The latest research progress in neurobiology

October 28, 2019 / BIOON / -- this issue brings you the latest research progress in neurobiology I hope readers will like it 1 Nature: a new study reveals that inhibiting the increase of age-related neural activity can prolong the life span of DOI: 10.1038/s41586-019-1647-8 In a study of nematodes, mice and humans, researchers from Harvard Medical School in the United States found that aging brings more neural activity throughout the animal kingdom, and that when this natural increase is limited, an individual's life span may be longer They highlighted a conserved transcription factor called rest, which may be key to regulating this age-related neural activity The relevant research results are published in the nature Journal on October 17, 2019, and the paper title is "regulation of lifespan by natural exception and rest" "This is a very interesting paper that provides us with food for the mind," said Shin Ichiro Imai, a developmental biologist at Washington University's St Louis School of medicine Joy Alcedo, who studies nematode and fruit fly aging at Wayne State University in the United States (who was not involved in the study), added, "this is a fascinating idea: as people age, our neurons may actually become more active, and simply suppressing this neural activity may be enough to prolong life." Bruce yankner, a neuroscientist and geneticist at Harvard Medical School and the corresponding author of the paper, said that as people grow older, gene expression patterns in the brain change in a non random way, so that young people and old people can be distinguished by their transcriptional characteristics Of course, all the old people are different Some are healthy, some are not so healthy Yankner and his colleagues are interested in whether certain expressive features are related to this difference Instead of dividing the elderly into specific groups based on health, longevity or any other parameters, the researchers asked the data to help them They obtained RNA from the frontal cortex of hundreds of deceased elderly subjects and sequenced it through a computational process called unsupervised hierarchical clustering In this process, the computer iteratively determines who is closest to whom The result, he said, is that the RNA transcripts "spontaneously divide into people younger than 80 and people older than 85 or 90, and this distribution can be observed in three different cohorts, so it has good repeatability." By studying the differences in key gene expression between the two groups, the researchers found that people who lived longer had fewer transcripts of genes involved in nerve excitation and synaptic function than those who died earlier To get their research beyond this interesting correlation, the researchers turned to animal models Yankner explained that Caenorhabditis elegans is a very convenient organism for studying aging, because "they only live for about three weeks." His team found that neurons in older nematodes tended to discharge faster than those in younger ones, but in mutant nematodes with significantly longer lifespans, neuronal activity "remained almost silent." "This is the softest nematode you can imagine." In addition, the use of drugs that inhibit neural activity can increase the life span of wild-type nematodes Li Huei Tsai, a neuroscientist at the Massachusetts Institute of Technology who was not involved in the study, said: "I personally think this is a very surprising result When you think about longevity, it's very mysterious You might think it could involve many different things But please note that [the researchers] adjust only one thing, which is enough to change life expectancy " The use of genetic tools to shut down excitatory or inhibitory neurons in nematodes results in longer or shorter life expectancy, respectively, just as they increase or inhibit the level of a transcription factor called spr-4 Spr-4 is a mammalian transcription factor rest homologue in nematodes, in which rest is a transcription repressor that shuts down neural genes Importantly, in human subjects, people who lived to be 100 or older had significantly higher levels of rest protein than those who died between the ages of 70 and 80 Moreover, brain scans showed a global increase in neural activity in genetically engineered mice lacking rest However, the effect of rest on the life span of mice has not been studied "If these authors were able to find ways to extend the lifespan of mice by increasing their levels of rest in the brain, then this would be closer to humans than nematode research," Imai said However, as he points out, life tests on mice that can survive two or three years are much more difficult than in nematodes If such a result can be confirmed and its mechanism understood, Imai said, it will open the door for potential manipulation of the system, and "anti-aging interventions may become a reality in the near future." 2 Science: great progress! The gene shisa7 controls the tranquilizing effect of benzodiazepines doi: 10.1126/science.aax5719 Between 1999 and 2017, the number of deaths caused by excessive use of Valium (also known as benzodiazepine, or diazepam) and other benzodiazepines in the United States increased tenfold For many years, scientists have believed that these powerful tranquilizers, used to treat anxiety, muscle spasms and sleep disorders, alone play a role in calming nerves Now, in a new study, researchers from the National Institutes of Health (NIH) in the United States have found that this view of the neural circuits of such drugs and their effects may have to change By studying mice, they found that this might require the help of a "sticky" gene named shisa7 The related research results were published in the Science Journal on October 11, 2019 The title of the paper is "shisa7 is a GABAA receiver auxiliary subunit controlling benzodiazepine actions", and Wei, researcher of the National Institute of health and the National Institute of neurological diseases and stroke (NINDS), USA "We found that shisa7 plays a key role in the regulation of inhibitory neural circuits and the sedative effect of some benzodiazepines on neural circuit activity," Lu said We hope that these results will help scientists design more effective treatments for various neurological and neuropsychiatric diseases caused by problems in these circuits " Lu lab has studied genes and molecules that control synapses There are trillions of synapses or communication points between neurons in the whole nervous system In the new study, his team worked with a team led by Chris J McBain, a senior researcher at the National Institutes of health and human development (NICHD), to study synapses that rely on the neurotransmitter GABA to calm the nerves When a neuron releases a large number of GABA molecules, these molecules will soon be detected on the surface of adjacent neurons by a protein called GABA type A (GABAA) receptor, which is the way that different neurons communicate through synapses Prior to this study, benzodiazepines were thought to independently enhance the neurosedative response of GABAA receptors Lu's lab found, on the contrary, that these reactions may largely depend on whether the protein encoded by the shisa7 gene is attached to the GABAA receptor Although these results could eventually help scientists better understand these sedatives, the study began with a simple question about shisa7 In 2004, Japanese researchers first discovered that the shisa gene played a role in the formation of frog heads, and named it after a mythical protective god with a large head depicted in a statue in southern Japan Like many scientists, Lu initially believed that shisa7 played a role in controlling completely different types of synapses - they rely on the neurotransmitter glutamate to activate rather than sedate neurons Recent studies have shown that shisa7 is attached to glutamate receptor with other proteins encoded by shisa gene Once attached, these "helper" proteins control the glutamate receptor's response to glutamate or its presence in the synapse However, a few years ago, Lu's team noticed something interesting in a scientific article about the shisa protein Lu said, "we found amazing results This article suggests that shisa7 is the only protein in this family that seems to have no effect on the activity of important types of glutamate receptors This attracted our attention and we decided to study it carefully " To this end, Dr Wenwen Han, a postdoctoral researcher of NINDS, worked with other researchers in Lu laboratory to systematically study the shisa protein in mouse neurons To their surprise, they found that shisa7 seemed to play a unique and crucial role in the GABA synapse, which calms nerves With the help of scientists from Dr Ling Gang Wu, senior researcher of NINDS, and Dr Ronald s petralia, National Institute of deaf mute and other communication disorders (NIDCD), National Research Institute of the United States, using advanced microscopy, these researchers found that shisa7 was closely clustered on the GABAA receptor on the synaptic surface The elimination of shisa7 from neurons by gene will reduce the number of GABAA receptors and the current intensity of synaptic GABAA receptor response Further experiments showed that shisa7 protein was directly attached to GABAA receptor Electrical recordings showed that shisa7 accelerated the response of GABAA receptor to GABA, a neurotransmitter, and almost doubled the response size in the presence of diazepam, indicating that the protein made the receptor more sensitive to benzodiazepines "These results suggest that shisa7 directly forms inhibitory synapses under a variety of conditions, including the presence of benzodiazepines," said Dr McBain Finally, the experiments in mice support that shisa7 also plays a role in the sedative effect of benzodiazepines For example, in a group of experiments, they tested the ability of diazepam to reduce the high level of anxiety in mice facing open elevated spaces To do this, they placed the mice in the middle of an elevated maze of two crossed arms One arm is covered and the other is open Consistent with previous studies, the researchers found that administration of diazepam to these mice increased the time that wild-type mice chose to walk on open arms, suggesting that the drug reduced anxiety In contrast, diazepam had no effect on mice genetically engineered to lack the shisa7 gene Whether injected with diazepam or placebo, the mice lacking the shisa7 gene spent the same amount of time exploring open arms In other experiments, the researchers found that shisa7 also affects the drowsiness and hypnosis of benzodiazepines Compared with wild-type mice, mice lacking shisa7 were much less likely to fall asleep after high-dose diazepam injection In addition, after the fall caused by diazepam, the ability of mutant mice to stand up was significantly improved In fact, some mutant mice showed resistance to fall Lu said,