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Category: neuroscience

Population-level age effects on the white matter structure subserving cognitive flexibility in the human brain

New in eNeuro from Wolfe et al: Brain structures related to shifting between tasks or updating information about the environment show signs of deterioration in late adulthood.

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Cognitive flexibility, a mental process crucial for adaptive behavior, involves multi-scale functioning across several neuronal organization levels. While the neural underpinnings of flexibility have been studied for decades, limited knowledge exists about the structure and age-related differentiation of the white matter subserving brain regions implicated in cognitive flexibility. This study investigated the population-level relationship between cognitive flexibility and properties of white matter across two periods of human adulthood, aiming to discern how these associations vary over different life stages and brain tracts among men and women. We propose a novel framework to study age effects in brain structure-function associations. First, a meta-analysis was conducted to identify neural regions associated with cognitive flexibility. Next, the white matter projections of these neural regions were traced through the Human Connectome Project tractography template to identify the white matter structure associated with cognitive flexibility. Then, a cohort analysis was performed to characterize myelin-related macromolecular features using a subset of the UK Biobank magnetic resonance imaging (MRI) data, which has a companion functional/behavioral dataset. We found that the wiring of cognitive flexibility is defined by a subset of brain tracts, which present undifferentiated features early in adulthood and significantly differentiated types in later life. These MRI-derived properties are correlated with individual subprocesses of cognition, which are closely related to cognitive flexibility function. In late life, myelin-related homogeneity of specific white matter tracts implicated in cognitive flexibility declines with age, a phenomenon not observed in early life. Our findings support the age-related differentiation of white matter tracts implicated in cognitive flexibility as a natural substrate of adaptive cognitive function.

Significance Statement Cognitive flexibility function facilitates adaptation to environmental demands. Brain changes affecting structural organization during the lifespan are theorized to impact cognitive flexibility. This study characterizes how the brain’s connectivity is correlated with cognitive flexibility function throughout adulthood. By analyzing myelin-related properties of white matter, this study found that certain parts of the brain’s wiring related to cognitive flexibility become more differentiated with advanced age. These age-related features appear as a natural characteristic of the human brain that may impact specific aspects of adaptive thinking, like shifting between tasks or updating information.

Uniform Amyloid Thresholds Across Populations

This diagnostic study validates the biological comparability of brain amyloid thresholds used in AlzheimerDisease diagnostics across racial and ethnic subgroups of older adults, with no significant differences by sex or APOE4 status.

Further research should determine whether uniform thresholds yield comparable prognostic utility in clinical practice.

Voxelizing the Human Brain

Dr. Martin Picard tells the ‘story behind the paper’ for “A human brain map of mitochondrial respiratory capacity and diversity”. An amazing effort with a valuable dataset as the result!

(https://martinpicard.substack.com/p/voxelizing-the-human-brain)

This is the story of how we produced the first brain map of mitochondria—or the human brain bioenergetic landscape. The paper was published in the journal Nature.

Computational model discovers new types of neurons hidden in decade-old dataset

“We saw some peculiar brain activity in the model,” Miller says. “There was a group of neurons that predicted the wrong answer, yet they kept getting stronger as the model learned. So we went back to the original macaque data, and the same signal was there, hiding in plain sight. It wasn’t a quirk of the model — the monkeys’ brains were doing it too. Even as their performance improved, both the real and simulated brains maintained a reserve of neurons that continued to predict the incorrect answer.”

The new work, published in Nature Communications, puts a name to these overlooked signals: incongruent neurons, or ICNs, and explores theories as to why a primate brain might want to keep alternate options in mind, even if they’re not the right ones at the moment.

Beyond identifying a previously unrecognized class of neurons involved in learning, the study shows that the model behaves like a brain and generates realistic brain activity, even without being trained on neural data. The findings could have major implications for testing potential neurological drugs and for using computational models to investigate how cognition emerges and functions.

Targeting key proteins in fight against ALS

Northwestern Medicine scientists have zeroed in on a cellular gatekeeper that may hold promise for treating abnormal protein accumulation in neurodegenerative diseases, according to a study published in Nature Communications. “In all neurodegenerative diseases, there is an accumulation of misfolded proteins,” said Robert Kalb, MD, the Joan and Paul Rubschlager Professor, chief of Neuromuscular Disease in the Ken and Ruth Davee Department of Neurology, and director of the Les Turner ALS Center, who was senior author of the study.

“We think that these misfolded proteins are a target for disease—the disease is actually driven by the accumulation of these misfolded proteins.”

In the current study, Kalb and his collaborators aimed to investigate the role of RAD23, a protein that is involved in the identification and disposal of damaged or misfolded proteins. Under normal circumstances, elimination of misfolded proteins is essential for maintaining a healthy collection of proteins in cells, a process known as protein homeostasis, or proteostasis.

Red light therapy shows promise for protecting football players’ brains

Punch-drunk syndrome, boxer’s madness, chronic traumatic encephalopathy (CTE). The name has changed over the years, but the cause is clear: repeated impacts can affect long-term brain health, with symptoms ranging from confusion to memory loss and potentially dementia. More than 100 former NFL football players have been posthumously diagnosed with CTE.

What’s less clear is how to fix the problem. Even impacts that don’t directly affect the head may cause microscopic damage or initiate toxic processes that unfold over time, and current therapies for concussion and head impacts tend to address symptoms, like headache and balance issues, that can arise well after the initial injury.

But an unorthodox treatment called red light therapy, which shines powerful near-infrared light at the brain through the skull, may be able to prevent or reduce subtle damage to the brain before symptoms start, by reducing brain inflammation caused by repetitive impacts.

Afg3l2 couples mitochondrial vitamin B12 trafficking to amino acid metabolism to safeguard hematopoietic stem cell homeostasis

To identify the critical mitochondrial protease regulating HSPC homeostasis, we performed real-time PCR to examine the expression levels of various mitochondrial proteases in EPCR+SLAM-HSCs from mouse bone marrow (BM). Among them, the m-AAA protease Afg3l2 was the most highly expressed (Figure S1 A),18 suggesting its potential significance in HSC regulation. Furthermore, we conducted a comprehensive analysis of Afg3l2 expression across the hematopoietic hierarchy by examining EPCR+ SLAM-HSCs, SLAM-LT-HSCs, SLAM-ST-HSCs, SLAM-MPPs (multipotent progenitors), LSK (Lin-Sca-1+c-Kit+) cells, Lin− cells, and mature blood cells (B cells, T cells, and myeloid cells). Our results demonstrate that Afg3l2 expression is highest in the most primitive EPCR+SLAM-HSC population and gradually decreases with differentiation, supporting its crucial role in hematopoietic stem cells (HSCs) (Figure S1 B). Afg3l2 dysfunction has been linked to neurodegenerative disorders such as spinocerebellar ataxia19,20,21; however, its role in hematopoietic cells and its broader metabolic implications remain unexplored. To systemically investigate the function of Afg3l2 in HSPCs, we generated a conditional knockout (KO) allele of the Afg3l2 gene (Afg3l2f/+), in which exons 4 and 5 were flanked by loxP sites (Figure S1 C). Afg3l2f/+ mice were then crossed with Mx1-Cre transgenic mice to obtain Afg3l2f/f;Mx1-Cre+ animals. Deletion of Afg3l2 in hematopoietic cells was induced by administering polyinosinic-polycytidylic acid (pIpC) to 6-to 8-week-old mice, and KO efficiency was confirmed by real-time PCR and western blot analysis (Figures S1 D–S1G). On day 14 after the final pIpC administration, complete blood count analysis revealed a significant reduction in white blood cell, lymphoid cell, and platelet counts in Afg3l2f/f mice (wild-type [WT]) compared to Afg3l2f/f;Mx1-Cre+ mice (KO) (Figures S1 H–S1J). Interestingly, red blood cell counts and hemoglobin levels remained comparable between WT and KO groups (Figures S1 K and S1L). Flow cytometry analysis of BM revealed a significant reduction in multiple hematopoietic populations in Afg3l2-KO mice, including LT-HSCs, ST-HSCs, MPPs, common myeloid progenitors, granulocytic/monocytic progenitors, and megakaryocyte/erythroid progenitors (Figures S1 M–S1P). Notably, the EPCR+SLAM-HSC population, a highly purified HSC subset, was also remarkably diminished (Figure S1 Q).

Consistently, functional colony-forming unit (CFU) assays showed that CFU-granulocyte, erythrocyte, macrophage, megakaryocyte (CFU-GEMM); CFU-granulocyte and macrophage (CFU-GM); and burst-forming unit-erythroid (BFU-E) were markedly decreased in Afg3l2-KO BM cells (Figures S1 R and S1S). These findings indicate that Afg3l2 deficiency causes leukopenia and impairs steady-state hematopoiesis.

To assess the in vivo function of Afg3l2 in HSPCs, we performed competitive BM transplantation. Lethally irradiated recipient mice (CD45.1) were transplanted with a 1:1 mixture of total BM cells from WT or Afg3l2-KO donor mice (CD45.2) and competitor BM cells (CD45.1/CD45.2) (Figure 1A). CD45 chimerism in peripheral blood (PB) was monitored every four weeks, and BM composition was analyzed 16 weeks post-transplantation. The percentage of donor-derived CD45.2+ cells in PB was significantly lower in recipients receiving Afg3l2-KO BM compared to those transplanted with WT BM (Figures 1B and 1C). The percentage of donor BM cells-derived CD45.2+ cells, HPCs, Lin−Sca-1+c-Kit+ (LSK) cells, HSCs, myeloid cells, B cells, and T cells was dramatically decreased in the BM of the Afg3l2-KO cell transplanted group 16 weeks after transplantation (Figures 1D and 1E).

A new atlas could help guide researchers studying neurological disease

Functioning brain cells need a functioning system for picking up the trash and sorting the recycling. But when the cellular sanitation machines responsible for those tasks, called lysosomes, break down or get overwhelmed, it can increase the risk of Alzheimer’s, Parkinson’s, and other neurological disorders.

“Lysosomal function is essential for brain health, and mutations in lysosomal genes are risk factors for neurodegenerative diseases,” said Monther Abu-Remaileh, a Wu Tsai Neuro affiliate and an assistant professor of chemical engineering in the Stanford School of Engineering and an assistant professor of genetics in the Stanford School of Medicine.

The trouble is, scientists aren’t sure exactly how lysosomes do their work, what’s going wrong with lysosomes that leads to neurodegeneration—or even in which cell types neurodegenerative disease begins. There might even be other lysosomal disorders yet to be discovered.

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