Biology subjects

Nelson, E. C.

Publications and source records attributed to Nelson, E. C..

6 recordsLinked to original sources

bioRxiv2025

Cornichon Homolog-3 (Cnih3) deletion impairs spatial memory, reward-cue association, and fentanyl self-administration behavior.

Opioid misuse remains rampant as new synthetic opioids reach the market. Large-scale genetic tools like the GWAS identify previously unrecognized targets and biomarkers in opioid misuse with hopes of combating the opioid epidemic. One such target is the AMPAR auxiliary protein Cornichon Homolog-3 (human analog: CNIH3, mouse analog: Cnih3), which determines AMPAR subunit composition and kinetics. Though CNIH3 was identified as a gene of interest in OUD, its role in opioid use and accompanying risk factors has not been studied. Using mice with Cnih3 deletion, we assess the role of CNIH3 in risk factors for opioid use, cognition, and opioid use itself. We find that Cnih3 deletion moderately impairs spatial memory, reward-cue association, and reversal learning. Cnih3 deletion also impairs fentanyl-cue association and blunts fentanyl intake during IVSA. We use principal component analysis to pinpoint the dimensions in which Cnih3 deletion impacts behavior in an unbiased manner. Additionally, we identify in previously published human data that single-nucleotide polymorphisms are more protective against progression to daily opioid use in women than in men, suggesting a potential sex-specific role of CNIH3. These findings highlight an important role of CNIH3 in opioid use through learning and memory processes that may differ between males and females.

neuroscience↗

bioRxiv2022

Typical hippocampal transcriptional response across estrous is dysregulated by Cnih3 gene deletion

The hippocampus is a critical brain region for coordinating learning, memory, and behavior. In females, the estrous cycle alters these functions through steroid hormone activity, with well-characterized effects on cellular physiology and behavior. However, the molecular basis of these outcomes has not been systematically explored. Therefore, we profiled the transcriptome of dorsal hippocampi from female mice in each estrous cycle stage, and contrasted it with that of males. We identify only subtle sex differences in gene expression between the sexes on average, yet comparing males to individual estrous stages reveals up to thousands of genes deviating from male expression patterns at specific estrous stages. These estrous-responsive genes are especially enriched in gene markers of oligodendrocytes and the dentate gyrus, and in functional gene sets relating to estrogen response, potassium channels, and synaptic gene splicing. Next we profiled Cnih3 knockouts across estrous to provide insight into their previously reported estrous-dependent phenotypes in hippocampal synaptic plasticity, composition, and learning and memory behaviors. Surprisingly, Cnih3 knockouts showed far broader transcriptomic differences between estrous cycle stages and males. Moreover, Cnih3 knockout drove subtle but extensive expression changes accenting sex differential expresssion at diestrus and estrus. Altogether, our profiling constitutes both a resource characterizing estrous-specific gene expression patterns in the adult hippocampus, which can provide insights into mechanisms of sex differential neuropsychiatric functions and dysfunctions, while also highlighting roles of Cnih3 as a buffer against transcriptional effects of estrous and providing insights into the molecular mechanisms that may underlie estrous-dependent phenotypes with its loss.

neuroscience↗

bioRxiv2019

Cornichon Homolog-3 (CNIH3) Modulates Spatial Memory in Female Mice

Cornichon homolog-3 (CNIH3) is an AMPA receptor (AMPAR) auxiliary protein that traffics AMPARs to the postsynaptic membrane and potentiates AMPAR signaling. AMPARs are key components of hippocampal synaptic plasticity and memory formation, however the role of CNIH3 in memory has yet to be elucidated. To study the role of CNIH3 on mouse behavior, we bred and characterized a line of Cnih3-/- mice from C57BL/6 Cnih3tm1a(KOMP)Wtsi mice obtained from the Knockout Mouse Project (KOMP). In agreement with previous studies of CNIH3 in the brain, we observed concentrated expression of Cnih3 in the dorsal hippocampus, a region associated with spatial learning and memory. Therefore, we tested Cnih3+/+, Cnih3+/-, and Cnih3-/- mice in the Barnes maze paradigm to measure spatial memory. We observed no change in spatial memory in male Cnih3+/- and Cnih3-/- mice compared to male Cnih3+/+ controls, however, Cnih3-/- female mice made significantly more primary errors, had a higher primary latency, and took less efficient routes to the target in the maze compared to Cnih3+/+ female mice. Next, to investigate an enhancement of spatial memory by Cnih3 overexpression, specifically in the dorsal hippocampus, we developed an AAV5 viral construct to express wild-type Cnih3 in excitatory neurons. Female mice overexpressing Cnih3 made significantly fewer errors, had a lower primary latency to the target, and took more efficient routes to the maze target compared to YFP expressing control females. No change in spatial memory was observed in male Cnih3 overexpression mice. This study, the first to identify sex-specific effects of the AMPAR auxiliary protein CNIH3 on spatial memory, provides the groundwork for future studies investigating the role of CNIH3 on sexually dimorphic AMPAR-dependent behavior and hippocampal synaptic plasticity.

neuroscience↗

bioRxiv2019

Single cell transcriptomics reveals opioid usage evokes widespread suppression of antiviral genes

Chronic opioid usage not only causes addiction behavior through the central nervous system (CNS), but it also modulates the peripheral immune system. However, whether opioid usage positively or negatively impacts the immune system is still controversial. In order to understand the immune modulatory effect of opioids in a systematic and unbiased way, we performed single cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from opioid-dependent individuals and non-dependent controls. We show that chronic opioid usage evokes widespread suppression of interferon-stimulated genes (ISGs) and antiviral gene program in naive monocytes and upon ex vivo stimulation with the pathogen component lipopolysaccharide (LPS) in multiple innate and adaptive immune cell types. Furthermore, scRNA-seq revealed the same phenomenon with in vitro morphine treatment; after just a short exposure to morphine stimulation, we observed the same suppression of antiviral genes in multiple immune cell types. These findings indicate that both acute and chronic opioid exposure may be harmful to our immune system by suppressing the antiviral gene program, our bodys defense response to potential infection. Our results suggest that further characterization of the immune modulatory effects of opioid use is critical to ensure the safety of clinical opioid usage.

genomics↗

bioRxiv2019

Stem-cell-ubiquitous genes spatiotemporally coordinate division through regulation of stem-cell-specific gene networks

Stem cells are responsible for generating all of the differentiated cells, tissues, and organs in a multicellular organism and, thus, play a crucial role in cell renewal, regeneration, and organization. A number of stem cell type-specific genes have a known role in stem cell maintenance, identity, and/or division. Yet, how genes expressed across different stem cell types, referred here as stem-cell-ubiquitous genes, contribute to stem cell regulation is less understood. Here, we find that, in the Arabidopsis root, a stem-cell-ubiquitous gene, TESMIN-LIKE CXC2 (TCX2), controls stem cell division by regulating stem cell-type specific networks. Development of a mathematical model of TCX2 expression allowed us to show that TCX2 orchestrates the coordinated division of different stem cell types. Our results highlight that genes expressed across different stem cell types ensure cross-communication among cells, allowing them to divide and develop harmonically together.

systems biology↗

bioRxiv2017

Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, United Kingdom, and United States, comprising a total of 52,506 phenotyped individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs at a genome-wide level of significance in KITLG, DOCK8, and a broad region of 9q32. In a bivariate analysis combining the nevus results with those from a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level of significance. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis via genes we can show to be expressed under control of the MITF melanocytic cell lineage regulator.

genetics↗