Biology subjects

Bartlett, J.

Publications and source records attributed to Bartlett, J..

10 recordsLinked to original sources

bioRxiv2026

Distinct Modulatory Effects on Affective Biases by Different Serotonergic Psychedelics and MDMA in Male Rats: Possible Implications for Antidepressant Effects

Affective biases are important neuropsychological mechanisms by which emotions modulate cognition, behaviour and the subjective experience of mood. Previous studies have shown that the rapid-acting antidepressant, ketamine, and serotonergic psychedelic, psilocybin, modulate affective biases in a translational rat model. Both treatments differ from conventional, delayed onset antidepressants in being able to attenuate negatively biased memories and facilitate re-learning with a more positive affective valence. Psilocybin, but not ketamine, also positively biased new experiences, an effect similar to conventional antidepressants. This study used the different affective bias test protocols, in adult male rats, to investigate the effects of acute treatment with the serotonergic psychedelics N,N-DMT, LSD and 5-MeO-DMT, and MDMA. These drugs have different pharmacology in relation to their effects on serotonin receptor subtypes and we hypothesised this may influence their modulation of affective biases. When comparing the ability to attenuate a negatively biased memory, only MDMA had specific effects although for all drugs tested, retrieval of the FG7142-induced negative affective bias was more variable and less robust statistically. LSD attenuated the negative bias at higher doses but had non-specific effects on memory retrieval. At 24hrs post treatment only N,N-DMT had a sustained effect and none of the treatments facilitated re-learning with a more positive affective valence. However, like psilocybin and conventional antidepressants, N,N-DMT positively biased new experiences. These findings suggest there are divergent affective bias modulating effects associated with different psychedelics which may be relevant to their antidepressant effects.

neuroscience↗

bioRxiv2026

A spoonful of what helps the medicine go down? Improving the reliability of voluntary ingestion for oral dosing in rats and mice

Voluntary ingestion is a refined method for substance administration that can replace oral gavage in rats and mice. It requires no physical restraint and has no associated risks of adverse effects, resulting in improved welfare and reduced distress for both animals and research staff. This method has been shown to be effective for a variety of compounds but is still not widely used due to concerns about accuracy and reliability. One potential issue is aversion to the taste of the compound being administered, including a common issue of bitter taste. In this study we tested compounds used in oral preparations for human medicines to mask bitter tasting drugs, including a commercial formulation designed for this purpose, Bitter Drug Powder (BDP). The masking agents were given in combination with a palatable vehicle (10% condensed milk) and the amount consumed and time to consume recorded. Animals were first habituated to the vehicle with reliable ingestion achieved within a few days. In the first studies, only BDP was fully effective at masking the bitter taste of quinine and preventing the progressive reduction in reliability of intake of the antidepressant, venlafaxine in mice and rats. We were able to replicate these effects using a combination of two different artificial sweeteners, saccharine and acesulfame K, and a thickening agent xanthan gum. These studies demonstrate that using a masking agent can improve the reliability of voluntary oral dosing in mice and rats and provide evidence to support a formulation which is readily available for researchers.

pharmacology and toxicology↗

bioRxiv2026

Inhibition of cortico-amygdala projections underlies affective bias modification by psilocybin

Psilocybin, a serotonergic psychedelic, can produce rapid and enduring antidepressant effects in patients with major depressive disorder (MDD)[1, 2], yet the neural mechanisms underlying these effects remain unclear. Negative affective biases are an important neuropsychological mechanism central to the development and perpetuation of MDD[3]. Using a translational rodent model, we previously demonstrated that psilocybin modulates negative affective biases which, we hypothesize, contribute to its antidepressant effects[4]. Here, we identify the prelimbic subregion (PrL) of the rat medial prefrontal cortex (mPFC) as a key locus for the modulation of affective biases by psilocin, the active metabolite of psilocybin, and reveal a cell-type-specific bidirectional regulation of synaptic transmission. Psilocin selectively suppressed excitatory synaptic input to cortico-amygdala (CA) projection neurons, but enhanced excitatory transmission to other, putatively cortico-cortical, targets. Interestingly, suppression of the excitatory input to CA cells by psilocin, and modulation of affective biases by psilocybin, were both dependent on 5HT1A and 5HT2A receptor signaling. Consistent with the long-term therapeutic effects of rapidly acting antidepressants[1, 2, 4, 5], psilocin produced sustained changes to affective biases evident 24 hours after PrL infusion. In parallel, the suppressed excitatory transmission shifted to enhanced inhibitory synaptic input selectively in CA cells. Finally, chemogenetic inhibition of CA neurons in PrL recapitulated both the acute and sustained modulation of negative affective biases by psilocybin, as well as positively biasing new reward memories. Together, these findings identify modulation of the PrL cortico-amygdala circuit as a key substrate for affective bias modification by psilocybin, an effect which could explain its rapid and sustained antidepressant actions.

neuroscience↗

bioRxiv2025

Modulation of negative affective biases in male rats may predict the rapid and sustained antidepressant effects of different NMDA antagonists

Affective biases influence cognitive and emotional behaviour and play a significant role in major depressive disorder. We have shown that the NMDA antagonist and rapid-acting antidepressant, ketamine, selectively modulates affective biases, a neuropsychological effect which may underlie its efficacy. Clinical studies with different NMDA antagonists have found mixed effects but the reasons for these differences in efficacy are not understood. This study used a rat model of negative affective biases to investigate if different NMDA antagonists also differentially modulated affective biases. Dose-response experiments using the NMDA antagonists lanicemine, memantine, CP101,606, phencyclidine (PCP) and ephenidine, and ketamine metabolite, (2R,6R)-hydroxynorketamine (HNK), were performed to test their acute and sustained (24hrs) effects, and specificity of affective bias modulation. Our results showed that HNK, PCP, lanicemine, and ephenidine acutely attenuate negative biases. HNK, CP-101,606, and ephenidines effects were sustained at 24hrs post-treatment with a positive bias observed for HNK and a tendency towards a positive affective bias for CP101,606 and ephenidine. Lanicemines effects were sustained at 24hrs but only at the highest dose and PCP and memantine had no effects. Considering these findings in the context of clinical observations, we suggest that the ability to induce a sustained modulation of affective biases corresponds with therapeutic effects. The differences in efficacy observed with NMDA antagonists may be related to their ion trapping properties and those with very high and low ion trapping properties are less effective than those with more moderate ion trapping effects such as ketamine or ephenidine or the subunit selective antagonist, CP101,606.

pharmacology and toxicology↗

bioRxiv2020

Detection of complex genetic architecture using two-locus population differentiation: modeling epistasis

Recent advances in genetics have increased our understanding of epistasis as important in the genetics of complex phenotypes. However, current analytical methods often cannot detect epistasis, given the multiple testing burden. To address this, we extended our previous method, Evolutionary Triangulation (ET), that uses differences among populations in both disease prevalence and allele frequencies to filter SNPs from association studies to generate novel interaction models. We show that two-locus ET identified several co-evolving gene pairs, where both genes associate with the same disease, and that the number of such pairs is significantly greater than expected by chance. Traits found by two-locus ET included those related to pigmentation and schizophrenia. We then applied two-locus ET to the analysis of preterm birth (PTB) genetics. Using ET to filter SNPs at loci identified by genome-wide association studies (GWAS), we showed that ET derived PTB two-locus models are novel and were not seen when only the index SNPs were used to generate epistatic models. One gene pair, ADCY5 and KCNAB1 5’, was identified as significantly interacting in a model of gestational age (p as low as 3 × 10−3). Notably, the same ET SNPs in these genes showed significant interactions in three of four cohorts analyzed. The robustness of this gene pair and others, demonstrated that the ET method can be used without prior biological hypotheses based on SNP function to select variants for epistasis testing that could not be identified otherwise. Two-locus ET clearly increased the ability to identify epistasis in complex traits.View Full Text

genetics↗

bioRxiv2020

MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in ALS-FTD

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative diseases that are increasingly understood to have long prodromal periods. Investigation of these early stages promises to yield valuable biomarkers of disease and will be key to understanding mechanisms underlying the genesis of ALS-FTD. Here, we use in vivo magnetic resonance imaging (MRI), histology and computed tomography to identify structural and cellular readouts of early stage disease in the TDP-43Q331K knock-in mouse model of ALS-FTD. Adult mutant mice demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of ALS-FTD. Subcortical, cerebellar and brain stem regions were also affected in line with observations in presymptomatic carriers of mutations in C9orf72, the commonest genetic cause of both ALS and FTD. Volume loss, as measured by MRI, was also observed in the dentate gyrus (DG) of the hippocampus, along with ventricular enlargement. Guided by these imaging findings, detailed post-mortem brain tissue analysis revealed reduced parvalbumin-positive (PV+) interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia were in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the DG, indicative of impaired adult neurogenesis, while a paucity of PV+ interneurons in juvenile mutant mice (P14) suggests that TDP-43Q331K disrupts neurodevelopment. Computerised tomography imaging also showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem prefrontal cortices confirmed a paucity of PV+ interneurons in the prefrontal cortex in cases with both sporadic ALS and ALS linked to C9orf72 mutations. This study suggests an important role for PV+ interneurons in regional brain vulnerability associated with ALS-FTD, and identifies novel MRI and histological biomarkers that will be of value in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice.

neuroscience↗

bioRxiv2020

Revealing heritability missed by single locus analyses by examining epistasis in mouse chromosome substitution strains

The genetic contribution of additive versus non-additive (epistatic) effects in the regulation of complex traits is unclear. While genome-wide association studies typically ignore gene-gene interactions, in part because of the lack of statistical power for detecting them, mouse chromosome substitution strains (CSSs) represent an alternate and powerful model for detecting epistasis given their limited allelic variation. Therefore, we utilized CSSs to identify and map both additive and epistatic loci that regulate a range of hematologic- and metabolism-related traits, as well as hepatic gene expression. Quantitative trait loci (QTLs) were identified using a CSS-based backcross strategy involving the segregation of variants on the A/J-derived substituted chromosomes 4 and 6 on an otherwise C57BL/6J genetic background. In the liver transcriptomes of offspring from this cross, we identified and mapped additive QTLs regulating the hepatic expression of 768 genes, and epistatic QTL pairs for 519 genes. Similarly, we identified additive QTLs for fat pad weight, platelets, and the percentage of granulocytes in blood, as well as epistatic QTL pairs controlling the percentage of lymphocytes in blood and red cell distribution width. The variance attributed to the epistatic QTL pairs was approximately equal to that of the additive QTLs; however, the SNPs in the epistatic QTL pairs that accounted for the largest variances were undetected in our single locus association analyses. These findings highlight the need to account for epistasis in association studies, and more broadly demonstrate the importance of identifying genetic interactions to understand the complete genetic architecture of complex traits.

genetics↗

bioRxiv2020

Role of the medial prefrontal cortex in the effects of rapid acting antidepressants on affective biases in a rodent decision-making task

Major Depressive Disorder is a significant and costly cause of global disability. Until the discovery of the rapid acting antidepressant (RAAD) effects of ketamine, treatments were limited to drugs that have delayed clinical benefits. The mechanism of action of ketamine is currently unclear but one hypothesis is that it may involve neuropsychological effects mediated through modulation of affective biases (where cognitive processes such as learning and memory and decision-making are modified by emotional state). Previous work has shown that affective biases in a rodent decision-making task are differentially altered by ketamine, compared to conventional, delayed onset antidepressants. This study sought to further investigate these effects by comparing ketamine with other NMDA antagonists using this decision-making task. We also investigated the subtype selective GluN2B antagonist, CP-101,606 and muscarinic antagonist scopolamine which have both been shown to have RAAD effects. Both CP-101,606 and scopolamine induced similar positive biases in decision-making to ketamine, but the same effects were not seen with other NMDA antagonists. Using targeted medial prefrontal cortex (mPFC) infusions, these effects were localised to the mPFC. In contrast, the GABAA agonist, muscimol, induced general disruptions to behaviour. These data suggest that ketamine and other RAADs mediate a specific effect on affective bias which involves the mPFC. Non-ketamine NMDA antagonists lacked efficacy and we also found that temporary inactivation of the mPFC did not fully recapitulate the effects of ketamine, suggesting a specific mechanism.

neuroscience↗

bioRxiv2019

Interaction between host genes and M. tuberculosis lineage can affect tuberculosis severity: evidence for co-evolution

Genetic studies of both the human host and Mycobacterium tuberculosis (MTB) demonstrate independent association with tuberculosis (TB) risk. However, neither explains a large portion of disease risk or severity. Based on studies in other infectious diseases and animal models of TB, we hypothesized that the genomes of the two interact to modulate risk of developing active TB or increasing the severity of disease, when present. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which there were 3 MTB lineages of which L4-Ugandan (L4.6) is the most recent. TB severity, measured using the Bandim TBscore, was modeled as a function of host SNP genotype, MTB lineage, and their interaction, within two independent cohorts of TB cases, N=113 and 122. No association was found between lineage and severity, but association between multiple polymorphisms in IL12B and TBscore was replicated in two independent cohorts (most significant rs3212227, combined p=0.0006), supporting previous associations of IL12B with TB susceptibility. We also observed significant interaction between a single nucleotide polymorphism (SNP) in SLC11A1 and the L4-Ugandan lineage in both cohorts (rs17235409, meta p=0.0002). Interestingly, the presence of the L4-Uganda lineage in the presence of the ancestral human allele associated with more severe disease. These findings demonstrate that IL12B is associated with severity of TB in addition to susceptibility, and that the association between TB severity and human genetics can be due to an interaction between genes in the two species, providing evidence of host-pathogen coevolution in TB.\n\nAUTHOR SUMMARYSusceptibility to tuberculosis (TB) is affected by genetic variation in both the human host and the causative bacterium, Mycobacterium tuberculosis. However, prior studies of the genetics of each species have not explained a large part of TB risk. The possibility exists that risk can be better estimated from patterns of variation in two species as a unit, such that some combinations provide increased risk, or in the presence of TB, increased disease severity. We hypothesized that alleles in the two species that have co-existed for long periods are more likely to reduce disease severity so as to promote prolonged co-occurrence. We tested this by studying TB severity in two patient cohorts from Uganda for which paired MTB-human DNA were available. We examined severity, as measured by the Bandim TBscore, and assessed whether there was an interaction between MTB lineage and SNPs in the host with this metric. Our results indicate that the most recent TB lineage (L4.6/Uganda) when found together with an ancestral allele in SLC11A1 resulted in more severe disease. This finding is consistent with the conclusion that MTB and human have coevolved to modulate TB severity.

evolutionary biology↗

bioRxiv2018

Meta-analysis of 1,200 transcriptomic profiles identifies a prognostic model for pancreatic ductal adenocarcinoma

BackgroundWith a dismal 8% median 5-year overall survival (OS), pancreatic ductal adenocarcinoma (PDAC) is highly lethal. Only 10-20% of patients are eligible for surgery, and over 50% of these will die within a year of surgery. Identify molecular predictors of early death would enable the selection of PDAC patients at high risk.\n\nMethodsWe developed the Pancreatic Cancer Overall Survival Predictor (PCOSP), a prognostic model built from a unique set of 89 PDAC tumors where gene expression was profiled using both microarray and sequencing platforms. We used a meta-analysis framework based on the binary gene pair method to create gene expression barcodes robust to biases arising from heterogeneous profiling platforms and batch effects. Leveraging the largest compendium of PDAC transcriptomic datasets to date, we show that PCOSP is a robust single-sample predictor of early death ([≤]1 yr) after surgery in a subset of 823 samples with available transcriptomics and survival data.\n\nResultsThe PCOSP model was strongly and significantly prognostic with a meta-estimate of the area under the receiver operating curve (AUROC) of 0.70 (P=1.9e-18) and hazard ratio (HR) of 1.95(1.6-2.3) (P=2.6e-16) for binary and survival predictions, respectively. The prognostic value of PCOSP was independent of clinicopathological parameters and molecular subtypes. Over-representation analysis of the PCOSP 2619 gene-pairs (1070 unique genes) unveiled pathways associated with Hedgehog signalling, epithelial mesenchymal transition (EMT) and extracellular matrix (ECM) signalling.\n\nConclusionPCOSP could improve treatment decision by identifying patients who will not benefit from standard surgery/chemotherapy and may benefit from alternate approaches.\n\nAbbreviations

genomics↗