Neuroscience

The causes of learning problems associated with an inherited brain tumor disorder are much more complex than scientists had anticipated, researchers at Washington University School of Medicine in St. Louis report.

The disorder, neurofibromatosis 1 (NF1), is among the most common inherited pediatric brain cancer syndromes. Children born with NF1 can develop low-grade brain tumors, but their most common problems are learning and attention difficulties.

“While one of our top priorities is halting tumor growth, it’s also important to ensure that these children don’t have the added challenges of living with learning and behavioral problems,” says senior author David H. Gutmann, MD, PhD, the Donald O. Schnuck Family Professor of Neurology. “Our results suggest that learning problems in these patients can be caused by more than one factor. Successful treatment depends on identifying the biological reasons underlying the problems seen in individual patients with NF1.”

The study appears online in Annals of Neurology.

According to Gutmann, who is director of the Washington University Neurofibromatosis Center, scientists are divided when considering the basis for NF1-associated learning abnormalities and attention deficits.

Mutations in the Nf1 gene can disrupt normal regulation of an important protein called RAS in the hippocampus, a brain region critical for learning. Initial work from other investigators had shown that increased RAS activity due to defective Nf1 gene function impairs memory and attention in some Nf1 mouse models.

However, earlier studies by Gutmann and collaborator David F. Wozniak, PhD, research professor in psychiatry, showed that a mutation in the Nf1 gene lowers levels of dopamine, a neurotransmitter involved in attention. In this Nf1 mouse model, Gutmann and his colleagues found that the branches of dopamine-producing nerve cells were unusually short, limiting their ability to make and distribute dopamine and leading to reduced attention in those mice.

The new research suggests that both sides may be right.

In the latest study, postdoctoral fellow Kelly Diggs-Andrews, PhD, found that the branches of dopamine-producing nerve cells that normally extend into the hippocampus are shorter in Nf1 mice. As a result, dopamine levels are lower in that part of the brain.

Charles F. Zorumski, MD, the Samuel B. Guze Professor and head of the Department of Psychiatry, showed that the low dopamine levels disrupts the ability of nerve cells in the hippocampus to modulate the way they communicate with each other. These communication adjustments are a primary way the brain creates memories.

Researchers then found that giving Nf1 mice L-DOPA, which increases dopamine levels, restored their nerve cell branch lengths to normal and corrected the hippocampal communication defect. L-DOPA also eliminated the memory and learning deficits in these mice.

“These results and the earlier findings suggest that there are a variety of ways that NF1 may cause cognitive dysfunction in people,” Gutmann says. “Some may have problems caused only by increased RAS function, others may be having problems attributable to reduced dopamine, and a third group may be having difficulties caused by both RAS and dopamine abnormalities.”

To customize patient therapy, Gutmann and his colleagues are now working to develop ways to quantify the contributions of dopamine and RAS to NF1-related learning disorders.

The brain’s perception of space can determine whether a part of a body which occupies that space is either healthy or “neglected”.

Lorimer Moseley, Chair in Physiotherapy and Professor of Clinical Neurosciences at the University of South Australia, describes recent outcomes of research into spatial perception of people with complex regional pain syndrome (CRPS) as “profound”.

CRPS is a disorder that can develop after a minor injury occurs to a limb and results in abnormal or severe pain developing out of proportion to the nature of the injury. Other problems also result, for example blood flow problems in which the painful arm or leg goes cold and blue, grows too much hair and stays swollen.

In a series of experiments using thermal imaging cameras, changes in the temperature of the hands of people with CRPS were recorded as they moved them across their body midline.

When only the affected hand was crossed over the midline, it became warmer and when only the healthy hand was crossed over the midline, it became cooler.

The temperature change of either hand was positively related to its distance from the body midline and crossing the affected hand over the body midline had small but significant effects on both spontaneous pain (which was reduced) and the sense of ownership over the hand (which was increased).

Professor Moseley said the results of this research indicated that CRPS involves more complex neurological dysfunction than has previously been considered.

“We conclude that impaired spatial perception modulated temperature of the limbs, tactile processing, spontaneous pain and the sense of ownership over the hands.

“This means that the problem that is occurring with the limb relates to the brain process that maps something into a space. It’s almost as though the brain has rejected the space which the limb inhabits.

"In strokes it’s called spatial neglect. This problem with space affects the way blood is sent to the body. If you remove the hand or limb away from that side of space it warms up.

“When you put a healthy hand into the negative space it cools down; the map of space is influencing the rules by which blood flows. Our current finding is clear evidence of the autonomic nervous system being influenced by the brain’s map of space.

“The space itself has adopted the signature of the disorder. This is a profound discovery, it’s a clear physiological phenomena.

“This midline effect changes how much the patient feels the arm belongs to them and how much it hurts.”

The two infamous proteins, amyloid-beta (Aβ) and tau, that characterize advanced Alzheimer’s disease (AD), start healthy neurons on the road to cell death long before the appearance of the deadly plaques and tangles by working together to reactivate the supposedly blocked cell cycle in brain cells, according to research presented on Dec. 17 at the American Society for Cell Biology’s Annual Meeting in San Francisco.

Working in a mouse model of AD, George Bloom, PhD, of the University of Virginia (UVA) reports that neurons in AD start dying because they break the first law of human neuronal safety ⎯ stay out of the cell cycle.

Most normal adult neurons are permanently postmitotic; that is, they have finished dividing and are locked out of the cell cycle. In contrast, AD neurons frequently re-enter the cell cycle but fail to complete mitosis, and ultimately die. By considering this novel perspective on AD as a problem of the cell cycle, Dr. Bloom and colleagues at UVA and at the University of Alabama, Birmingham, have discovered what they call an “ironic pathway” to neuronal cell death. The process requires the coordinated action of both Aβ and tau, which are the building blocks of plaques and tangles, respectively. Dr. Bloom’s results show just how toxic the two proteins can be even when free in solution and not aggregated into plaques and tangles.

Using mouse neurons grown in culture, the UVA researchers found that Aβ oligomers, which are small aggregates of just a few Aβ molecules each, induce the neurons to re-enter the cell cycle. Interestingly, the neurons must make and accumulate tau in order for this cell cycle re-entry to occur. The mechanism for this misplaced re-entry into the cell cycle requires that Aβ oligomers activate multiple protein kinase enzymes, each of which must then attach a phosphate to a specific site on the tau protein.

Following up on the cell culture results, Dr. Bloom and colleagues confirmed that Aβ-induced, tau-dependent cell cycle re-entry occurs in the brains of mice that were genetically engineered to mimic brains with human AD. The mouse brains were found to accumulate massive numbers of neurons that had transitioned from a permanent cell cycle stop, known as G0 (G zero), to G1, the first stage of the cell cycle, by the time they were 6 months old. Remarkably, otherwise identical mice that lacked functional tau genes showed no sign of cell cycle re-entry, confirming the cell culture results.

Neuronal cell cycle re-entry, a key step in the development of AD, can therefore be caused by signaling from Aβ through tau. Thus, Aβ and tau co-conspire to trigger seminal events in AD pathogenesis independently of their incorporation into plaques and tangles. Most important, Dr. Bloom believes that the activated protein kinases and phosphorylated forms of tau identified in this study represent potential targets for early diagnosis and treatment of AD.

In the late Devonian period, roughly 365 million years ago, fish-like creatures started venturing from shallow waters onto land.

Among the various adaptations associated with the switch to land life was the conversion of fins into limbs. This transition allowed animals to both navigate aquatic habitats and walk on land.

We already know that fins and limbs share the same genetic program for their induction and early development. But due to their divergent morphological traits (form and structure), it was unknown how a fin could evolve into a limb.

But now, a paper published in the journal Developmental Cell by Renata Freitas and colleagues from the University of Andalusia (Seville, Spain), suggests the key to fin-to-limb transition lies in the regulation of the homeotic (responsible for the formation of body parts) gene hoxd13.

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