Emily Haines, MSc, PhD (c) – Brain Blogger http://brainblogger.com Health and Science Blog Covering Brain Topics Wed, 30 May 2018 15:00:03 +0000 en-US hourly 1 https://wordpress.org/?v=4.9.6 Smells Like Parkinson’s Disease http://brainblogger.com/2012/04/08/smells-like-parkinsons-disease/ http://brainblogger.com/2012/04/08/smells-like-parkinsons-disease/#comments Sun, 08 Apr 2012 10:59:45 +0000 http://brainblogger.com/?p=10285 Parkinson’s disease has always been primarily seen as a movement disorder resulting in symptoms of shaking, tremors, rigidity, and trouble walking. Interestingly, however, at least 90% of patients with Parkinson’s experience either loss or decreases in the sense of smell. Studies have shown that problems with olfaction actually generally precede the onset of other motor symptoms. Most people are not personally aware of changes in their olfactory acuity, but the increasing range and prevalence of smell tests offer a quick, easy, cheap, and non-invasive diagnostic test, as well as a measure of disease progression. In addition, the shift of focus for researchers from Parkinson’s as a motor disorder to a more global neurodegenerative disorder allows consideration of new paradigms about the causes and disease progression.

The cellular basis of olfactory dysfunction in Parkinson’s remains an enigma. Post-mortem studies have confirmed shrinkage of the olfactory bulb, but this fails to shed light onto the root causes as it only demonstrates the end effect. Experimental models of Parkinson’s have demonstrated various results such as protein aggregation in the olfactory bulb, changes in levels of neurotransmitters, microglial activation, and loss of cells in the olfactory bulb. However, as all of these effects are inter-related, none of these clarify the actual initial cause of damage.
Many of the hypotheses as to why olfactory dysfunction occurs and precedes other symptoms remain grounded in the long-held paradigm of Parkinson’s as a motor disease caused by the loss of dopaminergic neurons in the substantia nigra. For example, in some experimental models an increase in dopamine was found in the olfactory bulb. The researchers suggested this occurs as a compensatory mechanism in response to the loss of dopamine in the substantia nigra. As it has also been shown that sense of smell is particularly vulnerable to changes in dopamine, excess dopamine in the olfactory bulb would, thus, lead to olfactory dysfunction.

However, a number of other theories have been proposed suggesting that perhaps the olfactory bulb is the first brain structure to exhibit signs of damage because Parkinson’s could be caused by respiratory viruses or inhaled toxins that enter the brain through the nose. The cause of Parkinson’s has not been conclusively determined. And while a genetic component has been uncovered, the causes are clearly much more complex with various environmental factors involved. A number of studies have been performed demonstrating Parkinson’s-like symptoms following exposure to viruses, heavy metals, and pesticides in experimental models. Epidemiological studies have also linked pesticides exposure to an increased risk of Parkinson’s. It is certainly an interesting hypothesis that inhaled toxins could cross the blood brain barrier, and that the damage in Parkinson’s could begin first in the olfactory bulb and then spread from there to the substantia nigra. In addition, as the olfactory bulb is heavily involved in adult neurogenesis, any damage to this structure could severely limit the brain’s ability to repair itself by replenishing damaged neurons with new ones. Perhaps, then, Parkinson’s disease does not depend on a single source of damage, but rather multiple insults occurring. For example, genetically induced damage to the dopaminergic neurons in the substantia nigra combined with inhaled toxins damaging the olfactory bulb could, together, cause Parkinson’s, while one or the other would be insufficient.

References

Prediger, R., Aguiar, A., Matheus, F., Walz, R., Antoury, L., Raisman-Vozari, R., & Doty, R. (2011). Intranasal Administration of Neurotoxicants in Animals: Support for the Olfactory Vector Hypothesis of Parkinson’s Disease Neurotoxicity Research, 21 (1), 90-116 DOI: 10.1007/s12640-011-9281-8

Doty, R. (2011). Olfaction in Parkinson’s disease and related disorders Neurobiology of Disease DOI: 10.1016/j.nbd.2011.10.026

Ubeda-Bañon, I., Saiz-Sanchez, D., Rosa-Prieto, C., & Martinez-Marcos, A. (2011). ?-Synuclein in the olfactory system of a mouse model of Parkinson’s disease: correlation with olfactory projections Brain Structure and Function DOI: 10.1007/s00429-011-0347-4

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Shifting Paradigms of White Matter Diseases http://brainblogger.com/2012/03/14/shifting-paradigms-of-white-matter-diseases/ http://brainblogger.com/2012/03/14/shifting-paradigms-of-white-matter-diseases/#comments Thu, 15 Mar 2012 00:28:17 +0000 http://brainblogger.com/?p=10225 Oligodendrocytes, the cells that make “white matter” white play an important role in conducting signals through the brain and spinal cord. The breakdown and loss of oligodendrocytes has long been implicated in demyelinating disorders, most notably multiple sclerosis (MS). However, scientists increasingly understand that oligodendrocytes dysfunction may be to blame for neuropsychological disorders such as bipolar disorder and schizophrenia.

Oligodendrocytes insulate neurons by wrapping layers of fat, or myelin, around the axons, the long processes of neurons that convey signals. A myelinated axon, thus, resembles a branch with a series of evenly spaced croissants wrapped around it. This allows a signal to jump along the spaces between the myelination instead of traveling along the entire axon. Myelination allows the neural equivalent of taking the subway instead of walking.

As oligodendrocytes play such an important role in information processing in the brain, the loss of myelination can be devastating. The most well known demyelinating disorder is MS, in which the immune system attacks oligodendrocytes and breaks down the myelin. If myelination is the neural equivalent of signals riding the subway, demyelinating disorders close the subway lines forcing passengers to walk. This then disrupts the coordination of signals sent through the brain. In MS, this results in problems with motor control and movement.

But movement is not the only brain function that requires the complex coordination of signals. The brain is constantly receiving and processing information, making decisions, and sending instructions. These processes also require the coordination inputs with appropriate decisions and actions. Furthermore, myelin is known to be intimately involved in higher brain functions like cognition and learning. As a result, scientist and neurologists have recently begun looking at the similarities between MS and other neuropsychiatric disorders such as schizophrenia and bipolar disorder. Oligodendrocyte dysfunction and a loss of white matter have been implicated in these neuropsychiatric disorders. Imaging studies have shown that patients with bipolar disorder and schizophrenia have less white matter than healthy patients. And post-mortem studies have demonstrated a cessation of development of new myelin in early adulthood in patients with bipolar disorder, compared to a steady decrease over a lifetime in healthy patients.

Although anti-psychotics have always been assumed to act on neurons, the evidence is mounting that they actually function by improving myelination. Lithium, for example, acts on a number of the pathways involved in myelination, and has even been effective in treating experimental models of MS. It seems, therefore, possible that the emotional and cognitive dysregulation in these disorders actually results from an inability of the brain to coordinate the flow of information received from the environment with the proper emotional output? If oligodendrocytes are, in fact, responsible these disorders, this could lead to additional innovative treatment strategies.

References

Emery, B. (2010). Regulation of Oligodendrocyte Differentiation and Myelination Science, 330 (6005), 779-782 DOI: 10.1126/science.1190927

Nave, K. (2010). Myelination and support of axonal integrity by glia Nature, 468 (7321), 244-252 DOI: 10.1038/nature09614

Bartzokis, G. (2012). Neuroglialpharmacology: Myelination as a shared mechanism of action of psychotropic treatments Neuropharmacology DOI: 10.1016/j.neuropharm.2012.01.015

Image via Donna Beeler / Shutterstock.

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The Many Emerging Roles of Astrocytes http://brainblogger.com/2012/02/03/the-many-emerging-roles-of-astrocytes/ http://brainblogger.com/2012/02/03/the-many-emerging-roles-of-astrocytes/#comments Fri, 03 Feb 2012 12:00:15 +0000 http://brainblogger.com/?p=9875 Astrocytes, the star-shaped glial cells in the brain, were long believed to play only supportive roles to the electrically active neurons involved in information processing in the brain. The past few decades, however, have seen an explosion of interest in and research on these cells. Scientists have unearthed an increasing number of functions for astrocytes in neural signalling. It has become clear that astrocytes were grossly underestimated in their size, capabilities, and complexity. Given this, is it possible that astrocytes not only support neural signalling, but themselves play a distinct and active role in the information processing of the brain?

Astrocytes are not electrically active in the classic way that neurons are. They were, therefore, long assumed not to play any active roles in neural signalling. However, experimental methods that allowed for the measurement of calcium release from cells, demonstrated that astrocytes communicated, not through electricity and voltage, but through calcium signalling. Calcium is involved in, but not necessarily responsible for neural signalling. By altering the calcium concentrations around a cell, the astrocytes can influence, but not initiate neural signalling. It could change the likelihood of a neuron firing, the speed at which a neuron could fire, or the size and strength of a connection between two neurons. Calcium, therefore, can add a level of sophistication in signalling to the otherwise binary code of neural processing.

In addition to playing complex roles in the brain, scientists grossly underestimated their size and reach. For many years, scientists used GFAP (glial fibrillary acidic protein), a protein known to be found on astrocytes, in order to view them under a microscope. Using GFAP, astrocytes look like stars: a cell body with processes extending into points. However, over the past decade, scientists began looking at astrocytes by injecting a dye into the cell that would stain the entire cell from the inside. These experiments showed that these initial GFAP-labelled processes actually branch into ever smaller processes, extending across a much greater area than previously seen. Astonishingly, GFAP had been labelling a mere 15% of the entire cell. The sheer extent of these cells is impressive. A single astrocyte in the human brain may have connections with as many as two million neurons. Their processes extend to every corner of the brain and spinal cord.

Astrocytes play a number of important roles in the developing, healthy, and diseased brain. They are involved in cerebral blood flow and metabolism, water transport, act as neural stem cells in neural development, and respond to damage in the brain. In addition, an increasing  number of functions for astrocytes in signalling and information processing have been proposed. Some of these new roles, such as the ability of astrocytes to release neurotransmitters, just like neurons, remain controversial. However, the sheer size and complexity of these cells suggests astrocytes form a sophisticated and interconnected network across the entire brain.

The human brain is significantly more complex than any other animal’s. And yet, other than increasing in number, neurons remain relatively similar across species, regardless of cognitive ability. Astrocytes, on the other hand, become larger, more complex, and more diverse in addition to more numerous as species go up the evolutionary chain. Could these long-underestimated cells be responsible for the complex cognitive tasks that separate the human brain from other animals?

References

Hamilton, N., & Attwell, D. (2010). Do astrocytes really exocytose neurotransmitters? Nature Reviews Neuroscience, 11 (4), 227-238 DOI: 10.1038/nrn2803

Freeman, M. (2010). Specification and Morphogenesis of Astrocytes Science, 330 (6005), 774-778 DOI: 10.1126/science.1190928

Giaume, C., Koulakoff, A., Roux, L., Holcman, D., & Rouach, N. (2010). Astroglial networks: a step further in neuroglial and gliovascular interactions Nature Reviews Neuroscience, 11 (2), 87-99 DOI: 10.1038/nrn2757

Nag S (2011). Morphology and properties of astrocytes. Methods in molecular biology (Clifton, N.J.), 686, 69-100 PMID: 21082367

Image via vetpathologist / Shutterstock.

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The Brain’s Border Patrol – Blood Brain Barrier http://brainblogger.com/2012/01/18/the-brains-border-patrol-blood-brain-barrier/ http://brainblogger.com/2012/01/18/the-brains-border-patrol-blood-brain-barrier/#comments Wed, 18 Jan 2012 12:00:27 +0000 http://brainblogger.com/?p=9223 The blood brain barrier (BBB) forms a tight security gateway between blood vessels and brain tissue. Blood flow throughout the brain is crucial to deliver the oxygen and nutrients required for the brain to function properly. Even though the brain comprises only about 2% of body mass, it is responsible for nearly a quarter of the body’s oxygen consumption. Blood flow is so crucial to the brain that when blood flow stops, brain functions halt within seconds. At the same time the brain also requires a very specific environment in order to function properly. Miniscule changes in pH, chemical concentrations, and protein composition around brain cells can have drastic and detrimental effects to cellular signaling and thus, brain function. The BBB acts as the border control to the brain, selectively allowing the necessary molecules to pass through while denying entry to everything else flowing through the blood vessels.

The BBB plays an important role in brain diseases. A tightly closed BBB prevents drugs from crossing into the brain to treat diseases. And, breakdown of this barrier has been implicated in a wide variety of neurodegenerative diseases including epilepsy, multiple sclerosis, Parkinson’s, and Alzheimer’s. Furthermore, an opening of the BBB following stroke and brain trauma appears to exacerbate damage and lead to worsened outcomes. Therefore, scientists are increasingly interested in learning how to manipulate the barrier: temporarily opening the BBB to deliver drugs to the brain, and closing it to prevent damage from diseases.

The mechanisms of BBB opening and closing are not yet fully understood. The barrier is made up of so-called tight junctions between the endothelial cells lining the blood vessels. These tight junctions are formed by a series of proteins on the outside of the cells that interlock with each other, much like a zipper, creating a seal between cells. On the brain tissue side of the BBB, astrocytes, neurons, and pericytes are able to modulate the tightness of the seal in response to a variety of conditions. BBB opening appears to play a beneficial role following disease and trauma. It may help in clearing cellular debris remaining from extensive cell death, as well as the damaging proteins that aggregate in Alzheimer’s and Huntington’s. But, in a variety of neurodegenerative disorders, a loss of tight junction proteins causes the BBB to become leaky, which has been associated with a worsening of symptoms. In some neurodegenerative disorders such as stroke and multiple sclerosis, it appears that BBB opening also allows immune cells from the rest of the body into the brain, and these cells exacerbate the damage by attacking healthy cells. As with many complex responses to damage in the brain, it seems likely that a small opening is helpful, but a prolonged, chronic opening is detrimental.

Due to its complexity, research on the BBB is technically difficult. However, scientists are beginning to understand the complex role this structure plays and how its opening and closing may be manipulated. There are a number of therapies currently in development that utilize this greater understanding of the BBB. Therapies targeting the BBB present an exciting opportunity to develop novel and unique therapies to treat brain disorders by temporarily opening a closed BBB to deliver drugs to the brain and closing an open BBB to prevent further damage.

References

Neuwelt, E., Bauer, B., Fahlke, C., Fricker, G., Iadecola, C., Janigro, D., Leybaert, L., Molnár, Z., O’Donnell, M., Povlishock, J., Saunders, N., Sharp, F., Stanimirovic, D., Watts, R., & Drewes, L. (2011). Engaging neuroscience to advance translational research in brain barrier biology Nature Reviews Neuroscience, 12 (3), 169-182 DOI: 10.1038/nrn2995

Zlokovic, B. (2011). Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders Nature Reviews Neuroscience DOI: 10.1038/nrn3114

Image via Johannes Kornelius / Shutterstock.

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Mighty Microglia – The Brain’s Immune Cells Key to Treating Brain Diseases http://brainblogger.com/2012/01/06/mighty-microglia-the-brains-immune-cells-could-be-the-key-to-treating-brain-diseases/ http://brainblogger.com/2012/01/06/mighty-microglia-the-brains-immune-cells-could-be-the-key-to-treating-brain-diseases/#comments Fri, 06 Jan 2012 12:00:49 +0000 http://brainblogger.com/?p=8940 Microglia, the immune cells of the brain, were long thought to be rather boring cells that existed in only two states — resting and activated. It was long believed that in the healthy brain microglia lay waiting doing nothing until serious damage was detected. If the brain was infected or damaged, microglia were thought to respond similarly to the immune cells in the rest of the body — swelling, fighting invading micro-organisms, then returning to a resting state and doing nothing further. However, over the past few years, increasingly sophisticated experiments have demonstrated that these cells are capable of a wide range of unexpected activities and responses. As a result, these previously ignored cells are turning out to be promising targets for new drugs to treat a wide range of neurodegenerative disorders.

Microglia, it turns out, actually play an important role in keeping the brain healthy. Improved microscopy has been able to show that while these cells appear to be “resting”, they, in fact, have very fine processes extending out from the cell bodies constantly searching the brain for damage. It has been estimated that every few hours the entire human brain has been checked for health. Like a sentry in a watchtower, in order to stay in this surveillance state microglia require a constant, “all is well,” signal from the surrounding cells. If they fail to receive this signal, the microglia jump into action to investigate the problem.

If damage has occurred, microglia are also capable of a sophisticated range of responses depending on the level of damage. If the damage is small, cells can send out a “find me” signal. The microglia are activated to a protective state and seek out these cells. They attempt to stabilise the damage and protect the nearby neurons. However, if the damage is greater or more dangerous to surrounding tissue, these cells will send out an “eat me” signal. The microglia then become fully activated to a toxic state. They can kill infected cells before infection spreads and clear any debris from damaged or dying cells.

Microglia thus must effectively decide whether to protect or destroy cells in response to insults. Unfortunately, as the brain ages, these cells seem to become less efficient at reacting. The same signal that induces microglia to a protective state in a young brain may induce a fully activated, toxic state in an older brain. It appears that in older brains, microglia overreact to damage and disease. Instead of protecting brain tissue from further damage, they aggravate the problem by becoming fully activated and attacking healthy brain cells.

Microglia are, therefore, a very interesting target for therapies for all neurodegenerative diseases such as Parkinson’s Disease, Alzheimers Disease, multiple sclerosis, stroke, and so on. The goal of many scientists is now to differentiate the types of signals that control the states of activation of microglia and exploit these in creating new drugs. While calming the microglia into a protective state will not cure the underlying neurodegenerative disorders, it could slow the damage and disease progression. This may even help the brain repair some of the damage, recover lost tissue, and ease the symptoms of these diseases.

References

Kettenmann, H., Hanisch, U., Noda, M., & Verkhratsky, A. (2011). Physiology of Microglia Physiological Reviews, 91 (2), 461-553 DOI: 10.1152/physrev.00011.2010

Nimmerjahn, A. (2005). Resting Microglial Cells Are Highly Dynamic Surveillants of Brain Parenchyma in Vivo Science, 308 (5726), 1314-1318 DOI: 10.1126/science.1110647

Hanisch, U., & Kettenmann, H. (2007). Microglia: active sensor and versatile effector cells in the normal and pathologic brain Nature Neuroscience, 10 (11), 1387-1394 DOI: 10.1038/nn1997

Image via Christopher Meade / Shutterstock.

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