Biology subjects

Sellers, K.

Publications and source records attributed to Sellers, K..

4 recordsLinked to original sources

bioRxiv2023

Estradiol regulates local synthesis of synaptic proteome via sex-specific mechanisms.

Estrogens, specifically 17{beta}-estradiol (estradiol), can modulate synaptic function by regulating the expression and localisation of synaptic proteins. However, the mechanisms underlying estradiols regulation of synaptic protein expression, and whether if they occur in a sex specific manner, is not well understood. In this study, using sex-specific hippocampal slice cultures and mixed-sex primary hippocampal neurons, we investigated whether local protein synthesis is required for estradiol- induced synaptic protein expression. Estradiol rapidly increased the rate of protein synthesis and the number of actively translating ribosomes along dendrites and near synapses in both male and female hippocampal neurons. Importantly, these effects occurred independently of gene transcription. Moreover, estradiol also increased the abundance of nascent proteins localised to synapses, independently of gene transcription. Specifically, estradiol increased the synaptic expression of GluN2B- containing N-methyl-D-aspartate receptors and PSD-95 in male and female hippocampus. Mechanistically, mTOR signalling was required for estradiol-induced increases in overall local protein synthesis only in male but not female hippocampus. Consistent with this, mTOR signalling mediated estradiol increases in GluN2B in male, but not female, hippocampus. Conversely, mTOR inhibition, blocked estradiol-induced increased PSD-95 expression in both male and female hippocampus. Collectively, these data suggest that the rapid modulation of local protein synthesis by estradiol is required for changes in the synaptic proteome in male and female hippocampus, and that the requirement of the mTOR signalling pathway in these effects occur in both a sex-specific and protein-dependent manner, with this signalling pathway have a greater role in male compared to female hippocampus.

neuroscience↗

bioRxiv2023

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target

With colorectal cancer (CRC) being the second most common cause of cancer-related deaths worldwide1, there is an urgent need for better diagnostic tools and new, more targeted therapies. Here we used genetically engineered mouse models (GEMMs), and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that unsupervised metabolic profiling can stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging (MSI) to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-mutant CRC, and propose one of its enzymes, i.e. adenosylhomocysteinase (AHCY), as a new therapeutic target. Collectively, we show that the profound genotype-dependent alterations in both lipid and small molecule metabolism in CRC may be exploited for tissue classification with no need for ion identification, and we applied further data analysis to expose a novel metabolic vulnerability of CRC.

cancer biology↗

bioRxiv2019

Brain-synthesized estrogens regulate cortical migration in a sexually divergent manner

Estrogens play an important role in the sexual dimorphisms that occur during brain development, including the neural circuitry that underlies sex-typical and socio-aggressive behaviors. Aromatase, the enzyme responsible for the conversion of androgens to estrogens, is expressed at high levels during early development in both male and female cortices, suggesting a role for brain-synthesized estrogens during corticogenesis. This study investigated how the local synthesis of estrogens affects neurodevelopment of the cerebral cortex, and how this differs in males and females by knockdown expression of the Cyp19a1 gene, which encodes aromatase, between embryonic day 14.5 and postnatal day 0 (P0). The effects of Cyp19a1 knockdown on neural migration was then assessed. Aromatase was expressed in the developing cortex of both sexes, but at significantly higher levels in male than female mice. Under basal conditions, no obvious differences in cortical migration between male and female mice were observed. However, knockdown of Cyp19a1 increased the number GFP-positive cells in the cortical plate, with a concurrent decrease in the subventricular zone/ventricular zone in P0 male mice. The opposite effect was observed in females, with a significantly reduced number of GFP-positive cells migrating to the cortical plate. These findings have important implications for our understanding of the role of fetal steroids for neuronal migration during cerebral cortex development. Moreover, these data indicate that brain-synthesized estrogens regulate radial migration through distinct mechanisms in males and females.

neuroscience↗

bioRxiv2017

Theta Oscillations Organize Spiking Activity in Higher-Order Visual Thalamus during Sustained Attention

Higher-order visual thalamus plays a fundamental but poorly understood role in attention-demanding tasks. To investigate how neuronal dynamics in higher-order visual thalamus are modulated by sustained attention, we performed multichannel electrophysiological recordings in the lateral posterior-pulvinar complex (LP/pulvinar) in the ferret (Mustela putorius furo). We recorded single unit activity and local field potential during the performance of the 5-choice serial reaction time task (5-CSRTT) that is used in both humans and animals as an assay of sustained attention. We found that half of the units exhibited an increasing firing rate during the delay period before stimulus onset (attention-modulated units). In contrast, the non-attention-modulated units responded to the stimulus, but not during the delay period. Spike-field coherence of only the attention-modulated neurons significantly increased from the start of the delay period until screen touch, predominantly in the theta frequency band. In addition, theta power and theta-gamma phase-amplitude coupling were elevated throughout the delay period. Our findings suggest that the theta oscillation plays a central role in orchestrating thalamic signaling during sustained attention.\n\nSignificanceImpaired sustained attention can be deadly, as illustrated by the number of motor vehicle accidents that are caused by drivers not reacting quickly enough to unexpected events on the road. Understanding how electrical signaling in higher-order visual nuclei, such as the LP/pulvinar, is modulated during tasks that require sustained attention is an important step in achieving a mechanistic understanding of sustained attention, which will eventually lead to new strategies to prevent and treat impairment in sustained attention.

neuroscience↗