ScienceDaily (June 15, 2010) — In what has been hailed as a breakthrough, scientists from Columbia University Medical Center and Weill Cornell Medical College have outlined the molecular mechanism of membrane transport. The research shows how a protein transforms its shape to transport substances across the cell membrane in order to regulate transmission of the brain's messages across the synaptic gap from one neuron to another.
Because widely used medications for depression modulate this transport process by binding to the transporters, the new findings help explain how the medications work, and the way in which stimulants like cocaine and amphetamine produce their effects. This new understanding should also prove useful in the development of more targeted medication therapies for anxiety, depression, schizophrenia and substance abuse.
The researchers looked at transporter proteins in the family of Na+ symporters, which remove neurotransmitters from the synapse in a process called reuptake that is essential to the proper function of neural transmission. Antidepressants such as Prozac and Zoloft, which are selective serotonin reuptake inhibitors (SSRIs), and cocaine interfere with the reuptake mechanism and alter the normal exchange process between cells.
The paper describing the new findings was published in the May 13 issue of Nature and was lauded as a significant contribution to the understanding of the dynamics of the transport cycle in the journal's News & Views section. The reviewers note that until now biologists have been unable to view transporters on a single-molecule detail, but the new research "lifts the curtain and shines a spotlight onto some of the choreography" of membrane transport. In this spotlight, the new research illuminates the pathway of transported molecules revealing how transporter proteins escort ions and molecules through membranes by forming passageways in a manner the researchers liken to gates opening and closing.
"The study of membrane transport proteins and the genes that encode them offers the opportunity to investigate many aspects of disease processes. The opening and closing of the transporter 'gates' is orchestrated by binding of the transported substances and by inhibitory drugs in ways that could not be determined by previous approaches that were unable to resolve movements in individual proteins," says one senior author, Dr. Jonathan Javitch, who is the Lieber Professor of Experimental Therapeutics in the Departments of Psychiatry and Pharmacology and the Center for Molecular Recognition at Columbia University Medical Center.
Exactly how the gates open and close, and why, is not yet fully understood; however, the results from this research are an important step in that direction.
"Advances in technology have enabled cell biologists to see molecular processes at a level of detail that was not possible even in the last decade. Just as the Hubble telescope and computer-assisted tomography have allowed scientists to view objects in outer space and inside the body more clearly and in greater detail, biologists now have new tools to view what is happening at the cellular level and powerful computational methods to mimic these processes in the computer. This research has brought both advances to bear on a fundamental problem in neural transmission," says study co-author Dr. Harel Weinstein, chairman and Maxwell M. Upson Professor of Physiology and Biophysics, and director of the Institute for Computational Biomedicine (ICB) at Weill Cornell Medical College.
Dr. Weinstein credits the work of his colleague Dr. Scott Blanchard, associate professor of physiology and biophysics at Weill Cornell Medical College, in providing the expertise in a new technology that is crucial to this research. Dr. Blanchard and his team developed this new technology over numerous years and it is now at a place where functional motions of individual proteins can be directly visualized in nearly real time.
"Understanding molecular movements is important because enzyme functions hinge on motion," says Dr. Blanchard, another senior author of the new study. "To observe molecules, we attach reporter molecules called fluorophores that can be directly measured at the single-molecule scale. In so doing, motional information can be obtained about the protein to which they are linked."
In the current study, the investigators used this technique to study the LeuT transporter. They were able to monitor changes of individual molecules and reported observing two distinct states which they believe report on the open and closed states of the gating mechanism.
Dr. Weinstein notes that SSRIs were developed without a real understanding of how they work and only now researchers are beginning to understand how they bind and affect the transporters. "These medications are effective in treating many mental illnesses, including depression, obsessive-compulsive disorder and panic disorder, suggesting that these disorders have some relation to serotonin levels in the brain. Our study is the start of understanding how SSRIs work at a mechanistic level, and why they work in some people and not in others."
The study's equally contributing lead authors are Dr. Yongfang Zhao of the Center for Molecular Recognition at Columbia University Medical Center, and Daniel Terry, a graduate student in the Tri-Institutional Program in Computational Biology and Medicine at WCMC; the study is co-authored by Dr. Lei Shi of the Department of Physiology and Biophysics and the ICB, Weill Cornell Medical College.
Wednesday, June 16, 2010
Friday, June 11, 2010
Early Alzheimer's Disease
Impaired memory is typically one of the first signs of Alzheimer's
disease, but difficulty recalling the names of friends or recent events is also common among normal elderly persons. The clinician is thus faced
with the difficulty of distinguishing between normal aging and the early stages of Alzheimer's disease. Mild cognitive impairment is an
intermediate state in which persons have more memory problems than would be considered normal for their age, but their symptoms are not as severe as the symptoms of Alzheimer disease and they do not have functional impairment.
Alzheimer's disease develops at a much higher frequency
among persons with mild cognitive impairment than among those with
normal aging. Determining when patients have reached the very early stage of Alzheimer's disease is not easy, particularly because it is likely that a preclinical stage of Alzheimer's disease exists in which senile plaques, neuritic plaques, and neurofibrillary tangles occur in
sufficient numbers to meet standard neuropathological criteria for Alzheimer's disease in the absence of overt symptoms or signs of dementia. Other causes of memory impairment must also be considered, such as cerebrovascular disease, hydrocephalus, hypothyroidism, vitamin B12 deficiency, central nervous system infection, a cognitive disorder related to human immunodeficiency virus infection, adverse effects of
prescribed medications, substance abuse, and cancer.
A substantial decline in verbal memory and executive function (e.g., the ability to perform sequential tasks) typically occurs at the onset of
Alzheimer's disease but may be difficult to document without formal neuropsychological testing.
Reduced independence in daily
activities (often recognized by the patient's family) is one of the strongest predictors of disease.16 Functional status can be measured by the Clinical Dementia Rating (CDR) scale, which evaluates cognitive and
functional performance on a scale ranging from 0 to 3, with higher
scores indicating a greater severity of impairment. This assessment requires a collateral source of information gathering concerning the patient's ability to function independently but can be performed in the primary care setting and is particularly useful for clinicians who do
not have ready access to formal neuropsychological testing.
Formal neuropsychological testing that shows a substantial
decline in verbal memory and executive function supports the diagnosis of Alzheimer's disease1 but requires a trained professional for administration and interpretation.
Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and
the N-methyl-D-aspartate receptor antagonist memantine are the only
treatments for Alzheimer's disease that have been approved by the Food and Drug Administration. Randomized, placebo-controlled clinical trials of cholinesterase inhibitors have included patients with mainly mild-to-moderate Alzheimer's disease and have shown significant but clinically marginal benefits with respect to cognition, daily function, and behavior. The condition of patients who are taking
these drugs remains stable for a year or more and then may decline,
though at a rate that is slower than that among untreated patients.
Although there are few studies directly comparing the three
cholinesterase inhibitors, a systematic review and meta-analysis of data from 27 randomized trials concluded that there were no significant
differences in effects on cognitive performance among these medications.
During the study period (usually, 3 to 6 months), the use of each of
these drugs as prescribed at a standard dose resulted in a mean
improvement of 2 to 3 points on the Alzheimer's Disease Assessment Scale
for cognition (a scale ranging from 0 to 70, with higher scores
indicating better cognition) or a decreased rate of decline, as compared with the placebo group (approximately a 3-point difference, with a minimal clinically important difference of 4 points).
On the basis of 14 studies that measured daily function, donepezil was
modestly but significantly more effective than rivastigmine. Donepezil was likewise modestly but significantly better than rivastigmine and galantamine with regard to behavior, as measured by the Neuropsychiatric
Inventory (on a scale ranging from 1 to 144, with higher scores
indicating a greater severity of disease). Patients receiving donepezil had a mean reduction of 4.3 points in the baseline score, as compared with a reduction of 1.4 for those receiving the other agents. The likelihood of an overall improvement in score was 1.9 times as great with donepezil as with placebo, 1.2 times as great with rivastigmine as
with placebo, and 1.6 times as great with galantamine as with placebo. Adverse effects (including nausea, vomiting, diarrhea, dizziness, and
weight loss) were frequent with all three medications, although slightly less frequent with donepezil than with the other medications.
The author note provides the following contact info: Address reprint
requests to Dr. Mayeux at the Taub Institute for Research on Alzheimer's Disease and the Aging
New England Journal of Medicine (Volume 36Number 23, June 10),
by Richard Mayeux, M.D
disease, but difficulty recalling the names of friends or recent events is also common among normal elderly persons. The clinician is thus faced
with the difficulty of distinguishing between normal aging and the early stages of Alzheimer's disease. Mild cognitive impairment is an
intermediate state in which persons have more memory problems than would be considered normal for their age, but their symptoms are not as severe as the symptoms of Alzheimer disease and they do not have functional impairment.
Alzheimer's disease develops at a much higher frequency
among persons with mild cognitive impairment than among those with
normal aging. Determining when patients have reached the very early stage of Alzheimer's disease is not easy, particularly because it is likely that a preclinical stage of Alzheimer's disease exists in which senile plaques, neuritic plaques, and neurofibrillary tangles occur in
sufficient numbers to meet standard neuropathological criteria for Alzheimer's disease in the absence of overt symptoms or signs of dementia. Other causes of memory impairment must also be considered, such as cerebrovascular disease, hydrocephalus, hypothyroidism, vitamin B12 deficiency, central nervous system infection, a cognitive disorder related to human immunodeficiency virus infection, adverse effects of
prescribed medications, substance abuse, and cancer.
A substantial decline in verbal memory and executive function (e.g., the ability to perform sequential tasks) typically occurs at the onset of
Alzheimer's disease but may be difficult to document without formal neuropsychological testing.
Reduced independence in daily
activities (often recognized by the patient's family) is one of the strongest predictors of disease.16 Functional status can be measured by the Clinical Dementia Rating (CDR) scale, which evaluates cognitive and
functional performance on a scale ranging from 0 to 3, with higher
scores indicating a greater severity of impairment. This assessment requires a collateral source of information gathering concerning the patient's ability to function independently but can be performed in the primary care setting and is particularly useful for clinicians who do
not have ready access to formal neuropsychological testing.
Formal neuropsychological testing that shows a substantial
decline in verbal memory and executive function supports the diagnosis of Alzheimer's disease1 but requires a trained professional for administration and interpretation.
Cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and
the N-methyl-D-aspartate receptor antagonist memantine are the only
treatments for Alzheimer's disease that have been approved by the Food and Drug Administration. Randomized, placebo-controlled clinical trials of cholinesterase inhibitors have included patients with mainly mild-to-moderate Alzheimer's disease and have shown significant but clinically marginal benefits with respect to cognition, daily function, and behavior. The condition of patients who are taking
these drugs remains stable for a year or more and then may decline,
though at a rate that is slower than that among untreated patients.
Although there are few studies directly comparing the three
cholinesterase inhibitors, a systematic review and meta-analysis of data from 27 randomized trials concluded that there were no significant
differences in effects on cognitive performance among these medications.
During the study period (usually, 3 to 6 months), the use of each of
these drugs as prescribed at a standard dose resulted in a mean
improvement of 2 to 3 points on the Alzheimer's Disease Assessment Scale
for cognition (a scale ranging from 0 to 70, with higher scores
indicating better cognition) or a decreased rate of decline, as compared with the placebo group (approximately a 3-point difference, with a minimal clinically important difference of 4 points).
On the basis of 14 studies that measured daily function, donepezil was
modestly but significantly more effective than rivastigmine. Donepezil was likewise modestly but significantly better than rivastigmine and galantamine with regard to behavior, as measured by the Neuropsychiatric
Inventory (on a scale ranging from 1 to 144, with higher scores
indicating a greater severity of disease). Patients receiving donepezil had a mean reduction of 4.3 points in the baseline score, as compared with a reduction of 1.4 for those receiving the other agents. The likelihood of an overall improvement in score was 1.9 times as great with donepezil as with placebo, 1.2 times as great with rivastigmine as
with placebo, and 1.6 times as great with galantamine as with placebo. Adverse effects (including nausea, vomiting, diarrhea, dizziness, and
weight loss) were frequent with all three medications, although slightly less frequent with donepezil than with the other medications.
The author note provides the following contact info: Address reprint
requests to Dr. Mayeux at the Taub Institute for Research on Alzheimer's Disease and the Aging
New England Journal of Medicine (Volume 36Number 23, June 10),
by Richard Mayeux, M.D
Individual Brain Cells Can ID Objects As Dissimilar As Cars and Dogs
ScienceDaily (June 9, 2010) — Researchers at MIT's Picower Institute for Learning and Memory found that single brain cells, if confronted with a difficult task, can identify objects as dissimilar as sports cars and dogs.
Cognitive neuroscience
Functional neuroimaging
Researchers have never been sure exactly how specialized cells in the brain can be. Do different neurons each contribute to unique thoughts or can some neurons be cognitive "generalists" and participate in multiple thoughts? To answer this, MIT researchers examined the prefrontal cortex, the brain's executive in charge of decision-making and planning.
In previous studies, Earl K. Miller, Picower Professor of Neuroscience, found that individual neurons in monkeys' brains can become tuned to the concept of "cat" and others to the concept of "dog."
This time, Miller and colleagues Jason Cromer and Jefferson Roy recorded activity in the monkeys' brains as the animals switched back and forth between distinguishing cats vs. dogs and sports cars vs. sedans. Although they found individual neurons that were more attuned to car images and others to animal images, to their surprise, there were many neurons active in both categories. In fact, these "multitasking" neurons were best at making correct identifications in both categories.
The study suggests that cognitive demands -- how much brainpower is needed for a particular task -- may determine whether neurons in the prefrontal cortex "multitask" or stick to specialized categories.
"This ability to 'multitask' allows the brain to re-utilize the same pool of neurons for different tasks. Without it, storage capacity for critical thought might be severely limited," Miller said. The work could lead to a better understanding of disorders such as autism and schizophrenia in which individuals become overwhelmed by individual stimuli. For instance, a person with autism, when asked to picture a dog, may be flooded with dozens of mental images of all the canines he had ever seen.
Whether or not prefrontal cortex neurons are generalists or specialists had been unresolved because virtually all neurophysiologists train monkeys on a single cognitive problem. In this study, Picower researchers investigated how the prefrontal cortex encodes multiple, independent categories in monkeys trained to randomly alternate between performing two category problems. Wearing devices that allowed researchers to identify activity in individual neurons, the monkeys were presented with morphed images, such as that of a sports car with attributes of a sedan or a cat with attributes of a dog. If the image was more than 50 percent like a sports car or a cat, the monkeys had to identify it as such to get a reward. The monkeys scored correctly 80 percent of the time.
Next steps: Researchers hope to explore further whether individual prefrontal cortex neurons are true "cognitive generalists," able to categorize stimuli across multiple modalities.
Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Massachusetts Institute of Technology. The original article was written by Deborah Halber.
Cognitive neuroscience
Functional neuroimaging
Researchers have never been sure exactly how specialized cells in the brain can be. Do different neurons each contribute to unique thoughts or can some neurons be cognitive "generalists" and participate in multiple thoughts? To answer this, MIT researchers examined the prefrontal cortex, the brain's executive in charge of decision-making and planning.
In previous studies, Earl K. Miller, Picower Professor of Neuroscience, found that individual neurons in monkeys' brains can become tuned to the concept of "cat" and others to the concept of "dog."
This time, Miller and colleagues Jason Cromer and Jefferson Roy recorded activity in the monkeys' brains as the animals switched back and forth between distinguishing cats vs. dogs and sports cars vs. sedans. Although they found individual neurons that were more attuned to car images and others to animal images, to their surprise, there were many neurons active in both categories. In fact, these "multitasking" neurons were best at making correct identifications in both categories.
The study suggests that cognitive demands -- how much brainpower is needed for a particular task -- may determine whether neurons in the prefrontal cortex "multitask" or stick to specialized categories.
"This ability to 'multitask' allows the brain to re-utilize the same pool of neurons for different tasks. Without it, storage capacity for critical thought might be severely limited," Miller said. The work could lead to a better understanding of disorders such as autism and schizophrenia in which individuals become overwhelmed by individual stimuli. For instance, a person with autism, when asked to picture a dog, may be flooded with dozens of mental images of all the canines he had ever seen.
Whether or not prefrontal cortex neurons are generalists or specialists had been unresolved because virtually all neurophysiologists train monkeys on a single cognitive problem. In this study, Picower researchers investigated how the prefrontal cortex encodes multiple, independent categories in monkeys trained to randomly alternate between performing two category problems. Wearing devices that allowed researchers to identify activity in individual neurons, the monkeys were presented with morphed images, such as that of a sports car with attributes of a sedan or a cat with attributes of a dog. If the image was more than 50 percent like a sports car or a cat, the monkeys had to identify it as such to get a reward. The monkeys scored correctly 80 percent of the time.
Next steps: Researchers hope to explore further whether individual prefrontal cortex neurons are true "cognitive generalists," able to categorize stimuli across multiple modalities.
Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Massachusetts Institute of Technology. The original article was written by Deborah Halber.
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