chemokine production, the compound protected nerve cells from further damage. NPD1=PD1 also reduced neuron firing so the injured animals felt less pain.

Ji believes that the new discovery has clinical potential. “Chronic pain resulting from major medical procedures such as amputation, chest and breast surgery is a serious problem,” he said. Current treatment options for neuropathic pain include gabapentin and various opioids, which may lead to addiction and destruction of the sensory nerves. 

On the other hand, NPD1=PD1 can relieve neuropathic pain at very low doses and, more importantly, mice receiving the treatment did not show signs of physical dependence or enhanced tolerance toward the lipid compound. 

"We hope to test this compound in clinical trials," Ji said. The initial stages of the trial could involve  DHA administration through diet and injection. "DHA is very inexpensive, and can be converted to NPD1 by an aspirin-triggered pathway," he said. The ultimate goal is to develop a safer approach to managing chronic pain.