Fornix subdivisions and spatial learning: a diffusion MRI study

The fornix is the major fibre pathway linking the hippocampal formation with distal brain sites. Human and animal lesion studies show that the connections comprising the fornix are vital for specific attributes of episodic and spatial memory. The fornix, however, interconnects the hippocampal formation with an array of subcortical and cortical sites and it is not known which specific connections support spatial-mnemonic function. To address this, utilizing a partly previously published dataset (Hodgetts et al., 2020), we applied a novel deterministic tractography protocol to diffusion-weighted magnetic resonance imaging (dMRI) data from a group of healthy young adult humans who separately completed a desktop-based virtual reality analogue of the Morris water maze task. The tractography protocol enabled the two main parts of the fornix, delineated previously in axonal tracing studies in rodents and primates, to be reconstructed in vivo, namely the pre-commissural fornix (connecting the hippocampus to medial prefrontal cortex and with basal forebrain) and the post-commissural fornix (linking the hippocampus and medial diencephalon). We found that inter-individual differences in pre-commissural - but not, surprisingly, post-commissural - fornix microstructure (indexed by free water corrected fractional anisotropy, FA) were significantly correlated with individual differences in spatial learning, indexed by reduction in search error as individuals learned to navigate to a hidden target location from multiple starting points. Specifically, higher FA in the pre-commissural fornix was associated with faster learning rates. This study provides novel evidence that flexible and/or precise spatial learning involves a hippocampal-basal forebrain/prefrontal network underpinned in part by the pre-commissural fornix.