Oestrogen changes neuroblastoma cells into neurons

The female sex hormone oestrogen can perform an important role in neuroblastoma, a form of cancer mainly affecting young children. In laboratory experiments, researchers at Karolinska Institutet in Sweden demonstrate that oestrogen treatment and overexpression of the oestrogen receptor cause malignant neuroblastoma cells to mature into neuron-like cells.

Neuroblastoma forms in the peripheral nervous system and is one of the most common forms of solid cancer in young children. The disease mainly affects babies and young children, and while in some cases the tumours can disappear of their own accord, the majority are aggressive, metastasising cancer tumours that are resistant to modern combinations of surgery, radiotherapy and intensive chemotherapy.

The most aggressive forms of neuroblastoma are often associated with a more active MYCN gene, which drives tumour cell growth and spread and inhibits the maturation of the cells. Researchers focus on the activity of this gene and how it relates to neuroblastoma. MYCN is often seen only as a marker for a poor prognosis, but it's critical to the disease and is a possible target for new drugs.

In a previous study, the group discovered that activation of MYCN results in the formation of specific microRNAs, which are relatively small RNA molecules that regulate proteins. Some of these microRNAs disable the oestrogen receptor ERalpha. The present study shows that the inhibition of these microRNA molecules or oestrogen therapy in combination with an overexpression of the oestrogen receptor can cause aggressive neuroblastoma cells with MYCN activation to mature into neuron-like cells which behave more like normal cells.

The researchers studied tumour tissue from patients, cultivated human tumour cells and tumours in mouse models for neuroblastoma. In the mice, the neuron-like cells did not grow as quickly as the original cancer cells, and analyses of the tumour tissue from patients show that those with a high level of the oestrogen receptor have a better survival rate than those with a low. Oestrogen could be a therapeutic method for patients who express high levels of the oestrogen receptor. Another therapy could involve deregulating MYCN or upregulating the oestrogen receptor and then treating with oestrogen.
          haleplushearty.blogspot.com

Roles of brain protein

A protein called AKT, is ubiquitous in brain tissue and instrumental in enabling the brain to adapt to new experiences and lay down new memories. AKT comes in three distinct varieties residing in different kinds of brain cells and affecting brain health in very distinct ways. It is a central protein that has been implicated in a bevy of neurological diseases.

Discovered in the 1970s and known best as an "oncogene" (one that, when mutated, can promote cancer), AKT has more recently been identified as a key player in promoting "synaptic plasticity," the brain's ability to strengthen cellular connections in response to experience. AKT is one of the first proteins to come up after observing scary objects, it is a central switch that turns on the memory factory.

For the study, Hoeffer's team silenced the three different isoforms, or varieties, of AKT in mice and observed their brain activity. They made a number of key discoveries: AKT2 is found exclusively in astroglia, the supportive, star-shaped cells in the brain and spinal cord that are often impacted in brain cancer and brain injury.

 AKT1 is ubiquitous in neurons and appears to be the most important form in promoting the strengthening of synapses in response to experience-memory formation. (This finding is in line with previous research showing that mutations in AKT1 boost risk of schizophrenia and other brain disorders associated with a flaw in the way a patient perceives or remembers experiences.)
AKT3 appears to play a key role in brain growth, with mice whose AKT3 gene is silenced showing smaller brain size.
           haleplushearty.blogspot.com

Dangers of using anaesthetics

A new understanding of the complex ways in which general anaesthetics act on the brain could eventually lead to improved drugs for surgery. It remains unclear how general anaesthesia works, even though it is one of the most common medical procedures worldwide.

University of Queensland researcher, Associate Professor Bruno van Swinderen, said his team had overturned previous understanding of what general anaesthetics do to the brain, finding the drugs did much more than induce sleep.

Researchers looked at the effects of propofol - one of the most common general anaesthetic drugs used during surgery - on synaptic release. Synaptic release is the mechanism by which neurons - or  nerve cells - communicate with each other.

From the previous research that general anaesthetics including propofol act on sleep systems in the brain like a sleeping pill. This study discovered that propofol also disrupts presynaptic mechanisms, probably affecting communication between neurons across the entire brain in a systematic way that differs from just being asleep.

 Propofol restricts the movement of a key protein (syntaxin1A) required at the synapses of all neurons. This restriction leads to decreased communication between neurons in the brain. The finding contributed to understanding how general anaesthetics worked, and could explain why people experienced grogginess and disorientation after coming out of surgery.

The discovery has implications for people whose brain connectivity is vulnerable, for example in children whose brains are still developing or for people with Alzheimer's or Parkinson's disease.
        haleplushearty.blogspot.com

Regulating asprosin levels can control appetite and weight

Researchers have discovered a new hormone called asprosin, that regulates blood-glucose levels. New studies on the hormones showed that asprosin also acts on the brain, stimulating the hunger center in the hypothalamus to control appetite and body weight. This opens an intriguing possibility for developing treatments for overweight people. They discovered asprosin when studying individuals affected by a rare medical condition called neonatal progeroid syndrome.

Patients with neonatal progeroid syndrome have a mutation in the FBN1 gene that causes them to lack a small piece of the fibrillin-1 protein. In individuals without the FBN1mutation, this small piece, which we named asprosin, is cut and released into the circulation from the end of the protein.
One of the cardinal features that defines neonatal progeroid syndrome is extreme thinness or very low body weight. This allowed measurement of how much food they ate relative to the number of calories they burned every day.

Compared with individuals with normal weight, neonatal progeroid syndrome patients have abnormally low appetite.
To investigate how the mutation affected the patients' appetite, the researchers genetically engineered mice to carry the same genetic mutation the patients have. The result was mice that mimicked the human condition; they had low blood asprosin levels, low appetite and were very thin.

In the mouse model, researchers were able to reverse the low appetite by administering asprosin to the mice.
To understand how asprosin controls appetite. Asprosin interacts with neurons in the appetite center of the hypothalamus. There are two types of neurons involved in appetite control. One type, the AgRP neurons, stimulates appetite while the other type, POMC neurons, suppresses it.

Asprosin works on both types of neurons in an opposite manner; it activates appetite-stimulating AgRP neurons and it deactivates appetite-suppressing POMC neurons. The resulting effect of these two asprosin actions in the brain is an increase in appetite, a phenomenon that is deficient in individuals and mice with neonatal progeroid syndrome. The researchers also studied individuals with obesity and found that they had increased levels of blood asprosin.
          haleplushearty.blogspot.com

Brain oxidative stress can cause migraine

Migraine are an integrated mechanism by which the brain protects and repairs itself. Migraine can be triggered by diet, stress, sleep disruption, noise and air pollution. It can increase brain oxidative stress, an imbalance between the production of free radicals and the ability of the body to counteract their harmful effects.

Oxidative stress is a useful signal of impending harm because a number of unfavorable conditions in the brain can give rise to it, targeting oxidative stress might prevent or preempt migraines. An interruption in blood supply each of the components is protective: strengthening antioxidant defenses, lowering the production of oxidants, lowering energy requirements and, especially, releasing growth factors into the brain that protect existing neurons and support the birth and development of new neurons.

There are feedback loops between these components of a migraine attack that tie them together into an integrated system, migraine attacks are not triggered by oxidative stress, they actively protect and repair the brain from it. The pain, nausea, and sensitivity to light and sound, fever and pain, or cough are not the disease itself but part of the body's defense against migraine.
          haleplushearty.blogspot.com

Schizophrenia disrupts the brain's communication system

Schizophrenia disorder is a systemic disruption to the brain's communication system. The white matter- fatty brain tissue enabling neurons to talk to each other. The study displaces a theory that schizophrenia manifests due to wiring problems in only the prefrontal and temporal lobes. These front-facing areas of the brain are responsible for personality, decision-making and hearing perception.

Schizophrenia is a disorder where white matter wiring is frayed throughout the brain, researchers found that frayed communication cords were present throughout the brains of people with schizophrenia, the poorly insulated wiring was most evident in the corpus callosum, which allows for communication between the brain hemispheres and in the frontal portion of the corona radiata, a key structure for information processing.

Schizophrenia has a biological effect on the entire brain. Current medical treatment for schizophrenia addresses only symptoms because the causes of the disease are still unknown. Many patients are asked to take antipsychotic drugs for the rest of their lives. Some individuals experience side effects such as significant weight gain, tremors, emotional numbing or extreme drowsiness.

Researchers analyzed the data people with schizophrenia and healthy people from Australia, Asia, Europe, South Africa and North America. The researchers examined data from diffusion tensor imaging, a form of MRI that measures the movement of water molecules in the white matter of the brain. These scans allow scientists to locate problem areas in the brain's normally insulated communication system. Schizophrenia is partly hereditary, so perhaps specific genes promote the disorder through slight alterations in brain wiring.
          haleplushearty.blogspot.com

Epigenetics of drug addiction

Epigenetic factor such as enzymes in the brain that alter the packaging and accessibility of genes without changing the genes themselves influence addiction, this a challenge in addiction science to understand how transient experiences lead to long-lasting risk for relapse in users who try to quit.

The brains of drug users who have progressed to addiction differ from those of irregular users. Long-lasting associations form between the early use of a drug and different aspects of the early drug-using environment, such as the location in which a drug was first taken or the emotions a user was experiencing at the time. This can cause addicted users who have quit to experience cravings when in a similar condition.

Understanding these could lead to better treatments for addiction, detecting which genes were activated in the early drug-using environment. The epigenetic enzyme histone deacetylase 5 (HDAC5) slows the rodent brain from forming associations between cocaine and simple cues in the environment, such as light and sound.

HDAC5 is found in high amounts in neurons in the nucleus accumbens, part of the reward center of the brain that reacts strongly to cocaine, opioids and alcohol in rodents and humans. When HDACs are in the nucleus of neurons, they change the way genomic DNA is packaged in the cell nucleus and often block the ability of certain genes to be turned on.

In the new study, rodents were trained to press a lever to receive a dose of cocaine. Each time they received a dose, a lamp went on above the lever and a brief sound was generated. These served as simple environmental cues for drug use. Next, some rodents were given a form of HDAC5 that traveled straight to the nuclei of neurons. Those rodents still pressed the lever just as many times to receive drug, meaning that HDAC5, on its own, was likely not blocking genes that promoted early drug-seeking behavior.

HDAC5 reduced drug-seeking behavior during abstinence. To simulate withdrawal and abstinence, rodents were given rest without cocaine for one week, followed by a period during which they had access to the lever again. To simulate relapse, the rodents were shown the environmental cues again, this time without having pressed the lever. The presentation of the cues triggered robust lever pressing, indicating drug seeking, in control animals, proving that the associations between drug and environment persisted in their brains.

In contrast, animals who had the nuclear form of HDAC5 did not press the lever nearly as often, even after the experimenters gave the animals a small priming dose of cocaine, which often produces strong drug-seeking behaviors. HDAC5, the gene suppressor, did not prevent addiction-like behaviors from forming, but it did prevent later drug seeking and relapse during abstinence in rodents.

The researchers next used a cutting-edge technique that encourages epigenetic enzymes to bind to DNA, allowing them to identify all the genes inhibited by HDAC5. The gene for NPAS4 was a top hit, and significant for an important reason: it is an early-onset gene, meaning that its effects could be exerted on the brain rapidly unless HDAC5 was there to inhibit it.

Animals with less NPAS4 in the nucleus accumbens took more time to form those early connections between
environmental cues and cocaine, but they still sought the drug just as often during later simulated relapse. Apparently, NPAS4 accounts for some addiction-related learning and memory processes in the brain, but not all of them, meaning that HDAC5 must be regulating additional genes that reduce relapse events.

Abstinent patients report cravings when given reminders of their drug-associated environment or cues, and animals and humans share similar enzyme pathways and brain structures. These processes may be similar in the transition to cocaine, alcohol and opioid addictions.
          haleplushearty.blogspot.com

Source of ageing process

Genes belong to a process called autophagy - this one of the cells most critical survival processes, it promotes health and fitness in young worms but drive the process of ageing later in life.

 Promoting longevity by closing down autophagy in old worms improves neuronal and subsequent whole body health. Getting old happens to every species, natural selection results in the fittest individuals for a given environment surviving to breed and pass on their genes to the next generation.

The more fruitful a trait is at promoting reproductive success, the stronger the selection for that trait will be. Some genes encourage ageing while still being essential for development, there are series of genes involved in regulating autophagy, which accelerate the ageing process.

The process of autophagy is a critical recycling process in the cell. Autophagy is known to become slower with age and closing it down in the initiation of the process allows the worms to live longer.

There are severe negative consequences when it breaks down and then you are better off bypassing it all together. In young worms, autophagy is working properly and is essential to reach maturity but after reproduction, it begins to malfunction causing the worms to age.

 By inactivating autophagy in the neurons of old worms they were able to prolong the worms life and increased the total health of the worms. Turning autophagy off only in one tissue and the whole animal gets a boost. The neurons are much healthier in the treated worms and keeps the muscles and the rest of the body in good shape.
          haleplushearty.blogspot.com

Activating brain region creates desire for cocaine

Researchers have identified a part of the brain that intensifies desire for rewards like addiction to cocaine. Activating part of the amygdala, an almond-shaped brain region, intensifies motivation to consume cocaine far beyond ordinary drug levels, similar to its ability to intensify motivation for sweet foods like sugar.

Amygdala plays a key role in drug addiction. For addicts, drugs become so attractive as to cause intense motivation focused entirely on obtaining drugs at the expense of other normal life enjoyment. Researchers implanted rats with a catheter that allowed them to earn doses of cocaine, activating brain region creates intense desire to use cocaine.

Researchers implanted rats with a catheter that allowed them to earn doses of cocaine by poking their noses into small holes in the wall. Whenever rats would poke their nose into one particular hole to earn intravenous cocaine, a laser light would also activate the neurons in the central amygdala at the same time

Poking their nose into a different hole earned identical cocaine, but never activated the amygdala. Rats focused only on the port that earned cocaine together with amygdala-activating laser, consumed much more cocaine than rats without amygdala activation, and avidly nibbled around the laser-cocaine hole for more.

The amygdala activation intensified motivation when cocaine was also present. By contrast, when the researchers temporarily inactivated the amygdala using a painless drug infusion, rats completely stopped responding for cocaine.
          haleplushearty.blogspot.com

Autoimmunity contributes to Parkinson's disease

 Autoimmunity  is when the immune system attacks the body's own tissues. Parkinson's disease is neurodegenerative movement disorder.
Malfunctioning immune system contributes to Parkinson's disease.

Two fragments of alpha-synuclein, a protein that accumulates in the brain cells of Parkinson's disease patients can activate the T cells involved in autoimmune attacks.

Dopamine neurons that are affected by Parkinson's disease are vulnerable because they have proteins on the cell surface that help the immune system recognize foreign substances.

 Researchers examined blood samples from 67 Parkinson's disease patients and 36 healthy controls to fragments of alpha-synuclein and other proteins found in neurons.

 The immune response was associated with a common form of a gene found in the immune system, which may explain why many people with Parkinson's disease carry this gene variant.

 Immunotherapy can be used to increase the immune system's tolerance for alpha-synuclein, which could help to prevent worst condition of Parkinson's disease.

      haleplushearty.blogspot.com

Roles of genetics in brain formation

Scientists at the Scripps Research Institute TSRI have discovered that neurons in brains that form networks in the absence of synaptic activity.

According to Maximov assembly of neutral circuits in areas required for cognition is controlled by intrinsic genetic programs that operate separately.

Daily experience makes every brain unique by changing the form and patterns of neuronal connections.

Our organs of vision, hearing, smelling, tasting and touching are very important in early postnatal life when synapses is formed.

Humans have innate behaviors that is consistent across generations, indicating that some synaptic connections are genetically predetermined.