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.

De novo genes and the long-term direction of their subsequent evolution

Joanna Masel from the University of Arizona, Department of Ecology & Evolutionary Biology

Most of the work in Joanna’s group these days is connected in some way to evolvability. Joanna is most interested in models that explicitly capture mechanistic constraints, whether from biochemistry, genetics, cellular biology, physiology, or ecology, and work out their evolutionary consequences. Specific interests at the moment include the robustness and evolvability of biological systems, the origins of coding sequences from non-coding ancestors, and the tension between relative and absolute competitions in evolution, ecology, and economics.

Host: Alan Moses

 

Sequence-function relationships in intrinsically disordered regions through the lens of evolution

PhD Exit Seminar

Taraneh Zarin (Moses lab)

Intrinsically disordered regions (IDRs) are regions of proteins that do not autonomously fold into stable secondary or tertiary structures. Though they defy the classical view of proteins as rigidly structured macromolecules, IDRs are widespread in living organisms, and are involved in a diverse array of functions. The majority of IDRs appear to be rapidly evolving at the level of the primary amino acid sequence, which makes it difficult to quantify evolutionary conservation and associate these regions with biological function using standard sequence analysis. The aim of my thesis research has thus been to understand evolutionary constraint and sequence-function relationships in IDRs. Using a functionally characterized IDR in the yeast protein Ste50, I first found that highly diverged amino acid sequences can encode conserved phenotypes in IDRs, showing that sequence divergence does not necessarily imply functional divergence in these regions. Using a phylogenetic comparative framework, I found that the net charge of the Ste50 IDR, rather than the precise amino acids, is a functional molecular feature that is preserved over evolution. I next expanded my evolutionary analysis of IDRs to the yeast proteome, and found that most highly diverged IDRs contain many molecular features that are preserved over evolution. I summarized the evolution of these molecular features with an “evolutionary signature” for each IDR, and found that groups of IDRs with similar evolutionary signatures are enriched for specific biological functions. I also found that IDRs with similar evolutionary signatures can rescue function in vivo despite negligible sequence similarity. Finally, I used these evolutionary signatures to train a statistical model, and found that they can be used to classify IDRs for a diverse set of biological functions. I identified the molecular features contributing to these functional predictions, and attributed distinct functions to specific IDRs in proteins with multiple IDRs. Overall, this work shows that there is rich functional information in IDR sequences, and that this information can be revealed through evolutionary analysis.