Characterization of Human Olfactory Amygdala Subregions

Specific Aims:

The human amygdala is part of primary olfactory cortex, in that it receives direct monosynaptic input from the olfactory bulb1-4. This suggests an important role for the amygdala in olfactory processing, yet the anatomical and functional properties of olfactory inputs to the human amygdala are largely unexplored. The overarching goal of this proposal is to elucidate the role of amygdala subregions in human olfactory processing.

The olfactory bulb projects in parallel to multiple cortical areas, each of which is thought to play a unique role in olfactory processing5-10. Within the amygdala, several distinct subregions receive direct, monosynaptic bulb input, suggesting distinct roles, yet their olfactory functions are not fully understood. Rodent studies have begun to explore potential roles for these subregions in olfactory-guided social and approach/avoid behaviors11- 15, with the first-ever recordings of the posterolateral cortical amygdala accomplished recently16. However, our understanding of these areas is still incomplete. Notably, most rodent studies on the olfactory amygdala subregions have focused on the accessory olfactory system, which humans lack. Furthermore, most human studies have not considered olfactory amygdala subregions separately17-21. This is a critical consideration, both because the majority of amygdala subregions do not receive olfactory inputs and because those that do likely play distinct roles in olfactory processing. These roles cannot be understood without analyzing the subregions separately. Thus, there is a strong need for more research into the role of the human amygdala subregions in olfaction. Importantly, olfactory amygdala subregions have been implicated in SUDEP22-26, the leading cause of death in temporal lobe epilepsy. Understanding the anatomical and functional properties of these regions is therefore of clinical importance as well.

This research will study human olfactory amygdala subregions using a multi-faceted, rigorous approach. It will combine specialized high-resolution diffusion-weighted imaging, high-resolution amygdala-targeted fMRI, rare direct electrical stimulation of the human amygdala (purely clinically prescribed) and human psychophysics, each suited to address a different question.

Aim 1: To anatomically and functionally characterize the primary olfactory cortical regions of the human amygdala. Experiments for this aim will carefully characterize human primary olfactory amygdala subregions at the anatomical and functional levels. Experiment 1A will use specialized diffusion- weighted imaging to localize olfactory tracts projecting to and from amygdala subregions. Experiment 1B will use resting fMRI and k-means clustering algorithms to parcellate and characterize amygdala subregions based on distinct whole-brain functional connectivity profiles. Experiment 1C will use event-related fMRI to functionally localize odor-responsive subregions of the amygdala. The hypothesis is that the medial, cortical and periamygdaloid subregions of the amygdala will exhibit structural connectivity with the olfactory bulb, enhanced odor-responsiveness compared to other subregions, and distinct whole-brain functional connectivity profiles.