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Imaging neural activity during spatial learning

Principal Supervisor: Professor Nick Hartell - Department of Neuroscience, Psychology and Behaviour

Co-supervisor: Dr. Todor Gerdjikov

PhD project title: Imaging neural activity during spatial learning

University of Registration: Leicester

Project outline:

Learning requires the brain to store information. Precisely how this is acheived remains largely unknown but we do know that changes in the strength of signalling between individual synapses alters the strength of connectivity between neurones. This in turn leads to persistant changes in the firing patterns of groups of neurones. The hippocampus is often referred to as the GPS of the brain because it is important for encoding information about our spatial location within our environment. Place cells exist within the hippocampus which fire in response to a particular spatial position. These cells use information acquired from the environment, including visual information and proprioceptive signals, to update an animal about its particular position. It has recently been shown that different pyramidal cells within different layes of the hippocampus (superficial vs deep) subserve different purposes. Those that are in deeper layers (i.e. closer to the stratum oriens) are more likely to update their activity in response to goal oriented tasks whereas those in superficial layers (i.e. closer to the stratum radiatum) hold a more permanent representation of space. This separation of function would allow animals to learn new information about an environment whilst preserving a stable copy of the environment itself.

We have developed a state-of-the-art, miniature microscope that is small and light enough to be be attached to a rat’s head and allows imaging in freely moving animals, overcoming the methodological limitations of imaging in head-fixed rodents. Using fluorescent protein calcium sensors that can be targeted to specific regions within the hippocampus, we intend to record the neuronal activity of large numbers of pyramidal cells within different regions of the hippocampus to record place cell activity in freely moving animals within an environment whilst they are learning a series of behavioural taks which are dependent upon hippocampal function.

Animals will receive a stereotactic injection of virus encoding the DNA for a calcium sensor called GCaMP6F which is a highly sensitive fluorescent protein that can report the activity of neurones that receive the DNA and express it. The injections will be made in specific regions of the hippocampus. A miniature lens will be implanted over the hippocampus along with a miniature baseplate that will support the microscope. Once the animals have recovered and after sufficient time for the GCaMP6F to be expressed, we will train the animals in a variety of behavioural tasks while simultaneously acquiring high speed images of neuronal activity. For example, we will perform a reward driven spontaneous object location task which we have previously shown to be impaired in aged animals and which is dependent upon the hippocampus.

We will then test the hypothesis that pyramidal cells in superficial vs deep layers of the CA1 region of the hippocampus respectively are more or less able to acquire information about position in space using a range of behavioural tasks known to require hippocampal function. We then aim to compare the ability of cells within each layer of the CA1 region of the hippocampus (deep and superficial) to acquire and or retain information in adult and aged animals. We will then compare these results to those obtained from aged animals to establish whether a selective inability to aquire new information in the superficial hippocampus is asscociated with the known age-related deterioration in hippocampal cognitive function. We will compare the acquisition of specific behaviours with the underpinning neuronal activity in adult and aged animals.

Spatial maps are best established in response to goal oriented learning tasks leading to a representation of the reward zone. It has recently been shown that dopaminergic input to the hippocampus is important for spatial learning. We will use optogentic techniques in CRE rats to selectively inhibit hippocampal dopaminergic projections to establish whether inhibition of dopaminergic inputs to the CA1 region disrupts goal-dependent spatial learning and/or the representation of spatial information in hippocampal pyramidal cells.

BBSRC Strategic Research Priority: Molecules, cells and systems

Techniques that will be undertaken during the project:

  • Neurosurgical techniques including stereotactic injections
  • Behavioural techniques associated with models of learning Imaging in vitro and in vivo
  • Computer programing related to software development for both data acquisition and analysis
  • The use of fluorescent protein sensors for measuring neuronal activity
  • Optical development

Contact: Professor Nick Hartell, University of Leicester

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