Biology subjects

Rahsepar, B.

Publications and source records attributed to Rahsepar, B..

3 recordsLinked to original sources

bioRxiv2024

Spatial mapping of immunosuppressive cancer-associated fibroblast gene signatures in H&E-stained images using additive multiple instance learning

The relative abundance of cancer-associated fibroblast (CAF) subtypes influences a tumors response to treatment, especially immunotherapy. However, the extent to which the underlying tumor composition associates with CAF subtype-specific gene expression is unclear. Here, we describe an interpretable machine learning (ML) approach, additive multiple instance learning (aMIL), to predict bulk gene expression signatures from H&E-stained whole slide images (WSI), focusing on an immunosuppressive LRRC15+ CAF-enriched TGF{beta}-CAF signature. aMIL models accurately predicted TGF{beta}-CAF across various cancer types. Tissue regions contributing most highly to slide-level predictions of TGF{beta}-CAF were evaluated by ML models characterizing spatial distributions of diverse cell and tissue types, stromal subtypes, and nuclear morphology. In breast cancer, regions contributing most to TGF{beta}-CAF-high predictions ("excitatory") were localized to cancer stroma with high fibroblast density and mature collagen fibers. Regions contributing most to TGF{beta}-CAF-low predictions ("inhibitory") were localized to cancer epithelium and densely inflamed stroma. Fibroblast and lymphocyte nuclear morphology also differed between excitatory and inhibitory regions. Thus, aMIL enables a data-driven link between tissue phenotype and transcription, offering biological interpretability beyond typical black-box models.

cancer biology↗

bioRxiv2022

Theta phase specific modulation of hippocampal memory neurons

I.The theta rhythm, a quasi-periodic 4-10 Hz oscillation, is observed during memory processing in the hippocampus, with different phases of theta hypothesized to separate independent streams of information related to the encoding and recall of memories. At the cellular level, the discovery of hippocampal memory cells (engram neurons), as well as the modulation of memory recall through optogenetic activation of these cells, has provided evidence that certain memories are stored, in part, in a sparse ensemble of neurons in the hippocampus. In previous research, however, engram reactivation has been carried out using open loop stimulation at fixed frequencies; the relationship between engram neuron reactivation and ongoing network oscillations has not been taken into consideration. To address this concern, we implemented a closed-loop reactivation of engram neurons that enabled phase-specific stimulation relative to theta oscillations in the local field potential. Using this real-time approach, we tested the impact of activating engram neurons during the peak (encoding phase) and trough (recall phase) of theta oscillations. Consistent with previously hypothesized functions of theta oscillations in memory function, we show that stimulating engram neurons at the trough of theta is more effective in eliciting behavioral recall than either fixed frequency stimulation or stimulation at the peak of theta. Moreover, phase-specific trough stimulation is accompanied by an increase in the coupling between gamma and theta oscillations in CA1 hippocampus. Oure results provide a causal link between phase-specific activation of engram cells and the behavioral expression of memory.

neuroscience↗

bioRxiv2020

Hippocampal cells multiplex positive and negative engrams

The hippocampus is involved in processing a variety of mnemonic computations specifically the spatiotemporal components and emotional dimensions of contextual memory.1-3 Recent studies have demonstrated vast structural and functional heterogeneity along the dorsal-ventral axis1, 5 of the hippocampus. The ventral hippocampus has been shown to be important in the processing of emotion and valence.6-9 Here, we combine transgenic and all-virus based activity-dependent tagging strategies to visualize multiple valence-specific engrams in the vHPC and demonstrate two partially segregated cell populations and projections that respond to appetitive and aversive experiences. Next, using RNA sequencing and DNA methylation sequencing approaches, we find that vHPC appetitive and aversive engram cells display distinct transcriptional programs and DNA methylation landscapes compared to a neutral engram population. Additionally, while optogenetic manipulation of tagged cell bodies in vHPC is not sufficient to drive appetitive or aversive behavior in real-time place preference, stimulation of tagged vHPC terminals projecting to the amygdala and nucleus accumbens (NAc), but not the prefrontal cortex (PFC), had the capacity drive preference and avoidance. These terminals can also undergo a "switch" or "reset" in their capacity to drive either, thereby demonstrating their adaptable contributions to behavior. We conclude that the vHPC contains genetically, cellularly, and behaviorally distinct populations of cells processing appetitive and aversive memory engrams. Together, our findings provide a novel means by which to visualize multiple engrams within the same brain and point to their unique genetic signatures as reference maps for the future development of new therapeutic strategies. One sentence summaryThe hippocampus contains neurons that correspond to positive and negative engrams, which are segregated by their molecular, cellular, and projection-specific features.

neuroscience↗