Principal Supervisor: Dr James McCutcheon - Department of Neuroscience, Psychology and Behaviour
Co-supervisor: Nick Hartell
PhD project title: Interactions between the neurocircuitry of addiction and the preference and motivation for protein
University of Registration: Leicester
The process of addiction involves changes in brain regions that, in healthy individuals, control motivation and pursuit of natural rewards such as food. Repeated chronic stimulation of these circuits can lead to the long-lasting molecular and cellular alterations that make addiction such a devastating, chronic disease. Addiction to drugs of abuse such as cocaine, heroin, and nicotine has been heavily researched but it is only recently that the possibility of similar dysfunction resulting from consumption of certain foods has been considered. For example, repeated exposure to both sugar and fat has been shown to cause changes in behaviour and neurobiology that resemble the alterations seen after exposure to drugs. So far, however, the third macronutrient – protein – has not been studied in detail. Interestingly, although often overlooked, protein intake is more tightly regulated than carbohydrate and fat. It has been suggested that changes in dietary protein could have major effects on the incidence of obesity. Our lab has shown that, under conditions of protein restriction, protein-containing solutions become highly preferred. We have also shown that this preference is associated with altered neuronal activity in areas of the brain associated with addiction. This PhD project will build on these data by determining to what extent these neural changes overlap with the patterns of activity seen during addiction.
To pursue this question the student will use a combination of state-of-the-art behavioural, physiological, and imaging techniques that involve both in vivo and in vitro approaches. To assess how preference and motivation for protein changes under different states of restriction, a suite of behavioural paradigms involving macronutrient consumption and manipulation of effort will be used. These tasks will be integrated with sophisticated methods of recording and/or manipulating neural activity. Primarily, fibre photometry will be used to measure changes in calcium fluctuations as a proxy for neural activity while awake, behaving rats consume solutions of differing nutritive value. A key advantage of fibre photometry is that the fluorescent indicator is expressed under genetic control allowing a high degree of cell type specificity. In parallel, we will study the cellular properties of neurons in the addiction circuitry using in vitro methods of whole-cell electrophysiology and super-resolution microscopy. These experiments will be conducted in close collaboration with Dr. Hartell’s lab and will allow dynamic alterations in spine size and shape to be monitored at high temporal and spatial resolution. Finally, to prove a causal role for observed changes in neural activity, optogenetic and chemogenetic techniques will be used to manipulate circuitry and determine its effect on preference and motivation for protein.
This novel interdisciplinary approach combining systems-level physiology and behaviour with advanced real-time optical imaging will provide insight into neural control of fundamental processes and will be achieved by the inclusion of both Dr. McCutcheon and Dr. Hartell on the supervisory team.
Specific Aims for each year are as follows:
- Year 1: Is enhanced preference and motivation for protein associated with altered neural activity in addiction-associated brain regions?
- Year 2: What are the cellular neuroadaptations produced during protein-seeking and how similar are these to an addiction-like phenotype?
- Year 3: Can manipulation of specific cell types or circuit elements modulate preference and motivation for protein?
The project is expected to cost approximately £15,000 per year, which is primarily animal costs (purchase, housing, surgical time) and consumables (surgical supplies and apparatus). The difference between this figure and bench costs provided by the program will be met by a BBSRC and European Commission grants to Dr. McCutcheon.
BBSRC Strategic Research Priority: Molecules, cells and systems
Techniques that will be undertaken during the project:
- Behavioural and surgical techniques for testing preference and motivation
- In vivo fibre photometry and optogenetic manipulation
- In vitro electrophysiology and super resolution microscopy
Contact: Dr James McCutcheon, University of Leicester