The main aim of this project is to track neuronal activity, in the hippocampus and in the striatal complex, in response to different spatial learning experiences and at different stages of the learning process. We propose to use the behavior-correlated and anatomically detailed IEG activation patterns to simulate hippocampus and hippocampal-striatal circuit dynamics in the BS and HPAC platforms.
Neuronal immediate early genes (IEGs) play an important role in the neuroplastic mechanisms supporting memory formation, and represent an useful tool to identify the level of neuronal activation during different types of learning or at different stages of the memorization process. We plan to use IEGs expression as a marker, to investigate simultaneously in the same subject the pattern of activation of a wide array of brain structures, with a particular focus on the hippocampus and the striatum in their different anatomical subregions. We will evaluate the expression of IEG such as Fos, Zif268 or Arc after behavioral testing in the Morris water maze using immunofluorescence in outbred wild type mice and/or the transgenic mouse line Arc:CreERT2/RC:LSL Tomato tamoxifen inducible (Denny et al., 2014), that will allow us to tag permanently neuronal activation during specific time windows, such as the acquisition or the recall process.
Although IEGs mapping, compared to electrophysiology, provides a type of information that is static and can be considered only a proxy for neural activity, we have chosen this approach because it also has several advantages over other methodologies. Notably, IEGs expression can be evaluated in intact animals and allows to probe a vast number of brain regions and subregions simultaneously in the same individual, with a very high spatial resolution. Moreover, state of the art transgenic animals and viral tools allow permanent tagging of activated neurons and identification of neurons activated by two different learning experiences or at different stages of the learning process in the same subject. Moreover, double/triple staining with cell-types specific markers will allow us to obtain also a more detailed morphological characterization of activated cells.
Currently many behavioural and electrophysiological evidence suggest a cross structural interplay between hippocampus and the striatal complex in the processing of spatial information, however not much is known on how the striatal circuits and their connections to the hippocampus are involved in the formation and storage of spatial memory. The tools available in the HBP infrastructure, and in particular the use cases for in silico experiments would allow to perform a deeper and more complex analysis that could really lead to a generation of a specific cell/structure activation model in response to different experimental conditions.
Collaboration with HBP
Joining the HBP Flagship, gives us the opportunity to collaborate with leaders in the field of neuroinformatics and brain simulation and access to state of the art computational and modeling resources.
Behavioural and anatomical readouts from wild type and transgenic mice, using different behavioral procedures, will be uploaded into the Knowledge Graph of the Neuroinformatics Platform and analysed to extract different navigational strategies that will be used to make comparison with IEGs expression within structures at various time points and carry out realistic modeling of the involved microcircuits. The simulations will be carried out using the BSP and the HPACP.
This project will contribute to the HBP objective by generating detailed and correlated behavioral and anatomical data that could contribute to building of realistic models of hippocampal-striatal circuits and could be used to carry on simulations of hippocampalstriatal interaction. Moreover both the biological data and the simulations will be available to the scientific community through the BSP.
Time frame: 2019 to 2020
Origin: HBP Voucher Programme