Role of the hippocampus in event memory in the rat

This thesis aims to examine the role of the hippocampus in declarative memory through the development of animal behavioural models of episodic memory for laboratory rats. Episodic memory- memory for unique events or episodes- is part of the declarative memory system thought to be mediated by the medial temporal lobe area of the brain in humans. One commonly used test of episodic memory in human subjects is paired associate learning. The first part of this thesis describes the adaptation of this human test for use with laboratory rats. Using their natural foraging tendency, rats were trained to search for different flavours of food at different locations within a large enclosure. When cued with a piece of food of a particular flavour in a separate box, rats learned to return to the place where that flavour of food had previously been found. This paradigm was used to investigate the role of the hippocampus in paired-associate learning using temporary pharmacological inactivation and permanent neurotoxic lesion techniques. The hippocampus has also been strongly implicated in spatial navigation, learning and memory in rats and humans. In the experiments described previously, attempts were therefore made to demonstrate that the results were not confounded by a simple deficit in spatial navigation. An alternative approach to studying episodic memory in the laboratory rat is to use the criteria established by Tulving in 1972 to describe episodic memory. He stated that episodic memory should encompass the memory for an event and the spatiotemporal context in which it occurred, i.e. the ”what”, ”where” and ”when” of an event. He later updated these criteria to include demonstration of autonoetic consciousness- most easily described as a sense of self awareness. Since this is difficult or impossible to demonstrate in animals, the term ”episodic-like” memory was coined (Clayton & Dickinson 1998) to describe the flexible use of information about the spatiotemporal aspects of an event by non-human species. Since it has been difficult to demonstrate the use of time (when) in rats (Bird et al; 2003, Babb & Crystal 2006a), Eacott & Norman (2004) suggested that the ”when” component could be replaced by context; i.e. another element specific to a particular event that they labelled ”which”. The next part of this thesis describes the use of the task published by Eacott & Norman to test episodic-like memory in the laboratory rat. Using the innate spontaneous behaviour of rats to explore novel aspects of their environment, they were exposed to multiple unique events. These consisted of various three-dimensional objects being presented in different locations within different contexts. Their memory for manipulations of the environment was then tested by presenting them with an event in which one combination of object, location and context was different from combinations which had previously been encountered. Due to their tendency to explore novel aspects of their environment, normal rats spent the majority of their time exploring the object that was in a novel location relative to the context in which it was presented. This successfully demonstrated integrated memory for what, where and which- similar to that previously defined by Tulving. The rats also showed that they could use this information flexibly because every trial involved unique combinations of objects, locations and contexts so there was no inadvertent semantic rule-learning involved. Permanent neurotoxic lesions of the hippocampus were used to determine the extent to which this structure is involved in memory for the what, where and which of an event. The experimental results presented in this thesis demonstrate an indisputable role for the hippocampus in a variety of tasks designed to parallel episodic memory in humans. The next steps in this line of research should involve characterisation of the roles of the various subregions of the hippocampus in episodic-like and paired associate memory

Effects of dietary fat manipulation on cognition in mice and rats:protocol for a systematic review and meta-analysis

INTRODUCTION AND OBJECTIVE: The Western diet that comprises high levels of long-chain saturated fats and sugar is associated not only with metabolic disorders such as obesity and type 2 diabetes but also has been recently linked to brain changes and cognitive dysfunction. However, in animal studies, reported effects are variable, and the mechanisms underlying these effects are unclear. In the proposed review, we aim to summarise the diverse evidence of the effects of so-called ‘high-fat’ and ketogenic diets on behavioural measures of cognition in postweaning mice and rats, relative to animals on standard diets and to determine potential underlying mechanisms of high-fat diet-induced effects. SEARCH STRATEGY: A comprehensive search strategy was designed to retrieve studies reporting use of a high-fat or ketogenic diet in postweaning mice and rats that included cognitive assessments. Three databases (Medline, SCOPUS and Web of Science) were searched and 4487 unique references were retrieved. SCREENING AND ANNOTATION: Studies were screened for inclusion by two independent reviewers, with 330 studies retained for analysis. Characteristics of disease model choice, experimental design, intervention use and outcome assessment are to be extracted using the Systematic Review Facility (http://syrf.org.uk/) tool. Studies will be assessed for study quality and risk of bias and confidence of mechanistic involvement. DATA MANAGEMENT AND REPORTING: For cognitive outcomes, effect sizes will be calculated using normalised mean difference and summarised using a random effects model. The contribution of potential sources of heterogeneity to the observed effects of diet on cognition will be assessed using multivariable meta-regression, with partitioning of heterogeneity as a sensitivity analysis. A preliminary version of this protocol was published on 9 April 2019 on the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies website (http://www.dcn.ed.ac.uk/camarades/research.html%23protocols). ETHICS AND DISSEMINATION: No ethical approval is required as there are no subjects in the proposed study

A high-fat diet induces rapid changes in the mouse hypothalamic proteome

Funding LMW, FMC, CG, ACM and C-DM were funded by the Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS). FHM was supported by an EASTBIO DTP BBSRC studentship. DS was supported by a SULSA studentship. CR was supported by the HOTSTART Scholarship Programme from the School of Medicine, Medical Sciences and Nutrition, University of Aberdeen. Availability of data and materials All data generated or analysed during this study are included in this published article [and its Supplementary information files].Peer reviewedPublisher PD

Rapid and reversible impairment of episodic memory by a high-fat diet in mice.

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. This work was supported by an EASTBIO BBSRC PhD studentship to F.H.M., L.M.W., C.G., A.C.M., G.W.H. and F.M.C. are supported by Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS).Peer reviewedPublisher PD

Early and reversible changes to the hippocampal proteome in mice on a high-fat diet

Funding LMW, FMC, CG, ACM and C-DM were funded by the Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS). FHM was supported by an EASTBIO DTP BBSRC studentship. DS was supported by a SULSA studentship.Peer reviewedPublisher PD