Biology subjects

Henderson, B.

Publications and source records attributed to Henderson, B..

6 recordsLinked to original sources

bioRxiv2025

Estrogen Receptor Beta Localized on Ventral Tegmental Area Dopamine Neurons Regulates Nicotine Self-Administration Acquisition in Ovary-Intact Female Rats

Women exhibit greater nicotine use vulnerability than men. High estradiol (E2) exacerbates nicotine use outcomes in women, effects which have been modeled in preclinical nicotine self-administration (SA) studies. Nicotine SA is maintained by dopamine (DA) release from the ventral tegmental area (VTA) to the nucleus accumbens (NA). E2 exerts its effects by binding to estrogen receptors (ER), including ER, ER{beta}, and G-protein coupled ER-1 (GPER-1)s. E2 action at ERs specifically has been shown to potentiate DA neuronal excitability within the VTA. Further, we have shown that ovariectomy decreases both nicotine use during SA and VTA ER{beta} protein. Despite clear evidence of mechanistic relationships between E2, ERs, DA, and nicotine, no studies to date have functionally evaluated the specific role of ER{beta} located on VTA DA cells in driving nicotine consumption during SA in females. There are currently no tools that allow for evaluations of relationships between nicotine neurobiology and ERs with cell-type specificity, as ER{beta} is also localized on other (non-DA) cell types within the VTA. As such, the goals of the present studies were (1) to build and validate a novel adeno-associated viral construct that produces long-term knockdown of ER{beta} specifically on VTA DA neurons, and (2) to determine if VTA DA ER{beta} viral knockdown reduces nicotine SA in ovary-intact female rats. Here we show that ER{beta} regulates VTA DA neuron excitability, and that ER{beta} knockdown in VTA DA neurons reduces DA neuron firing frequency. We also show that VTA ER{beta} knockdown in DA neurons reduces nicotine SA acquisition in ovary-intact female rats. Together, our results demonstrate a critical role of ER{beta} in driving nicotine use in females, underscoring the need for future studies to evaluate neurobehavioral mechanisms of smoking through the lens of sex differences.

neuroscience↗

bioRxiv2025

Exhaled breath profiling for non-invasive monitoring of cognitive functioning in children

IntroductionChildhood is a critical period for the development of executive functioning skills, including selective attention and inhibitory control, which are essential for cognitive development. Optimal brain development during this time requires appropriate levels of macronutrient intake. Metabolomics can offer valuable insights into which metabolites cognitive functioning and the underlying gut-brain interactions. ObjectivesThis study aimed to explore to use of breathomics to investigate associations between exhaled metabolites and executive functioning in children. MethodsChildren (8-10 years; N = 31) were recruited via flyers at schools and after-school care. The assessment of executive functioning was done using Eriksen flanker task. Breath samples were collected in Tedlar(R) bags and analyzed with proton transfer reaction-mass spectrometry (PTR-MS). On-breath peaks were selected and subjected to partial least squares (PLS) regression. Significance multivariate correlation (sMC) was used afterwards to select metabolites bearing predictive power towards executive functioning. ResultsGut microbiome-related metabolites (methane, ethanol, and butyric acid) present in exhaled breath were associated with an improved executive functioning, whereas isoprene was linked to reduced executive functioning. Additionally, increased levels of inflammatory markers, ethylene and acetaldehyde, were associated with a higher compatibility effect in error rates, suggesting diminished cognitive control. These VOCs were putatively linked with specific gut microbial taxa; for instance, reduced Bacteroidetes abundance (associated with methane production) is associated with decreased inhibitory control, while Enterobacteriaceae were linked to lipopolysaccharide-induced inflammation which is also a process that causes increased ethylene production. ConclusionThis proof-of-concept study demonstrates that VOCs in exhaled breath could serve as a promising non-invasive tool for assessing gut-brain interactions related to executive functioning in children.

biochemistry↗

bioRxiv2022

PAX6 LIMITS THE COMPETENCE OF DEVELOPING CEREBRAL CORTICAL CELLS

The development of stable specialized cell types in multicellular organisms relies on mechanisms controlling inductive intercellular signals and the competence of cells to respond to such signals. In developing cerebral cortex, progenitors generate only glutamatergic excitatory neurons despite being exposed to signals with the potential to initiate the production of other neuronal types, suggesting that their competence is limited. Here we tested the hypothesis that this limitation is due to their expression of transcription factor Pax6. We used bulk and single cell RNAseq to show that conditional cortex-specific Pax6 deletion from the onset of cortical neurogenesis allowed some progenitors to generate abnormal lineages resembling those normally found outside the cortex. Analysis of selected gene expression showed that the changes occurred in specific spatiotemporal patterns. We then compared the responses of control and Pax6-deleted cortical cells to in vivo and in vitro manipulations of extracellular signals. We found that Pax6 loss increased cortical progenitors competence to generate inappropriate lineages in response to extracellular factors normally present in developing cortex, including the morphogens Shh and Bmp4. Regional variation in the levels of these factors could explain spatiotemporal patterns of fate change following Pax6 deletion in vivo. We propose that Pax6s main role in developing cortical cells is to minimize the risk of their development being derailed by the potential side-effects of morphogens engaged contemporaneously in other essential functions.

neuroscience↗

bioRxiv2020

Discordant transcriptional signatures of mitochondrial genes in Parkinson's disease human myeloid cells

An increasing number of identified Parkinsons disease (PD) risk loci contain genes highly expressed in innate immune cells, yet their potential role in pathological mechanisms is not obvious. We have generated transcriptomic profiles of CD14+ monocytes from 230 individuals with sporadic PD and age-matched healthy subjects. We identified dysregulation of genes involved in mitochondrial and proteasomal function. We also generated transcriptomic profiles of primary microglia from autopsied brains of 55 PD and control subjects and observed discordant transcriptomic signatures of mitochondrial genes in PD monocytes and microglia. We further identified PD susceptibility genes, whose expression, relative to each risk allele, is altered in monocytes. These findings reveal that transcriptomic mitochondrial alterations are detectable in PD monocytes and are distinct from brain microglia, and facilitates efforts to understand the roles of myeloid cells in PD.

neuroscience↗

bioRxiv2019

Intensive infection control responses and whole genome sequencing to interrupt and resolve widespread transmission of OXA-181 Escherichia coli in a hospital setting

BackgroundOXA-48-like carbapenemases have become increasingly prevalent in healthcare settings worldwide. Their low-level activity against carbapenems makes them difficult to identify, causing problems for infection control. Here we present an outbreak of Escherichia coli producing OXA-181 (part of the OXA-48 family of carbapenemases) in a Queensland Hospital, and describe how we used whole genome sequencing (WGS) to identify the outbreak strain, determine the extent of transmission within the hospital and support infection control responses. Methods116 isolates were collected and sequenced on an Illumina NextSeq to determine species, sequence type (ST) and presence of resistance genes. Core single nucleotide polymorphisms were used to determine strain relatedness. Three isolates were also sequenced on an Oxford Nanopore MinION to determine the context of the resistance genes. ResultsOf 116 isolates, 85 (84 E. coli and one K. pneumoniae) from 78 patients (and two environmental sources) were related to the ongoing outbreak. The outbreak E. coli strain was found to be ST38 and carried blaOXA-181, blaCTX-M-15 and qnrS1 genes. Long read sequencing revealed blaOXA-181 to be carried on an IncX3 plasmid with qnrS1. blaCTX-M-15 was chromosomally integrated (via ISEcp1 insertion) in close proximity to a second qnrS1 gene. A search of the laboratory database identified an isolate with an identical unusual antibiogram from a patient recently admitted to a hospital in Vietnam, suggesting that the strain was introduced to the hospital. This conclusion was supported by WGS, as comparison of the strain to public data identified a close match to an E. coli recovered from Vietnam in 2011. ConclusionA blaOXA-181-carrying E. coli ST38 strain was introduced to a Brisbane hospital and spread undetected throughout multiple wards over several months. Using WGS, we characterized the outbreak strain and unambiguously detected its presence throughout the hospital. We show how both WGS and infection control measures can be utilized to effectively terminate widespread transmission of an elusory pathogen.

microbiology↗

bioRxiv2019

Single cell transcriptome analysis reveals markers of naive and lineage-primed hematopoietic progenitors derived from human pluripotent stem cells.

During embryogenesis the hematopoietic system develops through distinct waves that generate progenitors with increasing lineage potential, ultimately producing haematopoietic stem cells (HSCs). In vitro differentiation of human pluripotent stem cells (hPSCs) follows the early steps of haematopoietic development but the production of HSCs has proven more challenging. To study the dynamics and heterogeneity of hematopoietic progenitor cells generated in vitro from hPSCs, we performed RNA sequencing of over 10000 CD235a-CD43+single cells. We identified the transcriptome of naive progenitors and those primed toward erythroid, megakaryocyte and leukocyte lineages, and revealed their markers by clustering, trajectory analyses and functional assays. CD44 marks naive clonogenic progenitors that express the transcription factor, LMO4 and can be expanded upon BMP4 stimulation. Naive progenitors give rise to primed CD326+erythroid, ICAM2+CD9+megakaryocyte, and monocyte, neutrophil and eosinophil progenitors. We have generated an online dataset of human hematopoietic progenitors and their transcriptional remodelling upon lineage priming.

developmental biology↗