Biology subjects

Hinchcliffe, J.

Publications and source records attributed to Hinchcliffe, J..

7 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

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↗

bioRxiv2026

Psilocybin rapidly, but not immediately, reverses reward learning deficits in a durable manner in an inflammatory rat model of depressive symptoms

The serotonergic psychedelic, psilocybin, shows potential for rapid and sustained antidepressant effects but the underlying mechanisms remain unknown. Using a chronic interferon-alpha-induced rat model of depression, we show acute psilocybin (0.3 mg/kg) reverses impaired reward-induced biases within 24hrs, with effects enduring for at least 7 days. This suggests psilocybin can restore blunted reward processing, an effect which could significantly contribute to its sustained antidepressant effects.

neuroscience↗

bioRxiv2025

Is poor dose selection undermining the translational validity of antidepressant research involving animal models?

BackgroundBehavioural studies in animal models represent a critical component of psychiatric drug development. Positive results in animal studies have identified novel therapeutic targets for major depressive disorder (MDD) but efficacy in humans has largely not been borne out in clinical trials. A possible reason for this failed translation is inappropriate dose selection and the engagement of mechanisms not directly relevant to antidepressant effects in patients. MethodsWe first used PubMed to identify preclinical rodent studies in two assays used to assess antidepressants; the conventional forced swim test, (FST) and more recently developed affective bias test, (ABT). Dose ranges were extracted, as well as information about subjects, timing and route of administration, and justification and efficacy of dose(s). Dose ranges were compared against calculated animal equivalent doses. ResultsThe median FST dose across all antidepressants was 10mg/kg, with median doses for each drug exceeding the relevant animal equivalent dose by 1.5-25x. In contrast, effective doses in the ABT showed closer alignment to those used clinically. In the second study, 232 ketamine and 202 fluoxetine papers involving MDD-related research in rodents were reviewed. The median dose was 10mg/kg for both drugs, exceeding animal equivalent doses by 1.6-3.2x and 3.2-6.5x for ketamine and fluoxetine, respectively. ConclusionsThe results indicate pervasive use of antidepressant doses in conventional models of MDD that may not correspond with doses used in clinical practice. We discuss the implications of using doses which exceed therapeutic levels and the potential to engage receptors and underlying mechanisms which are not relevant to clinical effects.

neuroscience↗

bioRxiv2023

Influence of pseudo-green water on growth, colouration, and survival in European lobster (Homarus gammarus) larvae

With the depletion of European lobster (Homarus gammarus) wild stocks from historic overexploitation, the attention has turned towards restocking, stock enhancement programs and farming potential. The early life larval stages of the European lobster present a major barrier to hatchery production efforts due to low survival rates. Green water techniques are rapidly growing due to their ability to improve nutrition quality. This study explores the potential benefits of using pseudo-green water. This is determined by adding microalgae to the rearing environment of larvae by analysing the effects on growth and survival. The commonly used algal species: Tetraselmis suecica (TS), Dunaliella salina (DS), and Nannochloropsis sp. (N) were added as monoculture or mixture treatments to a controlled European lobster larvae-rearing environment over thirteen days. The trial consisted of seven permutations of algal treatments (TS, DS, N, TS+DS, TS+N, DS+N, and TS+DS+N) and one control group, with clear water conditions using length measurements, survival rates and colouration to determine treatment impacts at the end of the trial. Results indicate that mixtures of algal species outperformed monocultures and clear water regarding growth performance. Nannochloropsis sp. is of significant benefit to growth performance. Algal mixes containing Nannochloropsis sp. resulted in significantly better growth than D. salina monoculture treatment. There were no significant differences in survival rates between treatment groups.

developmental biology↗

bioRxiv2021

Key Drivers of Ecological Assembly in the Hindgut of Atlantic Cod (Gadus morhua) when Fed with a Macroalgal Supplemented diet - How Robust Is the Gut to Taxonomic Perturbation?

The microbiota in the gastrointestinal tract of any species is shaped by internal and external cues in addition to random events which can be difficult to disentangle from a range of interacting variables. Estimating ecological assembly processes can help elucidate these factors. In our study, farmed Atlantic cod (Gadus morhua) were fed a diet of 10% macroalgae supplement (Ulva rigida species [ULVA] or Ascophyllum nodosum [ASCO] or a non-amended control diet [CTRL]) over a 12-week period and the ecological assembly processes quantified. The CTRL samples showed selection (variable selection - divergence in communities related to selective environmental conditions) as a key assembly process, while dispersal limitation (limited movement results in divergent communities through stochastic processes) was a driver of the gut microbiome for fish fed the macroalgae supplemented diet at Week 12 (i.e., ASCO and ULVA). Fish from the ASCO grouping diverged into ASCO_N (normal) and ASCO_LG (lower growth), where ASCO_LG individuals found the diet unpalatable. The recruitment of new taxa over time was altered in the ASCO_LG fish, with the gut microbiome showing phylogenetic under dispersion (nepotistic recruitment of species). Finally, the gut microbiome (CTRL and ULVA only) showed increasing robustness to taxonomic disturbance over time and an increase in functional redundancy. This study advances our understanding of the ecological assembly and succession in the hindgut of juvenile Atlantic cod across dietary regimes. Understanding the processes driving ecological assembly in the gut microbiome, in fish research specifically, could allow us to manipulate the microbiome for improved health or resilience to disease for improved aquaculture production.

microbiology↗

bioRxiv2020

Temporal changes in the gut microbiota in farmed Atlantic cod (Gadus morhua) outweigh the response to diet supplementation with macroalgae.

BackgroundAquaculture successfully meets global food demands for many fish species. However, aquaculture production of Atlantic cod (Gadus morhua) is modest in comparison to market demand. For cod farming to be a viable economic venture specific challenges on how to increase growth, health and farming productivity need to be addressed. Feed ingredients play a key role here. Macroalgae (seaweeds) have been suggested as a functional feed supplement with both health and economic benefits for terrestrial farmed animals and fish. The impact of such dietary supplements to cod gut integrity and microbiota, which contribute to overall fish robustness is unknown. The objective of this study was to supplement the diet of juvenile Atlantic cod with macroalgae and determine the impacts on fish condition and growth, gut morphology and hindgut microbiota composition (16S rRNA amplicon sequencing). Fish were fed one of three diets: control (no macroalgal inclusion), 10% inclusion of either egg wrack (Ascophyllum nodosum) or sea lettuce (Ulva rigida) macroalgae in a 12-week trial. ResultsThe results demonstrated there was no significant difference in fish condition, gut morphology or hindgut microbiota between the U. rigida supplemented fish group and the control group at any time-point. This contrasts with the A. nodosum treatment. Fish within this group were further categorised as either Normal or Lower Growth. Lower Growth individuals found the diet unpalatable resulting in reduced weight and condition factor combined with an altered gut morphology and microbiome relative to the other treatments. Excluding this group, our results show that the hindgut microbiota was largely driven by temporal pressures with the microbial communities becoming more similar over time irrespective of dietary treatment. The core microbiome at the final time-point consisted of the orders Vibrionales (Vibrio and Photobacterium), Bacteroidales (Bacteroidetes and Macellibacteroides) and Clostridiales (Lachnoclostridium). ConclusionsOur study indicates that U. rigida macroalgae can be supplemented at 10% inclusion levels in the diet of juvenile farmed Atlantic cod without any impact on fish condition or hindgut microbial community structure. We also conclude that 10% dietary inclusion of A. nodosum is not a suitable feed supplement in a farmed cod diet.

microbiology↗