Integrity of the Uncinate Fasciculus Predicts Emotional Pattern Separation-Related fMRI Signals in the Hippocampal Dentate and CA3

Alterations in white matter integrity have been demonstrated in a number of psychiatric disorders that involve disruptions in emotional processing. One such pathway - the uncinate fasciculus (UF) - connects the orbitofrontal cortex (OFC) to the medial temporal lobes (MTL) and has been associated with early life adversity, maltreatment, anxiety, and depression. While it is purported to play a role in episodic memory and discrimination, its exact function remains poorly understood. We have previously described the role of the amygdala and dentate (DG)/CA3 fields of the hippocampus in the mnemonic discrimination of emotional experiences (i.e. emotional pattern separation). However, how this computation may be modulated by connectivity between the medial temporal lobes and the orbitofrontal cortex remains unknown. Here we ask the question of whether the uncinate fasciculus plays a role in influencing MTL subregional activity during emotional pattern separation. By combining diffusion imaging with high-resolution functional MRI, we found that reduced integrity of the UF is related to higher activation in the DG/CA3 subregions of the hippocampus during an emotional pattern separation task. We additionally report that higher levels of DG/CA3 activity are associated with poorer memory performance, suggesting that hyperexcitability in this network (which may be driven by CA3 recurrent collaterals) is associated with memory errors and that the UF may allow the OFC to exert inhibitory control on this network and improve discrimination of emotional experiences. This work provides novel mechanistic insight into the role of prefrontal interactions with the MTL, particularly in the context of emotional memory.