Category: News

Identification of CD33m as a new protective factor in Alzheimer’s Disease development.

Immune cells in the brain, called microglia, are thought to be critical in Alzheimer’s disease (AD) development through numerous functions, including their ability to remove amyloid beta (Aβ), which is protein that accumulates in the brains of AD patients. In this study, Ghazaleh Eskandari-Sedighi, working in Matthew Macauley’s laboratory at the University of Alberta, focused on understanding the mechanism of action of a protein called CD33, which has been identified as one of the top-ranked drivers in the development of AD and that is predominantly found in microglia in the brain. By transferring different versions (called isoforms) of this protein in a mouse model of AD, they were able to show that these different isoforms have opposite effects on microglial cells and AD progression.

CD33 is a receptor that modulates immune response that exists in two forms:  a long isoform CD33M (Major) and a short isoform: CD33m (minor). Understanding how CD33 isoforms differentially impact microglial cell function has been challenging due to functional divergence between CD33 from mouse and humans. In this study, the researchers introduced the human CD33 gene in a mouse model of AD, which accumulates Aβ protein. In these mice, they found that CD33 isoforms have opposing effects on the response of microglia to Aβ accumulation. The larger CD33M increases the total level of Aβ and formation of plaques with a diffuse nature, which correlates with fewer number of microglia as well as higher number of dysfunctional neurons. In contrast, CD33m gives rise to opposite outcomes; beyond decreasing total Aβ levels, CD33m skews formation of compact Aβ deposits, correlating with increased microglia and fewer dysfunctional neurons. Overall, this work reveals how CD33, as a top genetic susceptibility factor for AD, is connected to microglial cell function.

Read the full story here: https://can-acn.org/brain-star-award-winnerghazaleh-eskandari-sedighi/

Scientific publication: Eskandari-Sedighi, G., Crichton, M., Zia, S. et al. Alzheimer’s disease associated isoforms of human CD33 distinctively modulate microglial cell responses in 5XFAD mice. Mol Neurodegeneration 19, 42 (2024).

https://doi.org/10.1186/s13024-024-00734-8

Better understanding the role of vision in the brain’s representation of space by studying freely moving primates

The hippocampus is a structure of the mammalian brain that has been implicated in spatial memory and navigation. Its role has been primarily studied in nocturnal mammals, such as rats, that lack many adaptations for daylight vision. Here, Diego B. Piza, working in the laboratory of Julio Martinez-Trujillo at Western University, demonstrates that during 3D navigation, the common marmoset, a New World primate adapted to daylight, uses different exploration–navigation strategies compared to rats. He further shows that maps of space in the marmoset brain depend on vision-related cues and object relationships used as landmarks for navigation. It is likely that similar encoding mechanisms exist in other diurnal mammals, including humans.

To explore their environment, marmosets predominantly use rapid head-gaze shifts for visual exploration while remaining stationary. During active movement, marmosets stabilize their head, in contrast to rats, who use low-speed head movements to scan the environment as they locomote. This work suggests that spatial memory in primates may rely on anchoring sequences of views to specific places, providing a unique mechanism for encoding spatial experiences.

This publication represents a major technical and conceptual achievement in neuroscience.

Read the full story: https://can-acn.org/brain-star-award-winner-diego-b-piza/

Article citation

Piza, D.B., Corrigan, B.W., Gulli, R.A., Do Carmo, S., Cuello, A.C., Muller, L., Martinez-Trujillo, J. Primacy of vision shapes behavioral strategies and neural substrates of spatial navigation in marmoset hippocampus. Nat Commun 15, 4053 (2024). https://doi.org/10.1038/s41467-024-48374-2

https://doi.org/10.1038/s41467-024-48374-2

Better understanding how ensembles of neurons are recruited in memory formation.

The hippocampus is a critical brain region for encoding and recall of episodic memories. The physical trace left in the brain by memory formation is called an ‘engram’, and the process by which new engrams are formed is still unclear. In this work, Andrew Mocle, working in the laboratory of Sheena Josselyn, used advanced imaging techniques to track neurons and their patterns of activity before, during, and after memory encoding. The resulting data prompted a new engram formation model, whereby small ensembles of neurons (instead of individual cells) are allocated to an engram depending on their average excitability at the time of learning. The demonstration that highly-excitable ensembles are preferentially allocated to encode newly learned information represents a major conceptual advance in the study of how memories are stored in the brain.

Read more: https://can-acn.org/brain-star-award-winner-andrew-mocle/

Featured scientific publication: Mocle, Andrew J., Adam I. Ramsaran, Alexander D. Jacob, Asim J. Rashid, Alessandro Luchetti, Lina M. Tran, Blake A. Richards, Paul W. Frankland, and Sheena A. Josselyn. “Excitability Mediates Allocation of Pre-Configured Ensembles to a Hippocampal Engram Supporting Contextual Conditioned Threat in Mice.” Neuron 112, no. 9 (May 1, 2024): 1487-1497.e6.

https://doi.org/10.1016/j.neuron.2024.02.007

Understanding how the brain’s network architecture shapes its capacity to transition between different states

To support the diversity of human cognitive functions, such as learning, thinking, reasoning, remembering, problem solving, decision making, and attention, brain regions flexibly form and dissolve connections on the fly. How is the brain’s capacity to transition between different functional configurations shaped by brain network architecture? Andrea Luppi, working in Bratislav Misic’s lab at McGill University and the Montreal Neurological Institute, investigated this question using engineering principles of network control to simulate transitions between behaviourally derived brain states. They identified >100 cognitively relevant brain states in a data-driven manner, corresponding to activation patterns aggregated over 14,000 fMRI studies from a large collaborative database called NeuroSynth, and effectively mapped how brain network organization and chemoarchitecture interact to manifest these brain states. By leveraging large-scale databases of network structure, functional activation and neurotransmitter systems, the present work provides an integrative framework for the systematic exploration of the full range of possible transitions between experimentally defined brain states. This systematic approach allowed the researchers to discover the key role of the brain’s wiring diagram in supporting flexible transitions with high energetic efficiency, and how this efficiency can be disrupted by disease and restored by targeted pharmacology.

Read the full story here: https://can-acn.org/brain-star-award-winner-andrea-luppi/

View the original research article here:

Andrea I. Luppi, S. Parker Singleton, Justine Y. Hansen, Keith W. Jamison, Danilo Bzdok, Amy Kuceyeski, Richard F. Betzel & Bratislav Misic. Contributions of network structure, chemoarchitecture and diagnostic categories to transitions between cognitive topographies. Nature Biomedical Engineering 8, 1142–1161 (2024).

https://doi.org/10.1038/s41551-024-01242-2