Microglia controls neuron production as brain develops

In a surprise breakthrough, researchers at the UC Davis MIND Institute and their colleagues have found that microglia remove healthy neural progenitor cells (NPCs) through phagocytosis to control neuron production during brain development. This newly discovered mechanism keeps neuron numbers in check, preventing brain overgrowth.

The discovery could open up new avenues for brain research and lead to therapies for a variety of neurological conditions.

The study was published online in the The Journal of Neuroscience.

Microglia are the immune component cell of the central nervous system. Similar to macrophages, microglia provide the brain’s primary defense against pathogens and foreign bodies, clear away dying cells and help repair neural damage. When inactive, they act as sentinels. When a problem is located, they activate and eliminate it. However, until recently, no one had realized the important roles they play in brain development.

"We have known for some time that neurons can undergo apoptosis, a form of cell death, and ultimately be removed by microglia," said Stephen Noctor, assistant professor in the Department of Psychiatry and Behavioral Sciences and the study’s lead author. "But this is new. Microglia are actually eating healthy progenitor cells, thereby regulating the number of neurons produced in the developing brain."

During development, NPCs produce neurons in the brain’s proliferative zones. However, creating too many or too few neurons can have dire consequences.

"If you have too many cells, there’s only so much trophic support (brain infrastructure for cell growth and survival) to keep neurons alive," Noctor said. "All these cells competing for resources could easily throw off connectional properties, altering the way surviving neurons interact. Likewise, having too few cortical cells would have profoundly negative consequences."

(Image: Antoine Triller, Alain Bessis & Serge Marty - Département de Biologie, ENS)

Neuroprosthesis gives rats the ability to ‘touch’ infrared light

Researchers have given rats the ability to “touch” infrared light, normally invisible to them, by fitting them with an infrared detector wired to microscopic electrodes implanted in the part of the mammalian brain that processes tactile information. The achievement represents the first time a brain-machine interface has augmented a sense in adult animals, said Duke University neurobiologist Miguel Nicolelis, who led the research team.

The experiment also demonstrated for the first time that a novel sensory input could be processed by a cortical region specialized in another sense without “hijacking” the function of this brain area said Nicolelis. This discovery suggests, for example, that a person whose visual cortex was damaged could regain sight through a neuroprosthesis implanted in another cortical region, he said.

Although the initial experiments tested only whether rats could detect infrared light, there seems no reason that these animals in the future could not be given full-fledged infrared vision, said Nicolelis. For that matter, cortical neuroprostheses could be developed to give animals or humans the ability to see in any region of the electromagnetic spectrum, or even magnetic fields. “We could create devices sensitive to any physical energy,” he said. “It could be magnetic fields, radio waves, or ultrasound. We chose infrared initially because it didn’t interfere with our electrophysiological recordings.”

Nicolelis and colleagues Eric Thomson and Rafael Carra published their findings February 12, 2013 in the online journal Nature Communications. Their research was sponsored by the National Institute of Mental Health.

Propping Open the Door to the Blood Brain Barrier

The treatment of central nervous system (CNS) diseases can be particularly challenging because many of the therapeutic agents such as recombinant proteins and gene medicines are not easily transported across the blood-brain barrier (BBB). Focused ultrasound can be used to “open the door” of the blood brain barrier. However, finding a way to “prop the door open” to allow therapeutics to reach diseased tissue without damaging normal brain tissue is the focus of a new study by a team of researchers at the Institute of Biomedical Engineering at National Taiwan University presenting at the 57th Annual Meeting of the Biophysical Society (BPS), held Feb. 2-6, 2013, in Philadelphia, Pa.

The group is investigating the feasibility of using heparin, a common anticoagulant, to enhance the delivery of therapeutic macromolecules using ultrasound into the brain. Heparin could be employed to increase treatment efficacy in patients with different types of CNS diseases under the guidance of medical imaging system providing new hope in these challenging cases. Initial results show that heparin does have the potential to optimize therapeutic delivery with ultrasound, acting as a “doorstop,” allowing drugs to better permeate the BBB and enhancing treatment success.

“A higher acoustic pressure and longer sonication, and/or a higher dose of microbubbles may increase the delivery of drugs or tracers into the sonicated brain tissue,” explains Kuo-Wei Lu, a member of the research team, “but side-effects, such as microhemorrhage, can also increase dramatically. The results of this study indicate that heparin may offer a safer way can to enhance the delivery of therapeutics to patients with CNS diseases.”

With these encouraging results, the next step for the team is to develop a focused ultrasound system with Magnetic Resonance Imaging (MRI) guidance to establish suitable parameters needed for patient clinical trials. “Focused ultrasound sonication is a noninvasive technology capable of localized and transient BBB opening for the delivery of CNS therapeutics,” Lu states. “We hope by developing suitable parameters and using chemical enhancers like heparin, this can be a valuable tool in the treatment of patients with CNS diseases, opening the door to better patient outcomes.”

(Image: Ben Brahim Mohammed)

Kynurenines in the CNS: recent advances and new questions

Various pathologies of the central nervous system (CNS) are accompanied by alterations in tryptophan metabolism. The main metabolic route of tryptophan degradation is the kynurenine pathway; its metabolites are responsible for a broad spectrum of effects, including the endogenous regulation of neuronal excitability and the initiation of immune tolerance. This Review highlights the involvement of the kynurenine system in the pathology of neurodegenerative disorders, pain syndromes and autoimmune diseases through a detailed discussion of its potential implications in Huntington’s disease, migraine and multiple sclerosis. The most effective preclinical drug candidates are discussed and attention is paid to currently under-investigated roles of the kynurenine pathway in the CNS, where modulation of kynurenine metabolism might be of therapeutic value.

A step towards repairing the central nervous system

Despite recent advances in understanding the mechanisms of nerve injury, tissue-engineering solutions for repairing damage in the central nervous system (CNS) remain elusive, owing to the crucial and complex role played by the neural stem cell (NSC) niche. This zone, in which stem cells are retained after embryonic development for the production of new cells, exerts a tight control over many crucial tasks such as growth promotion and the recreation of essential biochemical and physical cues for neural cell differentiation.

According to the first author of the paper, Zaida Álvarez, from the Group on Biomaterials for Regenerative Therapies of the Institute for Bioengineering of Catalonia (IBEC), “in order to develop tissue-engineering strategies to repair damage to the CNS, it is essential to design biomaterials that closely mimic the NSC niche and its physical and biochemical characteristics”.

In the study headed by Soledad Alcántara of the Department of Pathology and Experimental Therapeutics, the team tested types of polylactic acid (PLA) with different proportions of isomers L and D/L, a biodegradable material allowing neural cell adhesion and growth, as materials for nerve regeneration. They found that one type, PLA with a proportion of isomers of 70/30, maintained the important pools of neuronal and glial progenitor cells in vitro. PLA 70/30 was more amorphous, degraded faster and, crucially, released significant amounts of L-lactate, which is essential for the maintenance and differentiation of neural progenitor cells. “The aim of the research was to find a biomaterial able to sustain the population of neural stem cells and to generate new differentiated cells in order to start the development of an implant that allows brain regeneration,” explains Dr Alcántara.

“The mechanical and surface properties of PLA70/30, which we used here in the form of microthin films, make it a good substrate for neural cell adhesion, proliferation and differentiation,” adds Álvarez. “The physical properties of this material and the release of L-lactate when it degrades, which provides an alternative oxidative substrate for neural cells, act synergistically to modulate progenitor phenotypes”, concludes the researcher.

The results suggest that the introduction of 3D patterns mimicking the architecture of the embryonic NSC niches on PLA70/30-based scaffolds may be a good starting point for the design of brain-implantable devices. “These will be able to induce or activate existing neural progenitor cells to self-renew and produce new neurons, boosting the CNS regenerative response in situ,” states Álvarez.

Enabling the CNS to regenerate could open doors to promising new strategies to tackle accidental damage as well as numerous diseases like stroke and degenerative disorders such as Parkinson’s and Alzheimer’s diseases.

A better way to culture central nervous cells

A protein associated with neuron damage in people with Alzheimer’s disease is surprisingly useful in promoting neuron growth in the lab, according to a new study by engineering researchers at Brown University. The findings, in press at the journal Biomaterials, suggest a better method of growing neurons outside the body that might then be implanted to treat people with neurodegenerative diseases.

The research compared the effects of two proteins that can be used as an artificial scaffold for growing neurons (nerve cells) from the central nervous system. The study found that central nervous system neurons from rats cultured in apolipoprotein E-4 (apoE4) grew better than neurons cultured in laminin, which had been considered the gold standard for growing mammalian neurons in the lab.

“Most scientists assumed that laminin was the best protein for growing CNS (central nervous system),” said Kwang-Min Kim, a biomedical engineering graduate student at Brown University and lead author of the study, “but we demonstrated that apoE4 has substantially better performance for mammalian CNS neurons.”

Kim performed the research under the direction of Tayhas Palmore, professor of engineering and medical science and Kim’s Ph.D. adviser. Also involved in the project was Janice Vicenty, an undergraduate from the University of Puerto Rico, who was working in the Palmore lab as a summer research fellow through the Leadership Alliance.

The results are surprising partly because of the association of apoE4 with Alzheimer’s. Apolipoproteins are responsible for distributing and depositing cholesterols and other lipids in the brain. They come in three varieties: apoE2, apoE3 and apoE4. People with the gene that produces apoE4 are at higher risk for amyloid plaques and neurofibrillary tangles, the hallmarks of Alzheimer’s. But exactly how the protein itself contributes to Alzheimer’s is not known.

This study suggests that outside the body, where the protein can be separated from the cholesterols it normally carries, apoE4 is actually beneficial in promoting neuron growth.

Prenatal inflammation linked to autism risk

Maternal inflammation during early pregnancy may be related to an increased risk of autism in children, according to new findings supported by the National Institute of Environmental Health Sciences (NIEHS), part of the National Institutes of Health.Researchers found this in children of mothers with elevated C-reactive protein (CRP), a well-established marker of systemic inflammation.

The risk of autism among children in the study was increased by 43 percent among mothers with CRP levels in the top 20th percentile, and by 80 percent for maternal CRP in the top 10th percentile. The findings appear in the journal Molecular Psychiatry and add to mounting evidence that an overactive immune response can alter the development of the central nervous system in the fetus.

“Elevated CRP is a signal that the body is undergoing a response to inflammation from, for example, a viral or bacterial infection,” said lead scientist on the study, Alan Brown, M.D., professor of clinical psychiatry and epidemiology at Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, and Mailman School of Public Health. “The higher the level of CRP in the mother, the greater the risk of autism in the child.”

Botox may help stroke patients

Injecting botox into the arm muscles of stroke survivors, with severe spasticity, changes electrical activity in the brain and may assist with longer-term recovery, according to new research.

Researchers at NeuRA (Neuroscience Research Australia) monitored nerve activity in the arms and brains of stroke survivors before and after botulinum toxin (botox) injections in rigid and stiff muscles in the arm.

They found that botox indeed improved arm muscles, but also altered brain activity in the cortex – the brain region responsible for movement, memory, learning and thinking.

“Botulinum toxin is used to treat a range of muscular and neurological conditions and our data shows that this treatment results in electrical and functional changes within the brain itself”, says Dr William Huynh, lead author of the study and a research neurologist at NeuRA.

“This effect of botox on the brain may arise because the toxin travels to the central nervous system directly, or because muscles treated with botox are sending different signals back to the brain”.

“Either way, we found that botox treatment in affected muscles not only improves muscle disorders in stroke patients, but also normalises electrical activity in the brain, particularly in the half of the brain not damaged by stroke”.

“Restoring normal activity in the unaffected side of the brain is particularly important because we suspect that abnormal information sent from affected muscles to the brain may be disrupting patients’ long-term recovery”, Dr Huynh concluded.

This paper is published in the journal Muscle and Nerve.