Decoding the Fruit Fly Brain: Largest Adult Connectome Revealed
Scientists supported by the NIH BRAIN Initiative mapped the first full connectome of an adult fruit fly brain, revealing over 50 million connections among more than 130,000 neurons. This detailed wiring diagram includes chemical synapses, cell types, and neural projections. Using advanced electron microscopy, researchers traced pathways linking sensory inputs to motor outputs, uncovering insights into how the brain controls behavior. The map also shows information flow between brain regions and hemispheres. As the largest connectome of an adult animal, this resource is freely available for exploration and integration with other fruit fly data. It marks a significant leap in neuroscience, laying the groundwork for future connectome projects in other species.
Image: Reconstructed neuron morphologies from FlyWire showing all neurons in the central brain and optic lobes. The image is mirror-inverted relative to the native fly brain. Synaptic boutons, neuron tracts, trachea, and cell bodies are visible. Neuropil regions are defined, excluding the lamina. Data resources include electron microscopy imagery, synapse and neurotransmitter predictions, and annotations for hemilineages and hierarchical classes. Scale bar: 10 μm.
Article and Image Credit: Dorkenwald S, et al. “Neuronal wiring diagram of an adult brain.” Nature. October 2, 2024. DOI: 10.1038/s41586-024-07558-y.
NINDS Director’s Message: BRAIN Initiative Researchers Complete Groundbreaking Map of the Fly Brain
NIH Director’s Blog: Complete Fruit Fly Brain ‘Connectome’ Advances Understanding of Essential Brain Functions in Health and Disease
Understanding Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
A team of 75 scientists from 15 research centers collaborated on a groundbreaking study to deeply phenotype post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS). They compared patients with PI-ME/CFS to healthy individuals and found that the syndrome is linked to changes in brain and immune function that disrupt how the brain decides how to exert effort—not just physical or mental exhaustion. The study revealed sex-based differences in gene expression profiles in muscle, immune cell populations, and metabolite markers. These findings provide crucial insights into the biology of PI-ME/CFS and highlight the complex ways it affects the body. This research could lead to better treatments for this complex and debilitating condition.
Image: Comparing sustained effort and motor performance in healthy volunteers (HV) and people with post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) in a repetitive grip strength test. Data reflect group differences in grip strength, brain activity, and fatigue response.a: Grip force normalized to maximum voluntary contraction (MVC). HV maintained higher grip force than PI-ME/CFS patients.b: Slope of the Dimitrov index (an index of muscle fatigue in Electromyography) showed a significant decrease in PI-ME/CFS patients compared to HV.c: Motor-evoked potential (MEP) amplitudes using transcranial magnetic stimulation decreased in HV as expected with post-exercise repression. In contrast, MEP amplitudes increased in PI-ME/CFS patients during the task.d: Brain regions where blood oxygenation level dependent (BOLD) signal changes decreased over grip strength blocks in PI-ME/CFS and contrast with it increasing in HV.e: Brain activation in those regions over four experimental blocks revealed significant differences between cohorts over the time blocks
Article and Image Credit: Walitt B, et al. “Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome.” Nature Communications. February 21, 2024. DOI: 10.1038/s41467-024-45107-3.
NINDS Press Release(s): NIH study offers new clues into the causes of post-infectious ME/CFS
The Brain’s Frontline Defense: Meet DALT
Scientists discovered a new immune structure in the dura mater, the outer membrane surrounding the brain and spinal cord. Called dura-associated lymphoid tissue (DALT), this structure contains immune cells that protect the central nervous system (CNS) and responds to circulating antigens and intranasal pathogens. Microcomputed tomography (micro-CT) data in adult mice revealed that the bony recess contained a DALT structure that we have termed the “rostral-rhinal venolymphatic hub.” Antigens from the blood were shown to accumulate in the DALT and activate and expand B cells. This unique location enables DALT to rapidly respond to viruses entering the body through the nasal passages. The introduction of vesicular stomatitis virus (VSV) led to B cell recruitment and activation in the DALT. These findings guide future research on immune responses to pathogens and opens research avenues to study whether the DALT is implicated in CNS autoimmune diseases.
Image: The development of the venous drainage system in the mouse head from postnatal day 8 (P8) to adulthood. Micro-computerized tomography (CT) images at P8 reveal the rostral rhinal venous hub (red box) and its connection to the superior sagittal sinus, olfactory sinus, and developing sinuses in the head. Sagittal view of the three-dimensional visualization of vessels, brain, and bone. The dural-associated lymphoid tissue (DALT) is within the depression in the skull bone and is connected to the olfactory and superior sagittal sinuses.
Article and Image Credit: Fitzpatrick Z, et al. “Venous-plexus-associated lymphoid hubs support meningeal humoral immunity.” Nature. March 20, 2024. DOI: 10.1038/s41586-024-07202-9.
How the Brain Chooses and Stores Memories: The Role of Sleep and Sharp-Wave Ripples
Scientists have discovered how the brain selects which memories to store. Two studies explored how experiences are tagged and consolidated into memories. One study recorded brain activity in mice during maze tasks and found that specific brain waves, sharp-wave ripples (SWRs), occur during reward consumption. These SWRs re-activated experiences during sleep, helping preserve and consolidate memories. The second study examined how sleep loss affects memory consolidation in rats. While brain cells (SWRs) can remain active during sleep deprivation, the brain can replay and store memories less. Although recovery sleep partially restored replay, it didn’t match the levels seen in natural sleep. Together, these studies highlight the critical role of sleep and SWRs in selecting and strengthening meaningful experiences for lasting memories. This work was supported in part by the NIH BRAIN Initiative and the NIH/National Science Foundation Collaborative Research in Computational Neuroscience (CRCNS) Program.
Image: Sleep deprivation reduces the brain’s ability to replay and consolidate memories. This image shows how hippocampal activity changes during natural sleep (NSD), sleep deprivation (SD), and recovery sleep (RS). Replays, which help store memories, became shorter and less frequent during SD and RS compared to NSD. Replay durations also decreased with continued SD and RS. Box plots show fewer replays and shorter durations during these periods, highlighting the impact of sleep loss on memory consolidation. These graphs demonstrate that the number and duration of memory replays decrease significantly during sleep deprivation and only partially recover after rest..
Article(s): Article and Image Credit:
1. Giri B, et al. “Sleep loss diminishes hippocampal reactivation and replay.” Nature. June 12, 2024. DOI: 10.1038/s41586-024-07538-2.
2. Article: Yang W, et al. “Selection of experience for memory by hippocampal sharp wave ripples.” Science. March 28, 2024. DOI: 10.1126/science.adk8261.
CHARM Offensive: New Tool Targets Deadly Prion Protein
Prion diseases are fatal brain disorders caused by misfolded prion proteins that trigger toxic clumps, leading to rapid dementia and death. There are no treatments or cures, but NIH-supported research offers hope. Using a tool called CHARM (Coupled Histone tail for Autoinhibition Release of Methyltransferase), scientists silenced the prion gene in mice using epigenetic editing, which turns off harmful genes without altering DNA sequences. Delivered via an adeno-associated virus (AAV) capable of crossing the blood-brain barrier, CHARM reduced prion protein levels by over 80%, far exceeding the 20% reduction needed to improve symptoms. Researchers also engineered CHARM to self-silence after targeting the gene, minimizing side effects. This innovative approach, which avoids the risks of gene editing, could pave the way for treatments for prion diseases and other neurodegenerative disorders. This work is co-led by NINDS and the National Center for Advancement of Translational Science (NCATS) and was supported in part by the NIH Common Fund as part of the NIH Somatic Cell Genome Editing (SCGE) Program.
Image:
This image shows how the CHARM system silences the prion protein gene (Prnp). CHARM is a protein that binds to the Prnp gene and recruits an enzyme called DNMT3A. DNMT3A then adds chemical tags (methyl groups) to the DNA, turning off the Prnp gene. The image also shows how CHARM can be delivered to the brain using a virus (AAV) and how it can be designed to self-destruct after some time.
Article and Image Credit: Neumann E, et al. “Brainwide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor.” Science. June 28, 2024. DOI: 10.1126/science.ado7082.
NIH Director’s Blog: Epigenetic Editor Silences Toxic Proteins in the Mouse Brain, Offering Promising Path to Treat Deadly Prion Diseases
Crossing the Blood-Brain Barrier: New Virus Vector Delivers Genes to the Brain
Researchers created BI-hTFR1, an adeno-associated virus (AAV) capsid, to improve gene therapy delivery to the central nervous system (CNS). This innovative vector binds to the human transferrin receptor (TfR1), enabling 40 to 50 times greater gene delivery efficiency than AAV9 in humanized mouse models. By targeting the CNS specifically, BI-hTFR1 offers a promising strategy for treating neurological disorders. In a study on Gaucher disease-related GBA1 mutations, BI-hTFR1 significantly increased brain and cerebrospinal fluid glucocerebrosidase activity. This breakthrough complements other gene therapy advances, such as epigenetic editing tools that silence harmful genes without altering DNA. Together, these innovations address key challenges in gene therapy, including delivery, safety, and effectiveness. This work was supported in part by the NIH Common Fund as part of the NIH Somatic Cell Genome Editing (SCGE) Program and the NIH BRAIN Initiative.
Image: This image shows that a modified virus (BI-hTFR1) successfully delivered a fluorescent protein (mScarlet) to different types of cells in the brains of mice. These cells include neurons (A), astrocytes (B), oligodendrocytes (C), and endothelial cells (D). The image demonstrates that the virus can effectively target and deliver genes to various cell types in the central nervous system.
Article and Image Credit: Huang Q, et al. “An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery.” Science. May 16, 2024. DOI: 10.1126/science.adm8386.
NIH Director’s Blog: Epigenetic Editor Silences Toxic Proteins in the Mouse Brain, Offering Promising Path to Treat Deadly Prion Diseases
A Voice for the Voiceless: A Brain-Computer Interface (BCI) Gives Hope to People with Paralysis
Scientists have developed a brain-computer interface (BCI) that gives hope to people with paralysis who can’t speak. A team from the University of California, Davis created the system, which translates brain signals into words. They implanted tiny electrodes in the part of the brain that controls speech in a man with amyotrophic lateral sclerosis (ALS). Using these signals, the BCI displayed his words on a screen and spoke them aloud using software designed to sound like his voice before ALS. After 30 minutes of practice, the system achieved 99.6% accuracy with a 50-word vocabulary. With more training, it expanded to 125,000 words, maintaining 97.5% accuracy for over eight months. The man used it to hold conversations at 32 words per minute. Technology like this speech BCI may be useful for people who can’t speak due to paralysis. This work was built on previous NIH BRAIN Initiative-funded research and funded largely in part by the National Institute on Deafness and Other Communications Disorders (NIDCD).
Image:This image shows how a brain-computer interface system works. (a) Black squares mark the approximate locations of microelectrode arrays on a 3D reconstruction of a participant’s brain. Colored areas highlight brain regions aligned to the Human Connectome Project’s atlas, focusing on the precentral gyrus. (b) A diagram illustrates how a computer decodes these brain signals. Neural activity is recorded from the left ventral precentral gyrus using four 64-electrode arrays. Machine learning decodes brain signals into English phonemes every 80 milliseconds. Language models process these phonemes to form words appearing on a screen as the participant attempts to speak. A voice simulation then reads the decoded sentences in the participant’s pre-ALS voice.
Article and Image Credit: Card N, et al. “An Accurate and Rapidly Calibrating Speech Neuroprosthesis.” New England Journal of Medicine. August 14, 2024. DOI: 10.1056/NEJMoa2314132.
NIH Research Matters News Article: Brain-computer interface helps paralyzed man speak
Balancing Seizure Control and Child Health: Findings from a Long-Term Study
A long-term study provides reassurance for women with epilepsy who take antiseizure medications during pregnancy. Researchers compared 298 children of women with epilepsy with 89 children of women without epilepsy and found no significant differences in verbal abilities at age 6. The study showed that two common antiseizure medications, lamotrigine and levetiracetam, did not harm children’s neurological development. Researchers also found adequate folate supplementation during early pregnancy, even at higher doses, improved cognitive and behavioral outcomes. However, some antiseizure medications may impact fetal development differently, highlighting the importance of balancing seizure control with minimizing risks to the fetus. These findings emphasize the critical role of folate and offer valuable guidance for managing epilepsy during pregnancy.
The image compares verbal scores of 6-year-old children of women with epilepsy (WWE) and healthy women (HW). A box plot shows no significant differences between the two groups in unadjusted and adjusted analyses. The bold dot marks the average score, while a central line in the box shows the median. The box edges represent the 1st and 3rd quartiles, and the whiskers show the range of most data points. Dots beyond the whiskers represent outliers. Verbal scores of children with imputed data are not included in this figure. Analyses found no meaningful difference between groups (P = .64).
Article and Image Credit: Meador KJ, et al. “Neuropsychological Outcomes in 6-Year-Old Children of Women With Epilepsy.” JAMA Neurology. November 25, 2024. DOI: 10.1001/jamaneurol.2024.3982.
NINDS Press Release(s): Newer epilepsy medications used during pregnancy do not affect neurological development in children
Towards Earlier and More Accurate Diagnosis of Synucleinopathies: Implications for Patient Care
Two studies highlight major progress in identifying biomarkers for synucleinopathies. Researchers demonstrated that a significant number of patients with conditions like Parkinson’s disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF) had phosphorylated α-synuclein in skin biopsies. This finding supports skin biopsy as a useful tool for detecting these disorders. Similarly, another set of scientists found a strong link between loss of smell (hyposmia) and α-synuclein seed amplification assay (αSyn-SAA) positivity in patients with DLB. This suggests smell tests could help in evaluating DLB. Together, these papers provide promising paths for earlier, more accurate diagnosis of synucleinopathies, improving patient care and guiding future research.
The image shows a Receiver Operator Characteristic (ROC) curve illustrating the predictive accuracy of continuous variables for αSyn-SAA positivity in patients clinically diagnosed with dementia with Lewy bodies (DLB). The ROC curve shows that the UPSIT percentile (ROC area: 0.87) is the strongest predictor of αSyn-SAA positivity in clinically diagnosed DLB, compared to MDS-UPDRS Part III (0.67) and MoCA (0.62).
Article(s): Article and Image Credit:
1. Article and Image Credit: Coughlin DG, et al. “Association of CSF α-Synuclein Seeding Amplification Assay Results With Clinical Features of Possible and Probable Dementia With Lewy Bodies.” Neurology. August 13, 2024. DOI: 10.1212/WNL.0000000000209656.
2. Article: Gibbons CH, et al. “Skin Biopsy Detection of Phosphorylated α-Synuclein in Patients With Synucleinopathies.” JAMA. March 20, 2024. DOI: 10.1001/jama.2024.0792.
TDP-43 Biomarkers and Precision Therapies for ALS, FTD, Alzheimer’s, and LATE
Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease, and Limbic Associated TDP-43 Encephalopathy (LATE) are all associated with a protein called TDP-43, which regulates how cells join RNA segments into correct instructions for cells to make proteins. Abnormal TDP-43 function causes errors in these instructions, including the addition of extra segments called cryptic exons. Researchers showed that such cryptic exons can lead cells to make abnormal proteins, which could play previously unknown roles in disease and might be used as biomarkers to aid early disease detection. Other researchers are harnessing cryptic exon processing to develop novel precision therapies.
Fluorescence microscopy images show spinal cord sections from TDP-43 cKO (left) and control (right) mice injected with an AAV containing TDP-REGv2 mScarlet (construct 7). Two magnified images of representative motor neurons are displayed below, with their locations indicated in the full images by white boxes. In the image: Blue represents DAPI, Yellow represents TDP-43, White represents VaChT, and Red represents mScarlet.
Article(s): Article and Image Credit:
1. Article: Irwin KE, et al. “A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD.” Nature Medicine. January 26, 2024. DOI: 10.1038/s41591-023-02788-5
2. Article and Image Credit: Wilkins OG, et al. “Creation of de novo cryptic splicing for ALS and FTD precision medicine.” Science. October 3, 2024. DOI: 10.1126/science.adk2539.
As another year has come to a close, I am again pleased to share with you a few of the exciting accomplishments of NINDS-funded scientists in 2024. NINDS supports and conducts research leading to new scientific knowledge in basic, translational, and clinical neuroscience. Each year there are far too many advances to cover in detail, but I have selected a number of highlights from 2024 that you can peruse above. In 2025, we look forward to reflecting on 75 years of NINDS research progress and engaging all corners of our community in imagining how we will overcome major challenges in understanding the nervous system and improving neurological health.
Scientific progress to improve the lives of those living with neurological disorders
One of NINDS’s key goals is to accelerate the development of treatments for people who have neurological disorders. Last May, NINDS and the Foundation for the NIH (FNIH) announced the launch of the Accelerating Medicines Partnership® for amyotrophic lateral sclerosis (AMP ALS). This public-private partnership is creating a large open data platform for ALS research, developing validated biomarkers and clinical outcome assessments to aid drug development and diagnosis, and promoting discovery of new biological targets for ALS treatment or prevention in people at risk. The AMP for Parkinson’s Disease (AMP PD) program also relaunched last year to build on its established infrastructure and expand to include a broader range of patients with PD and other related disorders that share similar symptoms and biological characteristics. The AMP PD and Related Disorders (AMP PDRD) aims to expedite the identification of biomarkers that differentiate related diseases, which could improve diagnosis, speed clinical trials, and inform new and personalized therapies. Lastly, the NINDS Ultra-rare Gene-based Therapy (URGenT) Network expanded last year to include funding, infrastructure, and expertise to support clinical trials to test promising new gene-based therapies for ultra-rare neurological diseases.
The National Advisory Neurological Disorders and Stroke (NANDS) Council and its expert working groups help us identify and make progress in strategic areas that support the mission of NINDS. Last May, a new research roadmap for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) was presented to the NANDS Council. This ME/CFS Research Roadmap identifies research priorities to move the field toward translational studies and clinical trials for this disease that has so far defied understanding and may be increasing due to the high risk of ME/CFS in individuals who were infected with SARS-CoV-2, the virus that causes COVID-19. In September, the NANDS Council Neural Exposome Top Priorities (NEXT) Working Group presented its recommendations to NANDS Council on opportunities for studying the role of environmental and other noninheritable factors (the neural “exposome”) in causing neurological disorders. Fundamental, basic research and discovery science is the essential fabric of NINDS science and the engine that enables broad progress throughout the Institute’s portfolio. In support of its mission, NINDS received key recommendations from the Fundamental Neuroscience Working Group (FNWG). This past year, we launched a program of interdisciplinary team science, the Collaborative Opportunities for Multidisciplinary, Bold, and Innovative Neuroscience (COMBINE) program, to engage scientists to solve vexing problems in their neuroscience fields, as well as a team science seminar series.
NINDS is the steward of taxpayers’ investment in neuroscience, and we continually engage with and learn from people experiencing the neurological health challenges that we strive to overcome. In many ways, scientific results have greater impact when individuals affected by neurological disorders contribute to the plans and priorities of the research, and in some cases, conduct the research, that will ultimately impact them and their loved ones.
Celebrations of important milestones for NIH-wide neuroscience programs
In 2024, the Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative®, celebrated its 10th year of advancing neuroscience and neurotechnology research. I would offer that no research program has ever had such a profound effect on brain science. It is truly revolutionizing the entire field. As part of the commemoration, a special “BRAIN at 10” blog series highlighted the work of each of the 10 participating NIH Institutes and Centers. I shared a BRAIN Blog post with insights into what makes the NIH BRAIN Initiative unique, how it has contributed tremendously to NINDS’s mission throughout the last 10 years, and how the Initiative has changed the field of neuroscience by allowing scientists to grasp the complexity of the brain. Some of BRAIN’s ground-breaking achievements from 2024 are highlighted in the carousel above, as well as in Director’s Messages from Dr. John Ngai, director of the NIH BRAIN Initiative.
In addition, the NIH Blueprint for Neuroscience Research marked 20 years of supporting cross-cutting research, unique training opportunities, and novel research tools and resources for the neuroscience community. Of note, the NIH Blueprint was an early sponsor of the BRAIN Initiative and continues to partner with and invest in BRAIN research.
Imagining the future of neuroscience
Since its establishment in 1950, NINDS has played a pivotal role in unraveling the complexities of the brain and nervous system. As we await a final Fiscal Year (FY) 2025 budget, NINDS is operating under a Continuing Resolution (at the FY 2024 enacted funding level) through March 14, 2025. Despite this challenging budgetary landscape, the science we fund has never been more exciting. We remain committed to advancing important neuroscience research and working with the neuroscience community, including nonprofit and patient advocacy organizations, professional societies, people with lived experience of neurological disorders, NINDS staff, researchers, academia, and other federal partners. NINDS looks forward to strengthening existing partnerships, building new connections, learning from one another, and making ongoing progress together in 2025.
As we commemorate our 75th anniversary, help us spread the word and stay tuned for celebration plans throughout the year!
