About Us - Neurotechnologies

Neurons communicate with each other, and with astrocytes and microglia in the brain, via neurotransmitters including glutamate and GABA. Fine tuning of this communication depends on a number of other neurotransmitters or neuromodulators, including dopamine, acetylcholine , serotonin and noradrenaline. Although broad relationships between neuromodulator activity and cognition are accepted, we know very little about the precise roles and mechanisms by which these neuromodulators regulate different cognitive domains. In addition, recent observations have raised the possibility that neuromodulators can also signal to astrocytes and microglia and that glial cells can in turn signal back to neurons, but how this reciprocal signaling regulates cognition is unknown. These gaps contribute to our poor understanding of the mechanisms by which treatments fail to restore synaptic and neurochemical pathways to improve cognitive function in disease.

We have a pipeline of more than 20 novel fluorescent biosensors (many generated by our collaborator Yulong Li) that enable us to observe neurochemicals and/or cellular activity with fibre photometry in vivo while mice perform touchscreen-based cognitive tests. This innovative approach builds on a G-protein coupled receptor scaffold for a given neurotransmitter, which is mutated and fused to conformational sensitive fluorescent proteins. These sensors respond with large fluorescent changes on millisecond time scales—a step change in sensitivity and temporal resolution compared to traditional methods such as microdialysis—and enable us to pinpoint neurochemical or population-level neural activity underlying specific stages or aspects of cognition with exquisite sensitivity. They can be expressed in distinct brain regions and genetically-identical cell types using Cre mouse lines or promoters packed in viral vectors.

Automated touchscreen behavioural tasks in rodents enable systematic high-throughput and translational cognitive assessment with standardized outputs that facilitate data reproducibility, analysis, and dissemination. Traditionally, lesion studies, in vivo electrical stimulation or infusion of drugs affecting local cellular activity within the brain has been used to investigate circuitry and connectivity function underlying behaviour. Unfortunately, these approaches lack of either cellular or temporal resolution to match millisecond scale events correlated with the onset of environmental contingencies. Over the last decade, a generation of genetically encoded proteins that change conformation in the presence of light (opsins) have been developed to alter excitability of specific cell populations in discrete brain regions. The use of this experimental tool is known as ‘optogenetics’, and it has enabled investigators to address whether specific cell populations or brain regions underlie behaviors relevant to psychiatric and neurodegenerative disorders. Moreover, because the optogenetic can regulate brain activity in sub-second scale resolution, it has become widely adopted as versatile tool to integrate with other neurotechnologies including touchscreens.

Numerous examples demonstrate that existing mouse models have not been fully successful in providing accurate information on how pathological changes impact cognition. For example, several mouse models have been generated that express transgenic human amyloid precursor protein (APP)—the precursor of the primary component of amyloid plaques (ß-amyloid peptide)—with familial Alzheimer’s Disease mutations using non-specific promoters. Unfortunately, in most of these models APP is overexpressed in circuits and cells without the spatiotemporal relevance required to model Alzheimer’s disease, leading to overexpression of a number of extra peptides in addition to ß-amyloid in the incorrect cell types and circuits. Similarly, Tau, a protein that when misfolded leads to neurofibrillary tangles, the second main biomarker in Alzheimer’s Disease, has also been overexpressed in myriad ways in mice, without modelling the specific Tau isoforms found in humans. Such models not only inadequately model disease pathology but, because of their severity, increase the likelihood of false positives on cognitive assays.

Thanks to recent developments (such as use of CRISPR/CAS) and multiple efforts from individuals and consortia (e.g., Model-AD), next generation mouse models in which specific humanized genes are knocked-in the mouse genome are slowly replacing first generation mouse models. The use of robust, automated, translational and reproducible touchscreen testing of high-order cognitive functions means that these subtler and more realistic mouse models, which may provide more relevant information but are also likely to display subtler cognitive impairments, can now be used. We have access to a number of these next-generation mouse models. Please download our application form or contact us for a list of available mouse lines.