Radically different
A study headed by researchers at King’s College London and the University of Porto has mapped the histamine system in the brain. Histamine, a molecule more commonly associated with allergies, plays a separate but poorly understood role in brain function. The new study addresses this gap, building the first multiscale map of the histamine system which spans from genetics to behavior and related mental health conditions.
The findings provide a new framework for understanding how this often-overlooked chemical system contributes to brain function and could point towards new treatment strategies for histamine-related conditions such as depression, ADHD, and schizophrenia. The study was funded by the National institute for Health and Care Research (NIHR) Maudsley Biomedical Research Centre.
Daniel Martins, MD, PhD, visiting senior research fellow at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) King’s College London, said, “This work provides a crucial foundation for future research. By integrating molecular biology, brain imaging, and computational analysis, it offers a new perspective on how neurotransmitter systems are organized across the human brain. As neuroscience moves toward more integrated and personalized models of mental health, understanding systems like histamine may prove essential for unlocking new approaches to diagnosis and treatment.”
Martins is first and corresponding author of the team’s published paper in Nature Mental Health, which is titled “Mapping histamine pathway networks in the human brain across cognition and psychiatric disorders.” In their paper the team concluded, “This study provides an integrated characterization of the histaminergic system in the human brain, leveraging transcriptomic, neuroimaging, and functional datasets to delineate its molecular organization and relevance to brain function underlying cognition and psychiatric disorders.”
Histamine is a neurotransmitter, a molecule crucial for neurons to communicate with one another, the authors explained. “Neuronal histamine plays a crucial role in the regulation of brain function, serving as a neuromodulator with widespread influence across multiple neurotransmitter systems.” However, neuroscience research has classically focused on understanding other neurotransmitter systems such as dopamine and serotonin.
As the investigators noted, the organization of histamine in the human brain remains incompletely characterized. However, they explained, dysregulation of the histaminergic system has been implicated in a number of neuropsychiatric conditions, including anxiety, depression, schizophrenia, and autism spectrum disorder (ASD), as well as neurodegenerative diseases including Alzheimer’s, Parkinson’s, and Huntington’s diseases. “Therefore, targeting the brain histamine system has garnered significant attention as a potential new therapeutic strategy for treating these disorders, with pharmacological interventions aimed at modulating histamine receptor activity showing promise in preclinical models.”
Histamine acts through four known histamine receptors, which are responsible for how the signal will influence receiver neurons. Each of these histamine receptors, (histamine receptor H1 (encoded by HRH1), H2 (HRH2), H3 (HRH3) and H4 (HRH4)), mediates distinct functions. For their newly reported study, Martins and colleagues carried out what they described as multimodal analysis, integrating transcriptomic, neuroimaging, developmental and functional datasets to map the architecture of the histaminergic system.
To build a comprehensive map of how histamine acts in the brain, researchers first combined genetic and molecular data with physical maps of the brain.
This revealed which brain regions receive more input from the brain’s histamine system, and which parts show greater capacity to respond to histamine. These molecular data were then linked with positron emission tomography imaging of histamine receptors in living individuals, as well as functional neuroimaging databases that map brain regions to specific cognitive processes and mental health conditions. This type of scan shows how different parts of the brain are working by tracking a tiny amount of radioactive tracer in real time.
Their results found that different histamine receptors were found on brain cells that either turn activity up (excitation) or turn it down (inhibition). “The findings reveal that histaminergic genes exhibit distinct cellular and regional expression profiles, closely aligning with known histaminergic neuroanatomy and function,” they wrote. “At the single-cell level, histamine receptor H1 and histamine receptor H2 were enriched in excitatory neurons, whereas histamine receptor H3 showed preferential expression in inhibitory populations.” This suggests histamine may be important in maintaining the balance between excitation and inhibition, a fundamental property of healthy brain function.
Brain regions with higher histamine-related gene expression were consistently associated with processes such as emotional regulation, stress and fear responses, decision-making, impulsivity, reward, sleep, and memory.
The parts of the brain where histamine-related genes were most active also overlapped significantly with brain regions known to be affected in several psychiatric conditions, including attention-deficit/hyperactivity disorder, major depressive disorder, schizophrenia, and anorexia nervosa. This is in keeping with previous hypotheses linking histamine to these disorders. “By linking histaminergic gene expression to brain-cell types, neurotransmitter systems, cognitive domains and psychiatric disorders, these correlational findings generate several hypotheses concerning histamine’s critical role in brain organization, neurodevelopment and mental health, which further experimental mechanistic work should prioritize and build onto investigate causal relationships,” the investigators concluded.
Martins said, “Current psychiatric treatments largely target neurotransmitters such as serotonin and dopamine, yet histamine interacts closely with these systems and influences their activity. By providing a detailed map of histamine-related pathways, this work suggests new opportunities for developing treatments that target this system more directly, particularly for symptoms such as cognitive dysfunction, fatigue, and impaired motivation.
While these findings do not establish a direct causal role, they suggest that histamine signalling may contribute to regional vulnerability in these disorders. This aligns with a growing view in psychiatry that mental health conditions arise from disruptions across interacting brain systems rather than a single chemical imbalance.”
This new map paints a neural picture of a previously lesser-studied molecule. It opens up future avenues of research into exactly what histamine is doing in various cell types and parts of the brain.
“We want to emphasise that these findings are hypothesis-generating and based on large-scale datasets that capture patterns rather than direct mechanisms,” commented senior author Steve Williams, PhD, professor of neuroimaging at IoPPN King’s College London. Future studies will focus on testing how histamine signaling changes in living individuals, for example through pharmacological interventions or longitudinal imaging approaches.
Co-author Daniel Van Wamelen, PhD, clinical senior lecturer in neuroscience at IoPPN, King’s College London and one of the authors on the paper said: “This kind of work is already taking place at King’s College London, for example in the iMarkHD project. In this project we use Positron Emission Tomography scans to study a specific histamine receptor (called H3) in people with Huntington’s disease, an inherited condition that affects the brain. The goal is to see how histamine activity changes in different parts of the brain over time, and how these changes relate to symptoms such as apathy, depression, and anxiety.”
The post Brain Histamine Map Links Genetic Factors to Mental Health and Psychiatric Disorders appeared first on GEN – Genetic Engineering and Biotechnology News.
Capsida Biotherapeutics said Tuesday that it still had no answers in its investigation into the death of a child in a gene therapy trial last September.
Its scientists’ efforts, it said, have been stymied because the hospital where the study was conducted has declined to share tissue samples from an autopsy.
The therapy, known as CAP-002, was the first of a wave of new gene therapies designed to deliver genes deep into the brain. Scientists around the world engineered viruses that could slide through the blood-brain barrier that walls off our most vital organ from the rest of the body. Companies spun up promising treatments for devastating rare genetic diseases and common conditions like Alzheimer’s and Parkinson’s.
Researchers at Garvan Institute of Medical Research have identified a previously underappreciated mechanism that may explain why some breast cancers return many years, even decades, after apparently successful treatment.
The study, published in Nature Communications, reveals that certain estrogen receptor-positive (ER+) breast cancer cells survive therapy not by entering complete dormancy, but by continuing to divide at an extraordinarily slow pace. These stealth-like cells can gradually form microscopic secondary tumors that remain undetectable for years before eventually triggering metastatic relapse.
The findings offer new insight into one of the most persistent challenges in breast cancer care: why relapse can occur long after patients are considered cancer-free.
ER-positive breast cancer is the most common subtype of breast cancer and is typically treated with hormone therapies designed to block estrogen signaling. These treatments are often highly effective at eliminating actively dividing tumor cells.
However, ER-positive disease has a unique clinical problem: recurrence risk persists for decades.
Even after five to ten years of endocrine therapy, up to 30% of patients can eventually develop metastatic relapse. Once breast cancer spreads to distant organs such as bone, lung, or brain, the disease becomes largely incurable.
Traditionally, relapse has been attributed to dormant cancer cells—cells that enter a state of complete hibernation before later “waking up.” But the new study suggests this may not be the only pathway.
“We have become very good at treating primary breast cancer, but late relapses remain a major challenge,” said Liz Caldon, associate professor and senior author of the study.
The researchers discovered that some breast cancer cells never fully stop proliferating during therapy. Instead, they survive by drastically slowing their rate of division.
This subtle distinction may be clinically critical.
Rather than entering complete cellular arrest, these cells continue to grow at an almost imperceptible pace, allowing them to evade therapies that primarily target rapidly dividing cells.
“Instead, they survive by growing extremely slowly in the background, until a tiny speck becomes a pebble,” Caldon explained.
Over many years, these microscopic lesions, known as micrometastases, can gradually expand until they become clinically detectable or disrupt vital organs.
The work challenges a long-standing binary view of cancer persistence in which tumor cells are considered either actively proliferating or fully dormant. Instead, the findings support the existence of an intermediate “slow-cycling” state that may be particularly effective at evading treatment.
Studying these rare cells was technically difficult because of their exceptionally slow growth.
The research team spent years isolating and cultivating these populations in the laboratory. Once established, they introduced the cells into preclinical models to determine whether slow proliferation impaired metastatic potential.
It did not.
Despite dividing slowly, the cells retained the ability to migrate throughout the body and colonize distant organs such as bone and lung.
“It took years to isolate these specific cells because they were dividing so slowly, almost in defiance of how we typically expect cancer to behave,” said Kristine Fernandez, first author of the study.
“These cells were migrating to organs like the bone and lungs, proving that speed isn’t everything when it comes to metastasis.”
The findings reinforce a growing understanding in oncology that aggressive cancer behavior is not solely defined by rapid proliferation. Cellular adaptability and survival under therapeutic pressure may be equally important.
After identifying the slow-growing cells, the researchers investigated what allowed them to survive.
The study pinpointed a signaling pathway centered on Rac1, a protein involved in cell movement, structural organization, and survival. Using advanced biosensor imaging, the team directly visualized Rac1 pathway activation inside live slow-growing cancer cells.
Inhibiting this pathway appeared therapeutically promising.
Experimental Rac1 inhibitors significantly reduced tumor size and tumor number in patient-derived breast cancer models.
This suggests that targeting Rac1-dependent survival programs could potentially eliminate slow-growing residual cancer cells before they evolve into clinically significant metastases.
The findings contribute to a broader shift in cancer biology away from viewing residual disease as uniformly dormant.
Instead, tumors may contain multiple survival states, including cells that persist through continuous but ultra-slow proliferation. These populations may be especially dangerous because they remain biologically active while escaping conventional therapeutic detection.
The work also raises important clinical questions about long-term endocrine therapy. Current treatment durations are largely standardized, yet some patients may harbor persistent slow-cycling tumor cells despite years of therapy.
“If we can understand the specific biology of these slow-growing cells, we might eventually be able to offer better ways to track whether a decade of hormone therapy is actually working and ultimately prevent recurrence,” Caldon said.
The study’s implications extend beyond breast cancer alone. Slow-cycling drug-tolerant cancer cells have increasingly been identified across multiple tumor types, including melanoma, lung cancer, and leukemia.
By identifying a concrete signaling mechanism underlying this state in ER-positive breast cancer, the research provides a potential therapeutic entry point for preventing relapse before metastatic disease emerges.
The next challenge will be determining whether Rac1 inhibitors, or similar approaches targeting slow-cycling survival programs, can safely and effectively eliminate residual cancer cells in patients.
If successful, such strategies could fundamentally alter how clinicians approach long-term relapse prevention in breast cancer, shifting the focus from simply suppressing visible disease to actively eradicating the hidden cellular reservoirs that remain years after treatment ends.
The post Slow-Growing Breast Cancer Cells May Explain Why Relapse Happens Decades Later appeared first on Inside Precision Medicine.
Focused ultrasound (FUS) was explored for neurological indications more than half a century ago, but only recent technological advances have enabled its practical transcranial use for movement and neuropsychiatric disorders. FUS can produce stereotactic thermal lesions via focused ultrasound ablation (FUSA), while non-thermal lesioning (e.g., FUS histotripsy) and non-ablative approaches such as neuromodulation and blood-brain barrier opening are under active clinical investigation. FUSA is FDA-approved for essential tremor and Parkinson’s disease, and is now being evaluated for additional syndromes, including epilepsy, dystonia, and treatment-resistant psychiatric disorders.
In a retrospective study of 40 individuals with Parkinson disease, lower visual equilibrium scores (as measured by the sensory organization test, condition 2) were significantly associated with a higher frequency of falls.
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Researchers at Cleveland Clinic have discovered that androgen hormones such as testosterone can limit the growth of glioblastoma tumors in men. Results published today in Nature show that men receiving testosterone supplements for reasons unrelated to cancer showed a 38% lower risk of death compared to patients not taking these supplements.
These findings are surprising because testosterone is known to contribute to the growth of other forms of cancer in men, such as prostate cancer, where hormone therapy is used routinely to decrease levels of androgen hormones and block cancer progression. However, these hormones were found to play a very different role in glioblastoma, an aggressive form of brain cancer that is more commonly diagnosed in men.
“This outcome is a welcome surprise and may potentially offer a lead for new treatments for a kind of cancer that is deadlier in men,” said Anthony Letai, MD, PhD, director of NIH’s National Cancer Institute (NCI).
In a mouse model of glioblastoma the researchers found that reducing levels of androgen hormones induced overdrive on the hypothalamus-pituitary-adrenal (HPA) axis, a brain circuit that controls reactions to stress and many physiological processes including hormone secretion. This caused a spike in stress hormones that led the brain to reinforce the protective function of the blood-brain barrier and create an immunosuppressive environment in the brain, reducing the ability of immune cells to fight against the tumor.
“The brain has evolved to keep stuff out and that includes immune cells from elsewhere in the body. It’s a delicate tissue that often doesn’t want huge immune reactions,” said Justin D. Lathia, PhD, professor of cancer sciences and scientific director of the Brain Tumor Center at Cleveland Clinic.
Importantly, this effect was only observed in male mice. In females, changes in testosterone levels did not produce the same effects.
These findings were then confirmed in human samples obtained from 1,300 men with glioblastoma participating in the NIH database Surveillance, Epidemiology, and End Results (SEER). An analysis showed that men who received supplemental testosterone for reasons unrelated to their glioblastoma diagnosis had a 38% lower risk of death than other male patients.
More research will be needed to better understand the complex pathway activated by testosterone and other androgen hormones. While the current study identified inflammation in the hypothalamus as a potential trigger of HPA axis activation, future work will look for the exact mechanism glioblastoma tumors employ to induce this reaction from an entirely different region of the brain.
Lathia noted that, although these results do not establish a causal link between testosterone and patient outcomes for men diagnosed with glioblastoma, the study opens the door for future clinical trials that dive deeper into the link between androgen hormones and glioblastoma tumor growth. He added, “An obvious follow-up study would be to find out whether androgen deprivation, which is a common treatment for cancer, is actually detrimental for glioblastoma.”
The post Glioblastoma: Testosterone Supplements Linked to 38% Lower Risk of Death appeared first on Inside Precision Medicine.
Background: Neurorehabilitation plays a key role in improving motor recovery for people with neurological conditions. Although 3D printing has emerged as a promising rehabilitation tool, little is known on how it is used for the rehabilitation of adults living with neurological conditions worldwide. Objective: We aimed to provide a comprehensive overview of 3D printing in neurorehabilitation and precisely explore how it is used to improve motor recovery for adults with neurological conditions living in higher- and lower-middle–income countries. Methods: We conducted a scoping review following the Joanna Briggs Institute guidelines. After searching 3 databases (MEDLINE, Web of Science, and Nursing and Allied Health Premium), 2 independent reviewers screened and selected English-language studies involving adults (≥18 years) published between 2019 and 2024 to capture the most recent advancements in this field. We extracted relevant information on neurological conditions, motor recovery outcomes, and types of 3D printing and offered a comparative analysis of 3D printing in physical neurorehabilitation from the perspective of national income levels using a modified Joanna Briggs Institute extraction form. We synthesized the findings narratively with tabular support. Results: After screening 2752 titles and abstracts and 103 (3.7%) full texts, we included 13 (0.5%) studies based on our inclusion criteria. All included studies were conducted in upper-middle–income or high-income countries, and most studies (9/13, 69.2%) focused on stroke, followed by spinal cord injury (2/13, 15.4%), Parkinson disease (1/13, 7.7%), and central nerve disease (1/13, 7.7%). The 3D-printed rehabilitation tools included orthotics (7/13, 53.8% for the upper extremities [UEs]; 3/13, 23.1% for the lower extremities [LEs]), an exoskeleton (1/13, 7.7%; UEs), a modular assistive hand device (1/13, 7.7%; UEs), and an insole (1/13, 7.7%; LEs). In total, 69.2% (9/13) of the studies targeted UE rehabilitation, measured using the Action Research Arm Test, active range of motion, the box and block test, the Fugl-Meyer Assessment, the Modified Ashworth Scale, the manual function test, range of motion, and the Toronto Rehabilitation Institute Hand Function Test, and 30.8% (4/13) targeted LE rehabilitation, measured using the 10-m walk test, anteroposterior ground reaction force analysis, the Barthel index, the Tinetti scale, the RehaWatch system, and the GaitWatch system. Conclusions: Used as a rehabilitation tool, 3D printing technology has demonstrated significant potential in improving upper and lower motor recovery for people with certain neurological conditions in high-middle–income countries. Future research should explore the implementation feasibility and effectiveness of these technologies across different neurological conditions and income settings, particularly in low- and lower-middle–income countries.
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