Closing the gap: insights into sex specific effects of hippocampal neuroinflammation

Intro

Just as ancient civilizations once believed Earth was the center of our solar system, so the male body has been the referential point in the study of human anatomy (Kropp et al., 2023; Zucker et al., 2023; Szadvári et al., 2022).  For too long, female physiology was thought to be just the same, despite the evident sexual dimorphism, the presence and role of different hormones, the different chromosomes, to name but a few. Moved by modern times and a change in our thinking, more and more research groups started to also cover the female counterpart in their studies (e.g., using female mice or including women in clinical trials). In this context, I will focus on a recent study investigating hippocampal neuroinflammation from a sex-specific perspective.

Background:

Alzheimer’s disease, multiple sclerosis, and depression commonly include disruption of motivated behaviour, such as the inability to carry out daily tasks like preparing meals, going to work, or engaging in social interactions, with these challenges being more pronounced in women. It has been speculated that hippocampal neuroinflammation might be the cause of this gender-specific alteration but it is not easy to understand if neuroinflammation alone is sufficient to cause such a behavioural change. In this preprint, Ganesan and colleagues try to answer this question.

Key findings:

LPS induces neuronal activity in neuronal and glial cocultures

Firstly, the authors conducted in vitro studies demonstrating that the administration of lipopolysaccharide (LPS) did not alter neuronal activity (measured by cFos expression) when applied to a monoculture of hippocampal neurons. On the contrary, it significantly increased neuronal activity when administrated to neuronal/glial cocultures (particularly astrocytes). Indeed, during neuroinflammation, microglia and astrocytes are subjected to changes in function and morphology which, inevitably, also affect their neighbouring neurons.

In vivo LPS administration affects multiple aspects of motivated behaviour in consistent or sex-specific ways

After in vitro validation, the researchers injected LPS directly into the dorsal hippocampus of female and male mice performing a wide range of behavioural tests. The impact of neuroinflammation on goal-directed behaviour was measured using a classical “press levers for rewards” test. Interestingly, mice of both sexes showed an increase in goal-directed action control. Additionally, a Pavlovian approach was used to evaluate head entries into the food magazine, where rewards were delivered. The main finding was that LPS-treated females showed fewer magazine entries, while LPS-treated males showed more.

LPS treatment modifies neuronal activity in vivo

To test the possible effect of LPS on neuronal activity, in the presence of astrocytes, the authors performed immunostaining for the neuronal marker NeuN and the activity marker cFos at the level of the dorsal hippocampus. The results suggest that hippocampal neuroinflammation does indeed produce sex-specific alterations in neuronal activity; particularly in the dentate gyrus (a region crucial for learning and memory processes), increasing it in females yet decreasing it in males. This represents the potential underlying mechanism for the observed sex-specific behavioural differences.

What’s the possible mechanism behind the sex-specific response to neuroinflammation?

The presence of different sex hormones might represent a good explanation for the different behavioural outcomes in male and female mice. Indeed, estrogen has been shown to increase neuronal excitability in the hippocampus, while androgens appear to have the opposite effect, decreasing it. Estradiol (a form of estrogen) is also known to be neuroprotective reducing the number of pro-inflammatory cytokines after LPS administration, facilitating brain repair. The authors thus speculate that an interaction between microglial/astrocytic activation and estrogen (or androgens) occurred in the current study, particularly in females, that could account for the changes in behaviour and neuronal activity.

Why I picked this preprint:

I found this preprint is fascinating for two main reasons: it shows that neuroinflammation alone can alter behavior without additional neuropathologies and does so in a sex-specific manner. It is one of many studies highlighting biological differences between males and females. Despite women representing the 50% of the population, medical devices, drugs, and even crash test dummies have historically been tested primarily on men, increasing women’s vulnerability. Thankfully, modern science is shifting to include women equally. To quote Simone de Beauvoir’s seminal work, women are not “the second sex”.

Questions for the authors:

• How do you think these findings would translate when using other neuroinflammation models, such as cytokine exposure or models of chronic inflammation?
• How did you decide on the specific behavioural tests used in this study? Do you think other tasks might reveal additional sex-specific effects of neuroinflammation on motivation or cognition?
• Given that estrogen and androgens can have such distinct effects on neuroinflammation, how might the stage of the estrous cycle or the age of the animals affect the results in females? Did you control for or consider these factors, and how might they impact the findings?
• Given your findings, do you believe there could be sex-specific treatments for neuroinflammation-linked diseases? How feasible do you think it would be to develop therapies that take sex-specific neuronal or hormonal responses into account?

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