Biological sex does not predict glymphatic influx in healthy young, middle aged or old mice

Giannetto, Michael; Xia, Maosheng; Stæger, Frederik Filip; Metcalfe, Tanner; Vinitsky, Hanna S.; Dang, Juliana A. M. L.; Xavier, Anna L.R.; Kress, Benjamin T.; Nedergaard, Maiken; Hablitz, Lauren M.

doi:10.1038/s41598-020-72621-3

Cited by 36 publications

(24 citation statements)

References 42 publications

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“…To our knowledge, these are the first observations pointing to the existence of a sex difference in CSF production. Because a recent study indicated that glymphatic CSF tracer influx is comparable in young, middle-aged, and aged C57BL/6J wild-type (WT) mice of both sexes ( Giannetto et al, 2020 ), our observation suggests that glymphatic fluid transport rate is not simply a downstream effect of CSF production.…”

Section: Resultsmentioning

confidence: 68%

“…A disconnect between CSF production and glymphatic transport was also noted when analyzing sex differences. We found that CSF production is 30% in higher in young female mice than in males, and yet there were no sex differences in glymphatic fluid transport between the two sexes in groups of young, middle-aged, and aged C57BL/6J WT mice ( Giannetto et al, 2020 ).…”

Section: Discussionmentioning

confidence: 70%

“…The larger variance in mean CSF production seen in female mice may reflect day-to-day changes in circulating sex hormones because we did not do experiments in phase with the 4- to 5-day mouse estrous cycle ( Byers et al, 2012 ). Of note, a recent report based on more than 400 mice documented that the activity of the glymphatic system (as distinct from CSF production) is comparable between male and female mice ( Giannetto et al, 2020 ). So, we conclude that there must be a dissociation between sex differences in CSF production rate versus CSF transport kinetics.…”

Section: Discussionmentioning

confidence: 99%

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Direct Measurement of Cerebrospinal Fluid Production in Mice

et al. 2020

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SUMMARY The emerging interest in brain fluid transport has prompted a need for techniques that provide an understanding of what factors regulate cerebrospinal fluid (CSF) production. Here, we describe a methodology for direct quantification of CSF production in awake mice. We measure CSF production by placing a catheter in a lateral ventricle, while physically blocking outflow from the 4 th ventricle. Using this methodology, we show that CSF production increases during isoflurane anesthesia, and to a lesser extent with ketamine/xylazine anesthesia, relative to the awake state. Aged mice have reduced CSF production, which is even lower in aged mice overexpressing amyloid-β. Unexpectedly, CSF production in young female mice is 30% higher than in age-matched males. Altogether, the present observations imply that a reduction in CSF production might contribute to the age-related risk of proteinopathies but that the rate of CSF production and glymphatic fluid transport are not directly linked.

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Section: Resultsmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

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Direct Measurement of Cerebrospinal Fluid Production in Mice

et al. 2020

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“…Two recent animal studies derived seemingly different results. Giannetto et al (2020) found that there was no sex difference in total influx or subregion-dependent tracer distribution in mice at different ages, while Liu' study (Liu et al, 2020) found elevated CSF production in female mice. Human imaging study also showed no difference of glymphatic clearance between males and females.…”

Section: Discussionmentioning

confidence: 91%

The Influence of Demographics and Vascular Risk Factors on Glymphatic Function Measured by Diffusion Along Perivascular Space

Zhang

et al. 2021

Front. Aging Neurosci.

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Assessing glymphatic function using in-vivo imaging method is of great value for understanding its contribution to major brain diseases. In the present study, we aim to validate the association between a variety of risk factors and a potential index of glymphatic function—Diffusion Tensor Image Analysis Along the Perivascular Space (ALPS index). We enrolled 142 subjects from communities and performed multi-modality magnetic resonance imaging scans. The ALPS index was calculated from diffusion tensor imaging data, and its associations with demographic factors, vascular factors were investigated using regression analyses. We found that the ALPS index was negatively associated with age (β = −0.284, p < 0.001). Compared to males, females had significantly higher ALPS index (β = −0.243, p = 0.001). Hypertensive subjects had significantly lower ALPS index compared to non-hypertensive subjects (β = −0.189, p = 0.013). Furthermore, venous disruption could decrease ALPS index (β = −0.215, p = 0.003). In general, our results are in consistent with previous conceptions and results from animal studies about the pathophysiology of glymphatic dysfunction. Future studies utilizing this method should consider introducing the above-mentioned factors as important covariates.

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“…Finally, almost all the studies conducted at ages other than adult have been conducted in male animals. It is known that the consequences, in term of neuroinflammation, neuronal death and functional deficits, vary by sex [ 228 , 229 ]. For example, following TBI in adolescence, sex-dependent alterations in executive function are seen in early adulthood [ 228 ].…”

Section: Discussionmentioning

confidence: 99%

Traumatic Brain Injury: An Age-Dependent View of Post-Traumatic Neuroinflammation and Its Treatment

et al. 2021

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Traumatic brain injury (TBI) is a leading cause of death and disability all over the world. TBI leads to (1) an inflammatory response, (2) white matter injuries and (3) neurodegenerative pathologies in the long term. In humans, TBI occurs most often in children and adolescents or in the elderly, and it is well known that immune responses and the neuroregenerative capacities of the brain, among other factors, vary over a lifetime. Thus, age-at-injury can influence the consequences of TBI. Furthermore, age-at-injury also influences the pharmacological effects of drugs. However, the post-TBI inflammatory, neuronal and functional consequences have been mostly studied in experimental young adult animal models. The specificity and the mechanisms underlying the consequences of TBI and pharmacological responses are poorly understood in extreme ages. In this review, we detail the variations of these age-dependent inflammatory responses and consequences after TBI, from an experimental point of view. We investigate the evolution of microglial, astrocyte and other immune cells responses, and the consequences in terms of neuronal death and functional deficits in neonates, juvenile, adolescent and aged male animals, following a single TBI. We also describe the pharmacological responses to anti-inflammatory or neuroprotective agents, highlighting the need for an age-specific approach to the development of therapies of TBI.

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Biological sex does not predict glymphatic influx in healthy young, middle aged or old mice

Cited by 36 publications

References 42 publications

Direct Measurement of Cerebrospinal Fluid Production in Mice

Direct Measurement of Cerebrospinal Fluid Production in Mice

The Influence of Demographics and Vascular Risk Factors on Glymphatic Function Measured by Diffusion Along Perivascular Space

Traumatic Brain Injury: An Age-Dependent View of Post-Traumatic Neuroinflammation and Its Treatment

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