Alcohol's effects on gene expression in the central nervous system

Alcohol's primary target is the central nervous system (CNS), where it influences neurotransmission to produce intoxication. Scientists can now use microarray technology to study brain function gene by gene. Symposium proceedings published in the February issue of Alcoholism: Clinical & Experimental Research address the effects of alcohol on what is called "gene expression" in the CNS regions of animal models.
"All of our cells have exactly the same deoxyribonucleic acid (DNA), which means they all have the same genes," explained William J. McBride, symposium organizer and professor of neurobiology at the Indiana University School of Medicine. "The reason that different cells can appear and work so differently with the same genes – giving us, for example, unique eyes, skin, or hair – is that only some genes are used or 'turned on' in each cell. This is called gene expression."
McBride said that researchers now know that alcohol can change gene expression in the brain, and that these changes are likely responsible for many of the 'symptoms' of addiction, such as tolerance, physical dependence, and craving, as well as the 'consequences' of alcoholism, such as brain damage.
"The challenge has been to find out which genes – out of more than 50,000 – are turned on or off in the brains of alcoholics," he said. "Microarray studies – the examination of a small glass microscope slide that has thousands of different DNA samples attached to it – that are applied to brain function are just beginning in the field of alcoholism. Several years ago, it was impossible to analyze more than a handful of these genes, however, microarray technology has changed that."
Symposium speakers at the June 2004 Research Society on Alcoholism meeting in Vancouver, B.C. presented the following findings from recent studies that used genetic animal models:


# Gene expression profiling in the nucleus accumbens, prefrontal cortex, and ventral tegmental areas show that distinct biological pathways are associated with alcohol's action in specific brain regions and certain mouse strains.


"We were able to use gene expression profiling to determine that alcohol produces multiple effects on different biological processes," said McBride, "and that these changes are different in several brain regions which may be involved in alcohol addiction."


# Researchers have identified individual genes and gene networks that may play an important role in determining the behavioral responses to alcohol as well as possibly influencing drinking behavior.


"Thus far, genes that appear to be responsive to alcohol include genes involved in the intracellular signaling process (which can alter how the neuron functions), neuropeptide signaling (which modulates nerve cell activity), and myelin structure (which is needed for communication between nerve cells)," said McBride. "Gene expression profiling has also been used to identify chromosomes and chromosomal regions that influence alcohol drinking and response to alcohol."


# Intracranial self-administration of ethanol into the posterior ventral tegmental area (VTA) of alcohol-preferring rats produced results suggesting that the reinforcing effects of alcohol are activating VTA dopamine neurons and producing changes in synaptic connections that resemble those that occur in memory and learning.


"Learning and memory require enhanced synaptic function between neurons," explained McBride. "Enhanced synaptic function is characterized by increased formation of synaptic proteins. The stimulation of VTA dopamine neurons by alcohol increases the expression of genes involved in the synthesis of synaptic proteins in target regions of the VTA. In short, these results suggest that alcohol can produce changes in the brain reward system that can further increase the rewarding effects of alcohol."


# Microarray techniques confirmed earlier reports indicating that chronic alcohol exposure/withdrawal differentially alters gene expression in the prefrontal cortex of mice. More than 300 genes were found to be altered by acute alcohol treatment.


"The prefrontal cortex is involved in motivated behaviors," noted McBride. "Studies with humans indicate that this brain region is sensitive to the effects of heavy alcohol drinking and repeated withdrawals. The microarray technique provides insight into cellular changes that occur over time with chronic alcohol drinking and repeated withdrawals."


Collectively speaking, added McBride, findings presented at the symposium demonstrate the quantitative and qualitative applications of microarrays to studying the genetic and biological bases of alcoholism and alcohol abuse within discrete brain regions.
"For researchers, microarray technology has the potential of studying the genetic and biological bases of alcohol's rewarding effects, sensitivity to the effects of alcohol, development of tolerance to the effects of alcohol, development of alcohol dependence, and alcohol withdrawal severity," he said. "For the average reader, knowing which genetic profiles might contribute to excessive alcohol drinking could be used to identify risk factors that contribute to alcoholism and alcohol abuse, and could aid in the development of selective treatment strategies for different subgroups of alcoholics."
McBride added that, despite recent advances, researchers need further developments in microarray technologies and bioinformatic approaches to better understand the complex neurobiological mechanisms underlying alcohol addiction. "Future research will need to determine changes in gene expression in very discrete neuronal pathways that may be involved in mediating the effects of alcohol that lead to addiction," he said. "Future studies will also require the integrative efforts of many investigators working with different animal models in order to identify the multiple genetic factors that contribute to the risk for alcoholism and alcohol abuse."

Source : Indiana University School of Medicine

Memories may skew visual perception

Taking a trip down memory lane while you are driving could land you in a roadside ditch, new research indicates. Vanderbilt University psychologists have found that our visual perception can be contaminated by memories of what we have recently seen, impairing our ability to properly understand and act on what we are currently seeing.


"This study shows that holding the memory of a visual event in our mind for a short period of time can 'contaminate' visual perception during the time that we're remembering," Randolph Blake, study co-author and Centennial Professor of Psychology, said.


"Our study represents the first conclusive evidence for such contamination, and the results strongly suggest that remembering and perceiving engage at least some of the same brain areas."


The study, led by research associate Min-Suk Kang, was recently published in the journal Psychonomic Bulletin & Review.


"There are numerous instances where we engage in visually guided activities, such as driving, while rehashing visual events in our mind's eye. Common sense tells us that this mental replay is harmless in that it does not interfere with our ability to register and react to objects within our visual field," Kang and his co-authors wrote. "Evidently, however, that is not always true when the contents of our working memories overlap with the contents of our perceptual world."


In this study, the researchers used a visual illusion called motion repulsion to learn whether information held in working memory affects perception. This illusion is produced when two sets of moving dots are superimposed, with dots in one set moving in a different direction from those in the other set. Under these conditions, people tend to misperceive the actual directions of motion, and perceive a larger difference between the two sets of motions than actually exists.


Ordinarily this illusion is produced by having people view both sets of motion at the same time. Kang and colleagues set out to determine if the illusion would occur when one set of motions, rather than being physically present, was held in working memory.


In the experiment, participants were shown a random pattern of dots and were asked to remember the direction in which the dots were moving. They were then were shown a second pattern of moving dots. They were asked to report on the direction of second dots' movement.


The research subjects' reports of the second dots' movement was exaggerated and influenced by what they had previously seen. If they were first shown dots moving in one direction and later shown dots moving in a slightly counterclockwise direction relative to the first presented dots, they reported the counterclockwise movement to be more dramatic than it had actually been.


"We find that observers misperceive the actual direction of motion of a single motion stimulus if, while viewing that stimulus, they are holding a different motion direction in visual working memory," the authors wrote.


The results provide further support for previous findings by Vanderbilt researchers Frank Tong and Stephanie Harrison that the contents of working memory may be represented in early visual areas in the brain, including the primary visual cortex, that were previously thought to play no role in higher cognitive functions such as memory.


"Our findings provide compelling evidence that visual working memory representations directly interact with the same neural mechanisms involved in processing basic sensory events," Kang and his colleagues wrote.

Source : Vanderbilt University

Stem cell study could aid motor neurone disease research

Scientists have discovered a new way to generate human motor nerve cells in a development that will help research into motor neurone disease.



A team from the Universities of Edinburgh, Cambridge and Cardiff has created a range of motor neurons – nerves cells that send messages from the brain and spine to other parts of the body – from human embryonic stem cells in the laboratory.


It is the first time that researchers have been able to generate a variety of human motor neurons, which differ in their make-up and display properties depending on where they are located in the spinal cord.


The research, published in the journal Nature Communications, could help scientists better understand motor neurone disease. The process will enable scientists to create different types of motor neurons and study why some are more vulnerable to disease than others.


Motor neurons control muscle activity such as speaking, walking, swallowing and breathing. However, in motor neurone disease – a progressive and ultimately fatal disorder – these cells break down leading to paralysis, difficulty speaking, breathing and swallowing.


Previously scientists had only been able to generate one particular kind of motor neuron, which they did by using retinoic acid, a vitamin A derivative.


In the latest study, scientists have found a way to generate a wider range of motor neurons using a new process without retinoic acid.


Professor Siddharthan Chandran, Director of the Euan MacDonald Centre for Motor Neurone Disease Research at the University of Edinburgh, said: "Motor neurons differ in their make-up, so understanding why some are more vulnerable than others to disease is important for developing treatment for this devastating condition."


Dr Rickie Patani, of the University of Cambridge, said: "Although motor neurons are often considered as a single group, they represent a diverse collection of neuronal subtypes. The ability to create a range of different motor neurons is a key step in understanding the basis of selective subtype vulnerability in conditions such as motor neuron disease and spinal muscular atrophy."

Source : University of Edinburgh