PhD Exit Seminar- Afif Aqrabawi

An Olfactory Memory Circuit

Episodic memory is defined simply as memory for what happened, when, and where. The hippocampus mediates episodic memory and represents contextual information using the parameters of space and time, including where an event unfolded and the sequential order of related events. Episodic recollections are characterized by rich multisensory details, yet the mechanisms underlying the reinstatement of these non-spatiotemporal aspects of experience are unknown. In this thesis, we identified direct, topographically organized hippocampal projections to a poorly understood ring-like structure known as the anterior olfactory nucleus (AON). We demonstrated that manipulation of the hippocampal-AON pathway can influence odour perception and odour-guided behaviours. Selective inhibition of hippocampal-AON projections impaired mice in their ability to recognize odours associated with the spatial and/or temporal aspects of their environment. We also revealed that AON activity is generated by coincident olfactory and contextual inputs arriving from the olfactory bulb and hippocampus, respectively. Thus, we hypothesized that the AON acts as the physical repository for populations of neurons representing previously encountered odours within the context in which they occurred. The precise pattern of activity produced by the AON therefore composes the olfactory memory trace, or “odour engram”. To this end, we used a tamoxifen-inducible Cre recombinase system to control the timing of gene expression in the AON. In combination with chemo- and optogenetic tools, we manipulated tagged AON neuronal populations in a carefully designed set of behavioural paradigms. We found that AON activity is necessary and sufficient for driving the behavioural expression of specific odour memories, thereby establishing the AON as the long-term storage site for contextually-based odour engrams. This thesis represents the first demonstration of the neural substrate of odour memory in vertebrates, satisfying all criteria used for defining an engram. The ease and suitability of using olfaction will undoubtedly position the hippocampal-AON pathway as an ideal circuit model for investigating fundamental mnemonic and cognitive principles. Indeed, this model can become particularly important in translational research that may yet lead to the development of therapeutic targets for disorders of memory, such as Alzheimer’s disease.