Neuroanatomy of the clitoris

Amazing stuff! However, this research is dated from March 2026, but has not come to my attention until now.

Notice how prevalent feminist ideology shines through in the context of this research! E.g. "Clitoris is one of the least studied organs" or "Cultural taboos around female sexuality". Is this not e.g. largely true for the penis too? E.g. is this some form of the infamous "penis envy" or phallic fantasies?

What is the first thing that comes to the mind of these Dutch researchers? Gender affirming surgery! Gross! Appalling!

From the abstract:

"The clitoris is one of the least studied organs of the human body [???]. The detailed anatomy of the clitoris is challenging to address through a gross dissection, as most of its parts are embedded internally, surrounded by pubic bone and several pelvic organs.

While clinical imaging methods such as magnetic resonance imaging can capture the gross 3D morphology, they lack the spatial resolution required to resolve the detailed structures.

In this study, we generated micron-scale computed tomography images of the female pelvises, leveraging a synchrotron radiation X-ray source. This unique data revealed the complex trajectory of the dorsal nerve of the clitoris, the main sensory nerve of the clitoris.

Notably, the nerve trunks within the clitoral glans were revealed, with the maximum diameter ranging from 0.2 to 0.7 mm. They showed a tree-like branching pattern projecting towards the surface of the glans.

We also revealed that some branches of the dorsal nerve of the clitoris ramify to innervate the clitoral hood and mons pubis.

Finally, the posterior labial nerve, a branch of the perineal nerves, was shown to innervate the surroundings of the clitoris and the labial structures.

These findings have an immediate impact on operations performed around the vulva area, such as gender-affirmation surgery and reconstruction surgery after genital mutilation."

Neuroanatomy of the clitoris | bioRxiv (preprint, open access)

Scientists Just Made the Most Complete Map of the Clitoris’s Sensory Nerve Network. Here’s What They Found (Smithsonian Institution news release) "Cultural taboos around female sexuality have hindered research on the organ. But a new study provides pivotal insights that can inform important surgeries and health care"

Credits: Major highway of the human nervous system gets a complete road map

Figure 1.

Dorsal nerve of the clitoris (DNC). (A, B). Overview of the clitoris. The colour coding is as follows: the dorsal nerve of the clitoris in yellow, the corpus cavernosum in green, the venous network in blue, the corpus spongiosum in magenta and the glans in transparent grey. Axes are on the left corners, with L, R, S, I, A, and P indicating left, right, superior, inferior, anterior, and posterior directions. (C-E). Cross sections of the clitoral body from proximal to distal. Yellow outlines indicate the DNC bundles. The cross sections are taken from the planes indicated in panel B (c-e). Scale bar = 1 mm. The width of the planes in Panel B is 1 cm.

"The clitoris is larger than most people think, and much of the organ is internal."

First comprehensive, baseline map of the human vagus nerve system covering all major organs

Good news! This seems to be a preliminary release.

"... Scientists have created the first comprehensive map of the human vagus nerve, tracing thousands of individual nerve fibers stretching from the lower brainstem to all major organs. The map—announced last week and detailed in a dataset released earlier this year—might help scientists and doctors more precisely stimulate the nerve as a potential treatment for conditions such as epilepsy, stroke, and inflammatory diseases.

The team analyzed 30 sets of left and right vagus nerves dissected from 30 human cadavers. The dissected nerves then underwent ultrasound to capture basic anatomy, micro-CT (a form of x-ray imaging) to trace the paths of nerve fibers, and finally, thousands of thin cross-sectional slices stained with antibodies bound to specific proteins. A machine learning model then analyzed the images and characterized individual fibers to functional classes—for example, distinguishing between sensory fibers that send signals from the organs to the brain and the motor fibers that orchestrate involuntary muscle contractions.

The new baseline map can help researchers get a better handle on variability, helping to explain “why there are people who are responsive to treatments and others that are not,” ..."

From the abstract:

"Study Purpose:

With its large numbers of afferent (sensory) and efferent (motor) fibers, the vagus is the main conduit for bidirectional communication between the brain and visceral organs and participates in autonomic reflexes regulating cardiorespiratory, gastrointestinal, and neuroimmune functions.

In the human vagus, nerve fibers are arranged in fascicles. Along the vagus, afferent and efferent fibers leave the fascicles and emerge from the nerve trunk to form branches, which in turn provide sensory and motor innervation to essentially all visceral organs in the neck, chest, and abdomen.

Even though much is known about the macroscopic and microscopic anatomy of the vagus, the spatial organization of fascicles and fibers within the nerve, as it relates to the innervated organs and the sensory and motor functions of the vagus, is largely unknown.

The spatial organization of fibers in the human vagus has implications for vagus neuromodulation therapies. The overall objective of this proposal is to create and share with the scientific community a quantified map of the fascicular and microscopic structure and the organ connectivity of the human vagus nerve, from the brainstem to the abdominal region, with several cross-registered layers of anatomical information at the organ branch, fascicle, and single fiber level.

Data Collection:

The dataset includes anatomical images and videos, ultrasound images and videos of the vagus nerve, microCT scans across the length of the nerve, and IHC images across multiple levels. The techniques include: anatomy (dissection), histology (immunohistochemistry), bioimaging (ultrasound), and microscopy (microCT).

Primary Conclusion:

The human vagus nerve exhibits an intricate anatomical organization. This is an ongoing study, and we will publish our initial conclusions once we have sufficient data."

ScienceAdviser

Major highway of the human nervous system gets a complete road map

Feinstein Institutes makes publicly available world’s first comprehensive human vagus nerve maps solidifying decades of leadership in bioelectronic medicine (original news release) "This pioneering dataset was funded through a $6.7 million NIH multi-year grant and offers unprecedented insights into the vagus nerve’s intricate anatomy"

Human vagus nerve anatomical reconstruction using microCT immunohistochemistry and ultrasound - f011 (open access?)

The human vagus nerve contains about 100,000 individual nerve fibers, some as small as 0.5 micrometers.

How the heart's 'little brain' helps it function and protects it against stress

Amazing stuff!

"... heart has its own network of nerves, the intrinsic cardiac nervous system (ICNS) ...

The heart's nerve cells fine-tune signals coming from the brain to control heart function, including heart rate. But because they are so few, doctors have struggled to determine exactly what they do. To solve this, researchers from Yale University School of Medicine genetically engineered adult mice so their heart nerves would glow, making them much easier to study.

After locating the nerves, the team analyzed which genes were active in them. They discovered that the nerves fell into two categories, which they called Npy neurons and Ddah1 neurons. ...

Mapping nerve pathways

To determine their exact roles, the researchers traced their pathways across the heart using 3D imaging. The images revealed that both groups were wired to completely different areas.

When the study authors tested the Npy neurons, they found that stimulating them slowed the heart. But when they destroyed the population of cells, heart function rapidly deteriorated, ultimately leading to death. This suggests that these nerves are vital for keeping the heart beating. ..."

From the highlights and abstract:

"Highlights

• Npy and Ddah1 mark two major neuronal subtypes in the intrinsic cardiac nervous system

• Npy+ and Ddah1+ intrinsic cardiac neurons differ in neural inputs and cardiac projections

• Npy+ intrinsic cardiac neurons control heart rate and support baseline cardiac function

• Ddah1+ intrinsic cardiac neurons are essential for cardiac stability during stress

Summary

The intrinsic cardiac nervous system (ICNS) is a key node in heart-brain communication and an emerging target for cardiac therapy, yet its physiological importance and functional organization remain poorly understood.

Here, we show that the ICNS is essential for cardiac performance and survival across conditions.

Using integrated genetic and imaging approaches in mice, we identify two molecularly distinct intrinsic cardiac neuron (ICN) subtypes that differ in extrinsic inputs, projection architectures, and physiological roles.

Npy⁺ ICNs preferentially receive vagal input and mediate parasympathetic control of heart rate and coronary perfusion, and their ablation leads to fatal cardiac failure. By contrast, Ddah1⁺ ICNs receive sympathetic input and are required to preserve electrical stability and prevent sudden cardiac arrest under extreme physiological or psychological stress, with their activation providing cardioprotection.

Together, these findings establish the ICNS as a critical regulator of cardiac function, providing a framework for precise, cell-type-targeted neuromodulatory therapies."

How the heart's 'little brain' helps it function and protects it against stress

The intrinsic cardiac nervous system is essential for cardiac function and survival (open access)

Graphical abstract

Figure 1 Molecular architecture of the ICNS reveals two major ICN subtypes

How neurons in C. Elegans sense bacteria in the gut

Amazing stuff!

"... In the new open-access study  ... identifies the specific chemicals that a key neuron in C. elegans senses, both in the bacteria that it eats and in the bacteria that it needs to avoid ingesting. ...

C. elegans a “bacterial specialist” because the tiny, transparent worm has evolved to eat bacteria as its diet, while also needing to avoid pathogenic bacteria that can prove to be its undoing. This has led it to develop a nervous system especially well-attuned to sorting out what is food and what is foe. ...

what the ion channels are detecting in the bacteria. To get started, they exposed worms to 20 different kinds of bacteria the worms are known to encounter and found that they all activated NSM activity to varying extents. Then they broke the bacteria down into more and more specific chemical components to see which one or ones triggered NSM. The experiments ruled out many components, including DNA, lipids, proteins, and simple sugars, and instead found that it’s specifically the polysaccharide sugars that coat many bacteria that drive NSM activation. In particular, in gram-positive bacteria, a chemical called peptidoglycan activated NSM. In gram-negative bacteria, a different polysaccharide was apparently in play. ...

Having shown what exactly triggers the worms to recognize their bacterial food, the researchers wondered whether they could also pinpoint a danger sign the worm finds in harmful bacteria.

For these experiments, they carefully used Serratia marcescens, a bacterium that’s also infectious for humans. Some strains of the bacteria have a red color, while others do not. The red ones, which have a pigment called prodigiosin, tend to be much more lethal for worms. In their testing, the researchers found that when NSM detected the non-pigmented bacteria, the neuron still activated and the worms still ingested the bacteria, but when prodigiosin was present, NSM did not activate and the worm did not pump it in or slow down to eat. ..."

From the highlights and abstract:

"Highlights

• The enteric sensory neuron NSM is activated by ingestion of diverse bacteria

• Bacterial polysaccharides, including peptidoglycans, are sufficient to activate NSM

• Bacterial polysaccharides drive serotonin-dependent changes in foraging behaviors

• Prodigiosin, produced by pathogenic S. marcescens, inhibits NSM activity

Summary

The bacterial microbiome influences many aspects of animal health and disease. Bacteria can have beneficial functions, for example providing nutrients, whereas others can act as pathogens.

Bacteria are sensed by host cells to induce adaptive changes in physiology and behavior. While immune and intestinal cells detect bacterial signals through well-characterized mechanisms, recent studies indicate that neurons can also directly sense bacteria.

However, the bacterial sensory mechanisms in neurons are less well understood. In Caenorhabditis elegans, the enteric sensory neuron NSM innervates the pharyngeal lumen and is directly activated by bacterial ingestion; in turn, NSM releases serotonin to induce feeding-related behaviors.

However, the molecular identities of the bacterial signals that activate NSM are unknown.

To identify them, we probed bacterial macromolecules from nutritive bacteria using biochemical approaches. We find that polysaccharides from bacteria are sufficient to activate NSM.

We further identify peptidoglycans from Gram-positive bacteria as specific components capable of activating NSM. NSM responses to polysaccharides require the acid-sensing ion channels DEL-3 and DEL-7, which localize to NSM's sensory dendrite in the pharyngeal lumen.

Ingestion of bacterial polysaccharides enhances feeding and reduces locomotion, matching the known effects of NSM on behavior.

We also examine signals produced by pathogenic bacteria. This approach identifies prodigiosin, from pathogenic Serratia marcescens, as a metabolite that prevents NSM activation by nutritive bacterial signals.

This study identifies molecular signals that underlie neuronal recognition of nutritive bacteria in the alimentary canal and competing signals from a pathogenic bacterial strain that can mask this form of recognition."

How neurons sense bacteria in the gut | MIT News | Massachusetts Institute of Technology "Neural interaction with bacteria has important effects on animal brains. A new study investigates how neurons sense bacteria by revealing, in nematodes, the bacterial signals that a key neuron detects."

Identification of bacterial signals that modulate enteric sensory neurons to influence behavior in C. elegans (open access)

Figure 1 Bacterial polysaccharides activate the enteric sensory neuron NSM

Figure 5 A Serratia marcescens metabolite, prodigiosin, inhibits NSM activity and associated behaviors

A nasal spray reversed brain aging and inflammation in just two doses

Good news! This could be a breakthrough!

"A nasal spray reversed brain aging and inflammation in just two doses, restoring memory and cognitive sharpness, in a Texas A&M study of mice that researchers say could reshape treatment for dementia."

"Summary: For decades, “neuroinflammaging”, the slow-burning inflammation that causes brain fog and memory decline, was considered an unavoidable part of getting older. However, a landmark study suggests the clock can be turned back.

Researchers developed a non-invasive nasal spray that uses microscopic “delivery parcels” to travel directly into the brain. With just two doses, the therapy dramatically reduced chronic inflammation, recharged cellular “power plants” (mitochondria), and restored memory and cognitive sharpness in aging models.

Key Facts

• Rapid & Lasting Results: Significant cognitive improvements were observed within weeks and, remarkably, persisted for months after only two doses.
• Universal Efficacy: Unlike many medical studies that show varying results by sex, this therapy proved equally effective in both males and females.
• Behavioral Recovery: Treated models showed a restored ability to recognize familiar objects and adapt to changes in their environment—key indicators of a healthy, functioning memory center.

..."

From the abstract:

"Neuroinflammaging, a moderate, chronic, and sterile inflammation in the hippocampus, contributes to age-related cognitive decline.

Neuroinflammaging comprises the activation of the nucleotide-binding domain, leucine-rich repeat family, and pyrin domain-containing 3 (NLRP3) inflammasomes, and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway that triggers type 1 interferon (IFN-1) signalling.

Studies have shown that extracellular vesicles from human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSC-EVs) contain therapeutic miRNAs that can alleviate neuroinflammation.

Therefore, this study examined the effects of late middle-aged (18-month-old) male and female C57BL6/J mice receiving two intranasal doses of hiPSC-NSC-EVs on neuroinflammaging in the hippocampus at 20.5 months of age. Compared with animals receiving vehicle treatment, the hippocampus of animals receiving hiPSC-NSC-EVs exhibited reductions in astrocyte hypertrophy, microglial clusters, and oxidative stress, along with elevated expression of antioxidant proteins and genes that maintain mitochondrial respiratory chain integrity.

Moreover, hiPSC-NSC-EVs therapy decreased the levels of various proteins involved in the activation of the NLRP3 inflammasome, p38/mitogen-activated protein kinase, cGAS-STING-IFN-1, and Janus kinase and signal transducer and activator of transcription signalling pathways.

Furthermore, in vitro assays using genetically engineered RAW cells and hiPSC-NSC-EVs, with or without targeted depletion of specific miRNAs, demonstrated that miRNA-30e-3p and miRNA-181a-5p, both present in hiPSC-NSC-EVs, can significantly inhibit the activation of the NLRP3 inflammasome and the STING pathway, respectively. Additionally, single-cell RNA sequencing conducted 7 days post-treatment revealed that hiPSC-NSC-EVs induce widespread transcriptomic changes in microglia, including increased expression of numerous genes that enhance oxidative phosphorylation and reduced expression of abundant genes that drive multiple proinflammatory signalling pathways.

These changes mediated by hiPSC-NSC-EVs were also associated with improved cognitive and memory function.

Thus, intranasal hiPSC-NSC-EVs therapy in late middle age can effectively diminish proinflammatory microglial transcriptome and signalling cascades that drive neuroinflammaging in the hippocampus, contributing to better brain function in old age."

Wednesday, April 15, 2026 - Join The Flyover

Nasal Spray Reverses Brain Aging and Inflammation

Scientists reverse brain aging, with a nasal spray (original news release) "New therapy is turning back the clock in aging brains, healing inflammation, restoring memory and reshaping the future of brain age-related therapies."

Intranasal Human NSC-Derived EVs Therapy Can Restrain Inflammatory Microglial Transcriptome, and NLRP3 and cGAS-STING Signalling, in Aged Hippocampus (open access)

Fig. 2 Intranasal administration of extracellular vesicles from human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSC-EVs) to late middle-aged mice reduced hypertrophy of astrocytes and microglial clusters.

New study identifies a key brain interhemispheric circuit for spatial memory in mice

Good news!

"A team ... has identified a brain circuit essential for spatial memory. The study ... describes for the first time a connection between the two hippocampal hemispheres, in which neurons in the CA1 region of the right hemisphere send projections to the left hemisphere, specifically to the subiculum.

The results show that this communication is necessary for navigation and remembering locations. Moreover, the study reveals that this circuit is altered in mice carrying a genetic mutation associated with schizophrenia. ...

In this work, the team identified one of these connections: a neuronal projection linking the CA1 region of the right hemisphere with the subiculum of the left hemisphere. To do this, the researchers used neuronal tracing techniques that allow them to follow the path of connections between neurons. ..."

From the highlights and abstract:

"Highlights

• CA1 pyramidal neurons project to contralateral subiculum

• This projection from the right CA1 supports spatial cognition in mice

• The Df16(A)+/− mouse model of 22q11.2 deletion syndrome exhibits impaired spatial cognition

• Df16(A)+/− mice exhibit impaired projections from dCA1 to the contralateral dorsal subiculum

Summary

Mapping hippocampal connectivity is essential to understand the neural mechanisms of learning and memory, yet interhemispheric connections between hippocampal formations remain poorly defined.

In rodents, two main commissural pathways are known: dentate gyrus hilar mossy cells project to the inner molecular layer of the contralateral dentate gyrus, and CA2/CA3 pyramidal neurons send collaterals to contralateral CA3, CA2, and CA1 regions. By contrast, commissural outputs from CA1 remain largely unexplored.

Here, we show that dorsal CA1 (dCA1) pyramidal neurons located in the right hemisphere project to contralateral dorsal subiculum (dSUB) in addition to contralateral dCA1.

We then assess the function of the projection from the right dCA1 to the left dSUB and find that this interhemispheric pathway supports spatial memory and spatial working memory, two cognitive functions altered in the Df16(A)+/− mouse model of 22q11.2 deletion syndrome (22q11.2DS) associated with schizophrenia. Notably, the right-to-left dCA1 interhemispheric projections are disrupted in Df16(A)+/− mice, suggesting that dysregulation of this circuit may contribute to 22q11.2DS-related cognitive deficits."

New study identifies a key brain circuit for spatial memory in mice

Interhemispheric CA1 projections to the subiculum support spatial cognition and are affected in a mouse model of the 22q11.2 deletion syndrome (open access)

Graphical abstract

Nerve growth factor alone triggers osteoarthritis-like joint changes in healthy mice

Good news!

"Nerve growth factor (NGF) is a specialized protein, also called a neurotrophin, that is critical for the development and survival of nerves responsible for our senses and the body's fight-or-flight response. While the presence of NGF is crucial during the embryonic stage, its presence in adults is often an indication of inflammation, as it is a key mediator of pain for conditions like osteoarthritis (OA). Now, a study ... shows that NGF is much more than a pain messenger—it can actually change the structure of a joint.

When the researchers injected NGF into healthy knee joints of mice, the joints gradually became swollen and much more sensitive to pain.

Over time, they began to look and behave as if they had osteoarthritis. Even though no visible damage appeared on the protective knee cartilage, the bone underneath became denser and small bony growths, also known as pre-osteophytes, began to form post the NGF injections. ..."

From the abstract:

"Objective

Nerve growth factor (NGF), a key mediator of pain, is increased in osteoarthritic (OA) joints.

Antibodies against NGF show analgesic effects in painful knee OA, but clinical development was stopped due to side-effects in the joints. Knowledge about the biological effects of NGF on joint tissues is limited. Therefore, we explored the effects of repeated intra-articular (IA) injections of NGF into naïve murine knee joints on sensitization, joint innervation and histopathology.

Methods

Naïve 10 to 15-week-old male wildtype C57BL/6 mice were injected with NGF (50 or 500 ng) or vehicle IA twice a week for 4 weeks, and assessed effects on knee swelling, knee hyperalgesia, joint histopathology, and bone. Single cell RNA sequencing (scRNAseq) of the synovium was performed. NaV1.8-tdTomato reporter mice were used to assess joint innervation. Dorsal root ganglia (DRGs) of mice underwent bulk RNA sequencing after 3 IA injections of NGF or vehicle.

Results

Compared to vehicle, repeated IA injections of NGF caused dose-dependent increases in knee swelling, knee hyperalgesia, synovial pathology, bone mineral density in the medial subchondral bone, and medial pre-osteophytes, but no overt cartilage damage.

NGF caused increased sprouting of nociceptors in the medial synovium, which was preceded by upregulation of axonal growth pathways in the DRGs. ScRNAseq of the synovium revealed upregulated genes related to neuronal sprouting, synovial fibrosis, and ossification, with a key role for lining fibroblasts.

Conclusions

In naive mouse knees, NGF induced many pathological changes observed in OA, including nociceptor sprouting, suggesting a critical role for NGF in OA pathogenesis."

Nerve growth factor alone triggers osteoarthritis-like joint changes in healthy mice

Nerve growth factor is sufficient to cause multiple osteoarthritis-relevant pathological features in naïve murine knee joints (open access)

Fig. 1 Schematic illustration of the 5 experiments performed, showing injection protocols, mouse strains (n), experimental endpoints, and outcome measures. ScRNAseq= single cell RNA sequencing. (Source)

Protecting biological assets at the genetic level: New DNA encryption protects engineered cells from within

Amazing stuff! In the future, hopefully AI will play the role of the red team in this iterative process to improve the encryption etc.!

"... a team ... researchers present a new approach to genetically securing precious biological material. They created a genetic combination lock in which the locking or encryption process scrambled the DNA of a cell so that its important instructions were non-functional and couldn't be easily read or used. ..."

From the abstract:

"The protection of high-value cell lines (assets) relies on physical security by limiting access to samples. We present a cybersecurity-inspired platform that protects biological assets at the genetic level. This technology uses a permutation lock design where an asset can only be decrypted using an authentication code r from a search space composed of n objects on a defined keypad.

Here, the genetic asset is designed as a scrambled DNA sequence, and the code is a temporal pattern of small molecules that regulate sets of recombinases that can unscramble a DNA sequence into the desired final sequence.

In this work, a “blue team” designed and built an encrypted (scrambled) DNA sequence, and a “red team” sought to break the code through an ethical hacking exercise. Two iterations of testing revealed a 0.2% (2 in 990) chance of gaining access to the asset by random search, which is on par with the theoretical goal of 0.1% (1 in 990).

"

Hackers meet their match: New DNA encryption protects engineered cells from within

Protecting cells at the genetic level and simulating unauthorized access via a biohackathon (open access)

Fig. 1. Biological security scenario “biohackathon” for designing, building, testing, and learning.

Fig. 2. Illustration of biological (genetic) asset encryption to decryption and nPr object engineering.

Dream control study to further dream engineering for more creativity and how sounds may be incorporated

Amazing stuff! I don't believe we have made much progress on dream research since the days when individuals would lay down to tell Sigmund Freud what they dreamed about lately! 😊

"Researchers have shown they can achieve some control over what people are dreaming ...

researchers at Northwestern University (NU) were particularly interested in finding out if they could harness dreams to work with the idea that sleeping on a problem can help people solve it.

So they recruited 20 people who were experienced in lucid dreaming, the ability to recognize that you're dreaming from within a dream and sometimes control what happens. Another dream-related study released this month showed that lucid dreams might be able to help with mental health therapy for conditions like PTSD and Parkinson's disease, and previous work with researchers from NU and other institutes showed a simple type of communication was possible between lucid dreamers and test administrators. ..."

"... A new study by neuroscientists at Northwestern University validates the possibility of influencing dreams and offers a crucial step to support the theory that dreams in REM sleep — the rapid eye movement phase of sleep in which lucid dreaming can occur — may be especially conducive to helping individuals come up with creative solutions to a problem. ..."

From the abstract:

"Dreams have arguably been a source of creative insight for millennia. The specific assertion that dreams during rapid eye movement (REM) sleep promote creative problem-solving, however, has only anecdotal support, lacking strong empirical support from rigorous studies. Experimental manipulations of dream content have been confounded by waking components, such that any boost in creative problem-solving could be attributable to waking cognition rather than sleep cognition. Likewise, correlational evidence cannot unequivocally establish that dreams cause insights. Evidence that memory reactivation during sleep promotes creative problem-solving is also insufficient for implicating dreaming per se. Better methods for directly manipulating REM-sleep dreaming are needed. Here, we studied individuals who frequently have lucid dreams—realizing they are dreaming while still asleep. Participants slept after failing to solve several puzzles that had unique soundtracks, and they were instructed to continue working on a puzzle if they heard its soundtrack in a dream. Half of the soundtracks were played during REM sleep to reactivate memories of corresponding puzzles, with the goal of biasing dreams to connect with those specific puzzles versus the remaining puzzles. Those sound cues reliably increased dreaming about the associated puzzles. Furthermore, a post-hoc analysis showed that, for participants with an increase in cue-related dreaming, cues boosted later puzzle-solving. We thus expanded on a well-known phenomenon, that sounds can be incorporated into dreams and can change dream content, by substantiating experimental procedures to align dreams with the search for creative answers to specific challenges. Results highlight that REM dreams can contribute to next-day problem solving."

Dream control study turns sci-fi to science fact

Dream engineering can help solve ‘puzzling’ questions "Study offers insights to optimizing sleep for creativity"

Creative problem-solving after experimentally provoking dreams of unsolved puzzles during REM sleep (open access)

Fig. 1 Experimental timeline.

(A) Overview of experimental timeline for most participants.

(B) Each in-lab session had an identical procedure, except with different puzzles. Lucid dreams were induced with targeted lucidity reactivation (TLR).

Reprogramming of brain glial cells to corticospinal neurons may treat ALS and spinal cord injuries

Good news!

"Harvard stem cell biologists have discovered a way to grow the type of brain cells that degenerate in patients with amyotrophic lateral sclerosis (ALS) and suffer damage in spinal cord injuries.

In a paper published in the journal eLife, researchers engineered a cocktail of molecular signals to coax some “progenitor cells” — precursors that can differentiate into other cell types — to generate corticospinal neurons (CSNs), brain cells vital to voluntary motor control. ...

“.progenitor population is that it’s already distributed throughout the brain ... They’re sitting there — resident stem cells.”

The new study offers the first-ever model for growing corticospinal neurons in the lab, opening new windows for researching and potentially regenerating neurons for two devastating neurological afflictions. ..."

"eLife Assessment

This study presents fundamental new findings introducing a new approach for the reprogramming of brain glial cells to corticospinal neurons. The data is highly compelling, with multiple lines of evidence demonstrating the success of this new assay. These exciting findings set the stage for future studies of the potential of these reprogrammed cells to form functional connections in vivo and their utility in clinical conditions where corticospinal neurons are compromised."

From the abstract:

"Corticospinal neurons (CSN) centrally degenerate in amyotrophic lateral sclerosis (ALS), along with spinal motor neurons, and loss of voluntary motor function in spinal cord injury (SCI) results from damage to CSN axons.

For functional regeneration of specifically affected neuronal circuitry in vivo, or for optimally informative disease modeling and/or therapeutic screening in vitro, it is important to reproduce the type or subtype of neurons involved. No such appropriate in vitro models exist with which to investigate CSN selective vulnerability and degeneration in ALS, or to investigate routes to regeneration of CSN circuitry for ALS or SCI, critically limiting the relevance of much research. Here, we identify that the HMG-domain transcription factor Sox6 is expressed by a subset of NG2+ endogenous cortical progenitors in postnatal and adult cortex, and that Sox6 suppresses a latent neurogenic program by repressing proneural Neurog2 expression by progenitors.

We FACS-purify these progenitors from postnatal mouse cortex and establish a culture system to investigate their potential for directed differentiation into CSN. We then employ a multi-component construct with complementary and differentiation-sharpening transcriptional controls (activating Neurog2, Fezf2, while antagonizing Olig2 with VP16:Olig2).

We generate corticospinal-like neurons from SOX6+/NG2+ cortical progenitors and find that these neurons differentiate with remarkable fidelity compared with corticospinal neurons in vivo. They possess appropriate morphological, molecular, transcriptomic, and electrophysiological characteristics, without characteristics of the alternate intracortical or other neuronal subtypes. We identify that these critical specifics of differentiation are not reproduced by commonly employed Neurog2-driven differentiation. Neurons induced by Neurog2 instead exhibit aberrant multi-axon morphology and express molecular hallmarks of alternate cortical projection subtypes, often in mixed form. Together, this developmentally-based directed differentiation from cortical progenitors sets a precedent and foundation for in vitro mechanistic and therapeutic disease modeling, and toward regenerative neuronal repopulation and circuit repair."

A ‘cocktail’ recipe for brain cells — Harvard Gazette "Stem cell biologists discover how to regenerate type damaged in ALS, spinal cord injuries"

Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors

Fig. 1 Identification and culture of SOX6+/NG2+ cortical progenitors with high purity and fidelity

Tumors Protect Themselves from Immune Attack by Talking to the Brain

Amazing stuff! Cancer is history (soon)!

"In many tumors, nerves from our peripheral nervous system establish themselves in the cancerous tissue. The new study found that tumors can hijack these nerves to send signals to the brain. This, in turn, triggers activity that blocks immune cells from infiltrating the cancer, which enables cancer growth. ...

The team then sought to understand why this happens. Using animal models of lung adenocarcinoma, they experimented with inhibiting and activating various subpopulations of neurons to see how this impacted cancer growth. They also used single cell sequencing to identify the types of neurons innervating tumors in the lung, as well as imaging techniques to visualize how nerve and cancer cells interacted with one another. Meanwhile, collaborators at the University of Pennsylvania studied the surrounding immune cells and their signaling in the cancer microenvironment. ..."

From the abstract:

"Body–brain communication has emerged as a key regulator of tissue homeostasis. Solid tumours are innervated by different branches of the peripheral nervous system and increased tumour innervation is associated with poor cancer outcomes. However, it remains unclear how the brain senses and responds to tumours in peripheral organs, and how tumour–brain communication influences cancer immunity.

Here we identify a tumour–brain axis that promotes oncogenesis by establishing an immune-suppressive tumour microenvironment.

Combining genetically engineered mouse models with neural tracing, tissue imaging and single-cell transcriptomics, we demonstrate that lung adenocarcinoma induces innervation and functional engagement of vagal sensory neurons, a major interoceptive system connecting visceral organs to the brain.

Mechanistically, Npy2r-expressing vagal sensory nerves transmit signals from lung tumours to brainstem nuclei, driving elevated sympathetic efferent activity in the tumour microenvironment. This, in turn, suppresses anti-tumour immunity via β2 adrenergic signalling in alveolar macrophages.

Disruption of this sensory-to-sympathetic pathway through genetic, pharmacological or chemogenetic approaches significantly inhibited lung tumour growth by enhancing immune responses against cancer.

Collectively, these results reveal a bidirectional tumour–brain communication involving vagal sensory input and sympathetic output that cooperatively regulate anti-cancer immunity; targeting this tumour–brain circuit may provide new treatments for visceral organ cancers."

Tumors Protect Themselves from Immune Attack by Talking to the Brain | Yale School of Medicine

Tumour–brain crosstalk restrains cancer immunity via a sensory–sympathetic axis (open access)

Fig. 1: LUAD is innervated by VSNs. [vagal sensory neuron]

A new molecular atlas of tau enables precision diagnostics and drug targeting across neurodegenerative diseases

Good news!

"Tau protein aggregation is a shared feature in over 20 neurodegenerative diseases (collectively referred to as "tauopathies"). New research led by Boston Children's Hospital challenges the current "one-size-fits-all" approach to diagnosing and treating these tauopathies. ...

analyzed brain tissue from 203 patients spanning several tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy (CTE). They used a novel mass spectrometry tool called FLEXITau which enables absolute quantification of pathological tau species, measuring both the identities and abundances of disease-relevant chemical modifications. ...

that tau chemistry changes as the disease advances, and that the p217 Tau modification ranked as the most accurate diagnostic for Alzheimer's. p217 is now an FDA-approved diagnostic marker for Alzheimer's disease. ...

Using FLEXITau, the researchers identified 145 post-translational modifications and 195 cleavage sites across tau. Machine-learning models then ranked the molecular features that best distinguished each disease based on quantified chemical changes. ..."

From the highlights and abstract:

"Highlights

• Comprehensive mapping of tau identifies 145 PTMs and 195 cleavage sites in tauopathies

• Provides tau molar abundance and peptide modification stoichiometry in disease

• Machine learning classifies tauopathies using tau molecular features

• Identified disease-specific features are potential drug targets and diagnostics

Summary

In Alzheimer’s disease (AD), pathological tau protein shows a progressive accumulation of post-translational modifications (PTMs), reflecting disease severity, progression, and prion-like activity. Although many neurodegenerative diseases with dementia display tau aggregates, the pathological proteoforms of tau protein from each disease type remain unknown.

Here, using a quantitative mass spectrometry-based proteomics platform, FLEXITau, deep characterization of pathological tau protein isolated from the brains of 203 human subjects with AD, familial AD (fAD), chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Pick’s disease (PiD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB)—a non-tauopathy symptomatic control—and healthy controls (CTR) is performed. Unsupervised data analyses and supervised machine learning identify distinct molecular features of pathological tau for each disease, enabling molecular disease stratification.

This study identifies potential disease-specific biomarkers and therapeutic targets for tauopathies and provides critical quantitative information for pharmacokinetic modeling required for therapeutic and disease mechanism studies."

A new molecular atlas of tau enables precision diagnostics and drug targeting across neurodegenerative diseases

Molecular features of human pathological tau distinguish tauopathy-associated dementias (open access)

Graphical abstract

Figure 1 Workflow and quantification of pathological insoluble tau and isoforms across tauopathies and control human subjects

New brain atlas of lysosomal proteins could help researchers studying neurological disease

Good news!

"In brief

• Stanford researchers created the first atlas of lysosomal proteins in the brain, crucial for understanding neurodegenerative diseases.
• The atlas highlights links between lysosomal dysfunction and disorders like Alzheimer’s and Parkinson’s, guiding potential therapeutic developments.
• The data is publicly accessible, promoting global collaboration and exploration of lysosomal roles in neurological conditions.

...

“Lysosomal function is essential for brain health, and mutations in lysosomal genes are risk factors for neurodegenerative diseases,” ..."

From the highlights and abstract:

"Highlights

• Lysosomal proteomics of brain cell types

• Identification of previously uncharacterized and cell-type-specific lysosomal proteins

• SLC45A1 is a neuron-specific lysosomal sugar transporter

• SLC45A1 loss drives lysosomal and mitochondrial dysfunction

Summary

Mutations in lysosomal genes cause neurodegeneration and neuronopathic lysosomal storage disorders (LSDs). Despite their essential role in brain homeostasis, the cell-type-specific composition and function of lysosomes remain poorly understood.

Here, we report a quantitative protein atlas of lysosomes from mouse neurons, astrocytes, oligodendrocytes, and microglia. We identify dozens of proteins not previously annotated as lysosomal and reveal the diversity of lysosomal composition across brain cell types.

Notably, we identified SLC45A1, a gene whose mutations cause a monogenic neurological disease, as a neuron-specific lysosomal protein.

Loss of SLC45A1 causes lysosomal dysfunction in vitro and in vivo. SLC45A1 functions as a lysosomal sugar transporter and impacts the stability of the V1 subunits of the vacuolar ATPase (V-ATPase). Consistently, SLC45A1 loss reduces lysosomal V1 subunits, elevates lysosomal pH, and disrupts iron homeostasis, causing mitochondrial dysfunction. Altogether, our work redefines SLC45A1-associated disease as an LSD and establishes a comprehensive map to study lysosome biology at cell-type resolution."

New atlas could help researchers studying neurological disease | Stanford Report "A database of lysosomal proteins is already guiding researchers in studying how brain cells’ waste and recycling systems work – or don’t – in Alzheimer’s and other neurological diseases."

Cell-type resolved protein atlas of brain lysosomes identifies SLC45A1-associated disease as a lysosomal disorder (open access)

Lysosomal Brain Protein Atlas

Graphical abstract

Broken bone: The same nerves that transmit the feeling of pain later enter a pro-regenerative state to heal the broken bone

Amazing stuff!

"... Breaking a bone hurts because sensory neurons are triggered by the trauma, and they signal pain to the brain. But that’s not these neurons’ only job, researchers discovered: They also step in to lead bone repair.

To discover this, researchers zoomed in on the nerves that penetrate into bone in mice, tracing them all the way back to the central nervous system, as well as sequencing individual neurons before and after fractures. “We created the first comprehensive single-cell atlas of bone-innervating sensory neurons,”  ... This revealed that the same nerves that transmit the feeling of pain later enter what the team calls a “pro-regenerative state … they produce and release proteins that promote the generation of new neurons, blood vessels, and of course, bone and cartilage.” Of particular importance is a protein called fibroblast growth factor 9 (FGF9), which is a key coordinator of bone repair, guiding stem cells to transform into bone-building cells. When the researchers removed the nerves that produce FGF9 from mice, their bones struggled to heal. ..."

From the abstract of the Perspective:

"The skeleton has a remarkable ability to grow: It greatly expands in size from birth to adulthood and continues to remodel throughout adult life, completely replacing itself every 10 years. 

But it is also able to regenerate after injury, efficiently regrowing lost bone. Bone injuries are common, with an estimated 6 million to 10 million fractures occurring each year in the United States.

A lack of efficient healing can result in long-term disability, and in the geriatric population, complications from fractures are associated with increased morbidity and mortality.

Because bone repair reflects the successful integration of multiple cellular and molecular processes, it is challenging to precisely define the signaling hierarchy that produces optimal healing. ... report an unexpected role for sensory nerves in bone healing, providing insights into communication between the nervous system and the cells responsible for bone repair."

From the editor's summary and abstract:

"Editor’s summary

Sensory neurons innervating bones can modulate the healing process (bone regeneration) after a fracture. Xu et al. used single-cell transcriptomics to characterize the bone-innervating dorsal root ganglia (DRG) neurons before and after an ulnar stress fracture in mice ... The experiments revealed temporally dynamic responses of the DRG neurons after the fracture. Moreover, the authors identified fibroblast growth factor 9, released by sensory neurons, as a major neural regulator in bone regeneration after injury. These findings show that pathways activated by bone-innervating neurons after an injury might be exploited for accelerating bone fracture repair. ...

Structured Abstract

INTRODUCTION

The profound pain accompanying bone fracture is mediated by somatosensory neurons, which also appear to be required to initiate bone regeneration. Primary somatosensory neurons comprise a diverse subset of neurons, which communicate information about the external environment and internal state to the central nervous system, enabling perception and reaction to a wide range of stimuli including pain.

RATIONALE

Most work in skeletal neurobiology has focused on understanding bone nociceptive pathways, but recent studies provide evidence that sensory nerves also function to initiate bone formation during skeletal morphogenesis. To what extent such bone morphogenic and nociceptive actions are mediated by distinct neuronal pathways has been difficult to study in part due to lack of tractable model systems for studying nerve-bone interactions and the extensive heterogeneity of peripheral sensory neurons.

RESULTS

To characterize neuroanatomical circuitry mediating skeletal nociception and regeneration, dorsal root ganglia (DRG) neurons innervating murine long bones were profiled by retrograde nerve labeling and single-cell transcriptomics before and after experimental fracture.

Highest labeling across CGRP+ and Aβ-Field LTMR neurons was identified, which have nociceptive or mechanoreceptive functions.

Dynamic changes associated with sensory neuron response to injury reflected the phasic nature of bone repair.

At early time points, DRG neurons showed signatures of pain perception and inflammatory responses.

At later time points, DRG neurons demonstrated transcriptomic changes more characteristic of a regenerative response, including mitogenic, angiogenic and osteogenic signals.

This includes expression of morphogens in the fracture reparative phase such as Tgfb1, Fgf9, and Shh.

Two methods to surgically or genetically denervate fractured bones were used to implicate defective mesenchymal cell proliferation and osteo differentiation as underlying poor bone repair with loss of innervation.

Finally, multitissue single-cell RNA-sequencing and interactome analyses implicated neuron-derived fibroblast growth factor 9 (FGF9) as a potent regulator of fracture repair, confirmed by in vivo sensory nerve–specific ablation studies.

CONCLUSION

In sum, somatosensory neurons innervating bone are a group of neurons with nociceptive and mechanoreceptive functions, which are transcriptionally responsive to bone injury in a temporal dynamic fashion and positively regulate fracture healing through FGF9-FGFR signaling."

ScienceAdviser

Not just a pain in the bone (Perspective, no public access) "Growth factors secreted by sensory nerves promote fracture healing"

Mapping somatosensory afferent circuitry to bone identifies neurotrophic signals required for fracture healing

Mapping Somatosensory Afferent Circuitry to Bone Identifies Neurotrophic Signals Required for Fracture Healing (preprint, open access, published in June 2024)

Fig. 2 Temporal responses of sensory neurons to fracture injury

When a bone is broken, sensory nerves alert the brain about the painful trauma. But after they’ve reported the break, they go into repair mode, producing FGF9 (red dots)—which, among other important messages, tells special stem cells to start the process of becoming bone cells (osteoblasts).

How antibody therapy clears Alzheimer's plaques: Key immune mechanism identified

Good news!

"Lecanemab, sold under the name Leqembi, is a monoclonal antibody therapy for Alzheimer's disease that clears toxic amyloid plaques and delays cognitive decline. ...

They showed that the "Fc fragment" of this monoclonal antibody is essential for engaging microglia—the immune cells of the brain—thus initiating the cellular machinery needed for plaque removal. This is the first direct mechanistic explanation for how this class of therapies works. It clarifies uncertainties in the field and offers a blueprint for developing safer, more effective Alzheimer's treatments.  ...

They identified key cellular machinery needed to clear the amyloid plaques: namely, phagocytosis and lysosomal activity.

Without the Fc fragment, none of these critical cellular processes were triggered. ...  uncovered a microglial gene program, marked by strong expression of the gene SPP1.  ..."

From the abstract:

"Controversies over anti-amyloid immunotherapies underscore the need to elucidate their mechanisms of action.

Here we demonstrate that Lecanemab, a leading anti-β-amyloid (Aβ) antibody, mediates amyloid clearance by activating microglial effector functions.

Using a human microglia xenograft mouse model, we show that Lecanemab significantly reduces Aβ pathology and associated neuritic damage, while neither fragment crystallizable (Fc)-silenced Lecanemab nor microglia deficiency elicits this effect despite intact plaque binding.

Single-cell RNA sequencing and spatial transcriptomic analyses reveal that Lecanemab induces a focused transcriptional program that enhances phagocytosis, lysosomal degradation, metabolic reprogramming, interferon γ genes and antigen presentation.

Finally, we identify SPP1/osteopontin as a major factor induced by Lecanemab treatment and demonstrate its role in promoting Aβ clearance.

These findings highlight that effective amyloid removal depends on the engagement of microglia through the Fc fragment, providing critical insights for optimizing anti-amyloid therapies in Alzheimer’s disease."

How antibody therapy clears Alzheimer's plaques: Key immune mechanism identified

New immune process identified that may alleviate Alzheimer's disease (original news release)

The Alzheimer’s therapeutic Lecanemab attenuates Aβ pathology by inducing an amyloid-clearing program in microglia (open access)

Fig. 1: Lecanemab drives strong transcriptional changes in human microglia associated with Aβ plaques.

Fig. 2: Lecanemab alleviates Aβ pathology by triggering effector functions in the microglia.

NAD+ Corrects RNA Splicing to Restore Alzheimer's Memory

Good news!

"Boosting levels of a certain molecule that declines with age was found to restore memory and brain function in Alzheimer’s disease (AD) models – not just by improving energy metabolism, as previously thought, but by fixing RNA splicing errors that disrupt hundreds of genes crucial to neuron health. ...

a team of scientists ... has uncovered a mechanism driven by the natural metabolite, oxidized nicotinamide adenine dinucleotide (NAD⁺), which can shield the brain from the progressive damage of AD. ...

"Preliminary studies have shown that supplementation with NAD⁺ precursors, such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), can offer therapeutic benefits in AD animal models and early clinical trials," ... "However, the molecular mechanisms behind these benefits remain largely unclear." ..."

"... The new study reveals that NAD⁺ works through a previously unidentified RNA-splicing pathway. This pathway is regulated by a protein called EVA1C, which plays an essential role in the process of RNA splicing. RNA splicing allows a single gene to produce multiple isoforms of a protein, and one isoform may show distinctive effects to the other isoforms. Its dysregulation is one of the most recently acknowledged risk factor for AD.

The researchers discovered that when NAD⁺ levels are increased, EVA1C helps correct mistakes in RNA splicing. This restoration process improves the function of hundreds of genes, many crucial for brain health, which can help reverse the neurodegenerative damage caused by tau. ..."

From the abstract:

"Dysfunctional alternative splicing events (ASEs) in RNA are markers of aging and Alzheimer’s disease (AD).

As a key neuronal resilience metabolite, the oxidized nicotinamide adenine dinucleotide (NAD+) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NAD+ enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive.

This study shows that NAD+ augmentation corrects the ASEs of many genes via a key protein, EVA1C (epithelial V-like antigen 1 homolog C), which is involved in neuronal development and activities.

EVA1C is reduced in the hippocampus in patients with AD compared to cognitively normal ones.

NAD+-induced memory retention is partially dependent on EVA1C, as adeno-associated virus–based Eva1c knockdown in the hippocampal CA1 region annuls NAD+-induced memory improvement in pathological Tau–bearing mice.

We propose that NAD+ reduces AD pathologies, at least partially, via amplification of the NAD+-EVA1C splicing axis, pointing to a potential splice-switching therapy for AD."

NAD+ Corrects RNA Splicing to Restore Alzheimer's Memory

NAD⁺ restores memory in Alzheimer’s’ disease models by correcting RNA errors "A groundbreaking international study shows how boosting a natural molecule can help restore memory in animal models of Alzheimer’s disease. The new study offers hope for developing new therapies for patients with Alzheimer’s disease."

NAD+ reverses Alzheimer’s neurological deficits via regulating differential alternative RNA splicing of EVA1C (open access)

Fig. 1. Compromised mRNA splicing in Tau pathology and aging.