11 research outputs found
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Lack of Pattern Separation in Sensory Inputs to the Olfactory Bulb during Perceptual Learning.
Recent studies revealed changes in odor representations in the olfactory bulb during active olfactory learning (Chu et al., 2016; Yamada et al., 2017). Specifically, mitral cell ensemble responses to very similar odorant mixtures sparsened and became more distinguishable as mice learned to discriminate the odorants over days (Chu et al., 2016). In this study, we explored whether changes in the sensory inputs to the bulb underlie the observed changes in mitral cell responses. Using two-photon calcium imaging to monitor the odor responses of the olfactory sensory neuron (OSN) axon terminals in the glomeruli of the olfactory bulb during a discrimination task, we found that OSN inputs to the bulb are stable during discrimination learning. During one week of training to discriminate between very similar odorant mixtures in a Go/No-go task, OSN responses did not show significant sparsening, and the responses to the trained similar odorants did not diverge throughout training. These results suggest that the adaptive changes of mitral cell responses during perceptual learning are ensured by mechanisms downstream of OSN input, possibly in local circuits within olfactory bulb
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Adult-born neurons facilitate olfactory bulb pattern separation during task engagement.
The rodent olfactory bulb incorporates thousands of newly generated inhibitory neurons daily throughout adulthood, but the role of adult neurogenesis in olfactory processing is not fully understood. Here we adopted a genetic method to inducibly suppress adult neurogenesis and investigated its effect on behavior and bulbar activity. Mice without young adult-born neurons (ABNs) showed normal ability in discriminating very different odorants but were impaired in fine discrimination. Furthermore, two-photon calcium imaging of mitral cells (MCs) revealed that the ensemble odor representations of similar odorants were more ambiguous in the ablation animals. This increased ambiguity was primarily due to a decrease in MC suppressive responses. Intriguingly, these deficits in MC encoding were only observed during task engagement but not passive exposure. Our results indicate that young olfactory ABNs are essential for the enhancement of MC pattern separation in a task engagement-dependent manner, potentially functioning as a gateway for top-down modulation
Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression
Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adap- tive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant, which THZ1 can exploit by blocking dynamic transcriptional responses, promoting remodeling of enhancers and key signaling outputs required for tumor cell survival in the setting of targeted therapy. These findings suggest that the addition of THZ1 to targeted therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations. SIGNIFICANCE: CDK7/12 inhibition prevents active enhancer formation at genes, promoting resistance emergence in response to targeted therapy, and impedes the engagement of transcriptional programs required for tumor cell survival. CDK7/12 inhibition in combination with targeted cancer therapies may serve as a therapeutic paradigm for enhancing the effectiveness of targeted therapies