Brain repair after injury and Alzheimer’s disease

Researchers at Penn State University have developed an innovative technology to regenerate functional neurons after brain injury, and also in model systems used for research on Alzheimer’s disease. The scientists have used supporting cells of the central nervous system, glial cells, to regenerate healthy, functional neurons, which are critical for transmitting signals in the brain.

Gong Chen, a professor of biology, the Verne M. Willaman Chair in Life Sciences at Penn State, and the leader of the research team, calls the method a breakthrough in the long journey toward brain repair. “This technology may be developed into a new therapeutic treatment for traumatic brain and spinal cord injuries, stroke, Alzheimer’s disease, Parkinson’s disease, and other neurological disorders,” Chen said. The research will be posted online by the journal Cell Stem Cell on 19 December 2013.

When the brain is harmed by injury or disease, neurons often die or degenerate, but glial cells become more branched and numerous. These “reactive glial cells” initially build a defense system to prevent bacteria and toxins from invading healthy tissues, but this process eventually forms glial scars that limit the growth of healthy neurons. “A brain-injury site is like a car-crash site,” Chen explained. “Reactive glial cells are like police vehicles, ambulances, and fire trucks immediately rushing in to help — but these rescue vehicles can cause problems if too many of them get stuck at the scene. The problem with reactive glial cells is that they often stay at the injury site, forming a glial scar and preventing neurons from growing back into the injured areas,” he explained.

So several years ago, Chen’s lab tested new ways to transform glial scar tissue back to normal neural tissue. “There are more reactive glial cells and fewer functional neurons in the injury site,” Chen said, “so we hypothesized that we might be able to convert glial cells in the scar into functional neurons at the site of injury in the brain. This research was inspired by the Nobel prize-winning technology of induced pluripotent stem cells (iPSCs) developed in Shinya Yamanaka’s group, which showed how to reprogram skin cells into stem cells,” Chen recalled.

Chen and his team began by studying how reactive glial cells respond to a specific protein, NeuroD1, which is known to be important in the formation of nerve cells in the hippocampus area of adult brains. They hypothesized that expressing NeuroD1 protein into the reactive glial cells at the injury site might help to generate new neurons — just as it does in the hippocampus. To test this hypothesis, his team infected reactive glial cells with a retrovirus that specifies the genetic code for the NeuroD1 protein. “The retrovirus we used is replication-deficient and thus cannot kill infected cells like other viruses found in the wild,” Chen said. “More importantly, a retrovirus can infect only dividing cells such as reactive glial cells, but it does not affect neurons, which makes it ideal for therapeutic use with minimal side effect on normal brain functions.”

In a first test, Chen and his team investigated whether reactive glial cells can be converted into functional neurons after injecting NeuroD1 retrovirus into the cortex area of adult mice. The scientists found that two types of reactive glial cells — star-shaped astroglial cells and NG2 glial cells — were reprogrammed into neurons within one week after being infected with the NeuroD1 retrovirus. “Interestingly, the reactive astroglial cells were reprogrammed into excitatory neurons, whereas the NG2 cells were reprogrammed into both excitatory and inhibitory neurons, making it possible to achieve an excitation-inhibition balance in the brain after reprogramming,” Chen said. His lab also performed electrophysiological tests, which demonstrated that the new neurons converted by the NeuroD1 retrovirus could receive neurotransmitter signals from other nerve cells, suggesting that the newly converted neurons had successfully integrated into local neural circuits.

In a second test, Chen and his team used a transgenic-mouse model for Alzheimer’s disease, and demonstrated that reactive glial cells in the mouse’s diseased brain also can be converted into functional neurons. Furthermore, the team demonstrated that even in 14-month-old mice with Alzheimer’s disease — an age roughly equivalent to 60 years old for humans — injection of the NeuroD1 retrovirus into a mouse cortex can still induce a large number of newborn neurons reprogrammed from reactive glial cells. “Therefore, the conversion technology that we have demonstrated in the brains of mice potentially may be used to regenerate functional neurons in people with Alzheimer’s disease,” Chen said.

To ensure that the glial cell-to-neuron conversion method is not limited to rodent animals, Chen and his team further tested the method on cultured human glial cells. “Within 3 weeks after expression of the NeuroD1 protein, we saw in the microscope that human glial cells were reinventing themselves: they changed their shape from flat sheet-like glial cells into normal-looking neurons with axon and dendritic branches,” Chen said. The scientists further tested the function of these newly converted human neurons and found that, indeed, they were capable of both releasing and responding to neurotransmitters.

"Our dream is to develop this in vivo conversion method into a useful therapy to treat people suffering from neural injury or neurological disorders," Chen said. "Our passionate motivation for this research is the idea that an Alzheimer’s patient, who for a long time was not able to remember things, could start to have new memories after regenerating new neurons as a result of our in vivo conversion method, and that a stroke victim who could not even move his legs might start to walk again."

Cells from the eye are inkjet printed for the first time

A group of researchers from the UK have used inkjet printing technology to successfully print cells taken from the eye for the very first time.

The breakthrough, which has been detailed in a paper published today, 18 December, in IOP Publishing’s journal Biofabrication, could lead to the production of artificial tissue grafts made from the variety of cells found in the human retina and may aid in the search to cure blindness.

At the moment the results are preliminary and provide proof-of-principle that an inkjet printer can be used to print two types of cells from the retina of adult rats―ganglion cells and glial cells. This is the first time the technology has been used successfully to print mature central nervous system cells and the results showed that printed cells remained healthy and retained their ability to survive and grow in culture.

Co-authors of the study Professor Keith Martin and Dr Barbara Lorber, from the John van Geest Centre for Brain Repair, University of Cambridge, said: “The loss of nerve cells in the retina is a feature of many blinding eye diseases. The retina is an exquisitely organised structure where the precise arrangement of cells in relation to one another is critical for effective visual function”.

“Our study has shown, for the first time, that cells derived from the mature central nervous system, the eye, can be printed using a piezoelectric inkjet printer. Although our results are preliminary and much more work is still required, the aim is to develop this technology for use in retinal repair in the future.”

The ability to arrange cells into highly defined patterns and structures has recently elevated the use of 3D printing in the biomedical sciences to create cell-based structures for use in regenerative medicine.

In their study, the researchers used a piezoelectric inkjet printer device that ejected the cells through a sub-millimetre diameter nozzle when a specific electrical pulse was applied. They also used high speed video technology to record the printing process with high resolution and optimised their procedures accordingly.

“In order for a fluid to print well from an inkjet print head, its properties, such as viscosity and surface tension, need to conform to a fairly narrow range of values. Adding cells to the fluid complicates its properties significantly,” commented Dr Wen-Kai Hsiao, another member of the team based at the Inkjet Research Centre in Cambridge.

Once printed, a number of tests were performed on each type of cell to see how many of the cells survived the process and how it affected their ability to survive and grow.

The cells derived from the retina of the rats were retinal ganglion cells, which transmit information from the eye to certain parts of the brain, and glial cells, which provide support and protection for neurons.

“We plan to extend this study to print other cells of the retina and to investigate if light-sensitive photoreceptors can be successfully printed using inkjet technology. In addition, we would like to further develop our printing process to be suitable for commercial, multi-nozzle print heads,” Professor Martin concluded.

Mapping the entire brain with new and improved Brainbow II technology

Among the many great talks at the recent annual meeting of the Society for Neuroscience were three special lectures given sequentially during the evenings. The first described how we might translate the known circuit diagram of the worm, and the range of neural activities it supports, into it’s play in a 2D world. The second followed with how we might trace the trickle of information from the larger 3D world, through the more complex theater of the fly brain, and back out again. The third, and most gripping story in the trilogy, was Jeff Lichtman’s talk about using his new technology—known as Brainbow II— to turn the wild synaptic jungle into a tame and completely taxonomized arboretum which we can browse at our leisure.

A movie of a millimeter-sized worm learning to recognize and wriggle free from a mini-lariat may not be the critics choice. However, considering that the critical neurons and synapses involved in this particular behavior can now be genetically isolated, and watched in detail, many neurobiologists are fairly excited. We still don’t have whole-brain electrical activity maps for the 302 neurons (and 50 glial cells) in this creature, or even high resolution calcium clips of these cells—but that may not be required. Many neurons do not bother to use discrete spikes when they are only sending signals across short distances, and sometimes they don’t even bother to build axons.

In this case, if we want to understand how the worm acquires the lariat escape trick, perhaps we might instead just watch its mitochondria as their host neurons stir in seeming alarm. Indeed if we were to watch nothing but mitochondria, most of what we might learn about a given neuron through the use of a whole host of other imaging technologies, is already contained within their dynamics. One could probably infer not just the membraneous outlines of a neuron by watching the limits of mitochondrial excursions, but also infer the changes in the shape of the individual neurites. Further in this vein, we also now appreciate that mitochondria don’t just respond to the calcium flows mentioned above, they are in fact calcium-controlling organelles by trade.

One thing that we learned from Brainbow I, which was further highlighted with the expanded palette of Brainbow II, is that labeling everything can be as bad as labeling nothing at all. Part of Brainbow II’s feature set, is more control for the selective labeling of synapses from different kinds of interneurons, and also the processes of glial cells. In order to reap the benefits of Brainbow II technology and create detailed computer reconstructed images of these cells, Lichtman’s group had to build high speed brain slicing and processing instruments, as well as high power electron microscopes to create the images.

Lichtman reported that together with Zeiss, a new high-throughput 61-beam scanning electron microscope is currently under development. This massive device does not look like something that could just be slid into an elevator and sent to a fourth-floor lab. I asked @zeiss_optics about pricing and availability on this behemoth, along with focused ion beam attachment, and they said that they are offering a nice rebate on orders of two or more. Even still, the result of many months of protected effort has thus far only yielded the structure of just a small piece of brain.

But what a structure it is. The crowning achievement, shown at the convention was distilled into a cylindrical EM reconstruction of a piece of mouse brain smaller than a grain of sand. In the center of this volume was the proximal shaft of a pyramidal cell apical dendrite surrounded by all manner of synaptic elements. If you were ever confounded by the famous 4-color mapping thereom, then Brainbow-style synapse tracing may not be for you. In this volume there are around 680 nerve fibers that can be resolved, together with 774 synapses. A key finding by Lichtman is that mere contact alone, does not a synapse make. By tracking perfectly resolved synaptic vesicles, he was able to show that of every ten plausible synaptic options, perhaps only one or two neighboring profiles turned out to be an actual synapse.

The final point Lichtman made is that now that it is possible to extract the complete membrane topology, including organelles, of an arbitrary region of the brain, formerly unimagined questions might be posed and answered with the click of a mouse. The question he alluded to is the one I raised above, namely, how are the mitochondria distributed, and what are they doing? While this is in large part, a question for live, video microscopy, much can be learned about the state of a given synapse just prior to being fixed by it’s mitochondria. Similarly, much might be also be inferred about the next plausible state of the neural geometry under consideration, provided one knows what to look for.

The one finding here that Lichtman mentioned was that axons have relatively small mitochondria compared to those in the body and dendrites. That may be a seemingly sterile finding when considered alone. But that same afternoon at the conference, there was an exciting talk describing how certain mitochondria are extravasated, or expelled, by axons in the visual system. They are then taken up by astrocytes for processing—a rather surprising finding. It has been known that in some organs mitochondria can be exchanged between cells, much to the benefit of the recipient cell, though for neurons, this is the first report of such phenomena. I did look later at the literature, and this fractionation of mitochondria by size in the polar elements of neurons has actually been known for some time, leading one to guess what other potential findings the Lichtman group might actually possess.

What Lichtman presented is really not a connectome, or a “netlist” of circuit board connections, per say. To date, nobody has even put force a reasonable transform to derive a connectome from a given 3D membrane mesh topology, or even of what use it would be if we had one. Meanwhile, attempts to model the fissions, fusions, and general ramblings of the mitochondria as a function of their genetic makeup, and the positions they take up inside the cell, have already begun. If genetically questionable mitochondria with expired membrane potentials tend to be degraded by fusion with lysosomes near the nucleus, we might ask, can they be blamed for pumping out axons and transporting themselves as far away as possible—even out of the cell entirely?

Clearly, anthropomorphizing mere motile sacks of DNA and enzymes is not the only tool we have to hack the brain. But insofar as the brain is just a complex system of microscopic tubes, it may make sense to take a closer look at the creatures that build and maintain them. In this light, the science of connectomes becomes the science of mitochondria, the mitochondriome perhaps. As much as we can better understand the collective activity of the brain through the remembrance of neurons as once-feral protists now encased in the skull, our understanding of neurons is enhanced by recalling their mitochondria as once-free bacteria now largely trapped in them.

Researchers make exciting discoveries in non-excitable cells

It has been 60 years since scientists discovered that sodium channels create the electrical impulses crucial to the function of nerve, brain, and heart cells — all of which are termed “excitable.” Now researchers at Yale and elsewhere are discovering that sodium channels also play key roles in so-called non-excitable cells.

In the Oct. 16 issue of the journal Neuron, Yale neuroscientists Stephen Waxman and Joel Black review nearly a quarter-century of research that shows sodium channels in cells that do not transmit electrical impulses may nonetheless play a role in immune system function, migration of cells, neurodegenerative disease, and cancer.

“This insight has opened up new avenues of research in a variety of pathologies,” Waxman said.  

For instance, Waxman’s lab has begun to study the functional role of voltage-gated sodium channels in non-excitable glial cells within the spinal cord and brain. They are currently investigating whether sodium channels in these non-excitable cells may participate in the formation of glial scars, thereby inhibiting regeneration of nerve cells after traumatic injury to the spinal cord or brain.

Do glial connectomes and activity maps make any sense?

"If all you have is a hammer, everything looks like a nail." This so-called "law of the instrument" has shaped neuroscience to core. It can be rephrased as, if all you have a fancy voltmeter, everything looks like a transient electrical event. No one in the field understands this more Douglass Fields, an NIH researcher who has re-written every neuroscience dogma he has turned his scrupulous eye to. In a paper published yesterday in Nature, Fields questions the conventional wisdom that informs recent efforts to map the brain’s connectivity, and ultimately, its electrical activity. In particular, he questions the value of making detailed maps of neurons, while at the same time neglecting the more abundant, and equally complex “maps” that exist for glia.

When first discovered, the “action potential” generated by a neuron was a rich and multiphysical event. It has since degenerated into a sterile, directionally-rectified electrical blip, whose only interesting parameter is a millisecond-scrutinized timestamp. In the last two years alone, Fields has re-generalized the spike. Having highlighted many of the fine scale physical events that accompany a neuron’s firing, like temperature and volume changes, optical effects, displacement, and myriad nonsynaptic effects, Fields demonstrated the intimate knitting of reverse propagating spikes into the behavior and function of neuronal networks. He also showed how spikes directly control non-neuronal events, in particular, myelination.

The Eyewire project at MIT is a fantastic effort to create detailed neuronal maps—it expands neuroscience to the larger community, and generates much worthwhile scientific spin-off. It is also completely absurd. To have so much talk about brain maps without drawing clear distinction between the glaring contrast in the value of white matter maps and grey matter maps is telling. Maps of the white matter will be indespensible to understanding our own brains. They are highly personal, yet at the same time will be one of the most valuable things we might soon come to share. For the moment here, we can liken them to the subway or transportation map of a complex city.

To try and map the grey matter, at least in our foreseeable era, is to attempt to record the comings and goings of all the people entering and exiting the doors of the trains of our subway system. Not only is the task infinitely harder, pound for pound, it is equally less valuable, and impermanent. Looked at another way, if we imagine some hyper-detailed ecologist mapping the different trees in a forest, one valuable piece of information to have would be the tree species or type. Their age, size, density and distribution would similarly be worthwhile parameters. Also maybe some detail about their finer structure would be predictive of what kind of animals species might live and move about their arbors. Eyewire, on the other hand, is mapping every twig down to the finest termination as a leaf. The problem is that leaves are shed and regenerated anew each year, and while Eyewire might map a few neurons in the same time, synapses morph to a faster drum.

The point of Field’s article is that glial trees have exactly the same level of detail and importance as neural trees, yet they are ignored in the aspirations of the connectomists. In fact, if neurons are like deciduous tress, with long, unpredictable, idiosyncratic and internexed branches, then glial cells, particularly astrocytes, are very much like conifers—they rigidly span nonoverlapping domains in the grey matter, in prototypical, scaffolded form, and with frequently symmetric repeatable structure. If we accept the results of neuroanatomy at face value here, grey matter might be imagined more like an astrocytic christmas tree farm superimposed on a neural rainforest. Stepping back, if given a choice between a grey matter connectome, and a white matter myelome, the latter is undoubtedly where the focus should be for now.

It may be a misstep in our study of glial cells to narrow-mindedly attempt to define for them, only that which has already been defined for neurons. The literature consists largely of a reattribution of transmitter or other chemical mechanisms of neurons to glia. The exceptioned qualifier here is that the speed of these processes—their electricality, directionality and extreme spatial aspect—is not a general feature of glial cells. For glial cells, new mechanisms need to be explored, and the most obvious among them perhaps, is that many of them, particularly the microglial cells, like to move.

It is increasingly appreciated nowadays, that much of the 10 or so watts attributed to the brain for its power budget, is purposed for things other then sending spikes and maintaining static electrical potentials. In the home, we can save on energy by dimming the lights, but to really make a dent, we need to turn off the things that move—things like fans, or the pumps in the HVAC systems. Much of the actual flow and motion inside the cerebral hive is transduced through glial cells. Undoubtedly axons drag diluent down their extent as they transport organelles across improbably expanses, and expel pressurized boluses of irritant (there may in fact be much to be said for an analogy with leaves powering fluid conduction in trees through local evaporation). It is however, the glial cells that seem to be the heavy lifters involved in flow. Transducing hand-picked intracellular flow, and bulk extracellular flow, sourced from the vasculature to neurons, they complete the so-called glymphatic circuit.

To be strict, perhaps we need to refigure this estimate of 10 watts, expanding it to include non-chemical sources, like the input of hydraulic power into the brain via the heart. If, for example, the brain consumes 20% of the flow from the heart, it also dissipates around 20% of the 100 or more watts of power generated by the heart. That should in fact be a significant contribution. By some estimates, we may have around 100,000 miles of myelinated axons in our brains, all surrounded by glial cells. Similarly, we may have the same amount, 100,000 miles, of capillary in the brain, all surrounded by astrocytic endfeet. Considering the scale of these numbers, it may be useful to start to look at the brain as more of a fluid-transporting machine, as opposed to mainly an electrical device.

The evidence is fairly clear that at the sensory and motor levels, spikes conduct much of the information about a stimulus or movement, particularly the short time scale components of that information. In moving more centrally from both sensory and motor ends, spikes tend to unhinge from real world metrics. If we are not careful to consider what neurons might actually be doing at a more global, physiologic level when they generate and propagate spikes, we may find that while we believe we are recording signals, we are actually just recording the noise of the pumps.

UC Davis team “spikes” stem cells to generate myelin

Findings hold promise for developing regenerative therapies for spinal cord injuries and diseases such as multiple sclerosis

Stem cell technology has long offered the hope of regenerating tissue to repair broken or damaged neural tissue. Findings from a team of UC Davis investigators have brought this dream a step closer by developing a method to generate functioning brain cells that produce myelin — a fatty, insulating sheath essential to normal neural conduction.

“Our findings represent an important conceptual advance in stem cell research,” said Wenbin Deng, principal investigator of the study and associate professor at the UC Davis Department of Biochemistry and Molecular Medicine. “We have bioengineered the first generation of myelin-producing cells with superior regenerative capacity.”

The brain is made up predominantly of two cell types: neurons and glial cells. Neurons are regarded as responsible for thought and sensation. Glial cells surround, support and communicate with neurons, helping neurons process and transmit information using electrical and chemical signals. One type of glial cell — the oligodendrocyte — produces a sheath called myelin that provides support and insulation to neurons. Myelin, which has been compared to insulation around electrical wires that helps to prevent short circuits, is essential for normal neural conduction and brain function; well-recognized conditions involving defective myelin development or myelin loss include multiple sclerosis and leukodystrophies.

In this study, the UC Davis team first developed a novel protocol to efficiently induce embryonic stem cells (ESCs) to differentiate into oligodendroglial progenitor cells (OPCs), early cells that normally develop into oligodendrocytes. Although this has been successfully done by other researchers, the UC Davis method results in a purer population of OPCs, according to Deng, with fewer other cell types arising from their technique.

They next compared electrophysiological properties of the derived OPCs to naturally occurring OPCs. They found that unlike natural OPCs, the ESC-derived OPCs lacked sodium ion channels in their cell membranes, making them unable to generate spikes when electrically stimulated. Using a technique called viral transduction, they then introduced DNA that codes for sodium channels into the ESC-derived OPCs. These OPCs then expressed ion channels in their cells and developed the ability to generate spikes.

According to Deng, this is the first time that scientists have successfully generated OPCs with so-called spiking properties. This achievement allowed them to compare the capabilities of spiking cells to non-spiking cells.

In cell culture, they found that only spiking OPCs received electrical input from neurons, and they showed superior capability to mature into oligodendrocytes.

They also transplanted spiking and non-spiking OPCs into the spinal cord and brains of mice that are genetically unable to produce myelin. Both types of OPCs had the capability to mature into oligo-dendrocytes and produce myelin, but those from spiking OPCs produced longer and thicker myelin sheaths around axons.

“We actually developed ‘super cells’ with an even greater capacity to spike than natural cells,” Deng said. “This appears to give them an edge for maturing into oligodendrocytes and producing better myelin.”

It is well known that adult human neural tissue has a poor capacity to regenerate naturally. Although early cells such as OPCs are present, they do not regenerate tissue very effectively when disease or injury strikes.

Deng believes that replacing glial cells with the enhanced spiking OPCs to treat neural injuries and diseases has the potential to be a better strategy than replacing neurons, which tend to be more problematic to work with. Providing the proper structure and environment for neurons to live may be the best approach to regenerate healthy neural tissue. He also notes that many diverse conditions that have not traditionally been considered to be myelin-related diseases – including schizophrenia, epilepsy and amyotrophic lateral sclerosis (ALS) – actually are now recognized to involve defective myelin.

Researchers find that alcohol consumption damages brain’s support cells

Alcohol consumption affects the brain in multiple ways, ranging from acute changes in behavior to permanent molecular and functional alterations. The general consensus is that in the brain, alcohol targets mainly neurons. However, recent research suggests that other cells of the brain known as astrocytic glial cells or astrocytes are necessary for the rewarding effects of alcohol and the development of alcohol tolerance. The study, first-authored by Dr. Leonardo Pignataro, was published in the February 6th issue of the scientific journal Brain and Behavior.

"This is a fascinating result that we could have never anticipated. We know that astrocytes are the most abundant cell type in the central nervous system and that they are crucial for neuronal growth and survival, but so far, these cells had been thought to be involved only in brain’s support functions. Our results, however, show that astrocytes have an active role in alcohol tolerance and dependence," explains Dr. Pignataro.

The team of researchers from Columbia and Yale Universities analyzed how alcohol exposure changes gene expression in astrocyte cells and identified gene sets associated with stress, immune response, cell death, and lipid metabolism, which may have profound implications for normal neuronal activity in the brain. “Our findings may explain many of the long-term inflammatory and degenerative effects observed in the brain of alcoholics,” says Dr. Pignataro. “The change in gene expression observed in alcohol-exposed astrocytes supports the idea that some of the alcohol consumed reaches the brain and that ethanol (the active component of alcoholic beverages) is locally metabolized, increasing the production free radicals that react with cell components to affect the normal function of cells. This activates a cellular stress response in the cells in an attempt to defend from this chemical damage. On the other hand, the body recognizes these oxidized molecules as “foreign objects” generating an immune response against them that leads to the death of damage cells. This mechanism can explain the inflammatory degenerative process observed in the brain of chronic alcoholics, allowing for the development of different and novel therapeutically approaches to treat this disease” added Dr. Pignataro.

The consequences of alcohol on astrocytes revealed in this study go far beyond what happens to this particular cell type. Astrocytes play a crucial role in the CNS, supporting normal neuronal activity by maintaining homeostasis. Therefore, alcohol changes in gene expression in astrocytes may have profound implications for neuronal activity in the brain.

These findings will help scientists better understand alcohol-associated disorders, such as the brain neurodegenerative damage associated with chronic alcoholism and alcohol tolerance and dependence. “We hope that this newly discovered role of astrocytes will give scientists new targets other than neurons to develop novel therapies to treat alcoholism,” Leonardo Pignataro concluded.

Monday’s medical myth: alcohol kills brain cells

Do you ever wake up with a raging hangover and picture the row of brain cells that you suspect have have started to decay? Or wonder whether that final glass of wine was too much for those tiny cells, and pushed you over the line?

Well, it’s true that alcohol can indeed harm the brain in many ways. But directly killing off brain cells isn’t one of them.

The brain is made up of nerve cells (neurons) and glial cells. These cells communicate with each other, sending signals from one part of the brain to the other, telling your body what to do. Brain cells enable us to learn, imagine, experience sensation, feel emotion and control our body’s movement.

Alcohol’s effects can be seen on our brain even after a few drinks, causing us to feel tipsy. But these symptoms are temporary and reversible. The available evidence suggests alcohol doesn’t kill brain cells directly.

There is some evidence that moderate drinking is linked to improved mental function. A 2005 Australian study of 7,500 people in three age cohorts (early 20s, early 40s and early 60s) found moderate drinkers (up to 14 drinks for men and seven drinks for women per week) had better cognitive functioning than non-drinkers, occasional drinkers and heavy drinkers.

But there is also evidence that even moderate drinking may impair brain plasticity and cell production. Researchers in the United States gave rats alcohol over a two-week period, to raise their alcohol blood concentration to about 0.08. While this level did not impair the rats’ motor skills or short-term learning, it impacted the brain’s ability to produce and retain new cells, reducing new brain cell production by almost 40%. Therefore, we need to protect our brains as best we can.

Excessive alcohol undoubtedly damages brain cells and brain function. Heavy consumption over long periods can damage the connections between brain cells, even if the cells are not killed. It can also affect the way your body functions. Long-term drinking can cause brain atrophy or shrinkage, as seen in brain diseases such as stroke and Alzheimer’s disease.

There is debate about whether permanent brain damage is caused directly or indirectly.

We know, for example, that severe alcoholic liver disease has an indirect effect on the brain. When the liver is damaged, it’s no longer effective at processing toxins to make them harmless. As a result, poisonous toxins reach the brain, and may cause hepatic encephalopathy (decline in brain function). This can result in changes to cognition and personality, sleep disruption and even coma and death.

Alcoholism is also associated with nutritional and absorptive deficiencies. A lack of Vitamin B1 (thiamine) causes brain disorders called Wernicke’s ncephalopathy (which manifests in confusion, unsteadiness, paralysis of eye movements) and Korsakoff’s syndrome (where patients lose their short-term memory and coordination).

So, how much alcohol is okay?

To reduce the lifetime risk of harm from alcohol-related disease or injury, the National Health and Medical Research Council recommends healthy adults drink no more than two standard drinks on any day. Drinking less frequently (such as weekly rather than daily) and drinking less on each occasion will reduce your lifetime risk.

To avoid alcohol-related injuries, adults shouldn’t drink more than four standard drinks on a single occasion. This applies to both sexes because while women become intoxicated with less alcohol, men tend to take more risks and experience more harmful effects.

For pregnant women and young people under the age of 18, the guidelines say not drinking is the safest option.

So while alcohol may not kill brain cells, if this myth encourages us to rethink that third beer or glass of wine, I won’t mind if it hangs around.