Using all-optical interrogation to study the brain
Dr. Huiqi Zhang (Post-doctoral Fellow)
[Supervisor: Professor Michael Hӓusser]

All-optical interrogation - the simultaneous combination of two-photon imaging and targeted optogenetic photostimulation - provides an unprecedented toolkit for reading and writing activity in the brain at cellular resolution. By enabling the precise observation and manipulation of intact neural circuits in real time in behaving mice, this strategy is revolutionizing the dissection of circuit dynamics, mapping of functional connectivity, and the forging of causal links between neural circuit activity and behaviour. To maximize the impact of this approach, optimizing photostimulation efficacy is critical. We systematically evaluated the impact of laser repetition rates and pulse widths during in vivo two-photon optogenetic photostimulation using ChRmine expressed in cortical pyramidal neurons. Lowering the repetition rate and pulse width (while matching average power) significantly enhanced single-cell activation efficacy, conforming to theoretical two-photon absorption predictions. These optimized parameters provide a foundation for robust high-throughput circuit manipulation, moving us closer to more powerful circuit interrogation and providing the basis for novel optical brain-computer interfaces.

β-catenin–induced serum amyloid a reprograms THBS1⁺ monocytes to drive immunotherapy resistance in CTNNB1-mutant hepatocellular carcinoma
Dr. Huajian Yu (Post-doctoral Fellow)
[Supervisor: Professor Stephanie Ma]

CTNNB1-mutant hepatocellular carcinoma (HCC) is refractory to immune checkpoint blockade (ICB), yet the underlying cellular mechanisms remain incompletely defined. Here, we identify a conserved population of monocyte cells marked by Thrombospondin-1 (THBS1) that is selectively expanded in CTNNB1-mutant tumors. These monocytes localize in proximity to CD8⁺ T cells at the tumor margin and suppress T cell proliferation and cytotoxic function. Myeloid-specific deletion of THBS1 restores anti-tumor CD8⁺ T cell function and suppresses tumor growth. Mechanistically, CTNNB1-mutant tumor cells secrete Serum Amyloid A (SAA) proteins to reprogram circulating naïve monocytes into THBS1⁺ immunosuppressive monocytes. Notably, high abundance of THBS1⁺ monocytes predict poor overall survival and primary ICB resistance exclusively in CTNNB1-mutant patients. Collectively, targeting this myeloid population may restore immunotherapy response in this genetically defined, treatment-refractory HCC subset.

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