Functional modules in the human temporal lobe found at the micro scale
Most of us are familiar with the different lobes of the brain that control general functions, like vision, motor control, and abstract thinking. But there is growing evidence for other layers of organization within each of these regions. Novel work is exploring this network organization in the temporal cortex, a region important for providing context to faces and other objects that a person sees in their visual field.
Dr. Julio Chapeton, research fellow in the Functional Neurosurgery Section at NINDS, set out to explore the human temporal cortex for evidence of smaller, organized regions that have unique processing functions. Small-scale recordings were performed in a group of patients with epilepsy who were having surgery to understand their brain’s epileptic regions. A small (4x4 millimeters, mm) grid of recording electrodes was placed in a non-epileptic region to analyze the activity of both the surface and deeper layers of the cortex. These recordings were performed while the patients viewed sets of images displaying persons, places, objects, and animals.
These recordings revealed small networks of neurons that activated together during presentations of the same image at different times throughout the experiment. This suggests that within the human temporal cortex there are very small functional modules, approximately 1.3 mm in diameter. These modules provide evidence of organization in the temporal cortex at the micro-scale. Similar observations have been made before in the human visual cortex; this new work in the temporal cortex indicates that functional modules may be a general property of the human cortex.
Research explores how new information is consolidated across the sleep-wake cycle
Using a mouse model, researchers have discovered a new daily rhythm in a type of synapse that dampens brain activity. Known as inhibitory synapses, these neural connections are rebalanced so that we can consolidate new information into long-lasting memories during sleep. In the study, Kunwei Wu, Ph.D., a postdoctoral fellow in Dr. Lu’s lab, examined what happens at inhibitory synapses during sleep and wakefulness in mice. Their experiments suggest that the accumulation of GABAA receptors during wakefulness may be key to building stronger, more efficient inhibitory synapses, a fundamental process known as synaptic plasticity.
The findings, published in PLOS Biology, may help explain how subtle synaptic changes enhance memory in humans. Humans and mice share similar neural circuits underlying memory storage and other essential cognitive processes. This mechanism may be a way for inhibitory inputs to precisely control the ebb and flow of information between neurons and throughout entire brain networks.
Because inhibition is essential for nearly every aspect of brain function, this study could contribute to helping scientists understand not just sleep-wake cycles, but neurological disorders rooted in abnormal brain rhythms, such as epilepsy.
The brain and spinal cord can be divided into “grey matter” and “white matter” regions. We’ve learned a lot about the cell types found in the gray matter by studying the brains of rodents. However, rodent brains have relatively little white matter, limiting our understanding of its detailed composition in healthy brains and of the white matter abnormalities that are hallmark of many neurological disorders. To address this gap, Drs. Jing-Ping Lin and Daniel Reich turned to the common marmoset, a powerful and emerging neurological model system that genetically bridges rodents and humans and has high content of white matter. They created a rich dataset by rigorously surveying the transcriptomes (all the gene readouts) of 0.5 million cells over 19 regions of the central nervous system. They carefully annotated this dataset to create a marmoset brain cell atlas resource, “Callithrix jacchus Primate Cell Atlas” (CjPCA), which is freely available through https://cjpca.ninds.nih.gov and is designed to inform future studies in evolutional, developmental, and pathological neurobiology. They also conducted initial analyses of these data, identifying the molecular signatures and spatial distributions of 87 distinct cell types in the marmoset brain and strong differences between glial cells found in the white and gray matter. Finally, they also explored how developmental processes, local microenvironment, and disease states shape these distinct cell types. This unique data set is expected to yield many other new insights, and the methods used to obtain it can be used as a framework for studying brain cell types in other regions or species.
Intrinsic Potential for Regeneration after Spinal Cord Injury
Spinal cord injury is a traumatic event that affects the intricate ecosystem of neurons and supporting cells in the spinal cord, often leading to paralysis. After spinal cord injury, “spared” tissue below the lesion contains undamaged cells that could augment or support recovery. However, targeting these cells requires a clearer understanding of their injury responses and capacity for repair.
In a recent publication, Dr. Ariel Levine and Kaya Matson profiled how each cell type in the spared tissue of the spinal cord changes over time after injury. They created an atlas of cell types, ranging from acute to chronic timepoints (https://seqseek.ninds.nih.gov/spinalcordinjury). The size and scope of this study allowed for identification of rare cells with the potential to support recovery. They identified neurons which had a gene signature of regeneration, normally only seen in peripheral neurons that regenerate after injury, and not in the central nervous system which is much more limited in its regenerative capability. The researchers identified the neurons with the pro-regenerative gene signature, including spinocerebellar neurons. They labeled spinocerebellar neurons and found that they remodeled after injury. This work shows the inherent potential for plasticity after injury in neurons important for coordination and movement after spinal cord injury.
Lewy body dementia (LBD) is a common form of dementia in the elderly population, affecting approximately 1.4 million people in the United States. LBD can cause symptoms that include visual hallucinations, changes in attention, and slowing of movement, among others. The cause of LBD is poorly understood, but genetic factors are thought to play a role.
In a recent study Dr. Sonja Scholz and her team examined the genomes from about 2,600 LBD patients and 4,000 controls who did not have a history of cognitive or neurological conditions. They were specifically looking at the GRN gene, which has been shown to be important in several cellular processes. These include cell growth, inflammation, and protein metabolism. Mutations in GRN have been previously linked to another serious neurological disease, frontotemporal dementia. Given that frontotemporal dementia and LBD share some overlap in their symptom presentation, there was interest in whether LBD cases would also be linked to GRN mutations.
When reviewing the genomes from the LBD patients, they discovered that these GRN mutations were in fact more common compared to the healthy control group. A further review of tissue samples from some of the mutation carriers also confirmed that the patients indeed showed features of both LBD and frontotemporal dementia. This suggests that molecular relationships may exist between these two understudied types of dementia, opening potential avenues for using genome sequencing as a diagnostic tool. In addition, this information may help to improve disease modeling and therapy development. As novel therapies targeting the GRN gene are already in the clinical trials stage, the study raises hopes that future trials could be expanded to LBD.
Cerebrospinal fluid (CSF) is a watery fluid that flows in and around the brain and spinal cord. This fluid physically protects the brain, delivers nutrients, and clears waste to maintain the normal functioning of neurons. The flow of CSF is neither passive nor constant. Rather, several physiological processes in the body, such as heart and breathing cycles, actively affect the pattern and rate of CSF flow.
Recent research in Jeff Duyn’s Advanced MRI section (AMRI) and several other groups has shown that CSF pulsations may not only result from cardiac and breathing cycles, but also from active contraction and dilation of the brain’s blood vessels. Despite evidence of this cerebrovascular effect on CSF flow, the relative importance of these novel CSF pulsations remained unclear.
This finding indicates an important role of cerebrovascular activity in CSF pulsations. Recently, it has been proposed that pulsatile movement of CSF may assist in the clearance of metabolic waste products from the brain that have been linked to neurodegeneration. Together, this suggests a potential link between impaired vascular reactivity and compromised waste clearance.
The small size of the pituitary gland belies its important role as master regulator of many of the hormones that our body needs to function properly. Tumors on the pituitary can occur in up to 10% of the general population. These tumors - called adenomas - are benign, in that they do not cause cancer. However, they can substantially disrupt the normal functions of the pituitary gland, with big consequences. Cushing’s disease is one such consequence. In this disease, the pituitary adenoma causes too much cortisol (a stress hormone) to be made, leading to a plethora of physical changes and systemic complications. While treatments exist, they cannot fully reverse the effects of ongoing cortisol overproduction. The best way to treat Cushing’s disease would be to stop the overproduction of cortisol at the source, by eliminating the pituitary adenoma.
Dr. Prashant Chittiboina, an investigator in the Neurosurgery Unit for Pituitary and Inheritable Diseases, studies the basic biology of pituitary adenomas to identify new ways to eliminate those that cannot be removed surgically. In a recently published study, his team collected cells from the adenomas and adjacent normal tissue of 34 patients during surgery. Using modern high-throughput molecular characterization techniques, they created an atlas of cell normal and abnormal pituitary cell types, and used this information to reveal a molecular signature unique to the adenoma cells. They showed that this molecular signature includes a trip-wire protein that should be toxic to the adenoma cells. However, adenoma cells were able to destroy this protein and protect their survival. Using a new mouse cell model, the group showed how to allow this trip-wire protein to accumulate in adenoma cells. To do this, the group used drugs that have already been approved for other conditions as pills. This study paves a smooth road to testing such treatments for Cushing’s disease in human patients.
“After publication, this work prompted a recent Nature Reviews Endocrinology article discussing these new mechanisms of Cushing disease that Dr. Chittioina and his team uncovered.”
Parkinson’s Disease (PD) is the second most common neurogenerative disease, causing symptoms such as tremor, bradykinesia, and gait problems. In general, 5-10% of cases are caused by a genetic mutation of a single gene, and therefore new therapies that can target these mutations may become important as future treatment options.
One potential target for gene therapy is PRKN, a gene that produces the protein Parkin. Parkin helps to rid the body of faulty or damaged mitochondria, which can wreak havoc on the health of cells, especially in the brain. Having mutations in both copies of PRKN causes PD. But does a single PRKN mutation also increase the risk of someone developing PD?
In a recent paper , Dr. Derek Narendra, Chief of the Inherited Movement Disorders Unit and a Lasker Clinical Research Scholar, investigated just this question. His team evaluated individuals with single PRKN mutations in two large groups of human research participants with available genetic data. One group reflected the general population and the other specifically included patients with PD.
Overall, they found that single PRKN mutations are common in the general population but occur as often in people with PD as those without PD. These results suggest that single PRKN mutations do not increase risk of PD. These findings will inform the counseling of patients with PD and their families, and help to better design gene therapy trials for PD.
Dr. Avindra Nath Investigates the Mysterious Ways Viruses Affect the Nervous System and is Featured on Global Documentary
The COVID-19 pandemic was not Avindra “Avi” Nath’s first face-off with an enigmatic, rapidly spreading virus. From the AIDS pandemic to the current pandemic, Dr. Nath is one of the world’s foremost experts on how viruses affect the brain. As the NINDS Clinical Director and the head of the Section of Infections of the Nervous System, he occupies a unique niche that requires expertise in two seemingly unrelated fields. “If you’re trained as a neuroscientist or neurologist, you understand the functions of the brain, but if you’re trained as a virologist, you study viruses, and there’s no way you would get exposed to the intricacies of the brain,” Dr. Nath explains. “I trained in both, so I was able to marry the two together.” Read more.
Dr. Nath was also featured on Here’s What We Know About COVID-19’s Impact on the Brain – a documentary produced by Science Magazine that focuses on the impact of COVID-19 in the brain, as well as novel therapeutic approaches to improve the symptoms of long COVID, such as autonomic rehabilitation, and an immune modulating drug trial awaiting regulatory approval. Renown scientists, like Dr. Nath, hope that the knowledge gained from long COVID will benefit those facing post-viral illnesses. You can watch the video in its entirety on YouTube.
Sensory hair cells of the inner ear required for hearing and balance rely on the mechanoelectrical transduction (MET) channel complex to convey mechanical signals from sound or head movements into electrical impulses. Transmembrane-like channel 1 and 2 (TMC1 and TMC2) are thought to form the ion conduction pore of the MET channel, yet the distinctive roles of the two proteins and how TMC1 mutations cause hair cell death remain elusive.
In this article published in BioRxiv, Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing, Drs. Angela Ballesteros and Kenton Swartz discover that TMC1 controls membrane homeostasis initiated by inhibition of MET channels and that deafness-causing mutations in TMC1 lead to constitutive phosphatidylserine externalization that correlates with the deafness phenotype, suggesting that the mechanisms of TMC1-related hearing loss may involve alterations in membrane homeostasis. Read more.
A study published in Cell Reports, led by Dr. Kunwei Wu and team from Dr. Wei Lu’s lab found the differential modulation of tonic inhibition by NMDA receptor subtypes and reveal distinct roles of GluN2A- and GluN2B-NMDA receptors in regulating ɑ5-GABAAA receptor trafficking, tonic inhibition and its homeostatic plasticity in hippocampal neurons. They also demonstrate the regulation of tonic inhibition by NMDA receptors in a kainate-induced seizure model. As dysregulation of tonic inhibition has been shown to be a mechanism underlying a number of pathological brain states, these findings provide insight into crosstalk between glutamatergic and GABAergic systems, as well as how dysregulation of this crosstalk could be involved in epileptic conditions. Read the full publication.
NIH study identifies possible target for certain neurodegenerative disorders. Neurons require mechanisms to maintain ATP homeostasis in axons, which are highly vulnerable to bioenergetic failure. Recent work from Dr. Zu-Hang Sheng and his team offers insights that advance our understanding of axonal energy metabolism; energy deficits are associated with a wide range of neurological disorders. Read full press release.
Adenosine A2A Receptor Activation Enhances Blood–Tumor Barrier Permeability in a Rodent Glioma Model
In a study by Dr. Sadhana Jackson and colleagues published in AACR Molecular Cancer Research, researchers characterize the time-dependent impact of regadenoson on brain endothelial cell interactions and paracellular transport, using mouse and rat brain endothelial cells and tumor models. Collectively, these findings demonstrate regadenoson's ability to induce brain endothelial structural changes among malignant glioma cells to increase BTB permeability. Read more.
Scientists Discover a New Molecular Pathway Shared by two Neurodegenerative Disorders
Finding provides a possible therapeutic target for ALS and FTD. Researchers from two independent research teams have discovered how the mislocalization of a protein, known as TDP-43, alters the genetic instructions for UNC13A, providing a possible therapeutic target that could also have implications in treating amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other forms of dementia. Read press release.
Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disorder that results in loss of voluntary muscle strength and movement. ALS usually affects middle-aged adults and progresses rapidly, but in the recent study Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis, published in Nature Medicine, an international team reported a new and unique, rare form of ALS with onset in young children followed by a somewhat slower but equally progressive course.
Identifying this new form of ALS was just the start towards a deeper understanding of the mechanisms driving the disease. Read the full NINDS press release, NIH Record article, and see international press coverage of this study.
Drs. Arvind Shukla, Kory Johnson, and Senior Investigator Ed Giniger are changing how we understand the role of genes and the microbiome in aging. Published in iScience, Common features of aging fail to occur in Drosophila raised without a bacterial microbiome reports on unexpected differences in gene expression between flies raised under normal conditions or in the absence of bacteria (with antibiotics). A large body of research has identified many genes that change their expression as an animal ages, and these genes are considered hallmarks of the aging process. In this study, however, the team found that 70% of these classic age-related genes did not change their expression over time when the flies were raised without bacteria, indicating that these genes are actually responding to the microbe-rich environment, rather than the animal's internal aging clock. Read the full NINDS press release, or see the buzz around the story on twitter!
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Researchers at the NNINDS led by Dr. Dorian McGavern have found a possible explanation for why some patients recover much more poorly from brain injury if they later become infected. The findings were published in Nature Immunology. Making use of a mouse model for mild TBI (mTBI) that they had developed previously, the team of researchers discovered that viral, fungal, or a mimic for bacterial infections all impacted blood vessel repair within the meninges. When they looked closer, they observed that some cells of the immune system no longer moved into the site of the injury, which occurred in the uninfected animals, suggesting they were responding to systemic infection. Read press release.
Investigators build a cellular blueprint of multiple sclerosis (MS) lesions providing a better understanding of the entire network of cells. Danny Reich and his team had a fascinating paper recently published in Nature, A lymphocyte–microglia–astrocyte Axis in Chronic Active Multiple Sclerosis. Chronic lesions with inflamed rims, or “smoldering” plaques, in the brains of people with MS have been linked to more aggressive and disabling forms of the disease. Using brain tissue from humans, Dr. Reich and colleagues built a detailed cellular map of chronic MS lesions, identifying genes that play a critical role in lesion repair and revealing potential new therapeutic targets for progressive MS. Read the full press release.
A NINDS team led by Senior Investigator Dr. Leonardo Cohen and staff scientist Dr. Ethan Buch recently published a study mapping out the brain activity that occurs when we learn a new skill and discovered why taking short breaks from practice is a key to learning. In a recent publication appearing in Cell Reports, the researchers used magnetoencephalography to record the brain waves of volunteers as they practiced rapidly typing a code and during short rests between practice. A machine learning approach allowed them to decipher the brain wave activity associated with typing a code. During rests between periods of practice, the brains of healthy volunteers rapidly and repeatedly replayed much faster, compressed versions of the brain waves that occurred during active typing practice. The more a volunteer's brain replayed the pattern during rest, the better they performed during subsequent practice sessions, suggesting rest strengthened the memory of the typing skill.
The study also identified the brain regions where this replay occurs. The researchers hope that the study sheds light not only on the role that rest can play in normal skill learning, but also points to strategies for enhancing skill learning, including as part of rehabilitation interventions after brain injury. Read the full press release, or listen to a short interview with Drs. Cohen and Buch that appeared in the Scientific American.
Distinguishing Type II Focal Cortical Dysplasias from Normal Cortex: A Novel Normative Modeling Approach
Seizure outcomes in epilepsy surgery are better when epileptogenic lesions are identified. There is no widely available automated method for aiding with detection of subtle focal cortical dysplasia lesions. In this study, the researchers describe a novel approach for aiding with detection of these lesions using structural MRI. Detection of subtle dysplastic lesions in individual patients undergoing epilepsy surgery has the ability to significantly improve seizure outcomes in these patients. Read more.
Genome Sequencing Analysis Identifies New Loci Associated with Lewy Body Dementia and Provides Insights into its Genetic Architecture
Led by Dr. Scholz, a team of investigators identified novel risk loci associated with this devastating disease, and they were able to show molecular relationships between Lewy body disease (LBD), Parkinson’s disease, and Alzheimer’s disease. The genome data described in this study constitute the largest sequencing effort in LBD to date and are designed to accelerate the pace of discovery in dementia research. Read more.
An Epilepsy-Associated GRIN2A Rare Variant Disrupts CaMKIIα Phosphorylation of GluN2A and NMDA Receptor Trafficking
In a project led by Dr. Marta Mota Vieira, we characterized a novel CaMKIIα phosphorylation site, S1459, in the GluN2A subunit of NMDA receptors. Phosphorylation of this residue promotes trafficking of the receptor to the neuronal surface, modulates receptor interactions with trafficking and scaffold proteins. This provides a previously unappreciated link between GluN2A-specific NMDA receptor function and the important synaptic signaling kinase CaMKIIα. Importantly, we found that an epilepsy-associated variant (S1459G) identified at the same residue decreases synaptic expression of NMDA receptors, spine density, and spontaneous post-synaptic currents, consistent with the epilepsy-related variant being a loss-of-function mutation. Read more.
Evidence for a Stereoselective Mechanism for Bitopic Activity by Extended-Length Antagonists of the D3 Dopamine Receptor
Investigators performed a high-throughput screen of a small molecule library to identify a D3R-selective agonist with low cross-reactivity with the closely related D2R. We then conducted a comprehensive structure–activity relationship investigation using iterative medicinal chemistry to establish the structural determinants for potency, efficacy, and selectivity of the agonist at the D3R. An optimized lead compound, ML417, was identified that promotes potent and selective D3R activation. ML417 shows almost no cross reactivity with other receptors, indicating it is globally selective for the D3R. They also identified amino acid residues in the D3R DAR that uniquely interact with ML417, explaining the compound’s unprecedented selectivity. In follow-up studies, ML417 was found to exhibit neuroprotection against toxin-induced neurodegeneration of dopaminergic neurons. Read more.