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Biology subjects

McDonald, K. O.

Publications and source records attributed to McDonald, K. O..

5 recordsLinked to original sources

Lets talk about sex: Male and female mice show similar fear memory retention despite hippocampal activity differences during encoding and consolidation

Accurate and efficient memory processing is essential for survival. A body of ongoing work in both human subjects and animal models suggests that memory processing may differ substantially between males and females. In mice, contextual fear memory (CFM) encoding, consolidation, and recall have been well studied, and the mouse hippocampus and amygdala have been implicated in these processes. The present study addresses whether the activation of these brain regions differs between male and female mice at each stage of CFM processing. We find that male and female C57BL6 mice show no differences in sleep behavior following single-trial contextual fear conditioning (CFC), which is essential for CFM consolidation. We also find no significant differences in CFM recall behavior between male and female mice. However, females - but not males - show significantly increased expression of cFos in dorsal hippocampal CA1 and CA2 neurons during CFM encoding. On the other hand, males - but not females - show increased cFos expression among dentate gyrus (DG) granule cells, and decreased cFos expression within dorsal CA1 and CA3 during CFM consolidation. Males also show significant decreases in dorsal CA1 cFos expression during memory recall. These findings highlight the idea that the neurobiological underpinnings of memory processing may differ between males and females, even when recall performance is identical. HighlightsHistorically, research on the neurobiological basis of memory processing has been carried out mainly in male subjects. Thus, our understanding of these mechanisms is biased towards male brain neurophysiology. This is problematic, as numerous studies have reported sex-based performance differences for episodic memory tasks, in which male subjects have variously performed better, worse, or the same as females. Here, we find that male and female mice perform similarly on a well-studied experimental memory task but nonetheless have differences in the relative activity of different brain structures during sequential stages of memory processing. This emphasizes the importance of including both males and females in memory studies, due to potential sex differences in the neurobiological substrates of memory.

neuroscience↗

Cell cycle re-entry in the aging Drosophila brain.

The brain is an organ comprised mostly of long-lived, quiescent cells that perform vital functions throughout an animals life. Due to the brains limited regenerative ability, these long-lived cells must engage unique mechanisms to cope with accumulated damage over time. We have shown that a subset of differentiated neuronal and glial cells in the fruit fly brain become polyploid during adulthood. Cell cycle re-entry in the brain has previously been associated with neurodegeneration, but there may be a more complex relationship between polyploidy and cell fitness in the brain. Here, we examine how known lifespan modifiers influence the accumulation of polyploidy in the aging fly brain. Flies aged at a low temperature, or with a low protein diet, accumulate polyploid cells in the brain more slowly than expected if this phenotype were solely regulated by lifespan mechanisms. Despite the slower accumulation of polyploid cells, animals under conditions that extend lifespan eventually reach similar levels of polyploidy in the brain as controls. Our work suggests known lifespan modifiers can influence the timing of cell cycle re-entry in the adult brain, indicating there is a flexible window of cell cycle plasticity in the aging brain.

developmental biology↗

Transcription factor-mediated generation of dopaminergic neurons from human iPSCs: a comparison of methods

Dopaminergic neurons are the predominant brain cells affected in Parkinsons disease. With the limited availability of live human brain dopaminergic neurons to study pathological mechanisms of Parkinsons disease, dopaminergic neurons have been generated from human skin cell-derived induced pluripotent stem cells. Originally, induced pluripotent stem cell-derived dopaminergic neurons were generated using small molecules. These neurons took more than two months to mature. However, transcription factor-mediated differentiation of induced pluripotent stem cells has revealed quicker and cheaper methods to generate dopaminergic neurons. In this study, we compare and contrast three protocols to generate induced pluripotent stem cell-derived dopaminergic neurons using transcription factor-mediated directed differentiation. We deviated from the established protocols using lentivirus transduction to stably integrate transcription factors into induced pluripotent stem cells, followed by differentiation using different media compositions. We introduced three transcription factors into the AAVS1 safe harbour locus of induced pluripotent stem cells, and in combination with small molecules, we generated more than 80% neurons in the culture, out of which more than 80% neurons were dopaminergic neurons. Therefore, a combination of transcription factors along with small molecule treatment may be required to generate a pure population of human dopaminergic neurons, a prerequisite for cell replacement therapies.

neuroscience↗

Intermittent systemic exposure to lipopolysaccharide-induced inflammation disrupts hippocampal long-term potentiation and impairs cognition in aging male mice

Age-related cognitive decline, a common component of the brain aging process, is associated with significant impairment in daily functioning and quality of life among geriatric adults. While the complexity of mechanisms underlying cognitive aging are still being elucidated, microbial exposure and the multifactorial inflammatory cascades associated with systemic infections is emerging as a potential driver of neurological senescence. The negative cognitive and neurobiological consequences of a single pathogen-associated inflammatory experience, such as that modeled through treatment with lipopolysaccharide (LPS), are well documented. Yet, the brain aging impacts of repeated, intermittent inflammatory challenges are less well studied. To extend the emerging literature assessing the impact of infection burden on cognitive function among normally aging mice, here, we repeatedly exposed adult mice to intermittent LPS challenges during the aging period. Male 10-month-old C57BL6 mice were systemically administered escalating doses of LPS once every two weeks for 2.5 months. We evaluated cognitive consequences using the non-spatial step-through inhibitory avoidance task and both spatial working and reference memory versions of the Morris water maze. We also probed several potential mechanisms, including cortical and hippocampal cytokine/chemokine gene expression as well as hippocampal neuronal function via extracellular field potential recordings. Though there was limited evidence for an ongoing inflammatory state in cortex and hippocampus, we observed impaired learning and memory and a disruption of hippocampal long-term potentiation. These data suggest that a history of intermittent exposure to LPS-induced inflammation is associated with a subtle but significantly accelerated trajectory of cognitive decline. The broader impact of these findings may have important implications for standard of care involving infections in aging individuals or populations at-risk for dementia.

neuroscience↗

Altered structure and dynamics of pathogenic cytochrome c variants correlate with increased apoptotic activity

Mutation of cytochrome c in humans causes mild autosomal dominant thrombocytopenia. The role of cytochrome c in platelet formation, and molecular mechanism underlying the association of cytochrome c mutations with thrombocytopenia remains unknown, although a gain-of-function is most likely. Cytochrome c contributes to several cellular processes, with exchange between conformational states proposed to regulate changes in function. Here we use experimental and computational approaches to determine whether pathogenic variants share changes in structure and function, and to understand how these changes might occur. We find that three pathogenic variants (G41S, Y48H, A51V) cause an increase in apoptosome activation and peroxidase activity. Molecular dynamics simulations of these variants, and two non-naturally occurring variants (G41A, G41T), indicate that increased apoptosome activation correlates with increased overall flexibility of cytochrome c, particularly movement of the Ω loops. This suggests that the binding of cytochrome c to apoptotic protease activating factor-1 (Apaf-1) may involve an "induced fit" mechanism which is enhanced in the more conformationally mobile variants. In contrast, peroxidase activity did not significantly correlate with protein dynamics suggesting that the mechanism by which the variants alter peroxidase activity is not related to the conformation dynamics of the hexacoordinate heme Fe state of cytochrome c analyzed in the simulations. Recent suggestions that conformational mobility of specific regions of cytochrome c underpins changes in reduction potential and the alkaline transition pK were not supported. These data highlight that conformational dynamics of cytochrome c drives some but not all of its properties and activities.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biochemistry↗