Much improved mind-Reading from fMRI

Amazing stuff!

"... A “mind-reading” AI model called Brain-IT ... can reconstruct [a visual] scene based solely on the brain activity of a person viewing it ...

Brain-IT, by contrast, recognizes patterns of brain activity that are shared by all of us, and translates them into images. ...

“There exist nowadays models that translate brain activity into images, and they can even produce impressive reconstructions that preserve the semantic meaning of the image reasonably well,” ... “However, they tend to make mistakes in basic features such as composition and color.

The new model we developed outperforms them in reconstructing both the content of the image and its details. What’s more, while every other model requires dozens of hours of brain scans to learn to ‘read’ a new person, our model needs only one hour.” ..."

From the abstract:

"Reconstructing images seen by people from their fMRI brain recordings provides a non-invasive window into the human brain. Despite recent progress enabled by diffusion models, current methods often lack faithfulness to the actual seen images.

We present ``Brain-IT'', a brain-inspired approach that addresses this challenge through a Brain Interaction Transformer (BIT), allowing effective interactions between clusters of functionally-similar brain-voxels. These functional-clusters are shared by all subjects, serving as building blocks for integrating information both within and across brains.

All model components are shared by all clusters & subjects, allowing efficient training with limited amount of data.

To guide the image reconstruction, BIT predicts two complementary localized patch-level image features:

(i) high-level semantic features which steer the diffusion model toward the correct semantic content of the image; and

(ii) low-level structural features which help to initialize the diffusion process with the correct coarse layout of the image.

BIT's design enables direct flow of information from brain-voxel clusters to localized image features.

Through these principles, our method achieves image reconstructions from fMRI that faithfully reconstruct the seen images, and surpass current SotA approaches both visually and by standard objective metrics.

Moreover, with only 1-hour of fMRI data from a new subject, we achieve results comparable to current methods trained on full 40-hour recordings."

The New Science of Mind-Reading | Weizmann Institute of Science "A new AI model, called Brain-IT, can “read” your brain activity and reconstruct what you see with striking speed and accuracy"

Brain-IT: Image Reconstruction from fMRI via Brain-Interaction Transformer (preprint, open access)

Surprisingly Complex brain Waves while processing memory

Amazing stuff!

"... emerging evidence in humans and animals suggests that traveling waves play a central role in how the brain functions. ...

In a study ... neuroscientists measured traveling waves of neural activity and observed a menagerie:
source waves that appear to emanate from one location,
sink waves that converge on a spot, and
vortex like spiral waves.

The team ... found that different behavioral tasks were associated with distinct wave patterns. ...

With the high-resolution method, ... observed two new classes of waves in awake humans for the first time.

One, emanating from an area of the cortex, was a concentric wave, like the ripples from a pebble dropped into a lake, or the reverse, in which waves converged on one region.

The other was a rotating spiral wave traveling in a clockwise or counterclockwise direction, like a hurricane or a flushing toilet. ..."

"A new study ... used direct recordings of brain activity from human participants to show how “traveling waves” of activity spread across different regions of the brain to coordinate memory formation and recall. The activity forms distinct patterns, such as spirals and concentric waves, that change depending on what the person was doing, including remembering individual items. ..."

From the abstract:

"A fundamental challenge in neuroscience is explaining how widespread brain regions flexibly interact to support behaviors.

We hypothesize that traveling waves of oscillations are a key mechanism of neural coordination, such that they propagate across the cortex in distinctive spatial patterns that control how different regions interact.

To test this hypothesis, we used direct brain recordings from humans performing multiple memory experiments and an analytical framework that flexibly measures the propagation patterns of traveling waves.

We found that traveling waves propagated along the cortex in not only plane waves, but also spirals, sources and sinks, and more complex patterns.

The propagation patterns of traveling waves correlated with novel aspects of behavior, with specific spatial patterns reflecting particular cortical processes and even individual remembered items.

Our findings show that large-scale cortical patterns of traveling waves reveal a diverse range of spatial patterns in the brain that are relevant for neural decoding."

Surprisingly Complex Waves Reveal the Brain’s Inner Workings | Quanta Magazine "Unexpected patterns traveling across the cortex may be reorganizing its activity in real time."

Spirals, sources, sinks, and planes: What brain waves can tell us about memory (original news release) "New research from UChicago and the University of Pittsburgh shows how the brain creates distinct patterns of activity as it processes memories."

Planar, spiral, and concentric traveling waves distinguish behavioral states in human memory (open access)

Fig. 1: Task structure and identification of stable periods of traveling waves.

Fig. 3: Classification of traveling waves.

Discovery of a second fear center in the brain and may explain why fear responses last so long

Amazing stuff!

"... Although the amygdala is widely considered the brain’s fear center, scientists have now discovered another area that responds to danger. The amygdalostriatal transition zone (ASt) is a small, long-overlooked region that sits alongside its more famous neighbor, and new experiments show that its neurons fire stronger and longer than those in the amygdala, which could explain why certain defensive behaviors persist. ..."

"Highlights

• Salk neuroscientists identify and characterize new region in the brain’s fear circuit called the amygdalostriatal transition zone (ASt)
• ASt neurons fire with more strength and for longer than the amygdala, which has historically been considered the brain’s fear center
• Findings explain why fear responses like freezing can last so long and point to therapeutic innovations for disorders like PTSD, anxiety

...

The ASt is tiny—it’s hard to reach, hard to study, and hard to distinguish from surrounding brain regions. Because of these challenges, the ASt has been relatively unexplored, leaving scientists unsure whether it is even a distinct brain region. This is the first landmark in the Salk paper: The researchers show that the mouse ASt is a distinct brain region, separate from the neighboring amygdala and striatum regions. ..."

From the highlights and abstract:

"Highlights

• ASt neurons have a unique genetic identity

• ASt neurons encode sustained responses to conditioned shock cues

• Activation of ASt neurons is sufficient to drive freezing and avoidance

• Drd2+ ASt neurons are necessary for expression of cued fear responses

Summary

To ensure survival, the brain must rapidly identify threats and maintain defensive behaviors for as long as danger is present. The amygdala has been studied as a key site for fear responses, but responses to threat cues in amygdala neurons are largely transient and shorter in duration than defensive responses observed.

Here, we present the amygdalostriatal transition zone (ASt) as a missing piece of the circuits mediating fear responses. Using single-nucleus RNA sequencing (snRNA-seq), we demonstrate that the ASt is genetically distinct from adjacent striatal and amygdalar structures.

In vivo electrophysiology and calcium imaging reveal that ASt neurons have robust, sustained responses to shock-predicting cues. Further, photostimulation of the ASt is sufficient to drive freezing and avoidance behaviors, and optogenetic inhibition experiments show that Drd2+ ASt neurons are necessary for cue-conditioned fear responses.

Our findings establish the ASt as a previously unappreciated yet critical structure for encoding learned associations and directing defensive behaviors."

ScienceAdviser

Why do we stay afraid for so long when the brain’s first alarm fires so fast?

Amygdalostriatal transition zone neurons encode sustained cue responses to guide defensive behaviors (open access)

Graphical abstract

Figure 1 The ASt is genetically distinct from the amygdala and striatum

Human brain is two separate organs

Amazing stuff!

"... But new research ... reveals that what we call the brain is two distinct organs that evolved independently over hundreds of millions of years. ...

"We've shown for the first time that the front of the brain arises from a totally different progenitor cell than the back of the brain," ..."

"... The new research finding shows that the human brain consists of two ancient nervous systems cleverly packaged together — a more primitive part that regulates our hearts’ beating, our breathing and other functions, and another that makes us distinctly human, capable of poetry, mathematics and wondering about our own origins. ...

The researchers’ breakthrough came from studying the earliest moments of embryonic development, during a stage called gastrulation when the body first takes shape. ... discovered that the hindbrain follows a separate developmental path, running in parallel to — rather than branching off from — the pathway that creates the forebrain and midbrain. ...

The team then examined the DNA packaging, or chromatin, in these cells. Chromatin is a way cells determine which genes can be easily accessed and which are bundled away out of reach. What they found was striking:

The anterior neural ectoderm (future forebrain and midbrain) and posterior neural ectoderm (future hindbrain) have fundamentally different chromatin configurations. These differences essentially locked each progenitor cell into its respective fate, like travelers on parallel tracks that never cross. ...

Armed with this knowledge, the researchers for the first time successfully coaxed human pluripotent stem cells (a kind of cell that can create any cell in the human body) to become functional hindbrain motor neurons in the laboratory. These lab-grown neurons displayed all the hallmarks of authentic hindbrain cells: They exhibited waves of electrical activity called action potentials and made proteins that identify the segments of the hindbrain that control facial and swallowing muscles.

Finally, the researchers looked back over 550 million years of evolutionary time. They found the same two-origin brain pattern in chickens; zebrafish; and, remarkably, in acorn worms, tiny creatures living on the ocean floor that share a distant common ancestor with humans. Jellyfish, which diverged from humans about 600 to 700 million years ago, have two nervous systems at different ends of their body. ..."

From the abstract:

"When and how different brain regions diversify from one another remains unresolved. Does a common neural ectoderm progenitor generate the entire brain? Or do multiple neural ectoderm progenitors exist, each restricted to form specific brain regions?

Here our lineage tracing studies of mouse embryos support the latter model. Two parallel brain progenitors emerge simultaneously during gastrulation:

anterior neural ectoderm (forebrain/midbrain progenitor) and posterior neural ectoderm (hindbrain progenitor).

Differentiation of human pluripotent stem cells into anterior or posterior neural ectoderm-like cells revealed these were lineage committed to forebrain/midbrain versus hindbrain fates, respectively.

They harbored diverging chromatin landscapes foreshadowing future forebrain/midbrain versus hindbrain identities. We further differentiated human pluripotent stem cells into hindbrain rhombomere 5/6-specific motor neurons, which were hitherto difficult to generate in vitro.

Hence, we postulate the brain is a composite organ emanating from two lineage-restricted progenitors; these dual progenitors may be evolutionarily conserved across 550 million years from hemichordates to mammals."

Human brain has a split origin, new research suggests

Human brain is two separate organs, Stanford Medicine-led research finds (original news release)

Two parallel neural ectoderm progenitors contribute to the developing brain (no public access)

Two parallel lineage-committed progenitors contribute to the developing brain (preprint, open access)

Fig. 1 Anterior and posterior neural ectoderm in vivo and in vitro.

Fast high resolution 3D video reveals how seizures move through the brain of a larval zebrafish

Amazing stuff!

"... Researchers from the University of Georgia have now developed an improved light-sheet microscope with the ability to perform fast 3D imaging of zebrafish seizures. ...

the researchers found that seizures originated in the hindbrain and propagated forward (anteriorly). This corroborates a previous study examining 3D imaging of zebrafish seizures, but contradicts two earlier studies of 2D imaging (reported in Frontiers in Neural Circuits and eNeuro) that observed propagation in the reverse direction. ..."

From the abstract:

"Light sheet microscopy is a powerful tool for imaging live organisms. To enable high-speed volumetric imaging, we have developed a light sheet system incorporating an electrically tunable lens (ETL) capable of capturing volumes up to 499 × 499 × 150 μm3 at 4 volumes per second with near diffraction-limited resolution. The system employs sensorless adaptive optics to correct ETL induced system aberrations, extending the usable field of view by fivefold.

We apply this system to image the propagation of seizures in zebrafish larvae and observe that seizures originate in the posterior brain, propagate anteriorly toward the optic tectum and gradually subside over tens of seconds."

Fast 3D imaging reveals how seizures move through the brain – Physics World

UGA study is among the first to provide a high-resolution 3D video of a seizure event (original news release)

Fast volumetric imaging of a zebrafish seizure model with adaptive optics light sheet microscopy (open access)

Mid-seizure activity Scientists capture a snapshot of a larval zebrafish brain during a seizure. White and red mark regions with the greatest neuronal activity, while blue tones indicate lower activity.

Can This End Addiction for Good? Using highly focused beams of ultrasound to target specific regions in the brain

Good news!

(234) Can This End Addiction for Good? - YouTube

Scientists grow human brain tissue inside a live mice skull

Amazing stuff!

"... a group from Stanford University has found a way to advance their usefulness for studying brain development and disease — by instead growing [organoids] inside mice that have had large parts of their own brains genetically removed. 

Neuroscientists say these “neuro-chimeric” mice, whose brains are half-human — by volume, not by number of neurons — are an important innovation for a field hampered by longstanding challenges in accessing human brain tissue for research. But such models also raise a host of ethical questions that will get thornier the more advanced they become. ..."

"... researchers succeeded in transplanting self-organizing bits of laboratory-grown human brain tissue called cortical organoids into mice specially bioengineered and bred so that almost all of their cerebral cortex was missing. (The cerebral cortex is the outermost “rind” of the brain, to which much of our higher-level functioning such as cognition, language, attention and decision-making is attributed.)

The resulting vastly enlarged cavity in the mice’s brains proved to be a hospitable environment. The human tissue survived, thrived, grew — and developed working connections to the mice’s brain and beyond to the spinal cord. ...

The new methodology should speed research into the underlying biological causes of schizophrenia, epilepsy, profound autism and cerebral palsy ..."

From the abstract:

"The inaccessibility of human brain tissue limits the study of human development and function, a challenge that human stem-cell-derived neural models are beginning to address.

Transplantation of neural organoids into rodent hosts enables the in vivo study of aspects of human neurodevelopment and circuit function, alongside behavioural phenotyping of the host animals. However, spatial limitations and competition with host circuits constrain the integration of neural organoids, which is critical for studying disease.

Here we establish a transplantation platform using a genetic strategy to effectively deplete glutamatergic neurons from mouse neocortex and hippocampus (apallial) and neonatally engraft the cortical cavity with human stem-cell-derived cortical organoids (hCO) to generate xenocortical mice.

This leads to robust graft growth with hCOs occupying most of the cortical volume and generating a diversity of human cortical cell types, including layer 5 extratelencephalic projection neurons.

Human cortical neurons integrate with the mouse nervous system, and in vivo cortical graft-wide calcium imaging and electrophysiological analyses revealed patterns of organized activity resembling developing circuits.

Behavioural analyses of apallial and xenocortical mice revealed broadly preserved locomotion alongside selective differences in limb coordination and altered organization of spontaneous behaviour.

Lastly, this platform enabled behavioural readouts in a model of injury to developing human cortical cells. We envision that xenocortication will be useful for obtaining circuit- and behaviour-level readouts using human neurons to study neurodevelopment, model disease and develop therapeutics."

Scientists grow human brain tissue inside mice. Here's why | STAT "Advance opens new ways to studying brain development and disease, but raises ethical concerns"

Stanford Medicine team creates advanced model for studying brain development, disorders "The ability to study brain disorders that arise before birth has taken a leap forward as Stanford Medicine researchers find a new way to grow human brain tissue outside of the human brain."

Developmental xenocortication using human-derived organoids in mice (open access)

Fig. 1: Characterization of the apallial mouse model.

Fig. 2: Transplantation of human cortical organoids into the apallial mouse.

Closed-loop auditory stimulation in phase with slow waves during sleep enhances cerebrospinal fluid flow in humans

Good news!

closed-loop auditory stimulation (CLAS)

Recurrent neural networks (RNNs)

"... In a new study, ... researchers have shown that they can strengthen these CSF waves through exposure to short bursts of a gentle, staticky sound known as “pink noise” during sleep. These bursts increase the amplitude of slow electrical waves in the brain, which then enlarges the CSF waves. ...

Their fMRI studies also revealed that the slow waves stimulate blood vessels to constrict and dilate, allowing them to act as a pump that drives CSF out of the brain. Slow waves are seen only during non-REM sleep, and they become more prominent in deeper stages of sleep. ..."

From the abstract:

"Cerebrospinal fluid (CSF) is a key component of healthy brain function, constantly circulating to maintain brain homeostasis.

Large waves of CSF flow appear in nonrapid eye movement (NREM) sleep, and these CSF flow waves are associated with neural slow waves in the electroencephalogram (EEG).

Whether neural slow waves are causally linked to CSF flow, and whether this flow can be enhanced, is not yet established.

We developed a technique for performing closed-loop auditory stimulation of sleep slow waves with simultaneous magnetic resonance imaging (MRI) using real-time denoising and a neural network–based strategy for stimulus targeting.

We first established that our technique could increase EEG slow waves during sleep inside the MRI scanner in healthy adults.

We then found that closed-loop auditory stimulation during sleep caused increased CSF flow waves.

Furthermore, this CSF flow effect was phase dependent and only apparent when auditory stimuli were aligned with slow-wave peaks. Widespread hemodynamic waves were also elicited by the stimulus, suggesting a brain-wide modulation contributing to this CSF flow effect.

This work demonstrates that closed-loop slow-wave neurofeedback causes waves of CSF flow and provides a technique for simultaneous modulation and imaging of CSF flow during sleep that can next be explored as a potential translational tool in clinical populations."

A burst of “pink noise” may lead to more restorative sleep | MIT News | Massachusetts Institute of Technology "Delivered at just the right time, this type of auditory stimulus can strengthen the flow of cerebrospinal fluid, which clears debris from the brain and keeps it healthy."

Closed-loop auditory stimulation in phase with slow waves during sleep enhances cerebrospinal fluid flow in humans | Science Translational Medicine

Fig. 1. An integrated RNN and real-time EEG-fMRI algorithm enables closed-loop slow-wave enhancement inside the MRI scanner.

Fig. 2. CLAS causes a CSF flow wave in the fourth ventricle.

New clues suggest how destructive immune cells wreak havoc in the brain from the neck

Good news! The best part is that a treatment of the lymph nodes in the neck can be very effective.

"In recent years, scientists have found CD8+ T cells—immune cells that recognize and respond to foreign threats—in the brain tissue of people who died with Alzheimer’s, and evidence suggests that they were harming, not helping. Now, researchers report that a type of dendritic cell in lymph nodes in the neck helps prime these T cells to multiply before they enter the brain and cause damage.

In mice bred to produce excess toxic tau, a key Alzheimer’s protein, those with the dendritic cells developed the expected severe brain damage.

Animals without the dendritic cells did not experience the same T cell infiltration, severe neurodegeneration or behavioral problems—even though they still had excess tau.

This finding suggests that while tau may not be completely harmless by itself, inflammation driven by T cells may amplify the damage. The T cells proliferated in the mice’s neck lymph nodes, where they were primed by the dendritic cells. The fact that this process occurs in the neck, not the brain, opens the door to using existing drugs that trap T cells in lymph nodes. ..."

"... Researchers ... have now discovered in mice that these immune cells, known as T cells, are receiving their instructions from lymph nodes outside of the brain. The team also showed they can block these instructions to dramatically mitigate neurodegeneration. The discovery reveals a previously unsuspected pathway that could potentially halt or slow the progression of Alzheimer’s disease and other diseases collectively called primary tauopathies ..."

From the abstract:

"Alzheimer’s disease and primary tauopathies are marked by changes in adaptive immunity, with increased brain CD8+ T cells correlating with tau pathology severity.

However, how peripheral T cells get primed to enter the brain and contribute to tau-mediated neurodegeneration remains unclear.

In different disease conditions, conventional type 1 dendritic cells (cDC1s) cross-present antigens to prime CD8+ T cells into effector cells.

We show that tauopathy mice lacking cDC1s or antigen cross-presentation are protected from neurodegeneration, with reduced brain CD8+ T cell infiltration and glial activation.

The remaining CD8+ T cells exhibit limited clonal expansion, consistent with impaired priming.

We further demonstrate that brain-derived antigens are presented in secondary lymphoid tissues, suggesting a site of T cell activation.

Together, these findings establish cDC1-dependent peripheral priming as a key driver of CD8+ T cell accumulation in the brain and tau-mediated neurodegeneration."

ScienceAdviser

New clues suggest how destructive immune cells wreak havoc in the brain (no public access) "Study in mice strengthens T cells’ ties to neurodegenerative conditions like Alzheimer’s"

Key path to Alzheimer’s-like brain damage starts outside the brain (original news release) "Study finds in mice that immune cells that drive neurodegeneration originate in body’s lymph nodes"

Priming of CD8+ T cells by peripheral dendritic cells exacerbates tau-mediated neurodegeneration (open access)

Fig. 4: cDC1 deficiency specifically prevents CD8+ T cells from accumulating in brain of tauopathy mice at 9.5 months of age.

Hippocampus-free memory consolidation

Amazing stuff! It took only two years from preprint to publication! Caution irony!

"During sleep, consolidation of all types of memories is thought to be initiated by hippocampal replay of spatiotemporal context. However, whether the hippocampus is the driver of, and needed for, memory consolidation in all conditions remains a matter of debate.

Thompson et al. showed that the consolidation of procedural memory occurs in the striatum, without the involvement of the hippocampus. Bilateral hippocampal lesions did not affect memory consolidation, suggesting that the hippocampus is not necessary for triggering procedural memory consolidation."

From the abstract:

"Sleep is crucial for consolidating all forms of memory and a core mechanism underlying this process is offline replay.

Current models propose that replay originates in the hippocampus and triggers reactivation across cortical and subcortical networks. However, conflicting evidence about the role of the hippocampus in offline consolidation of nondeclarative memories raises the question of whether hippocampal replay drives their consolidation.

Here we show that replay occurs in the dorsal striatum during offline consolidation of a procedural memory in mice, independently of the hippocampus, and that its content predicts subsequent performance improvements.

Neural sequences linked to salient behavioral events were prioritized for replay, with positive and negative behavioral outcomes having opposing effects on individual replay events.

All features of replay persisted despite complete bilateral hippocampal lesions. These findings demonstrate that procedural replay occurs independently of the hippocampus, indicating that replay-driven memory consolidation can operate through parallel, independent mechanisms."

In Other Journals | Science

Replay of procedural memory is independent of the hippocampus (open access, preprint published in 2024)

Fig. 1 Fig. 1: Learning and execution of the sequence learning task is dependent on the DLS.

Fig. 3 Replay of procedural neural activity in the striatum during sleep

Comparison of male and female fly brains is unlocking the secret workings of the mind by sex

Amazing stuff! This is huge! Mind boggling!

"An international team ... has mapped every neuron in the male Drosophila fly’s brain and nerve cord, to produce a wiring map of the 166,700 neurons and the millions of connections between them. ...

Since the female Drosophila fly brain has previously been mapped, involving the same group, this new work allowed the researchers to directly compare male and female connectomes and pinpoint differences between them.

This revealed that neurons can reroute sensory information into sex-specific behavioural circuits to drive different male and female responses to the same stimuli.

For example, male flies detect the smell of another male fly and respond with aggressive behaviour, whereas female flies respond to the same smell with courtship behaviour. ...

This is the first full-scale connectome of an adult animal’s brain and nerve cord ever produced. The entire dataset now exists as a public resource, openly available as a reference and tool for other researchers. ..."

From the highlights and abstract:

"Highlights

• Whole male Drosophila CNS connectome enables sensory-to-motor circuit analysis

• First synaptic-resolution comparison of male and female brains

• Sex-specific and dimorphic neurons concentrate in higher-order, integrative centers

• Analysis of visual, auditory, olfactory, and taste pathways reveals shared principles

Summary

Sex differences in behavior exist across all animals, typically under strong genetic regulation. In Drosophila, fruitless/doublesex transcription factors identify dimorphic neurons, but their organization into functional circuits remains unclear. We present the connectome of the entire Drosophila male central nervous system. This contains 166,700 neurons spanning the brain and nerve cord, fully proofread and annotated, including fruitless/doublesex expression and 11,710 neuron types.

We provide the first comprehensive comparison between male and female brain connectomes to synaptic resolution, finding 8,069 isomorphic, 138 dimorphic, 289 male-specific, and 71 female-specific types.

This resource enables analysis of full sensory-to-motor circuits underlying complex behaviors and the impact of dimorphic elements.

Sex-specific/dimorphic neurons are concentrated in higher brain centers, while the sensory and motor periphery is largely isomorphic.

Within higher centers, male-specific connections are organized into hotspots defined by male-specific neurons or arbors. Dimorphic neurons reroute information across sexes."

Comparison of male and female fly brains is unlocking the secret workings of the mind | University of Cambridge "Scientists have produced the first full scale wiring map of a male adult animal’s brain and nerve cord, enabling unprecedented insights into how the brain works and controls behaviour."

5 amazing visuals show how the male fruit fly’s brain map is advancing neuroscience "A years-long project by HHMI Janelia, Google Research, and collaborators has built the first complete brain map for a male fruit fly, a key model organism in science."

Sexual dimorphism in the complete Drosophila male central nervous system connectome (open access)

Graphical abstract

Figure 1 A densely annotated and cross-matched male CNS connectome

Figure 2 Information flow from sensory input to motor output organizes circuits spanning the brain and nerve cord

Figure 3 Sexual dimorphism in the fly brain

Are predatory brain immune cells eating nerve cells in Amyotrophic lateral sclerosis (ALS)?

Good news!

"Highlights

• Salk scientists discover that central nervous system-resident immune cells called microglia use TAM receptors (discovered by study senior author Greg Lemke in 1991) to eat specific nerve cells in mouse model of ALS
• The study is the first to show TAM receptors can be used to kill living nerve cells
• The insights contribute to ongoing efforts to harness TAM receptors in clinical settings to treat cancers, autoimmune disorders, and more

...

Neurons are often the center of attention in brain and neurodegeneration research, but other cells in the central nervous system are important, too. Recent studies have shown microglia, which are immune cells specific to the brain and spinal cord, are very active during human ALS. The question is: Why? ...

Active microglia can be easily identified in research by assessing their expression of TAM receptors. ... discovered this family of proteins, which are critical bridges between the immune system and the rest of the body, more than three decades ago. ...

To determine whether the TAM system was the link between microglia activation and motor neuron death in ALS, the ... researchers started with the most widely used mouse model of ALS, called SOD1. These mice express a mutant SOD1 protein that causes ALS in people.

They first found that many motor neurons had been eaten in the spinal cords of SOD1 mice. The levels of TAM proteins were also elevated in these mice, particularly Axl and Mer.

Looking closer at the motor neurons, the scientists noticed those “eat me” signs, which are little molecules called phosphatidylserine, were being displayed on cells when they shouldn’t be. From there, the TAM system springs into action, guiding microglia to their next meal: a live neuron.

The natural next question ... is “what happens when we eliminate Axl and Mer?” Without these two TAM family proteins, the mice got sicker faster but lived longer. ...

“When we looked at how many motor neurons mice without Axl and Mer had, compared to mice with Axl and Mer, we found losing the TAM proteins meant preserving muscle controls.” ..."

From the abstract:

"Activation of microglia is a prominent feature of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that leads to the death of motor neurons.

A key component of this activation is elevated expression of the TAM receptor tyrosine kinases Axl and Mer (gene name Mertk).

Here we show that germline and microglial-restricted inactivation of the Axl and Mertk genes in the SOD1G93A mouse model of ALS leads to an extension of lifespan, which is tied to the preservation of cholinergic motor neurons and neuromuscular synapses.

Also elevated on SOD1G93A neuronal surfaces is the essential TAM co-ligand phosphatidylserine, a potent ‘eat-me’ signal through which apoptotic cells are engulfed by microglia.

Correspondingly, we find that microglial lysosomes are filled with the remains of cholinergic neurons in the SOD1G93A spinal cord, whereas this accumulation is markedly reduced in the SOD1G93AAxl-/-Mertk-/- cord.

Together, these results suggest that microglia phagocytically kill living neurons, and thereby hasten death in ALS."

Are predatory brain immune cells eating nerve cells in ALS? – Salk Institute "Salk Institute scientists discover central nervous system immune cells find and kill specific nerve cells in the spinal cords of mice with late-stage ALS, exacerbating the condition; findings could be harnessed in cancer and autoimmune therapy innovation efforts"

Microglia deploy TAM receptors to kill motor neurons in a mouse model of amyotrophic lateral sclerosis (open access, but still in press)

Microglia (green) contain the remnants of motor neurons (purple) inside microglial lysosomes (yellow).

Key brain circuit regulating the entry into hibernation found at last

Amazing stuff!

Notice here the emphasis is on entry into hibernation not hibernation in general.

Notice Google Search was not able to find a news release regarding this discovery neither did the Whitehead Institute for Biomedical Research publish one although many of the authors of this study are affiliated with the WI. That is disappointing.

"... Now, in a preprint posted on bioRxiv, researchers studying hibernating Syrian hamsters have pinpointed for the first time a brain circuit that regulates an animal’s entry into hibernation. The results reveal a “key, really, in the network” and provide “more solid [evidence] than anything we had before” of an ancient hibernation circuit within the mammalian brain ..."

From the abstract:

"Evolution of seasonal hibernation has enabled mammals to survive harsh conditions by entering a state of prolonged hypometabolism and hypothermia with body temperatures as low as 0-4°C1–6.

Despite decades of physiological studies, the genetic tools to study hibernation have remained limited and the mechanisms that induce hibernation entry are still unknown.

Focusing on the brain, we map state-dependent neuronal activity across the hibernation cycle in Syrian hamsters and identify the hypothalamic anterior preoptic area (aPOA) as a key regulator of hibernation entry.

Single-nucleus RNA and chromatin profiling provided a map of neuronal populations present in the hamster POA and enabled the discovery and design of an enhancer AAV that selectively targets hibernation-associated aPOA subpopulations.

Using this genetic approach, we show that Samd3-positive aPOA glutamatergic neurons are necessary for entry into hibernation and that their activation is sufficient to induce a prolonged hypothermic state with associated nesting behavior.

Together, we identify the first neuronal population that controls entry into hibernation, opening new avenues for investigating and manipulating the metabolic and physiological mechanisms underlying this extreme state of “suspended animation” and its potential applications in aging and disease."

Key brain circuit regulating hibernation found at last | Science | AAAS

Preoptic Neurons that Control Entry into Hibernation

Fig. 2: Identification of anterior preoptic area activity as necessary for deep torpor entry.

UK brain Surgeons Use AI To Save Man’s Eyesight with Palki Sharma

Amazing stuff!

"The patient, a 48-year-old [man], had a tumour near the pituitary gland, a tightly packed area surrounded by blood vessels and nerves linked to vision. A mistake of even one millimetre could have caused blindness, stroke or death."

(241) UK Surgeons Use AI To Save Man’s Eyesight | The Palki Sharma Show | IGR | India Global Review - YouTube

Ketamine increases neuroplasticity in female mice but not in males

Amazing stuff! Good news!

"Doctors use ketamine on patients as general anesthesia before surgery. They also prescribe it in low doses for pain management, and more recently, it’s been used for treatment-resistant depression where other drugs have failed.

It works by dampening communication between brain cells. But a new study reveals that its effects on the brain are different in male and female mice. This insight—if reproduced in humans—could change the way we test the efficacy of drugs and unlock better treatments for depression. ...

discovered that when female mice are recovering from a single ketamine sedation, their brains become more active than their male counterparts, specifically their microglia. These specialized brain cells began reaching out with their branch-like arms to intermingle with surrounding brain cells. This increased activity led to the removal of the extracellular matrix—the proteins and molecules surrounding, supporting, and giving structure to cells—and created space that allowed new synapses to form and remodel the neural network, thereby increasing neuroplasticity. Researchers didn’t observe this behavior in male mice. ...

Neuroplasticity is a delicate balance: too much or too little have both been linked to neuropsychiatric disorders. ..."

From the abstract:

"Anesthesia recovery is critical for resuming normal physiological and neuronal functions; however, the mechanisms involved remain elusive.

Here, we identify a female-selective corticosterone-mediated microglia-neuron interaction during ketamine anesthesia recovery, absent in males.

This microglia-neuron interaction induces plastic and functional neuronal changes, as evidenced by increased mEPSC frequency, which was occluded upon microglia depletion.

We showed that this process is driven through up-regulation of the stress-responsive co-chaperone Fkbp5 mRNA and its protein, Fkbp51, in female microglia. Fkbp5/Fkbp51 is a key intermediary in a corticosteroid-induced stress response, and its involvement points toward a critical interface between endocrine signaling and microglia.

To counteract the observed ketamine anesthesia-mediated increase in blood corticosterone during recovery, we removed the primary source of corticosterone by adrenalectomy. Close microglia-neuron interaction was reduced and increased again following corticosterone injection.

Our findings identify a sex-specific microglia-mediated mechanism of neuronal plasticity during anesthesia recovery, driven by corticosterone, thereby enhancing our understanding of sex differences in brain function."

Ketamine increases neuroplasticity in female mice but not in males "The surprising finding could help scientists develop better treatments for depression"

Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia (open access)

Distribution of microglia (green) across the different cortical layers (orange) in the mouse visual cortex

Fig. 1. Female microglia interact with neurons, promoting spinogenesis and plasticity upon ketamine recovery.

Tuberculosis Vaccine (BCG) Reprograms Brain Immunity in Small Trial

Amazing stuff! Good news, but older news!

"... Since then, with billions of doses given, the shot has surprised scientists with its capabilities beyond preventing tuberculosis. Researchers have found that BCG also helps prevent type 1 diabetes, reduce multiple sclerosis relapse, and treat bladder cancer. Scientists have uncovered how BCG programs the peripheral immune system to induce these effects.

However, the vaccine’s impact on the central nervous system (CNS) and immune cells within it remains poorly understood, despite retrospective studies revealing a link between the vaccine and the brain: People who received BCG for bladder cancer also showed reduced incidence of Alzheimer’s disease (AD).

Now, in a small clinical trial, researchers found that BCG triggered immune remodeling in the cerebrospinal fluid (CSF) of older adults and reduced AD-related biomarkers. The findings, published in Communications Medicine, suggest that vaccine-induced immune reprogramming could be used as a strategy to target early neurodegeneration. ..."

From the abstract:

"Background

Immune aging may contribute to Alzheimer’s disease. Bacillus Calmette–Guérin (BCG), a vaccine known to induce trained immunity, has been linked to reduced Alzheimer’s risk in prior studies. However, whether trained immunity can be observed in the human central nervous system remains unclear. We assessed whether BCG induces trained immunity–like responses in adults with and without Alzheimer’s-related changes.

Methods

We conducted two related one-year, open-label clinical trials in adults aged 55 years or older (n = 12 without Alzheimer’s-related pathology; n = 11 with Alzheimer’s-related pathology) recruited at a single center.

Participants received two intradermal BCG vaccinations one month apart. Protocol-defined objectives included safety, neurocognitive outcomes, and longitudinal immune and Alzheimer’s biomarker changes in blood and cerebrospinal fluid.

Immune responses were assessed using cytokine assays and single-cell profiling. All enrolled participants were included where data were available; longitudinal changes were analyzed using mixed-effects models.

Results

Here we show that BCG induces persistent, trained immunity–like changes in immune cells in cerebrospinal fluid, including enhanced innate responsiveness and associated transcriptional programs.

These responses differ from blood, suggesting compartment-specific immune imprinting.

In participants without Alzheimer’s-related changes, these immune shifts are accompanied by decreased amyloid-β levels in cerebrospinal fluid and increased levels in blood. BCG was well tolerated, with no unexpected safety signals observed.

Conclusions

These findings suggest trained immunity–like responses in the central nervous system that may influence Alzheimer’s-relevant pathways.

This approach may represent an early neurodegenerative intervention strategy, although larger controlled studies are needed to confirm these observations."

BCG Vaccine Reprograms Brain Immunity in Small Trial | The Scientist "The BCG vaccine altered Alzheimer’s disease biomarkers and brain immune cells in older adults, hinting at its potential to target neurodegeneration."

Bacillus Calmette–Guérin (BCG) immunotherapy reprograms CNS immunity and alters Alzheimer’s biomarkers: results from two open-label clinical trials (open access)

Fig. 1: Study design and trained immunity-associated cytokine responses in PBMCs. [Peripheral blood mononuclear cells]

Fig. 2: BCG induces compartment-specific transcriptional training in human monocytes.

Brain organoids, kept alive more than five years, matured like human brains

Amazing stuff! This could be a breakthrough!

"... scientists feared ruining their oldest brain organoids. Instead, the tiny models kept developing, revealing remarkable internal clock"

"... ‘Mini Brains’ Offer Major Breakthrough in Neural Research

In a new research milestone, scientists have kept human brain organoids—tiny, lab-grown neural tissue clusters—alive and developing for up to five years, a dramatic time extension that unlocks new opportunities to investigate neural development, disease, and potential treatments ..."

From the abstract:

"The human brain develops and matures over an exceptionally prolonged period of time that spans nearly two decades of life. Processes that govern species-specific aspects of human postnatal brain development are difficult to study in animal models.

While human brain organoids offer a promising in vitro model, they have thus far been shown to largely mimic early stages of brain development.

Here we develop human brain organoids for 5 years in culture, optimizing growth conditions to extend excitatory neuron viability beyond previous limits. Using maturation-associated modules derived from endogenous human brain, we show that brain organoids transcriptionally age with cell type specificity over years in culture.

Whole-genome methylation profiling reveals that the predicted epigenomic age of organoids correlates precisely with time spent in vitro, and parallels epigenomic ageing in vivo.

Notably, we show that in chimeric organoids generated by mixing neural progenitors of different ages, old progenitors rapidly produce late neuronal fates, skipping the production of earlier neuronal progeny, therefore showing that progenitors that age in organoids retain a memory of the time spent in vitro.

The data indicate that human brain organoids can continue to mature and record the passage of time over many years in culture."

Stat Daily Recap

Johns Hopkins Bloomberg School of Public Health: Global Health NOW

‘Mini brains’ kept alive for years appear to age like real brains "Miniature models of the human brain can be kept alive for years, allowing scientists to study neural development and brain diseases"

Lab-grown brain ‘organoids’ set longevity record (original news release) "Researchers show that brain cells cultured in a dish can mimic normal cerebral development and even retain “memory” of their own histories"

Scientists kept brain organoids alive for years. Then they looked inside | STAT "Eraser-sized balls of tissue could aid research on early stages of neurological diseases"

Human brain organoids record the passage of time over multiple years (open access)

Fig. 1: Cortical organoids undergo progressive maturation during long-term culture.

Fig. 3: Activity-permissive medium enhances the maturation of cortical organoids.

Chronic stress causes brain cells to rapidly age

Amazing stuff (but a little bit aged news)!

"... In a recent study, a team of neurologists has now traced a pathway back to cells called astrocytes located in the amygdala, the region of the brain responsible for processing emotions. ...

But in chronically stressed mice, the researchers found that these cells rapidly age, preventing them from properly communicating with other neurons . As a result, mice with damaged astrocytes showed heightened activity in the amygdala, which is closely associated with both anxiety and with decreased insulin production (and thus higher blood glucose levels).

The researchers were able to reverse the effects of cellular aging by providing the mice with senolytic drugs that target senescent cells or by supplementing their diets with L-serine, an amino acid important for establishing the link between astrocytes and neurons. ..."

From the highlights and abstract:

"Highlights

• [Chronic stress] lowers amygdaloid astrocytic HK2 via PBX1, driving cellular senescence

• Astrocytic HK2 deficiency limits the “serine shuttle” and disrupts synaptic stability

• Stress shifts amygdala output to sympathetic bias, promoting hyperglycemia

• L-serine or dasatinib/quercetin restores neurobehavior and blood glucose homeostasis

Summary

Chronic stress (CS) exacerbates anxiety and hyperglycemia, emerging as a key risk factor for type 2 diabetes, yet the mechanism remains unclear.

Here, we found that CS induces hyperglycemia and enhanced amygdaloid astrocytic senescence in mice. 

The amygdaloid astrocytic senescence was mediated by the reduction of hexokinase 2 (HK2) driven by pre-B cell leukemia homeobox transcription factor 1 (PBX1). The astrocytic Hk2 deletion mice and amygdala-specific astrocytic Hk2 knockdown mice both display anxiety-like behaviors and hyperglycemia.

The reduction of HK2 in astrocytes reduces L-serine synthesis and decreases the supply to neurons for the generation of D-serine by disrupting the astrocyte-neuron serine shuttle.

Reduced neuronal D-serine level in the amygdala impaired the balance of sympathetic and parasympathetic amygdala-pancreas projections, leading to hyperglycemia.

L-serine supplementation or dasatinib/quercetin administration to eliminate senescent cells alleviates both CS-induced neurobehaviors and peripheral hyperglycemia.

Together, these findings reveal that HK2 in amygdaloid astrocytes mediates CS-induced neurobehaviors and hyperglycemia."

ScienceAdviser

Amygdala astrocyte senescence drives stress-induced anxiety and hyperglycemia (no public access)

Graphical abstract