The struggle is real when word retrieval goes wrong: see what’s happening in the brain during tip-of-the-tongue moments
Category: neuroscience
Frontiers: As a significant mental health disorder worldwide
The treatment of depression has long faced the challenges of a low treatment rate, significant drug side effects and a high relapse rate. Recent studies have revealed that the gut microbiota and neuronal mitochondrial dysfunction play central roles in the pathogenesis of depression: the gut microbiota influences the course of depression through multiple pathways, including immune regulation, HPA axis modulation and neurotransmitter metabolism. Mitochondrial function serves as a key hub that mediates mood disorders through mechanisms such as defective energy metabolism, impaired neuroplasticity and amplified neuroinflammation. Notably, a bidirectional regulatory network exists between the gut microbiota and mitochondria: the flora metabolite butyrate enhances mitochondrial biosynthesis through activation of the AMPK–PGC1α pathway, whereas reactive oxygen species produced by mitochondria counteract the flora composition by altering the intestinal epithelial microenvironment. In this study, we systematically revealed the potential pathways by which the gut microbiota improves neuronal mitochondrial function by regulating neurotransmitter synthesis, mitochondrial autophagy, and oxidative stress homeostasis and proposed the integration of probiotic supplementation, dietary fiber intervention, and fecal microbial transplantation to remodel the flora–mitochondrial axis, which provides a theoretical basis for the development of novel antidepressant therapies targeting gut–brain interactions.
Depression is a disorder that severely affects the mental health of the global population and is characterized by persistent low mood, loss of interest and cognitive dysfunction (GBD 2017 Disease and Injury Incidence and Prevalence Collaborators, 2018; COVID-19 Mental Disorders Collaborators, 2021; Salari et al., 2020). Globally, depression is one of the leading causes of mental disability. According to the World Health Organization (WHO), the global prevalence of depression is approximately 4.4%, which means that more than 300 million people worldwide suffer from depression (Xu et al., 2024). In addition, depression is one of the major causes of suicide deaths, with nearly 800,000 people worldwide dying by suicide each year (World Health Organization, 2021).
How multiple sclerosis kills neurons
MS is typically diagnosed when clinicians see lesions in the myelin-rich white matter of the brain on MRI scans. White matter is made of the nerves that link brain cells and it looks white on a brain scan.
The brain’s grey matter, which houses the “bodies” of the brain cells, can also have MS lesions, especially in its outer layers. These lesions are less common — and harder to see on a brain scan — but they are a sign of chronic and disabling MS.
The scientists wanted to learn more about the neurons that died in these grey-matter lesions, which express a gene called CUX2. In the first study, they looked at developing mouse brains to see how CUX2 neurons are born. This occurs early in life, when the brain is growing quickly, putting cells under tremendous stress.
The cells relied on a mechanism to repair their DNA as they rapidly multiplied, fanned out into the far reaches of the brain and wired up with one another. The mechanism depends on a stress-response gene called ATF4 to keep chromosomes intact. When the team removed ATF4, the growing neurons were rife with DNA damage, and this prevented the frontal part of the brain from forming.
In the second study, the team found DNA damage in grey matter lesions from people with MS involving the same neurons.
In mouse models of MS, the researchers saw that inflammation sparked chemical reactions that damaged DNA in CUX2 neurons. The repair systems that protect these neurons from the stresses of development could no longer keep up; and this led to brain damage.
Together, the two studies outline the natural way the brain’s outer layer neurons cope with DNA damage — and how that system breaks down in MS. ScienceMission sciencenewshighlights.
Scientists uncover brain circuits for impulsivity
Scientists from the Lee Kong Chian School of Medicine at Nanyang Technological University, Singapore, have uncovered how different brain regions work together to enable self-control—the ability to suppress impulsive behaviors and wait for the right moment to act. Their findings advance the understanding of conditions such as attention-deficit hyperactivity disorder (ADHD) and addiction, and could lead to more effective management of these disorders.
According to the researchers, this is the first time that this interplay underlying self-control has been found in the brain. The findings were reported in Science Advances.
Blood test can predict Alzheimer’s disease progression years before symptoms or brain scan changes
A study by investigators at Mass General Brigham has found that a blood test of plasma phosphorylated tau 217 (pTau217), an Alzheimer’s disease biomarker, can predict the progression of amyloid PET scan changes and cognitive decline in cognitively healthy older adults. The findings may help push back the clock to enable simpler, earlier disease prediction and indicate who may be at risk for cognitive decline. The results are published in Nature Communications.
“We used to think that PET scan detection was the earliest sign of Alzheimer’s disease progression, revealing amyloid accumulation in the brain 10 to 20 years before symptoms appear,” said lead author Hyun-Sik Yang, MD, a neurologist with Mass General Brigham Neuroscience Institute and an associate member of the Broad Institute of MIT and Harvard. “But now we are seeing that pTau217 can be detected years earlier, well before clear abnormalities appear on amyloid PET scans.”
Last year, the U.S. Food and Drug Administration cleared the first blood test for Alzheimer’s disease, paving the way for a cheaper, less invasive alternative to lumbar punctures and PET scans. The new study by Yang and colleagues adds important evidence about the predictive potential of these kinds of blood tests.
Proteomic insights into troponin elevation following COVID-19 infection
Background Raised cardiac troponin-I is a common finding in patients hospitalised with acute viral infections, including but not limited to COVID-19. This often occurs in the absence of overt myocardial injury presenting a challenge for interpretation. The mechanisms underlying troponin elevation are uncertain.
Methods The CISCO-19 (Cardiovascular Imaging in SARS-CoV-19) study (NCT04403607) is a prospective, multicentre cohort study, in which hospitalised PCR-confirmed COVID-19 participants (N=267) underwent multisystem evaluation at enrolment and at 28–60 days. The study incorporated plasma proteomics (SOMAscan V.4.1), cardiovascular MRI and clinical biomarkers. Of these, 211 had baseline plasma proteomic data and 185 completed follow-up sampling. Matched proteomic and imaging data were available for 155 participants (mean age: 55 years (SD 12); 43% female).
Results A high likelihood of myocarditis was identified in 13.2% (N=21/159) of participants. High-sensitivity troponin-I was modestly elevated at enrolment (median 3 ng/L; IQR 2–6; n=159). Among males (n=90), 9.3% had a high-sensitivity troponin that exceeded 34 ng/L. Among females (n=69), 4.5% exceeded 16 ng/L. Smooth muscle myosin light chain proteins were downregulated at follow-up (log2 fold change −0.12 to −0.6; all adjusted p0.02) and positively correlated with high-sensitivity troponin-I, but not N-terminal brain natriuretic peptide or cardiac MRI indices (n=155).
APOE4, the Alzheimer’s risk gene, silently undermines bone quality in women
Scientists at the Buck Institute for Research on Aging, along with collaborators at UC San Francisco, have discovered that APOE4, the most common genetic risk factor for Alzheimer’s disease, causes bone quality deficits specifically in female mice, through a mechanism that is invisible to standard imaging and can emerge as early as midlife. The findings, published in Advanced Science, reveal an unexpected biological link between Alzheimer’s risk and skeletal health, and identify a new molecular pathway that could one day inform earlier diagnosis of cognitive decline or guide treatment for bone quality loss in women who carry the APOE4 gene.
“What makes this finding so striking is that bone quality is being compromised at a molecular level that a standard bone scan simply will not catch,” says Buck professor Birgit Schilling, Ph.D., a senior author of the study. “APOE4 is quietly disrupting the very cells responsible for keeping bone strong, and it is doing this specifically in females, which mirrors what we see with Alzheimer’s disease risk.”
Physicians have long observed that people with Alzheimer’s disease suffer bone fractures at higher rates, and that a diagnosis of osteoporosis in women is actually the earliest known predictor of Alzheimer’s. But the underlying mechanism connecting brain and bone health has remained elusive.
Pain-sensing neurons mapped in unprecedented detail, pointing to new chronic pain drug targets
One in five people worldwide suffers from chronic inflammatory pain. Meanwhile, about two thirds of those affected find little relief from existing pain medications; new therapeutic approaches are urgently needed. “We first must understand precisely how sensory nerve cells trigger pain at the molecular level—in other words, which proteins are involved,” says Professor Gary Lewin, Group Leader of the Molecular Physiology of Somatosensory Perception lab at the Max Delbrück Center in Berlin.
To unravel these molecular processes, Lewin—who has been studying pain for four decades and recently discovered a previously unknown ion channel involved in pain perception—is working closely with systems biologist Dr. Fabian Coscia, Group Leader of the Spatial Proteomics lab at the same center. Coscia co-developed a method called Deep Visual Proteomics that makes it possible to determine the proteome —the complete set of proteins—of specific cells and to create maps detailing the spatial locations of individual proteins.
The researchers combined this technology with electrophysiological methods from Lewin’s group. This enabled them to first identify specific subtypes of pain neurons based on their function and then analyze their protein profiles. The result is a high-resolution molecular map of these nerve cells, which has been published in Nature Communications. The team also demonstrated how the technology can identify potential new drug targets to treat chronic pain.
