Keeping track of things: Forming associations between temporally separated events

When there is a time gap between events, we are less able to make a connection between them in learning and later memory. Thus it is harder to keep track of things that could in fact be causally related, in order - for example - to know that even distant engine noise can predict a future hazard or to anticipate dinner based on the smell of raw ingredients. The ability successfully to bridge a time gap between events is known to deteriorate with age. This project will investigate the underpinning brain substrates of this important cognitive ability in relation to its psychological bases. One possibility is that the mental image of the first event fades before the association at issue can be made. An alternative possibility is that other intervening events interfere with the association between the first event and the outcome event. The differential role of time versus interference will be examined in experiments which systematically compare how learning is reduced by a time gap between the end of the first event and the start of the outcome event, relative to the reduction in learning produced by events of extended duration which do not terminate before the start of the outcome event (such that the overall time duration to be bridged is equivalent). In the first scenario the potential for competing events to interfere with conditioning is much greater. These experiments will be conducted on rats using highly controlled presentation of events such as a distinctive noise followed by a mild foot shock.
Because the 'events' presented in such controlled experimental studies are somewhat artificial (e.g., a pure tone stimulus) we will also test the effects of the same interventions in the brain on the recognition of three-dimensional objects. In a complementary series of experiments we will present the objects with and without a time delay before familiarity is tested, with and without the presentation of intervening objects.
The brain interventions will be precisely targeted in both cortical and sub-cortical areas implicated in these processes. The present project will advance on previous findings in that we will selectively interfere with chemical signalling within these pathways, both by depleting brain chemicals in specific pathways and by targeted drug delivery.
In parallel with the experimental programme, we will visit schools and use sixth form outreach programmes to explain the importance of animal work of this kind. Once we have identified the psychological bases of deficits produced by depletion within a pathway, we will engage with contacts in the pharmaceutical industry to ensure that we follow-up on the most important findings with the most appropriate drug tests.

Trace conditioning is held to measure declarative memory and to be susceptible to age-related cognitive decline. Whilst we already know something of the neuropsychology of trace conditioning, we need neuropsychopharmacological studies to take the model to the next level and identify potential drug treatments for age-related cognitive decline. The present project will first examine the effects of DA versus 5-HT depletion in sub-regions of nucleus accumbens and prefrontal cortex on trace conditioning, tested over short and long intervals suitable to detect impaired and increased trace conditioning, respectively. Where trace conditioning is shown to be impaired by neurotransmitter depletion, the role of trace decay versus interference will be examined in follow-up experiments which systematically compare conditioning over a short trace interval (which would normally allow some conditioning) with delay conditioning (across the equivalent time interval but with no requirement to bridge the association in the absence of the conditioning stimulus). Variants of the standard object recognition procedure will be used to provide complementary evidence on the role of trace decay versus interference in disrupting normal memory. Finally experiments using discrete drug delivery into selected CNS areas will identify the receptor sub-types through which trace conditioning is modulated, both in the sub-regions of nucleus accumbens and prefrontal cortex identified in year 1 and in interconnected regions of the hippocampus. Conventional lesion studies have already implicated these structures in the learning and memory processes under test. The unique contribution of the present project will be the delineation of the role of neuromodulators within the network. We have previously found that selective neurotransmitter depletions can have opposite effects on behaviour to those reliably demonstrated using conventional lesions in the same brain regions.

In addition to the academic beneficiaries described earlier, there will be wider benefits of the research to be conducted in the present project. Figure 3 (in the Pathways to Impact attachment) shows the impact activities in relation to the experimental milestones and the scientific objectives over the 3 year time frame of the project (please see also the workplan attachment).

WHO WILL BENEFIT FROM THIS RESEARCH?
RESEARCH STAFF: Both Dr Pezze and the research technician will be given every opportunity to develop generic skills.
POSTGRADUATES: We have a lively postgraduate community who attend research seminars and group meetings weekly.
UNDERGRADUATES: Our teaching is research led; both applicants teach undergraduates and make full use of our own findings to excite the interest of the final year students.
SCHOOL CHILDREN: Outreach activities are an invaluable part of our widening participation programme, to attract the best university applicants to our BSc courses, irrespective of their background and prior expectations. The organisation Understanding Animal Research school visits allow the benefits of essential research with animals to be communicated at the earliest suitable opportunity.
PHARMACEUTICAL INDUSTRY: Currently, the applicants collaborate with AstraZeneca, F.Hoffmann-La Roche, Institut de Recherches Servier.
MANAGED ANIMALS: Associative learning, the prime focus of the project, is a fundamental mechanism of animal cognition (and an important component of the the Welfare of Managed Animals Priority).

HOW WILL THEY BENEFIT FROM THIS RESEARCH?
RESEARCH STAFF: Effectively explaining research findings (both to experts and during the course of the planned outreach activities) will improve general communication and presentational skills. The research technician will also be encouraged to present findings within the university and to attend staff training events. As appropriate, we also support research technicians to attend external scientific meetings. The University of Nottingham is fully committed to embedding the principles of the 2008 Concordat. In addition to the generic skills training provided for early career research staff through our Graduate School, we have an active 'Research-only' staff group which reports to the University's Research and Knowledge Transfer Board.
POSTGRADUATES: Postgraduates may not be directly supported by standard BBSRC project grants. Nonetheless, it may be appropriate to provide them with additional training opportunities. Any such placements would be fully consistent with the research objectives of the project and Home Office regulations.
UNDERGRADUATES: Final year students are similarly welcome in our laboratories, in this case to observe and assist only with non-regulated procedures. We regularly support summer interns as well as final year project students. This gives them the hands on experience which is so important to secure a funded PhD place in the area of behavioural neuroscience or psychopharmacology (and only the experience provided by such placements can tell them whether they have the aptitude to work on projects of this kind).
SCHOOL CHILDREN: The experiences provided by our outreach activities help prospective undergraduates to make informed decisions as to what they might apply to study at university. Young people also appreciate the opportunity to discuss the use of animals in research in relation to evidence, and to have their specific questions answered. Feedback suggests that this kind of activity is particularly effective when they are given the opportunity to engage with younger researchers.
PHARMACEUTICAL INDUSTRY: In the longer term, the findings of the present project will tell us where - in principle, when they become available - targeted brain interventions should be applied (e.g., using selective gene silencing in particular dopamine signalling pathways).
MANAGED ANIMALS: Evidence-based welfare is fundamental to best practice.