Biology subjects

Craske, M.

Publications and source records attributed to Craske, M..

2 recordsLinked to original sources

bioRxiv2021

Differential Expression of α,β, and γ Protocadherin Isoforms During Differentiation, Aging, and Cancer

The cadherin family of cell surface glycoproteins plays a fundamental role in cell-cell recognition, thereby participating in diverse biological process such as embryonic morphogenesis and oncogenic transformation. The subset of clustered protocadherin (PCDH) genes generated from the , {beta}, and {gamma} loci, have been widely studied for their potential role in neuronal cell-cell recognition and neurogenesis, however their broader role in normal embryonic development and cancer has not been examined in detail. We utilized human embryonic stem (hES) cells to model early human development in vitro, comparing PCDH isoform transcription in diverse types of embryonic progenitors with normal adult-derived and cancer counterparts. Embryonic progenitors express genes from the and {beta} cluster at levels comparable to that seen in the CNS, while fetal and adult-derived cells express primarily from the {gamma} cluster. Replicative senescence left fibroblasts with markedly lower expression of all isoforms. We observe that an embryonic pattern of clustered protocadherin gene expression and associated CpG island methylation is commonly associated with cancer cell lines from diverse tissue types. The differential regulation of the , {beta}, and {gamma} loci coincide with alternate regions of DNA accessibility at CTCF binding sites and lamina-associated domains and CPL expression correlated with the expression of LMNA and LMNB1. These observations support a potential role for the differential regulation of genes within the clustered protocadherin locus in selective cell-cell adhesion during embryogenesis, regeneration, cancer and aging.

developmental biology↗

bioRxiv2018

The effects of the angiotensin II receptor antagonist losartan on appetitive versus aversive learning

Exposure therapy is a first-line treatment for anxiety disorders but remains ineffective in a large proportion of patients. A proposed mechanism of exposure involves a form of inhibitory learning where the association between a stimulus and an aversive outcome is suppressed by a new association with an appetitive or neutral outcome. The blood pressure medication losartan augments fear extinction in rodents and might have similar synergistic effects on human exposure therapy, but the exact cognitive mechanisms underlying these effects remain unknown. In this study, we used a reinforcement learning paradigm with compound rewards and punishments to test the prediction that losartan augments learning from appetitive relative to aversive outcomes. Healthy volunteers (N=53) were randomly assigned to single-dose losartan (50mg) versus placebo. Participants then performed a reinforcement learning task which simultaneously probes appetitive and aversive learning. Participant choice behaviour was analysed using both a standard reinforcement learning model and by analysis of choice switching behaviour. Losartan significantly reduced learning rates from aversive events (losses) when participants were first exposed to the novel task environment, while preserving learning from positive outcomes. The same effect was seen in choice switching behaviour. Losartan enhances learning from positive relative to negative events. This effect may represent a computationally defined neurocognitive mechanism by which the drug could enhance the effect of exposure in clinical populations.

neuroscience↗