Biology subjects

Maiya, R.

Publications and source records attributed to Maiya, R..

4 recordsLinked to original sources

bioRxiv2024

BLAKOR inputs to the BNST regulate social stress-escalated alcohol consumption

BackgroundAversive social experiences can lead to escalated drug consumption and increase the risk of relapse to drug seeking. Individuals who consume alcohol to alleviate the effects of social stress are more likely to develop an alcohol use disorder (AUD). Repeated social defeat stress (SDS) enhances the rewarding and reinforcing effects of alcohol. However, the neural mechanisms that underlie social stress-escalated alcohol drinking are not well understood. Here we explored the role of the dynorphin/kappa opioid receptor (Dyn/KOR) system in regulating social stress-escalated alcohol consumption. MethodsMale and female mice were subjected to repeated SDS for 10 days following which they were left undisturbed in their home cages. They were then subject to intermittent access (IA) two-bottle choice alcohol consumption procedure. The effects of systemic and BNST-specific KOR antagonism using the selective KOR antagonist NorBNI on stress-escalated drinking were evaluated. Using chemogenetic approaches in Oprk1-Cre mice, we examined the role of KOR expressing cells in the basolateral amygdala (BLAKORs) and BLAKOR-BNST pathway in social stress-escalated alcohol consumption. ResultsRepeated SDS increased alcohol consumption and preference in both males and females. Systemic KOR antagonism attenuated SDS-escalated alcohol consumption in both males and females. BNST -specific KOR antagonism also attenuated stress-escalated drinking in males. Finally, selective chemogenetic activation of BLAKORs and BKAKOR-BNST pathway attenuated social stress-escalated alcohol consumption in both sexes. ConclusionOur results suggest a significant role for BLAKOR projections to the BNST in regulating social stress-escalated alcohol consumption. Our results provide further evidence that the Dyn/KOR system maybe a viable target for medications development to tareat comorbid stress and AUD.

neuroscience↗

bioRxiv2024

Standard rodent diets differentially impact alcohol consumption and preference and gut microbiome diversity

Alcohol Use Disorder (AUD) is a complex and widespread disease with limited pharmacotherapies. Preclinical animal models of AUD use a variety of voluntary alcohol consumption procedures to recapitulate different phases of AUD including binge alcohol consumption and dependence. However, voluntary alcohol consumption in mice is widely variable rendering it difficult to reproduce results across labs. Accumulating evidence indicates that different brands of commercially available rodent chow can profoundly influence alcohol intake. In this study, we investigated the effects of three commercially available and widely used rodent diet formulations on alcohol consumption and preference in C57BL/6J mice using the 24h intermittent access procedure. The three brands of chow tested were LabDiet 5001 (LD 5001), LabDiet 5053 (LD 5053), and Teklad 2019S (TL2019S) from two companies (Research Diets and Envigo respectively). Mice fed LD5001 displayed the highest levels of alcohol consumption and preference followed by LD5053 and TL2019S. We also found that alcohol consumption and preference could be rapidly switched by changing the diet 48h prior to alcohol administration. Sucrose, saccharin, and quinine preference were not altered suggesting that the diets did not alter taste perception. We also found that mice fed LD5001 displayed increased quinine-resistant alcohol intake compared to mice fed TL2019S, suggesting that diets could influence the development of "compulsive" like alcohol consumption. We profiled the gut microbiome of water and alcohol drinking mice that were maintained on different diets and found significant differences in bacterial alpha and beta diversity, which could impact gut-brain axis signaling and alcohol consumption.

neuroscience↗

bioRxiv2022

The interplay of active and passive mechanisms in slow axonal transport

A combination of intermittent active movement of transient aggregates and a paused state that intervenes between periods of active transport has been proposed to underly the slow, directed transport of soluble proteins in axons. A component of passive diffusion in the axoplasm may also contribute to slow axonal transport, although quantitative estimates of the relative contributions of diffusive and active movement in the slow transport of a soluble protein, and in particular how they might vary across developmental stages, are lacking. Here, we propose and study a model for slow axonal transport, addressing data from bleach-recovery measurements on a small, soluble, protein, Choline Acetyltransferase (ChAT), in thin axons of the lateral chordotonal (lch5) sensory neurons of Drosophila. ChAT is mainly present in soluble form in the axon and catalyses the acetylation of choline at the synapse. It does not form particulate structures in axons and moves at rates characteristic of slow component b ({approx} 1-10 mm/day or 0.01-0.1 m/s). Using our model, which incorporates active transport, paused and diffusive states, we predict bleach recovery and cargo trajectories obtained through kymographs, comparing these to experimental observations at different developmental stages. We show that changes in the diffusive fraction of cargo during these developmental stages dominate bleach recovery and that a combination of active motion with a paused state alone cannot reproduce the data. We compared predictions of the model with results from photoactivation experiments. The importance of the diffusive state in reproducing the bleach recovery signal in the slow axonal transport of small soluble proteins is our central result. STATEMENT OF SIGNIFICANCEWhile the fast axonal transport of cargo in axons is by now well-understood, the nature of slow transport remains controversial. A number of different models having been proposed for slow axonal transport, including models which allow for transitions between an intermittently moving molecular-motor driven state and a stalled state. How mechanisms for slow axonal transport are modulated during development is unexplored. We study a number of different models for slow axonal transport, comparing their predictions to data on transport of the enzyme Choline Acetyltransferase (ChAT) in thin lateral chordotonal (lch5) sensory neurons of Drosophila larva, across developmental stages where flux increases significantly. We show that accounting for changes in the diffusive fraction of cargo during these developmental stages is essential and diffusion cannot be neglected in the modelling of the slow axonal transport of small soluble proteins.

biophysics↗

bioRxiv2021

Cargo crowding, stationary clusters and dynamical reservoirs in axonal transport

Molecular motors drive the directed transport of presynaptic vesicles along the narrow axons of nerve cells. Stationary clusters of such vesicles are a prominent feature of axonal transport, but little is known about their physiological and functional relevance. Here, we develop a simulation model describing key features of axonal cargo transport with a view to addressing this question, benchmarking the model against our experiments in the touch neurons of C. elegans. Our simulations provide for multiple microtubule tracks and varied cargo motion states while also incorporating cargo-cargo interactions. Our model also incorporates obstacles to vesicle transport in the form of microtubule ends, stalled vesicles, and stationary mitochondria. We devise computational methodologies to simulate both axonal bleaching and axotomy, showing that our results reproduce the properties of both moving as well as stationary cargo in vivo. Increasing vesicle numbers leads to larger and more long-lived stationary clusters of vesicular cargo. Vesicle clusters are dynamically stable, explaining why they are ubiquitously seen. Modulating the rates of cargo motion-state switching allows cluster lifetimes and flux to be tuned both in simulations and experiments. We demonstrate, both in simulations and in an experimental system, that suppressing reversals leads to larger stationary vesicle clusters being formed while also reducing flux. Our simulation results support the view that the physiological significance of clusters is located in their role as dynamic reservoirs of cargo vesicles, capable of being released or sequestered on demand.

biophysics↗