Neural adaptation to sensory stimuli by regulation of dendritic spikes and synaptic plasticity.

Throughout life the brain is bombarded with ever-changing sensations from our environment that it must understand correctly so that we can respond to them in the best way possible. Because our sensory experiences are always changing, the brain must constantly adapt to ensure it can identify these stimuli correctly. Our ability to adapt in this manner determines a large part of our cognitive capabilities and disruptions to this process occur in diseases such as schizophrenia and Alzheimer's disease. In this proposal, we aim to uncover and define ways in which the brain manages to maintain this adaptability.

The building blocks of the brain are nerves cells, also called neurons, which are connected to each other by synapses. Information is encoded within the brain by neurons responding selectively to specific features of sensory stimulation, for example the smell of peppermint or a particular tone in a piece of music. Neurons are able to do this because they receive and integrate specific synaptic inputs that guide their responses. However, the brain is not static and constantly adapts its responses in order to adapt our behaviour to the changing environment. Perhaps the most important waythe brain manages to adapt is by adjusting the strength of connections between particular neurons in response to changing sensory stimuli, a process termed synaptic plasticity. Understanding what regulates synaptic plasticity and subsequent behavioural adaptation is an important research goal. In this BBSRC project, we aim to investigate the brain activity patterns that control the processes enabling synaptic plasticity and therefore adaptation of responses to sensory stimulation.

Synaptic plasticity is triggered by the influx of calcium ions across the synaptic membrane through proteins called NMDA receptors which are activated when multiple synaptic inputs are activated simultaneously creating a localized "hotspot" of activity in a specific region of the neuron. The creation of this hotspot is extremely sensitive to the amount of NMDA receptor activation. We have recently found that the neurotransmitter acetylcholine, which is released in the brain during specific behavioural states, can regulate the intrinsic properties of neurons and thus provide a potentially exquisite control of NMDA receptors and induction of synaptic plasticity. This suggests an explanation for the common observation that behavioural states play a major role in determining whether we remember things, or forget them.

We are going to investigate the mechanisms by which acetylcholine controls adaptation of neuronal responses to sensory stimulation by performing experiments to find out how acetylcholine regulates the hotspots of NMDA receptor activation and therefore the induction of synaptic plasticity. To do this we will fill neurons with dyes that fluoresce when calcium ions are present. We will also measure whether a synapse has strengthened or weakened by recording electrical activity from the neurons. These techniques will enable us to visualize hotspots of synaptic activity and the process of synaptic plasticity.

This work is important because it will lead to a wealth of new information about synaptic plasticity and its role in adapting neuronal responses. Dysfunctional synaptic plasticity is thought to underlie the altered neuronal activity in several brain diseases, such as Alzheimer's disease and schizophrenia. The most common and effective treatment currently available for Alzheimer's patients are drugs that mimic or enhance the actions of acetylcholine. Therefore, the mechanisms that we will study in this research will add to our knowledge about these debilitating diseases, and may contribute to developing novel therapies.

A central function of the brain is to enable adaptation of behaviour to the environment which is underpinned by synaptic plasticity. This fundamental process determines how we are able to adapt our brain function based on our varying experiences throughout life and thereby ultimately determines our cognitive ability. Crucially, synaptic plasticity, and learning, are selectively engaged for salient/important stimuli signified by the release of neuromodulators. The aim of this project is to investigate how neuromodulators regulate synaptic plasticity and long-term adaptation of neuronal responses to sensory stimuli.

We will use the somatosensory system in mice where individual neurons in the primary somatosensory cortex are tuned to specific features of whisker stimulation. This tuning is generated by NMDA receptor-mediated localised dendritic spikes which in turn can cause synaptic plasticity and are highly sensitive to modulation by membrane conductances. We have previously shown that calcium-activated potassium channels (SK channels) inhibit NMDA receptor activity and are themselves inhibited by neuromodulators such as acetylcholine. Therefore we hypothesise that acetylcholine acting through SK channels promotes NMDA receptor activation and dendritic spikes and we propose that this enables the long-term adaptation of neuronal responses to sensory stimulation by the process of synaptic plasticity.

Here, we will address these hypotheses using in vivo electrophysiological recording and imaging to measure neuronal responses to whisker stimulation coupled with optogenetic techniques to stimulate the cholinergic system. Integrated ex vivo slice experiments will enable detailed mechanistic investigation of the regulation of dendritic spikes and synaptic plasticity which will inform subsequent in vivo experiments. The goal is to understand when synaptic plasticity and sensory adaptation can occur and how they are regulated by acetylcholine.

Who will benefit from the research?
As well as specific academic beneficiaries, the public (particularly school pupils and teachers) and wider academic community will benefit from the increase in knowledge about the role of synaptic plasticity in adapting responses to sensory stimulation. In addition, sectors of the pharmaceutical industry working to develop effective drug therapies for neurological diseases will also benefit from the proposed work. Indirectly, and in the long term, people suffering from such diseases may also benefit. Therefore, there is the potential for beneficial impact on both the health and wealth of the UK.
How will they benefit from this research?
Public: Our work will impact several public audiences, including school pupils, teachers and the general public. As mentioned above, we know that understanding more about the functioning of the brain, including fundamental processes like learning and memory, is of significant interest to many groups. At a recent public engagement event for schools and families (Changing Perspectives) neuroscience activities were one of the most popular of the range of hands-on science stalls on offer. School pupils were engrossed by testing their memories, and these activities could easily be expanded to include the effects of emotional state on memory and learning. Other neuroscience activities led by Bristol researchers - for example during Brain Awareness Week and Discover - are equally popular with public audiences, as are public talks on neuroscience topics held regularly by Bristol Neuroscience.
Teachers: Impacts on the teachers with whom we engage are likely to be significant. The Science Learning Centres are developing continuing professional development programmes that introduce teachers to neuroscience, and organisations such as the University of Bristol-based Neuroeducation Network provide resources for teachers interested in integrating the latest neuroscience research into educational practice. We anticipate that our research could impact how teachers manage emotional states in the classroom to facilitate learning.
Pharmaceutical industry: Research into numerous neurological diseases such as schizophrenia, autism and Alzheimer's disease has found deficits in synaptic plasticity that could contribute to disease symptoms. Our close working relationship with specific pharmaceutical companies means our work is likely to enhance their understanding of the fundamental science of learning and memory, pharmacological approaches to manipulating it and putative novel drugs and targets. JRM and MCA have ongoing collaborations with Eli Lilly & co (through the Centre for Cognitive Neuroscience) to study the effects of acetylcholine receptor agonists and neurodegenerative disease on synaptic function. JRM and MCA co-supervise CASE award studentships at Bristol University. Through the research described in this proposal we can offer these companies academic expertise to further this goal. This is particularly important since Eli Lilly & co are developing receptor selective agonists for use in the treatment of neurodegenerative and cognitive disorders.
The social impact and economic costs of the diseases mentioned above are enormous. Therefore our work will benefit society from the advances we make in investigating mechanisms that may underlie such diseases, and will benefit the economy both in terms of costs saved in care for patients suffering from these conditions, and also in profits from pharmaceuticals developed and sold by UK-based companies. We acknowledge that these indirect benefits may take several years before they are realised.
Educational impact: We will train a new generation of scientists by training the staff in our laboratory and by teaching at summer schools. By teaching at Bristol, MCA and JRM will train a new generation of non-academic workers in the UK, teaching a solid skillset for working in pharmaceutical or biotechnological companies.