Preservation of criticality in hypoxic, dissociated neural networks, via oestrogen triggered synaptic modulation
Lead Research Organisation:
University of Reading
Department Name: Sch of Biological Sciences
Abstract
Billions of interconnected neurons communicate electrically and form activity patterns in a critical state, finely balanced between order and chaos. Criticality is believed to underlie encoding and transferring of information, so it is a fundamental property enabling information processing in the brain but it can be disrupted when a traumatic event, such as an ischemic stroke, occurs. On the other hand, evidence has shown that specific biomolecules, such as oestrogen, can be neuroprotective, during traumatic events.
In this project, we will examine how oestrogen can salvage neuronal network activity, under neurodegenerative conditions. We will culture in vitro neural networks on multi-electrode arrays (MEA) and chemically treat them to emulate brain pathology. We will then examine how the structure of the neural networks (synaptic connections) and their activity patterns change under different conditions and investigate the neuroprotective effects of oestrogen. The project will conclude with the proposition of a model that links the transition of neural activity between critical and non-critical states and the mechanism of action of oestrogen. Our long term aim is to identify new strategies for the pharmacological treatment of stroke and other neurodegenerative conditions, harnessing oestrogen's neuroprotective action.
In this project, we will examine how oestrogen can salvage neuronal network activity, under neurodegenerative conditions. We will culture in vitro neural networks on multi-electrode arrays (MEA) and chemically treat them to emulate brain pathology. We will then examine how the structure of the neural networks (synaptic connections) and their activity patterns change under different conditions and investigate the neuroprotective effects of oestrogen. The project will conclude with the proposition of a model that links the transition of neural activity between critical and non-critical states and the mechanism of action of oestrogen. Our long term aim is to identify new strategies for the pharmacological treatment of stroke and other neurodegenerative conditions, harnessing oestrogen's neuroprotective action.
Organisations
People |
ORCID iD |
| Evangelos Delivopoulos (Primary Supervisor) | |
| Ruby VAJARIA (Student) |
| Description | 17ß- Estradiol is a steroid hormone exhibiting neuroprotective properties in stroke and ischemia. Typically, estrogen is associated as a female hormone as it is known for regulating menstruation and the development of reproductive organs. However, in recent years, estrogen has been reported to mediate neurophysiological functions in the central nervous system in females and males. The woman's ovaries make most estrogen hormones but can also be produced by no-gonad organs, such as the liver, heart, skin, and brain. The importance of estrogen stemmed from clinical observations that highlighted an increased risk of neurodegeneration and cognitive dysfunction in postmenopausal women due to hypoestrogenicity in the brain. The brain-derived estrogen is synthesised in specific brain regions from steroid precursors called androgens; this process is known as 'de novo' synthesis. De novo synthesis occurs from steroid precursors such as endogenous testosterone, which is converted to estrogen by an enzyme called aromatase (CYP19a1) by a chemical process called aromatisation. Estrogens are lipophilic neurosteroids and can easily pass the blood-brain barrier, typically exerting neuroprotective properties. In males, however, systemic estrogen is not readily available; therefore, lower estrogen levels reach the brain, so how does estrogen exert neuroprotection in the male brain? Behavioural studies have reported that the aromatisation of testosterone to estrogen can also occur in the brain as aromatase is expressed in various brain regions, such as the hippocampus, hypothalamus, and cortex. However, how does estrogen mediate these neurophysiological functions? Estrogen has been reported to regulate cognitive function and synaptic plasticity in females and males, actions of estrogen are mediated by estrogen receptors (ERs), and cell signalling occurs via genomic and non-genomic signalling. In the genomic signalling pathway, the steroid hormone binds to its receptor located in the cytoplasm; through a series of downstream signalling, it can activate or inhibit gene transcription. In the non-genomic signalling pathway, steroid hormones act through membrane receptors and initiate cytosolic signalling cascades, modulating the activation of various proteins and second messenger systems. Estrogen has also been shown to act as a free radical scavenger and reduce the reactive oxygen species, thus decreasing neuronal apoptosis. We investigate the prefrontal cortex; the PFC has been heavily implicated in executive function, including working memory and objective place memory. The medial prefrontal cortex (mPFC) is known for maintaining the emotional information of the working memory; here, studies have shown estrogen has been shown to improve cognition and learning by increasing dendritic spines. However, how estrogen regulates these processes and whether estrogen is produced via 'de novo' synthesis in the PFC in males remains elusive. Identifying estrogen production in the prefrontal cortex contributes to understanding the critical interactions of estrogen with oxidative stress and neurotransmitter systems that increase neuronal viability. Our study aims to measure estrogen production in PFC in male mice and use electrophysiology techniques to assess how estrogen can act as a neuroprotective steroid after administering a hypoxic insult. A novel method was developed to measure neuroestrogen production via de novo synthesis in adult male mice with viable coronal prefrontal cortex slices. Furthermore, to test the hypothesis that estrogen is neuroprotective against hypoxia in the PFC in males, in vitro prefrontal, coronal slices from 8-10 weeks old adult male mice were used on a multi-electrode array. Extracellular field EPSPs (fEPSPs) were recorded from the medial PFC by stimulating the hippocampal to prefrontal afferent fibres |
| Exploitation Route | The current research explores estrogen-mediated neuroprotection in the PFC of male mice and estrogen-mediated- neuroprotection. The future directions of this study are the following: using electrophysiology techniques, one could explore different agonists and antagonists for estrogen receptors to investigate how estrogen mediates in PFC. We have managed to create a hypoxic insult to mimic stroke-like events in the presence of estrogen, this was to see whether estrogen can serve as a neuroprotectant. Here, one could use in vivo models as opposed to in vitro, to assess this response of estrogen post-stroke on learning behaviours and motor tasks. |
| Sectors | Education,Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | Our findings provide that there is estrogen production in the male brain, this is a new area of research, our novel method of measuring estrogen from the brain serves as a new avenue to measure other steroidogenic precursors and investigative other proteins and hormones from a viable brain slice over a long period of time. Our findings are still preliminary, however, estrogen could be a possible therapeutic for post-stroke patients and help improve their recovery. |
| First Year Of Impact | 2019 |
| Sector | Education,Healthcare,Pharmaceuticals and Medical Biotechnology |