Biology subjects

Zhao, X.-Y.

Publications and source records attributed to Zhao, X.-Y..

3 recordsLinked to original sources

bioRxiv2024

Hijacking a dedicated entorhinal-hippocampal extinction circuit to remove traumatic memory

Effective psychotherapy of post-traumatic stress disorder (PTSD) remains challenging due to the fragile nature of fear extinction, for which ventral hippocampal CA1 (vCA1) region is considered as a central hub. However, neither the core pathway nor the cellular mechanisms involved in implementing extinction are known. Here, we unveil a direct pathway, where layer 2a fan cells in the lateral entorhinal cortex (LEC) target parvalbumin-expressing interneurons (PV-INs) in the vCA1 region to propel low gamma-band synchronization of the LEC-vCA1 activity during extinction learning. Bidirectional manipulations of either hippocampal PV-INs or LEC fan cells suffice fear extinction. Gamma entrainment of vCA1 by deep brain stimulation (DBS) or noninvasive transcranial alternating current stimulation (tACS) of LEC persistently enhances the PV-IN activity in vCA1, thereby promoting fear extinction. These results demonstrate that the LEC-vCA1 pathway forms a top-down motif to empower low gamma-band oscillations that facilitate fear extinction. Finally, application of low gamma DBS and tACS to a mouse model with persistent PTSD shows potent efficacy, suggesting that the dedicated LEC-vCA1 pathway can be hijacked for therapy to remove traumatic memory trace. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/593830v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@ca6768org.highwire.dtl.DTLVardef@4ae574org.highwire.dtl.DTLVardef@11e4ff5org.highwire.dtl.DTLVardef@1136cc2_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Neuropeptide Y co-opts neuronal ensembles for memory lability and stability

Memory engrams are formed by activity-dependent recruitment of distinct subsets of excitatory principal neurons (or neuronal ensembles) whereas inhibitory neurons pivot memory lability and stability1-5. However, the molecular logic for memory engrams to preferentially recruit specific type of interneurons over other subtypes remains enigmatic. Using activity-dependent single-cell transcriptomic profiling6-8 in mice with training of cued fear memory and extinction, we discovered that neuropeptide Y (NPY)-expressing (NPY+) GABAergic interneurons in the ventral hippocampal CA1 (vCA1) region exert fast GABAergic inhibition to facilitate the acquisition of memory, but bifurcate NPY-mediated slow peptidergic inhibition onto distinct sub-ensembles underlying the extinction of single memory trace. Genetically encoded calcium and NPY sensors revealed that both calcium dynamics of NPY+ neurons and their NPY release in vCA1 ramp up as extinction learning progresses while behavioral state switches from "fear-on" to "fear-off". Bidirectional manipulations of NPY+ neurons or NPY itself demonstrated NPY is both necessary and sufficient to control the rate and degree of memory extinction by acting on two physically non-overlapping sub-ensembles composed of NPY1R- and NPY2R-expressing neurons. CRISPR/Cas9-mediated knockout of NPY2R or NPY1R further unravels that NPY co-opts its actions on these two sub-ensembles to gate early fast and late slow stages of extinction. These findings exemplify the intricate spatiotemporal orchestration of slow peptidergic inhibitions from single subtype of GABAergic interneurons to fine-tune engram lability verse stability of memory.

neuroscience↗

bioRxiv2023

Inducible nitric oxide synthase (iNOS) is necessary for GBP-mediated T. gondii restriction in murine macrophages via vacuole nitration and intravacuolar network collapse

Toxoplasma gondii is an obligate intracellular, protozoan pathogen of rodents and humans. T. gondiis ability to grow within cells and evade cell-autonomous immunity depends on the integrity of the parasitophorous vacuole (PV). Interferon-inducible guanylate binding proteins (GBPs) are central mediators of T. gondii clearance, however, the precise mechanism linking GBP recruitment to the PV and T. gondii restriction is not clear. This knowledge gap is linked to heterogenous GBP-targeting across a population of vacuoles and the lack of tools to selectively purify the intact PV. To identify mediators of parasite clearance associated with GBP2-positive vacuoles, we employed a novel protein discovery tool automated spatially targeted optical micro proteomics (autoSTOMP). This approach identified inducible nitric oxide synthetase (iNOS) enriched at levels similar to the GBPs in infected bone marrow-derived myeloid cells. iNOS expression on myeloid cells was necessary for mice to control T. gondii growth in vivo and survive acute infection. T. gondii infection of IFN{gamma}-primed macrophage was sufficient to robustly induce iNOS expression. iNOS restricted T. gondii infection through nitric oxide synthesis rather than arginine depletion, leading to robust and selective nitration of the PV. Optimal parasite restriction by iNOS and vacuole nitration depended on the chromosome 3 GBPs. Notably, GBP2 recruitment and ruffling of the PV membrane occurred in iNOS knockouts, however, these vacuoles contained dividing parasites. iNOS activity was necessary for the collapse of the intravacuolar network of nanotubular membranes which connects parasites to each other and the host cytosol. Based on these data we conclude reactive nitrogen species generated by iNOS cooperate with the chromosome 3 GBPs to target distinct biology of the PV that are necessary for optimal parasite clearance in murine myeloid cells.

immunology↗