Imagine a world where every fleeting thought and trivial detail were permanently etched into your long-term memory. Your cognitive faculties would quickly become overwhelmed with irrelevant information, hindering your ability to focus on what truly matters. Memory triage is the brain's solution to this dilemma. When we sleep, it selects and strengthens the memories that are most relevant, significant, or emotionally charged while allowing less crucial information to fade away. In our age of information overload and digital distractions, our memory systems are constantly under pressure. As we absorb vast amounts of data daily, our brains must efficiently prioritise what to remember and what to discard. Failure in this process can lead to cognitive overload, reduced productivity, and heightened stress. Additionally, as we age, the quality and duration of our sleep tend to decline. This in turn can affect memory consolidation, a sleep-dependent process, leading to memory problems and cognitive decline. Understanding the mechanisms behind memory triage, and its relationship with sleep, can inform interventions to alleviate these age-related memory issues, enhancing the quality of life for older individuals. In this proposal we will examine neural replay, the spontaneous reactivation of memory traces by the hippocampus, which we hypothesize to be the mechanism central to the memory prioritisation process. We will test our model, where replay activity in the awake state tags important memories that should be prioritised later during sleep, which then increases the amount of replay for this memory during sleep, which speeds up the consolidation process. We will use a combination of optogenetics, electrophysiology, pharmacology, and behaviour to interrogate the relationship between awake and sleep replay, within the context of memory prioritisation.

OCT-OVA is an innovative, multi-lab, multi-disciplinary project that straddles both basic and translational science. It aims to investigate how a single neurotransmitter receptor, and highly promising target for vector control, is necessary for viable egg production in female mosquitoes. In the process, OCT-OVA will provide both big data and transgenic resources for the community and give evolutionary insight into what might be a distinct system for the neuromodulation of fertility in a facultative blood-feeder. Mosquitoes require protein-rich blood in order to lay eggs, and it is this blood-feeding behaviour which leads to the spread of debilitating diseases such as malaria. Once they have acquired a bloodmeal, the process of ovulation begins, followed by fertilisation. We have found that mutation of the gene encoding Octbeta2R leads to a complete disruption of fertilisation. Octbeta2R is a G Protein- Coupled Receptor (GPCR) that is bound by octopamine - a neuroactive molecule that in invertebrates, acts as the functional homologue of adrenergic transmitters. GPCRs are highly "druggable". Molecules that block Octbeta2R could thus act as mosquito contraceptives, preventing them from laying fertile eggs and controlling populations. However, the cause of this phenotype is unclear. Which cells are responsible for the defect and what do they do? I would like to use state-of-the-art methods to molecularly profile the female mosquito reproductive system. I will then identify clusters of cells that express Octbeta2R, and using transgenic drivers and responders, explore which cell types are responsible for the fertility defect. This project will bridge the gap between genes, circuits and fertility, and reveal how molecular cell state influences organismal reproductive state. Understanding Octbeta2R-dependent mosquito sterility will galvanise the development of much needed mosquito control tools, in line with EU strategies for epidemic management and preparedness.

Tuberculosis (TB) remains one of the leading infectious causes of death. At present, the World Health Organization (WHO) recommends treating drug susceptible pulmonary TB (pTB) with a two-month course of Rifampicin, Isoniazid, Pyrazinamide and Ethambutol (RHZE), followed by a four-month course of Rifampicin and Isoniazid (RH). Some patients are unable to adhere to this protracted treatment and discontinue treatment prematurely. This often results in TB recurrence and development of drug resistance. TB requires protracted treatment because Mycobacterium tuberculosis (Mtb), the causative agents for TB, exists as a heterogenous population of bacilli, a fraction of which are tolerant to anti-TB agents. New TB treatment regimens that are more effective against drug-tolerant Mtb would therefore help improve outcomes of TB treatment. While more than 800,000 people are successfully cured of TB every year, all-cause mortality rates are 6 times higher in TB survivors than in the general population. This is in-part because up to half of pTB survivors sustain severe lung damage and develop post-tuberculosis lung disease (PTLD) . At present, there are no interventions for preventing or managing PTLD. PTLD is largely caused by host responses to Mtb. Anti-Mtb host responses also promote Mtb drug tolerance. Host-directed therapies could therefore help alleviate both PTLD and Mtb drug tolerance. More than a hundred host molecular pathways, and even more genes, have been implicated in the evolution of PTLD and Mtb drug tolerance. It remains unclear which of these genes, or combinations of genes, should be targeted to reduce Mtb drug tolerance and/or PTLD. While single-gene-knockout experiments can be performed relatively easily, it is difficult to simultaneously knockout multiple genes to identify the ideal combination of genes to target to reduce Mtb drug tolerance or PTLD, given the myriad possibilities. Further, as most of the genes and pathways have been identified from animal models and in-vitro experiments, their relevance in natural human Mtb infections remains unclear. We, therefore, propose to leverage 1) single-cell transcriptomics of lung airway cells from pTB patients, 2) functional assessment of lung injury, and 3) sputum microbiologic assessment to identify the host cell types and molecular pathways associated with Mtb drug tolerance and PTLD. We will then leverage computational biology and machine learning to perform in-silico knock-up and knock-down experiments to hasten identification of single or combination host-directed therapeutics for reversing host transcriptomic perturbations associated with Mtb drug tolerance and PTLD. Finally, we will test the predicted compounds in an ex-vivo Mtb-human alveolar macrophage infection model.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Males of many different mammal, bird and invertebrate species respond to their social and sexual environment. These responses have profound effects on their reproductive success. For example, males of many species that perceive rivals transfer more sperm to females during mating, to increase their share of paternity. However, the complete pathway from the detection of cues from rival males, to effects on the composition of the male ejaculate through to ultimate reproductive success is not known. Nor do we know the effects on ageing for males of responding to rivals. The discovery of the pathway between rival detection and paternity represents the next key stage in understanding the evolution of male mating success. In this proposal we aim to provide the first case study, using the fruitfly. The fruitfly offers a unique opportunity, its genome has been sequenced and there are many different genetic reagents available with which to manipulate a male's perception of the number of rivals present. We have also generated a substantial amount of relevant and novel background data. For example, males respond to the presence of rivals before mating, and subsequently mate for longer when they do meet a female. More importantly, during those longer matings they transfer more of key ejaculate components, which increase the overall number of offspring fathered. Males appear to detect rivals by smelling a particular male pheromone. Importance for pure research: The work tackles questions of fundamental importance: how do males respond to rivals and what are the fitness consequences of doing so. When ejaculates are limiting (e.g. when males that mate just a few times become exhausted), males partition their ejaculates among different matings and different females, according to how many rival males are present. However, despite the wealth of studies showing that males do this, key questions remain: (i) what are molecular mechanisms by which males signal and perceive rivals? and (ii) what are the overall consequences, particularly the impact on ageing, for males that respond to the presence of rivals. These are the questions we will answer. Importance for applied research: Of equal importance, our work will provide techniques to improve insect pest control. Insect pests are the source of the world's most serious agricultural (and health) problems. Research is focusing on methods whose basic principles lie in biological control. However, males produced for control often have poor mating success. We aim to provide methods to improve this (e.g. simple husbandry rules to increase exposure to rivals or pheromones) using the fruitfly, which is the only species in which the relevant background data and genetic reagents are available. We plan to apply our findings to pests in the future. Methodology: We will manipulate male numbers and length of exposure to rivals, and the smell pathways that our work has highlighted as important. We can test the amount of ejaculate proteins transferred to females during mating using a method developed by our project partner, Mariana Wolfner from Cornell University. We can test for sperm transfer by staining and counting the sperm transferred. To test for the effects of responding to rivals on male ageing, we will compare the lifespan and reproductive success of males that mate following exposure, or not, to rivals. Timeliness and originality: Our proposal will provide the first investigation of the complete pathway by which males respond to rivals. The work is timely given the recent elucidation of smell receptors, our recent discoveries of changes to ejaculate composition in the presence of rivals and the recent surge of developments in genetic insect pest control.