Lifeboat Foundation: Safeguarding Humanity
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Category: neuroscience – Page 108

As humans, we have the ability to recall detailed information, even from years in the past, indicating a powerful memory system. Newly encoded explicit memories initially depend on the hippocampus1,2,3,4. Memory reactivation, mediated by a hippocampo-cortical dialog, leads to a gradual maturation of neocortical engrams over time5,6,7,8,9. After this systems consolidation process, the neocortex can store information for decades.

It is well established that consolidation relies on non-rapid eye movement (NREM) sleep10,11,12,13,14,15. This brain state gives rise to characteristic patterns in the electroencephalogram, including slow waves (∼ 0.5–4 Hz), sleep spindles (∼ 10–16 Hz) and hippocampal ripple oscillations (∼ 80–120 Hz in humans)16,17,18. During slow wave activity (SWA), neocortical neurons exhibit synchronous membrane potential changes, referred to as UP and DOWN states19,20,21,22. UP states are periods of increased neural activity, giving rise to depolarization of neurons23,24. Conversely, DOWN states are silent periods, associated with hyperpolarization25,26. In the human neocortex, prominent SWA occurs in supragranular layers 2 & 321,27. Several studies have demonstrated that precise temporal coupling of spindles and ripples to SWA promotes engram reactivation28,29,30,31,32,33,34 and determines success of memory consolidation18,35,36,37,38. Consequently, brain stimulation methods that boost SWA or enhance coupling have a positive effect on memory performance in rodents and humans39,40,41,42,43,44. These observations suggest that SWA and the underlying membrane potential UP and DOWN states initiate mechanisms that augment memory functions. However, in the human brain such mechanisms remain elusive.

One possibility is that UP and DOWN states modulate excitatory synapses in the neocortex to increase synaptic strength during SWA-coupled neural activity. While action potentials (AP) are necessary to initiate transmission in the mammalian neocortex, it has been demonstrated in laboratory animals that presynaptic signals below the AP-threshold (i.e., subthreshold signals) have a modulatory effect on synaptic strength45,46,47,48,49,50,51,52,53,54. For instance, at synapses between neocortical pyramidal neurons in ferrets46 and rats47 a 1-second-long subthreshold depolarization preceding an AP leads to an increase in synaptic amplitude. Through such mechanisms, UP and DOWN states could tune local synaptic networks to promote long-term synaptic plasticity, which is believed to be fundamental for memory consolidation2,55.

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Objective: Intermittent energy restriction (IER) is an effective weight loss strategy. However, little is known about the dynamic effects of IER on the brain-gut-microbiome axis.

Methods: In this study, a total of 25 obese individuals successfully lost weight after a 2-month IER intervention. FMRI was used to determine the activity of brain regions. Metagenomic sequencing was performed to identify differentially abundant gut microbes and pathways in from fecal samples.

Results: Our results showed that IER longitudinally reduced the activity of obese-related brain regions at different timepoints, including the inferior frontal orbital gyrus in the cognitive control circuit, the putamen in the emotion and learning circuit, and the anterior cingulate cortex in the sensory circuit. IER longitudinally reduced E. coli abundance across multiple timepoints while elevating the abundance of obesity-related Faecalibacterium prausnitzii, Parabacteroides distasonis, and Bacterokles uniformis. Correlation analysis revealed longitudinally correlations between gut bacteria abundance alterations and brain activity changes.

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Researchers at Baylor College of Medicine, Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital and collaborating institutions have gained new insights into the molecular changes leading to Rett syndrome, a severe neurological disorder caused by mutations in the MeCP2 gene encoding methyl-CpG binding protein 2 (MeCP2).

The team reports in the journal Neuron that loss of MeCP2 in adulthood causes immediate progressive dysregulation of hundreds of genes—some are activated while others are suppressed—and these changes occur well before any measurable deficiencies in neurological function.

The MeCP2 protein is most highly expressed in neurons— where, like an orchestra conductor, MeCP2 directs the expression of hundreds of genes. When mutations produce a nonfunctional MeCP2 protein, the conductor is no longer present to direct the harmonious expression of genes needed for normal brain function. The resulting discord in leads to Rett syndrome.

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Dr. Ariel Zeleznikow-Johnston hopes to pick up the movement where Jones left off, albeit with the significant twist that his version does not require freezing. A research fellow at Melbourne’s Monash University, Zeleznikow-Johnston wrote the new book, “The Future Loves You: How and Why We Should Abolish Death,” which makes the case that cryopreservation is possible and should be more widely available. Rejecting the popular notion that death endows life with meaning as “palliative philosophy,” Zeleznikow-Johnston’s book instead argues a human’s connectome — a high-resolution map of all their brain connections — could be theoretically recorded perfectly before they die.

Once that happens, that same internal brain activity could be recreated through high-powered computers, while a new brain is grown in a vat via stem cells or some combination of the two. As such, Zeleznikow-Johnston is proposing a spiritual descendant to the cryonics movement (which he dismisses as “unscientific” and “unsubstantiated”), one where the focus is not on preserving tissues but on the “data,” so to speak, of our distinct connectomes.

“We have very strong evidence that the static structure of the neurons is enough to hold onto someone’s memories and personality.”

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22q11.2 deletion syndrome (22q) raises schizophrenia risk through skull malformations linked to the Tbx1 gene, affecting cerebellar development. This highlights how non-brain factors like bone defects can influence neurological disorders.

The chromosomal disorder 22q11.2 deletion syndrome (22q) has emerged as one of the strongest risk factors for schizophrenia. Scientists at St. Jude Children’s Research Hospital identified malformed regions of the cerebellum in both laboratory models and patients with 22q, attributing these malformations to improper skull formation.

Additionally, the researchers linked the skull malformation to the loss of a single gene: Tbx1. This research highlights that neurological disorders can arise from sources outside the nervous system, such as defects in skull development. The findings were published in Nature Communications.

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Because glucose metabolism is disrupted in several different neurodegenerative disorders, this treatment strategy also shows promise for other brain conditions.

“The beneficial effect on brain metabolism by IDO1 inhibition cuts across different types of pathology,” Andreasson said.

“It is exciting to think that this may be a more general mechanism that could be targeted in other neurodegenerative disorders, like Parkinson’s disease, where you have accumulation of a-synuclein, or ALS, where there is accumulation of tdp-43.”

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Summary: SUMO proteins play a key role in activating dormant neural stem cells, vital for brain repair and regeneration. This finding, centered on a process called SUMOylation, reveals how neural stem cells can be “woken up” to aid in brain recovery, offering potential treatments for neurodegenerative diseases.

SUMO proteins regulate neural stem cell reactivation by modifying the Hippo pathway, crucial for cell growth and repair. The study’s insights lay foundational groundwork for developing regenerative therapies to combat conditions like Alzheimer’s and Parkinson’s disease.

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Brain edema can accompany large ischemic strokes and can increase stroke-related morbidity and mortality. The past few decades have seen no advances in pharmacologic treatment of brain edema. These investigators conducted a manufacturer-funded, randomized, placebo-controlled trial of glibenclamide, a sulfonylurea 1–receptor inhibitor that can decrease brain edema. (Glibenclamide is approved to treat type 2 diabetes.) In a previous study, it was associated with fewer deaths from neurologic causes, but its use in patients with stroke is not widespread.

Eligible patients had large ischemic strokes that could be treated within 10 hours of onset. A large hemispheric infarct in at least the middle cerebral artery territory was defined as either an Alberta Stroke Program Early CT Score of 1 to 5 or lesion volumes of 80 mL to 300 mL on computed-tomography perfusion or diffusion-weighted imaging. Glibenclamide (8.6 mg) was given to half the study participants intravenously over 72 hours.

The study was halted early due to underenrollment. Of 535 enrolled patients, 431 were in the intended age range (18–70) and had complete data (mean age, 58; 33% women; median NIH Stroke Scale [NIHSS] score, 19). Treatment began at an average of 9 hours after symptom onset. No favorable shift with glibenclamide occurred on the primary outcome, the 90-day modified Rankin Scale (mRS). Mortality was similar in the two groups (glibenclamide, 32%; placebo, 29%). Hypoglycemia was seen in 6% of glibenclamide recipients and 2% of placebo recipients. Subgroup analysis revealed a signal of potential benefit with glibenclamide in patients with NIHSS scores of 20 or less.

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The findings suggest that biochemical and physical effects of exercise could help heal nerves. There’s no doubt that exercise does a body good. Regular activity not only strengthens muscles but can bolster our bones, blood vessels, and immune system.

Now, MIT engineers have found that exercise can also have benefits at the level of individual neurons. They observed that when muscles contract during exercise, they release a soup of biochemical signals called myokines. In the presence of these muscle-generated signals, neurons grew 4X farther compared to neurons that were not exposed to myokines. These cellular-level experiments suggest that exercise can have a significant biochemical effect on nerve growth.

Surprisingly, the researchers also found that neurons respond not only to the biochemical signals of exercise but also to its physical impacts. The team observed that when neurons are repeatedly pulled back and forth, similarly to how muscles contract and expand during exercise, the neurons grow just as much as when they are exposed to a muscle’s myokines.

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