Thalamic control of cortical dynamics during slow wave sleep via GABAergic interneurons

We sleep almost one third of our life and adequate sleep is necessary for mental health. Indeed, lack of sleep is associated with attention deficit, fatigue, reduced performance and increased risk of obesity and other diseases.

Sleep is essential for memory. For the memory of today's events to stick in our brains, a good night's sleep is necessary. More precisely, it is the deep sleep stages that are crucial for memory. These stages occur primarily during the first sleep cycles early during the night. They are characterised by synchronous activity throughout the brain. The synchronisation of neuronal activity is necessary for memory bits to be transferred from one brain area to another and for them to be consolidated or eliminated. A brain that lacks this synchronisation property would lose its ability to organise and retain information. We want to understand where this synchronisation comes from and what mechanisms are responsible. We have identified a site in the brain known as higher-order thalamic nuclei that could act as a conductor of brain synchronisation of neuronal activity.

We will investigate this in mice by studying how disrupting the thalamic activity affects the synchronicity of neuronal activity. To control the thalamic activity we will use a new technique known as optogenetics, which permits us to activate or silence part of the mouse brain using a laser. Simultaneously we will use electrical recording of brain activity to evaluate the degree of synchronisation. We will test whether activating the thalamus with precise timing would enhance synchronisation of brain areas and whether silencing the thalamus would disorganise the brain synchronicity. The results of this study would identify a conductor for neuronal synchronisation and give insight into how to improve sleep quality.

We have previously reported that activation of GABA(B) receptors is responsible for the UP-to-DOWN state transition during slow oscillations in brain slices. Furthermore, in preliminary data here, we show that activation of layer 1 (L1) interneurons can induce this transition. The overall aim of this proposal is to extend our research on UP-to-DOWN state transition by 1) identifying the population of L1 interneurons responsible for the GABA(B) receptor activation and thus UP-to-DOWN transition, and 2) identifying the mechanism underlying the synchronous UP-to-DOWN transition across cortical areas. Based on previous studies from our group and others, local cortical GABA interneurons can induce an UP-to-DOWN transition and L1 neurogliaform cells (NGFC) can activate pre and post-synaptic GABA(B) receptors. Therefore we will test whether L1 NGFC can induce this transition. We will test this using a new CRE mouse line that labels specifically L1 NGFC combined with optogenetics to either stimulate or inhibit these neurons during UP-states. Thanks to a collaboration with Janelia and their sequencing platform, we have obtained a transgenic CRE line that specifically label higher-order thalamic neurons that project to L1. Our preliminary data indicate that these neurons project to multiple cortical areas where they primarily connect to L1 NGFC, indirectly activating post-synaptic GABA(B) receptors on L2/3 neurons. We will test whether this connection is sufficient to induce the UP-to-DOWN state transition locally in the cortex. Because thalamic neurons project broadly to multiple cortical areas, we hypothesise that these nuclei could together act as a conductor of cortical synchronisation. We will address this question by performing multi-site recordings of the cortical activity during slow wave sleep while activating or silencing thalamic activity using optogenetic or chemogenetic tools.

We have identified three areas of possible impact:
1. Patients and healthcare professionals. Better understanding of sleep mechanisms could have consequences for treatment of normal age-related memory decline as well as memory disorder such as dementia. In particular, it could generate new hypotheses of memory impairment in diencephalic syndromes such Korsakoff syndrome. Moreover, poor sleep quality is correlated with metabolic diseases like diabetes and with anxiety and ADHD, and this research may help find new ways to improve patient quality of life. We will share our insights with clinicians to enable them to utilise new basic understanding for treating patients.
2. Education and economy. The economic cost of lack of sleep is estimated to more than £30 billions in the UK alone. Moreover, one third of school kids do not get enough sleep and teachers report a reduced attention span, increase of attention disorders and fatigue that impairs learning. A better understanding of the mechanisms of sleep will give insight into how to improve learning quality and productivity at work.
3. Computational and high-tech. Our project aims to describe how a hub structure can contribute to the synchronisation of distant cortical areas, thus allowing reset of their parameters and be ready simultaneously for new computations. This concept could be applicable to machine learning and high-tech, for example in the development of more dynamic memory and storage options in computer science. Indeed, we propose that resetting followed by synchronous processing would enable self-update and compression of memory.

Who will benefit from the research?
In addition to academic beneficiaries, high-tech industry, the education sector, and parts of the pharmaceutical industry working to develop effective drug therapies for neurological diseases would benefit from the proposed work. In addition, school children and adults suffering from lack of sleep and the general public will benefit from an increase in general knowledge about sleep mechanisms. Therefore, there is good potential for beneficial impact on both health and wealth of the UK.

How will they benefit from this research?
Sleep occupies one third of our lifetime. Many cognitive processes happen during the deep stages of sleep, including memory consolidation of relevant information and deletion of irrelevant memories. Lack of sleep is associated with higher risk of developing certain diseases, increased stress and anxiety or loss of productivity. Therefore, gaining knowledge about the mechanisms of sleep dynamics is of interest not only to the academic community but also to the wider public.
Pharmaceutical industry: Numerous neurological diseases, including Alzheimer's disease and diencephalic amnesias, are associated with a decrease of sleep quality. The social impact and economic costs of these diseases are enormous. Therefore our work might in the longer-term benefit society from better understanding of the mechanisms that underlie such diseases, and could benefit the economy both in terms of costs saved in care for patients suffering from these conditions, and in benefits from drugs developed and sold by UK-based companies. We acknowledge that these indirect benefits may take decades before they are realised.
Educational and economic impacts: Basic understanding of sleep processes and their associated consequences on memory formation and consolidation may lead to improvements in the uptake of take-home messages on the importance of sleep for performing optimally at school and at work. This project could also help develop new strategies to improve sleep quality and therefore quality of life.
High-tech industry: Our work could benefit developers of smart technologies, since the mechanisms of synchronicity of brain activity explored in this project might inspire new parallel computation algorithms and new implementations in neuromorphic engineering.