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Prefrontal control of hypothalamic feeding circuits: Balancing executive control of eating

Principal Supervisor: Dr. John Apergis-Schoute, Department of Neuroscience, Psychology and Behaviour

Co-supervisor: Dr. James McCutcheon

PhD project title: Prefrontal control of hypothalamic feeding circuits: Balancing executive control of eating

University of Registration: University of Leicester 

Project outline:

In nature the critical need to achieve energy homeostasis produces a fascinating repertoire of complex behaviour performed by insects, fish, birds, and mammals. For meeting these energetic needs a multitude of neural systems are required to act cooperatively influencing one another’s activity for effective foraging behaviour. Through controlled laboratory work scientists have been able to begin to bridge the gaps in our understanding on how the anatomy of the nervous system functions for orchestrating the activity of sensorimotor, memory, reward, fear, and decision making circuits for producing such rich and biologically-crucial behaviour. Much experimental work has revealed how primary feeding circuits of the hypothalamus respond and drive feeding behaviour through bottom-up processing. It has been shown that the hypothalamus in many ways acts as a “sixth” sensory system responding to peripheral energy-related cues and interoceptive signals (i.e. glucose, insulin) for guiding appropriate feeding behaviour for meeting the animal’s energy demands. Under appropriate circumstances, higher-order brain regions, such as the prefrontal cortex (PFC), are required to impose “cognitive control over the hedonic urge to eat for maintaining a healthy energy balance. In extreme cases this top-down regulation of eating is disrupted resulting in maladaptive eating behaviour.

It is thought that diminished or excessive control over the drive to eat witnessed in eating disorders results from under- or over-activation of prefrontal cortical (PFC) brain regions important in decision-making. To investigate the executive control over eating this project aims to link the underlying circuitry between the PFC and feeding-promoting circuits of the hypothalamus to eating. Novel circuit-mapping strategies will be implemented to determine the functional relation between the two structures. This information will set the groundwork for relating PFC and hypothalamic activity in a rodent eating disorder model that promotes under- or over-eating. By consisting of two phases, one where animals restrict their food intake, the other where they over-consume food, we will monitor and relate changes in PFC and hypothalamic activity across phases where animals exhibit distinct feeding patterns. Finally, we will attempt to normalise this under-/over-eating by manipulating prefrontal inputs to the hypothalamus, thus determining a causal role for this circuit in influencing eating. In addition to linking executive circuits with feeding circuits this project aims to provide insight into the neural mechanisms underlying maladaptive eating behaviour.

Thus, the aim of this project is to take a multi-modal approach in determining the impact PFC-hypothalamic projections have on feeding behaviour.

To probe the neural circuits involved in this process this oject will combine advanced network imaging tools with optogenetic circuit mapping strategies both in and ex vivo in rodent eating disorder models (binge-eating paradigm).

This project has recently been funded by a Wellcome Trust Seed Award, providing all the experimental resources including a postdoctoral fellow (2 years) to carry out the proposed work.

Aim 1 will implement anatomical and in vitro optogenetic circuit mapping tools to map out the spatial organisation and synaptic impact of mPFC inputs to hypothalamic circuits.

Aim 2 will implement the rodent binge-eating behavioural paradigm together with recording methods to monitor and relate the activity of PFC and LH networks to food intake.

Aim 3 will implement the same behavioural paradigm with in vivo optogenetic loss/gain of function techniques to determine a causal role for prefrontal control of eating at the level of the hypothalamus.

This project will combine the different skill-sets of Dr. Apergis-Schoute (PI) and Dr. McCutcheon (Co-I) to yield interdisciplinary findings on the synaptic, network, and behavioural impact of PFC inputs to the hypothalamus. Dr Apergis-Schoute has publications using advanced circuit mapping strategies both in and ex vivo and has recorded extensively in hypothalamus. Dr. McCutcheon has extensive experience conducting in vivo physiology experiments and is an expert on feeding behaviour and motivation.

Reference:

  1. Aitta-aho T, Phillips BU, Pappa E, Hay YA, Harnischfeger F, Heath CJ, Saksida LM, Bussey TJ, Apergis-Schoute J. (2017) Accumbal cholinergic interneurons differentially influence motivation related to satiety signaling. eNeuro. 4:ENEURO-0328.
  2. Apergis-Schoute J, Iordanidou P, Faure C, Jego S, Schöne C, Aitta-Aho T, Adamantidis A, Burdakov D. (2015) Optogenetic evidence for inhibitory signaling from orexin to MCH neurons via local microcircuits. Journal of Neuroscience. 35:5435-41.
  3. Shipton OA, El-Gaby M, Apergis-Schoute J, Deisseroth K, Bannerman DM, Paulsen O, Kohl MM. (2014) Left–right dissociation of hippocampal memory processes in mice. Proceedings of the National Academy of Sciences. 111:15238-43.
  4. Cone JJ, Fortin SM, McHenry JA, Stuber GD, McCutcheon JE, Roitman MF. (2016) Physiological state gates acquisition and expression of mesolimbic reward prediction signals. Proceedings of the National Academy of Sciences. 113:1943-8.

BBSRC Strategic Research Priority: Molecules, cells and systems  

Techniques that will be undertaken during the project:

Advanced anatomical tracing techniques; behavioural studies of feeding for nutritional needs as well as hedonic eating; advanced surgical skills; optogenetic circuit interrogation (in vivo and in vitro); in vivo recordings.

Contact: Dr. John Apergis-Schoute, University of Leicester