Community Research and Development Information Service - CORDIS

Periodic Report Summary 1 - POST-INGEST MESOLIMB (Post-ingestive effects on mesolimbic circuitry)

Objectives and background
The overarching objective of this project is to identify how the nutritional value of food affects the brain. In this context, nutritional value refers to the caloric content of foods. I am especially interested in identifying how nutritional value interacts with the taste of food to motivate consumption. For example, how does the motivation to consume a diet soft drink compare to motivation for a sugar-filled soft drink? In particular, what parts of the brain might be responsible for controlling this process?
To address these questions I am using an animal model in which nutritional value and taste can be varied independent of one another. This can be accomplished by infusing nutrients directly into the stomach. Activity in the brain – for example, the firing of neurons or release of chemicals – is monitored in various ways while rats respond for different foods. I will also directly examine activity at a cellular level by making recordings from brain slices.

Progress to date
Since the beginning of the grant, I have worked to establish my laboratory at University of Leicester. I have set up various techniques that will enable the planned work to take place including: fast scan voltammetry, electrophysiology, surgical catheterisation and implantation, and fibre photometry. In addition, I have applied for several sources of additional funding and been awarded a project grant from the BBSRC (3 years; ~£464K) to expand the remit of this project.

1. Implementation of post-ingestive conditioning
The ability for an animal to learn about the nutritional value/caloric content of a food is central to the success of this proposal. I have successfully implemented this procedure, which requires implantation of an intragastric catheter, in my lab in Leicester. Post-ingestive conditioning is demonstrated by the strong preference rats display when given a choice between a glucose-paired and water-paired flavour (Fig. 1A). This form of conditioning has also been integrated with methods of recording neural activity as described below.

2. Measurement of dopamine with voltammetry
Dopamine is one of the most important neurochemicals in the mesolimbic circuit. It can be measured in vivo in the brain using an electrochemical technique known as fast scan voltammetry. Dopamine release events recorded in my lab are shown to be reduced by intragastric infusion of glucose (Fig. 1B).

3. Recording of neural activity using photometry
A newly-developed technique, fibre photometry, can be used to record neural activity in specific populations of neurons or their terminals. This method can be produce similar results as voltammetry if dopamine neurons are targeted. However, photometry also offers several advantages including the option to target different cell types and to perform longitudinal studies. Consequently, I have invested time in adopting this technique and have completed a study in which mesolimbic neurons in nucleus accumbens were recorded during the post-ingestive conditioning process. These data are currently being analysed; preliminary results show that post-ingestive conditioning modulated neural activity in mesolimbic circuits (Fig. 1C).

4. Development of a model for protein appetite
My initial studies are focusing on caloric content of food but, of late, I have become interested in how the macronutrient content of food drives appetite, particularly in situations in which diets are imbalanced. To begin this work, I have focused on dietary protein as it is thought to be tightly regulated in animals including humans. To this end, I have developed a model of protein appetite in which protein-restricted rats show an increased preference for protein over carbohydrate, relative to control and food-restricted rats (Fig. 1D). I am exploring this phenomenon by looking for neural correlates that might explain the shift in preference.

Expected final results and potential impact
Over the following two years I will continue using the techniques I have established to map out the parts of mesolimbic circuitry that are important for driving behaviour towards nutritionally-valuable foods. Gaining a fuller understanding of what promotes food intake will have important ramifications for tackling obesity, one of the most important healthcare crises facing the world. Obesity and related diseases exert a massive toll on society that affects quality of life as well as the economy. Although certain dietary components (e.g. sugar and fat) have been heavily researched for their role in obesity, protein has been relatively understudied. Therefore, I hope that my emerging avenues of study will uncover novel mechanisms that can help to alleviate obesity-related issues.

See attachment for figures.
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