On the occasion of the prestigious Jenkinson Memorial Lecture, we had the pleasure to host the renowned Professor Liqun Luo from the School of Humanities and Sciences of Stanford University. Professor Luo presented his recent work on the assembly and organization of neuronal circuit using mouse and fruit fly as models.
The number of synapses exceeds by far the number of neurons, and there still exist many unknowns in our understanding of how the neurons connect to each other in the brain during development. Professor Luo is tackling these difficult questions to understand the logic of brain wiring using cutting-edge genetic tools.
In his talk, he first detailed his research findings on the assembly of the fly olfactory circuit. In the antennal lobe of Drosophila, the axons of a single type of olfactory receptor neuron (ORN) synapse with dendrites of a single type of projection neuron (PN). This characteristic makes the antennal lobe an ideal neural circuit to understand how wiring specificity between specific cell types is established during development.
We learned that the PN dendrites pre-pattern the antennal lobe and that the ORN axons find their respective PN matches afterwards. More precisely, the PN dendrite targeting is mediated through different gradient levels of Semaphorin proteins. These Semaphorins instruct the position of the PN dendrites in the antennal lobe and thus help specify the different olfactory connections. The targeting of ORN axons also uses Semaphorins for their trajectory choices and their expression is inhibited through Notch signaling. These examples indicated to us that the same molecules can be used at different times and place and that dividing the task into consecutive steps can save molecules and increase fidelity.
Secondly, we were shown the crucial role of the evolutionarily conserved transmembrane Teneurin proteins in the brain wiring. There are two Teneurin gene copies in the fruit fly and four in mouse and human. The Teneurin proteins instruct the direct molecular recognition and matching specificity between PN dendrites and ORN axons. This suggests that molecules can specify connection at the level of a single type of neuron and synapse. Professor Luo also talked about the importance of Teneurin for the wiring specificity of the mouse hippocampal circuit. In the mouse hippocampus, the neurons of the CA1 region require the Teneurin-3 protein for proper targeting in the subiculum.
Finally, the discussion ended on a new genetic tool he developed to probe neural circuit assembly and organization. In neurobiology, the targeting of genetically encoded tools for neural circuit dissection to relevant cell populations is a major challenge. The new technique known as TRAP (targeted recombination in active population) is used in mice to obtain genetic access to the neurons that were activated by defined stimuli, utilizing an immediate early gene promoter (Fos) of neuronal activity to drive a tamoxifen-inducible Cre recombinase.
The addition of the tamoxifen drug allows the labelling of neurons that are active during a time window of less than a dozen hours and provides selective access to neurons activated by specific sensorial stimuli. We were shown how TRAP can mark neurons and reveal circuits involved in thirst motivation and remote memory. The genetic access to neurons based on their activity, in combination with other tools for tracing, labeling, recording and manipulating neurons, is a fantastically powerful method for understanding how the brain processes information and generates behavior.
At the end, we were left amazed by the wave of fascinating and avant-garde data presented to us. We are thankful to Professor Luo for delivering such an exciting Jenkinson Memorial Lecture, and look forward to learning more has he and his team continue to develop this field.
Guillaume Poncelet is a Graduate student interested in answering major questions in the field of evolutionary biology.