Bridging further animal and human memory function using functional magnetic resonance imaging in awake rats and molecular imaging

Abstract

The Medial Temporal Lobe (MTL) of the brain has been established to be crucial for memory function. Damage to this area, as seen, for example, in aging or patients suffering from amnesia, leads to severe memory deficits. The MTL comprises the Hippocampus (HIP) and cortical areas surrounding the HIP: the parahippocampal areas. Despite decades of research on memory function, the specific role of these subareas in episodic memory, as well as their functional relationship, remains unclear. Partly because MTL damage in patients often extends to more than one MTL subregion, thereby preventing a dissociation of their function. Notably, the function and cytoarchitecture of the MTL are conserved across a various range of species, including rodents. This allows for the use of rodent models, in which invasive targeted manipulations can be implemented, to tackle questions under debate in humans. Yet, principally because of different modus operandi, findings are transferable between species only to a limited extent. For example, in functional magnetic resonance imaging (fMRI) studies, rats are usually tested under sedation while humans are awake during testing. In the present thesis, the use of two different human-to-rat translational approaches to study the role of the HIP in episodic memory was proposed. A 9.4 Tesla (T) functional MRI approach in awake rats to achieve the standard whole-brain analyses conducted in human fMRI studies was established, and a human-to-rat behavioral paradigm with a cellular resolution imaging technique based on Immediate Early Gene detection combined. Using a high throughput MRI-compatible olfactometer (Chapter 2) and a memory paradigm for awake rats that was adapted to 9.4T fMRI, we report results similar to those observed in humans, including a more important role of the HIP in processing odors for which memory could be formed in contrast to odors newly experienced (Chapter 3). Furthermore, we showed that only the contribution of some parahippocampal areas to recognition memory (such as the lateral entorhinal cortex) is inversely correlated to hippocampal function (Mahnke et al., 2021). Here we used an imaging technique with a spatial resolution high enough to dissociate the source of activity even between adjacent brain areas. The findings emerging from these two studies suggest that even though very challenging, human-to-rat translational approaches open up very promising avenues for future cross-species studies.