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Posts Tagged ‘neurobiology

Neural Progenitor Cells As Reservoirs For HIV In The Brain

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Impaired brain function is a prominent and still unsolved problem in AIDS. Shortly after an individual becomes infected with HIV, the virus can invade the brain and persist in this organ for life. Many HIV-infected individuals experience disturbances in memory functions and movement, which can progress to serious dementia. How the virus causes brain disease is still unclear.

HI-Virus leaving a cell. (Credit: NIH)

Dr. Ruth Brack-Werner and her team at the Institute of Virology of the German Research Center for Environmental Health previously demonstrated that HIV invades not only brain macrophages but also astrocytes. Astrocytes are the most abundant cells in the brain. They perform many important activities which support functions of nerve cells and protect them from harmful agents. HIV-infected astrocytes normally restrain the virus and prevent its production. However, various factors can cause astrocytes to lose control over the virus, allowing the virus to replicate and to reach the brain. There HIV can infect other brain cells as well as immune cells that patrol the brain and may carry the virus outside the brain.

Thus astrocytes form a reservoir for HIV in infected individuals and represent a serious obstacle to elimination of the virus from infected individuals. Whether this also applies to other types of brain cells was unclear until now. In a study recently published in AIDS, Dr. Brack Werner, together with Ina Rothenaigner and colleagues present data indicating that neural progenitor cells can also form HIV reservoirs in the brain. Neural progenitor cells are capable of developing into different types of brain cells and have an enormous potential for repair processes in the brain.

Dr. Brack-Werner’s team used a multi-potent neural progenitor cell line, which can be grown and developed to different types of brain cells in the laboratory, for their studies. After exposing these neural progenitor cells to HIV, they examined the cultures for signs of virus infection for 115 days. HIV was found to persist in these cultures during the entire observation period.

The cultures released infectious HIV particles for over 60 days and contained information for production of HIV regulatory proteins- Tat, Rev and Nef- for even longer. Dr. Brack-Werner and her team also examined neural progenitor cell populations cells with persisting HIV for differences from uninfected cells. They found that HIV persistence had an influence on the expression of selected genes and on cell morphology, but did not prevent their development to astrocytes. Thus HIV persistence has the potential to change neural progenitor cells.

Dr. Brack-Werner’s summarizes, “Our study indicates that neural progenitor cells are potential reservoirs for HIV and that HIV persistence has the potential to change the biology of these cells.” In future studies the researchers are planning to investigate the influence of HIV infection on important functions of neural progenitor cells. These include migration to diseased regions of the brain and development of different types of brain cells. Subsequently they will investigate how HIV changes neural progenitor cells and, importantly, how to protect neural progenitor cells from harmful effects of the virus in HIV infected individuals.

AIDS. 2007 Nov 12;21(17):2271-81.
Long-term HIV-1 infection of neural progenitor populations.
Rothenaigner I, Kramer S, Ziegler M, Wolff H, Kleinschmidt A, Brack-Werner R.

GSF–National Research Center for Environment and Health, Institute of Molecular Virology, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany.

BACKGROUND: HIV can reside in the brain for many years. While astrocytes are known to tolerate long-term HIV infection, the potential of other neural cell types to harbour HIV is unclear. OBJECTIVE: To investigate whether HIV can persist in neural progenitor cell populations. DESIGN: A multipotent human neural stem cell line (HNSC.100) was used to compare HIV infection in neural progenitor and astrocyte cell populations. METHODS: Expression of cellular genes/proteins was analysed by real-time reverse transcriptase PCR, Western blot, immunocytochemistry and flow cytometry. Morphological properties of cells were measured by quantitative fluorescent image analysis. Virus release by cells exposed to HIV-1IIIB was monitored by enzyme-linked immunosorbent assay for Gag. Proviral copy numbers were determined by real-time PCR and early HIV transcripts by reverse transcriptase PCR. Rev activity was determined with a fluorescent-based reporter assay. RESULTS: Progenitor populations differed from astrocyte populations by showing much lower glial fibrillary acidic protein (GFAP) production, higher cell-surface expression of the CXCR4 chemokine receptor, higher Rev activity and distinct cell morphologies. HIV-exposed progenitor cultures released moderate amounts of virus for over 2 months and continued to display cell-associated HIV markers (proviral DNA, early HIV transcripts) during the entire observation period (115 days). Differentiation of HIV-infected progenitor cells to astrocytes was associated with transient activation of virus production. Long-term HIV infection of progenitor populations led to upregulation of GFAP and changes in cell morphology. CONCLUSION: These studies suggest that neural progenitor populations can contribute to the reservoir for HIV in the brain and undergo changes as a consequence of HIV persistence.

Written by huehueteotl

March 7, 2008 at 12:56 pm

Posted in HIV

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‘Satiety Center’ Of The Mouse Brain

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By pitting two forces — hunger and circadian rhythms — against each other, researchers at Rockefeller University have identified the region of the mouse brain that first registers changes in food availability. The research, as aforesaid in mice, suggests that shifting the timing of a meal increases mental alertness even during times when they are usually at rest, findings that, perhaps, may have implications for targeting health concerns such as obesity and diabetes as well as optimizing performance on tasks that require sustained vigilance in humans.

To pit the need for food against the need for sleep, scientists led by Donald Pfaff, head of the Laboratory of Neurobiology and Behavior, gradually shifted the mice’s mealtime during the night, when mice are most active, to a four-hour window during the day, when they are usually at rest. Three days after the mealtime shift, the mice began to show classic signs of anticipatory behavior: wheel-running an hour or two before the timed meal. Compared to control animals, the shifted mice ran three times the distance on the wheel — increased activity signaling a heightened sense of alertness. This behavior also suggests that the light-dark cycle no longer regulated the mice’s behavioral arousal; food did.

The researchers used immunocytochemistry to test where in the brain these two arousal pathways converge. Out of the 16 brain regions tested, only one had become activated: the ventromedial hypothalamus, a group of neurons known as the satiety center of the brain. Animals, including humans, tend to stop eating when this region is activated, and damage to this group of neurons leads to obesity. The activity of the paraventricular nucleus, a region that produces many hormones, was decreased.

“Since we examined the brain as close as possible to the development of this anticipatory behavior,” says postdoc Ana Ribeiro, “the neuronal changes we observed are the ones most likely causing the changes in behavioral arousal. These regions are thus the best targets for modulating arousal.”

As about implications for humans, first author Ribeiro daringly claims that to optimize performance on tasks that require sustained vigilance, ones performed by air-traffic controllers, physicians, the military and others, understanding the neural mechanisms and molecules involved in mediating arousal becomes important. “This research,” she says, “gives us a big clue as to what these mechanisms may be.”

PNAS | December 11, 2007 | vol. 104 | no. 50 | 20078-20083
Two forces for arousal: Pitting hunger versus circadian influences and identifying neurons responsible for changes in behavioral arousal
Ana C. Ribeiro*,{dagger}, Evelyn Sawa*, Isabelle Carren-LeSauter*, Joseph LeSauter{ddagger}, Rae Silver{ddagger},§, and Donald W. Pfaff*,{dagger}

*Laboratory of Neurobiology and Behavior, The Rockefeller University, New York, NY 10021; {ddagger}Department of Psychology, Barnard College, New York, NY 10027; §Department of Psychology, Columbia University, New York, NY 10027; and Department of Anatomy and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032

Contributed by Donald W. Pfaff, October 24, 2007 (received for review July 6, 2007)

The mechanisms underlying CNS arousal in response to homeostatic pressures are not known. In this study, we pitted two forces for CNS arousal against each other (circadian influences vs. restricted food availability) and measured the neuronal activation that occurs in a behaviorally defined group of animals that exhibited increased arousal in anticipation of feeding restricted to their normal sleeping time. The number of c-FOS+ neurons was significantly increased only in the ventromedial nucleus of the hypothalamus (VMH) in these mice, compared with control animals whose feeding was restricted to their normal active and feeding time (P < 0.01). Because the activation of VMH neurons coincides with the earliest signs of behavioral arousal preceding a change in meal time, we infer that VMH activation is involved in the increased arousal in anticipation of food.

Written by huehueteotl

January 29, 2008 at 9:54 am