Age-related and cell-type-specific changes in auditory cortical processing

Lead Research Organisation: University of Strathclyde
Department Name: Inst for Biomedical Science

Abstract

Ageing is unavoidable. Of age-related changes in our body, age-related hearing loss (ARHL) is a serious issue for us. ARHL is one of the top three most common chronic health conditions affecting individuals aged 65 years and older in the US. In the UK nearly 6.4 million elderly people suffer from some form of hearing loss. It is predicted that this number will increase further. Indeed the World Health Organisation predicts that by 2030 adult onset hearing loss will be in the top ten disease burdens in the UK, above diabetes.

Although ARHL per se won't kill us, its impact is huge: ARHL significantly decreases the one's ability to communicate with others, resulting in a significant impact on daily life. Another change in hearing with age is the slowness of auditory processing. Again this age-related slowness in auditory processing leads difficulty in daily communication. One way to address these societal issues is a better understanding of the ageing auditory system.

In this proposal we will investigate how ageing affects auditory information processing in the auditory brain, particularly the auditory cortex, which is essential for speech comprehension in humans. In the auditory cortex there are lots of types of neurons, but we know little about how such diverse neurons communicate with each other and how neuronal communications are changed with age.

In this proposal we will particularly focus on one of two major neuron groups, called inhibitory neurons because we know that inhibitory circuits are affected by ageing in other auditory brain areas, but we know little about inhibitory circuits in the ageing auditory cortex.

We will test the hypothesis that auditory processing in the auditory cortex is changed with age depending on cell-types.

To this end, we will combine advanced technologies in animal models. One technology is called massively parallel neural recording technique, which allows us to readout activity from a hundred of neurons simultaneously. Another technology is called optogenetics, which allows us to control neuronal activity with light in a cell-type-specific manner.

We are specifically aiming to achieve two goals in this proposal: firstly we will characterise how ageing affects information processing in inhibitory neurons of the auditory cortex.
Secondly by activating inhibitory neurons with light we will assess how ageing can change abilities of inhibitory neurons in the auditory cortex.

Our study will provide further insights into the mechanisms of age-related changes in auditory processing and the development of novel intervention strategies for the ageing auditory system.

Technical Summary

The neocortex, including the auditory cortex, consists of highly diverse neuronal populations, with the anatomically prominent six-layered structure. Although different cortical layers and cell-classes encode auditory information differently, it still remains poorly understood how auditory coding across cortical layers is changed with age. In this proposal, we will test the hypothesis that auditory coding in the primary auditory cortex (A1) is changed with age in a cell-type-specific manner. Because the reduction of inhibitory neurotransmission has been observed throughout the ageing auditory pathway and has been implicated in the slowness of auditory processing in the ageing brain, we will specifically focus on one of major cortical cell groups, GABAergic inhibitory neurons, which are further classified into diverse subtypes. Combining in vivo electrophysiological and optogenetic approaches in mice at different ages, we will characterise age-related changes in information processing across A1 layers. We will specifically address two specific issues:
Aim 1. Age-dependent and cell-type-specific auditory coding
We will apply optogenetics to identify a specific type of GABAergic neurons in vivo. We will ask how activity in a specific type of GABAergic neurons is changed with age, in terms of spontaneous activity and auditory evoked responses across cortical layers. This study will provide further insights into the mechanisms of age-related neural slowness in the auditory cortex.

Aim 2. Age-related changes in inhibitory effects on cortical computation
We will optogenetically activate a specific type of GABAergic neurons during sound presentations. Then we will ask how effects of GABAergic neural activation on auditory coding are changed with age. This study will shed light on age-related changes in capabilities of GABAergic neurons on cortical computations and provide further insights into the development of strategies to improve auditory processing.

Planned Impact

Four areas can be identified for economic and societal impact:

1. Ageing population
Because ageing is one of the most serious societal challenges in developed countries and the auditory system is particularly relevant to this aspect, our proposed project will contribute to a better understanding of the ageing auditory system and to the development of novel intervention strategies to improve auditory processing.

2. Engaging with industry
Because we are currently working with AstraZeneca in the BBSRC industrial CASE studentships scheme, it will be feasible to develop this collaboration further in terms of the ageing auditory neuroscience in near future.

3. Enhancing public awareness of neuroscience
Because this project and other ongoing projects in my laboratory will contribute to a better understanding of neural information processing, we will contribute to enhancing public awareness of the importance of brain sciences. Because our CeNsUS (Centre for Neuroscience, University of Strathclyde) has been working on public engagement (e.g., attending local primary schools and holding an event at the Glasgow Science Centre), it is feasible to achieve this impact through this type of activity. PhD students or postdoctoral researchers in my laboratory will also participate in this activity.

4. Contributing to 3Rs
Our in vivo electrophysiological method can contribute to the reduction of the 3Rs because our method allows us to monitor activity from many neurons simultaneously and thereby fewer animals are required to collect enough data compared to conventional methods. Eventually our experimental data will contribute to building in silico models to replace animal experimentations in future.
 
Description With the advent of recent genetic technologies for mice, it is now feasible to investigate the circuit mechanisms of brain functions in an unprecedented manner. Although transgenic mice are commonly used on C57BL/6J (C57) background, hearing research has typically relied on different genetic backgrounds, such as CBA/Ca or CBA due to the genetic defect of C57 mice for early age-related hearing loss. This limits the utilization of available genetic resources for hearing research. Here we report congenic (>F10) Cre-dependent channelrhodopsin2 (ChR2) mice on CBA/Ca background. By crossing this line with Cre-driver mice on C57 background, F1 hybrids restored the hearing deficit of C57 mice. We also found a linear relationship between aging and hearing loss, with progression rates varied depending on genetic backgrounds (3.39 dB/month for C57; 0.82 dB/month for F1 hybrid). We further demonstrate that this approach allows to express ChR2 in a specific type of inhibitory neurons in the auditory cortex and that they can be identified within a simultaneously recorded population of neurons in awake mice. Thus, our Cre-dependent optogenetic transgenic mice on CBA/Ca background are a valuable tool to investigate the circuit mechanisms of hearing across lifespan.
Exploitation Route Data generated in this research can be re-used for other projects, such as computational neuroscience projects.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

URL https://www.frontiersin.org/articles/10.3389/fnagi.2019.00029/abstract
 
Description During the project, we have developed a novel wireless data transmission system by collaborating with Professor Keith Mathieson. This device allows us to monitor brain activity with hgher data transmisson rate compared with conventional radio frequency-based technologies. Based on this technology, we have filed a patent to spin out a company to disseminate this technology widely.
First Year Of Impact 2018
Sector Electronics,Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Title Data for: "Cre-dependent optogenetic transgenic mice without early age-related hearing loss" 
Description "Data for the published work. There are three folders for each figure. Each folder contains the original excel files and an illustrator file for each figure. " 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact
 
Title Data for: "Distinct temporal coordination of spontaneous population activity between basal forebrain and auditory cortex" 
Description Dataset for manuscript "Distinct temporal coordination of spontaneous population activity between basal forebrain and auditory cortex". Data files contains all original spike trains for all figures. README describes further details. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact Unknown