Traumatic Brain Injury (TBI) is a leading cause of death and long-term disability in the developed world. It is estimated that every year over 10 million people worldwide suffer from traumatic brain injury as a result of head injuries caused by a hard object, a blow, an explosion, road accidents, sports injuries, etc. Such traumas can lead to physical, cognitive, behavioral and emotional damage and is also a risk factor for diseases such as Alzheimer’s and Parkinson’s.

At this point, despite the high frequency of brain injuries, there is no proven effective treatment that can help those suffering from this injury.

A new international study piloted by the Tel Aviv University determines that a ketogenic diet may reduce the effects of brain damage after traumatic injury. The study indicates that the diet improves spatial memory and visual memory, lowers brain inflammation indices, causes less neuronal death and slows down the rate of cellular aging.

The study was led by Prof. Chaim (Chagi) Pick, Director of the Sylvan Adams Sports Institute and a member of the Sagol School of Neuroscience, and Ph.D. student Meirav Har-Even Kerzhner, a registered dietitian and brain researcher, both from the Sackler Faculty of Medicine at Tel Aviv University. The findings were published in Scientific Reports, a syndicate journal from the publishers of Nature.

What does a ketogenic diet consist of?

A ketogenic diet which involves changes in the consumption of common foods is based on high-fat percentages and aims to mimic a state of fasting. As part of the diet, the intake of foods that contain carbohydrates (e.g., bread, sugar, grains, legumes, snacks, pastries and even fruits) are significantly restricted and, at the expense of this restriction, high-fat products such as meat, fish, eggs, avocado, butter etc. – are eaten.

This is a diet that can be continued for extended periods of time. The diet causes an increased production of ketone bodies in the liver that are used to generate energy. These ketone bodies are transferred via the bloodstream to the brain providing optimal nourishment.

The diet has been used as a treatment in Israel and around the world for almost 100 years, among children with epilepsy, while in recent years, the ketogenic diet has become popular among those who want to lose weight. It is important to note that, due to the significant nutritional restrictions, it is necessary to consult with a professional such as a doctor or a registered dietitian.

Inspiring Hope

In the study, conducted on model animals, the researchers identified that the ketogenic diet greatly improves the patient’s brain function. For this purpose, the researchers used advanced methods that included, among other things, behavioral-cognitive tests, biochemical tests and immunohistochemical cell staining (a technique in biology for the detection and placement of proteins in a cross section of tissue). The mechanism by which a ketogenic diet succeeds in benefiting the results of brain damage has not yet been fully revealed, but studies show that it has an antioxidant and metabolic effect on mitochondria (essential organelles in the cell, the its primary function of which is energy production and respiration), lowers free radical production and raises ATP (a major molecule in cellular biochemical channels). 

“The findings were unequivocal and showed that the ketogenic diet improves spatial memory and visual memory, lowers indices of inflammation in the brain and in addition, also slows the rate of cellular aging,” says Prof. Pick. “These results may open the door to further research that will inspire hope for those suffering from traumatic brain injuries, and their family members.”

Featured image: Prof. Chaim Pick and Ph.D. student Meirav Har-Even Kerzhne

Phages are viruses that attack bacteria. Many phages can exist in one of two states: active (lysis), in which the phages attack and destroy bacteria, or dormant, in which they remain passive within the bacteria, replicating themselves but doing no damage (lysogeny). Phages of this type must decide whether to be active or dormant every time they infect a new host. If they decide to be dormant for a time, they must also decide when to ‘wake up’ and attack. As in all dilemmas, it’s important to base the decision upon solid, reliable information.

Researchers at Tel Aviv University have discovered that just like humans with Game Theory, phages weigh all their options and make an informed decision on whether it is time to exit the dormant state and attack their bacterial host. The study was led by Prof. Avigdor Eldar of The Shmunis School of Biomedicine and Cancer Research at Tel Aviv University, together with his students and partners from the Weizmann Institute of Science. The paper was published in December 2021 in the journal Nature Microbiology.

According to the researchers, it has been assumed for some time that a phage bases its decision to exit the dormant state on information regarding the condition of its bacterial host: when the host shows signs of substantial DNA damage (death throes, so to speak), it is in the phage’s interest to leave it and try to infect other bacteria.

The new study discovered an additional mechanism of communication between bacteria and phages: apparently, some phage families have developed a more complex decision-making strategy, a kind of ‘phage game theory’, in which the phage receives information not only from its own host but also from neighboring bacteria.

What’s Going On in The Neighborhood?

Prof. Eldar explains: “When a phage is dormant within a bacterial cell, it forces its host to constantly produce small communication molecules called arbitrium, to which the phage listens via a special receptor. Thus, the presence of high levels of these molecules indicates that neighboring bacteria also contain phages. When this happens, even if its own host exhibits DNA damage, the phage refrains from becoming active. Since every bacterium can only host one dormant phage, the phage makes an informed decision: it’s better to let the host try to repair itself than to ‘betray’ it, since all neighboring bacteria are already taken.”

Prof. Eldar and his team used a range of genetic and biomolecular methods to track the biochemical communication signals passing between the bacteria and phages. In a former study they used a fluorescent marker to show that communication methods used by phages, as well as a large family of similar communication systems (know generally as ‘quorum sensing’) are used only to get signals from close neighbors. “Essentially, the bacteria have developed two separate communication systems – one for long-range communication, and the other for short distances only, used to sense the state of their immediate neighbors,” says Prof. Eldar. “In the phage’s case, it controls communication, and is only interested to know whether its close neighbors, which it might easily infect, are already occupied.”

Prof. Eldar concludes: “Several years ago, Prof. Rotem Sorek and his team at the Weizmann Institute identified communication between phages for the first time. Such systems had been known to exist between other molecular parasites hosted by bacteria (called plasmids). Our new discovery is the fact that phages use communication even in their dormant state. We have identified components critical for understanding how phages combine information about their host’s condition with information about their neighbors. This is one more important step on the way to deciphering the communication and ‘behavioral economics’ of viruses. Phages have an excellent ability to process information and make the right decision to ensure optimal survival. It will be interesting to see whether viruses residing in more complex organisms but facing similar decisions have also developed comparable systems of communication.”

Our brain has a large amount of G protein-coupled receptors (GPCR). Activation of these proteins causes a chain of chemical reactions within the cell. These proteins are very common in the brain and are involved in almost every brain activity, such as learning and memory. The nerve cells in which GPCRs are common, experience changes in their electrical voltage.

20 years ago, it was unexpectedly discovered that GPCRs are voltage-dependent, meaning that they sense the changes in the electrical voltage of nerve cells and change their function. However, to date, it has not been clarified whether the voltage dependence of GPCR proteins has a physiological significance that affects brain activity, our perception, and behavior. In fact, the scientific mindset was that this voltage dependence has no physiological significance.

The study, published recently in the prestigious journal Nature Communications, was conducted by Dr. Moshe Parnas and his team from the Sackler Faculty of Medicine and the Sagol School of Neuroscience at Tel Aviv University.

The Protein that Influences our Sense of Smell

Dr. Parnas and his team investigated, by means of the olfactory system of the fruit fly, whether the voltage dependence of GPCRs is important for brain function. To this end, the researchers decided to focus on one receptor from the G protein-coupled receptor family called “Muscarinic Type A”. This protein is involved, among other things, in habituation to an odor, a process in which the intensity of the reaction to the odor decreases as a result of continuous exposure to it. Thanks to this mechanism, a few minutes after entering a room containing a distinct odor – we stop smelling it.

Dr. Parnas explains: “Nerve cells are able to communicate with each other and brain flexibility is expressed in the ability of nerve cells to set up new connections with each other and change existing connections – and thus influence behavior. Muscarinic Type A protein is involved in strengthening the bond between nerve cells, and strengthening of this bond causes fruit flies to get used to the odor and indicates normal brain flexibility.”

During the course of the study, the researchers were able to neutralize the voltage sensor of the “Type A” Muscarinic protein by means of genetic editing, and thus eliminate its dependence on the electrical voltage of the nerve cell. The researchers found, by applying molecular, genetic and physiological methods, that disabling the voltage sensor actually causes uncontrolled brain flexibility and consequently the process of excessive and uncontrolled habituating to an odor.

Dr. Moshe Parnas

Control Mechanism Uncovered

Dr. Parnas adds: “We found that the receptor in question is very much involved in strengthening the intercellular bond in the brain, much more than what we thought. When we turned off its voltage sensor, the connection between the nerve cells became too strong.”

According to Dr. Parnas, “These findings change our perception of G-protein-coupled receptors. To date, no reference has been made to the effect of electrical voltage on their function and its implications on brain flexibility and conduct. These receptors are involved in many systems and brain diseases and we have now discovered a control mechanism upon which an attempt at drug treatment can be based.”

“Following this, we are continuing to investigate additional receptors. It is reasonable to assume that their dependence on the electrical voltage is important in other systems and not only in the olfactory system [i.e. the bodily structures that serve the sense of smell].”

This study by Dr. Parnas is a follow-up to a study conducted by his parents about two decades ago, which focused solely on the protein level. The current study by Dr. Parnas and his team advances to the next stage, connecting molecules, brain and conduct and indicating, for the first time, that eliminating their ability to sense electrical voltage affects brain activity and our ability to optimally adapt to the environment.