Biology subjects

Newell, B.

Publications and source records attributed to Newell, B..

5 recordsLinked to original sources

bioRxiv2024

Ventral pallidal GABAergic neurons drive consumption in male, but not female rats

Food intake is controlled by multiple converging signals: hormonal signals that provide information about energy homeostasis, but also hedonic and motivational aspects of food and food cues that can drive non-homeostatic or "hedonic "feeding. The ventral pallidum (VP) is a brain region implicated in the hedonic and motivational impact of food and foods cues, as well as consumption of rewards. Disinhibition of VP neurons has been shown to generate intense hyperphagia, or overconsumption. While VP gamma-Aminobutyric acidergic (GABA) neurons have been implicated in cue-elicited reward seeking and motivation, the role of these neurons in the hyperphagia resulting from VP activation remains unclear. Here, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to activate or inhibit VP GABA neurons in sated male and female rats during chow and sucrose consumption. We found that activation of VP GABA neurons increases consumption of chow and sucrose in male rats, but not female rats. We also found that, while inhibition of VP GABA neurons tended to decrease sucrose consumption, this effect was not statistically significant. Together, these findings suggest that activation of VP GABA neurons can stimulate consumption of routine or highly palatable rewards selectively in male rats.

neuroscience↗

bioRxiv2024

Pavlovian cue-evoked alcohol seeking is disrupted by ventral pallidal inhibition

Cues paired with alcohol can be potent drivers of craving, alcohol-seeking, consumption, and relapse. While the ventral pallidum is implicated in appetitive and consummatory responses across several reward classes and types of behaviors, its role in behavioral responses to Pavlovian alcohol cues has not previously been established. Here, we tested the impact of optogenetic inhibition of ventral pallidum on Pavlovian-conditioned alcohol-seeking in male Long Evans rats. Rats underwent Pavlovian conditioning with an auditory cue predicting alcohol delivery to a reward port and a control cue predicting no alcohol delivery, until they consistently entered the reward port more during the alcohol cue than the control cue. We then tested the within-session effects of optogenetic inhibition during 50% of cue presentations. We found that optogenetic inhibition of ventral pallidum during the alcohol cue reduced port entry likelihood and time spent in the port, and increased port entry latency. Overall, these results suggest that normal ventral pallidum activity is necessary for Pavlovian alcohol-seeking.

neuroscience↗

bioRxiv2023

Numerical Simulation of Transdermal Delivery of Drug Nanocarriers Using Solid Microneedles

Solid microneedles can successfully puncture the stratum corneum and thus enable the drugs to migrate from the adhesive patch to the viable skin tissues for therapy. The treatment in different skin layers can vary greatly. However, how to improve its effectiveness remains less understood. In this study, numerical simulation is employed to predict the transport and disposition of drugs in each skin layer and blood using a skin model rebuilt from the real skin anatomical structure. The therapeutic effect is assessed by exposure to drugs over time. Results reveal the dominance of diffusion in determining the transport of nanosized drug carriers and free drugs in viable skin tissues. Delivery outcomes are highly sensitive to drug delivery system properties. Increasing the nanocarrier partition coefficient or diffusion coefficient in the skin can successfully enhance the treatment in entire skin tissue and blood. The enhancement can also be obtained by reducing the microneedle spacing or patch thickness. However, several properties should be optimised individually with respect to the target sites location, including the microneedle length, diffusion coefficient of nanocarriers in the skin, drug release rate and nanocarrier vascular permeability. Drug concentrations in the blood can be effectively increased when administered to skin areas rich in capillaries; whereas, the treatment in the skin tissues slightly would reduce simultaneously. Furthermore, delivery results are insensitive to changes in lymphatic function and the properties of free drugs introduced by the medicated patch. These findings can be used to improve transdermal drug delivery for better treatment.

bioengineering↗

bioRxiv2023

Ventral pallidum projections to the ventral tegmental area reinforce but do not invigorate reward-seeking behavior

Reward-predictive cues acquire motivating and reinforcing properties that contribute to the escalation and relapse of drug use in addiction. The ventral pallidum (VP) and ventral tegmental area (VTA) are two key nodes in brain reward circuitry implicated in addiction and necessary for the performance of cue-driven behavior. Evidence suggests that VP neurons projecting to the VTA (VP[->]VTA) promote cue-induced reinstatement of drug-seeking, but the mechanisms by which these neurons do so are undefined. In addition, the role of these neurons in the pursuit of non-drug reward is not known. In the current study, we used in vivo fiber photometry and optogenetics to record from and manipulate VP[->]VTA in rats performing a discriminative stimulus task (DS task) with sucrose reward to determine the fundamental role these neurons play in invigoration and reinforcement by reward and associated discriminative cues. We find that VP[->]VTA neurons are selectively active during reward consumption, that optogenetic stimulation of these neurons paired with reward consumption biases choice, and that VP[->]VTA optogenetic stimulation is reinforcing. Critically, we found no significant encoding of cue-elicited reward-seeking vigor and acute optogenetic stimulation of these neurons paired with cue onset did not enhance the probability or vigor of reward-seeking. Our results suggest that VP[->]VTA neurons are active during the consumption of natural reward and that this activity reinforces seeking behavior.

neuroscience↗

bioRxiv2021

Ultra-rapid somatic variant detection via real-time threshold sequencing

Molecular markers are becoming increasingly important for cancer diagnosis, proper clinical trial enrollment, and even surgical decision making, motivating ultra-rapid, intraoperative variant detection. Sequencing-based detection is considered the gold standard approach, but typically takes hours to perform. In this work, we present Threshold Sequencing, a methodology for designing protocols for targeted variant detection on real-time sequencers with a minimal time to result. Threshold Sequencing analytically identifies a time-optimal threshold to stop target amplification and begin sequencing. To further reduce diagnostic time, we explore targeted Loop-mediated Isothermal Amplification (LAMP) and design a LAMP-specific bioinformatics tool--LAMPrey--to process sequenced LAMP product. LAMPreys concatemer aware alignment algorithm is designed to maximize recovery of diagnostically relevant information leading to a more rapid detection versus standard read alignment approaches. Coupled with time-optimized DNA extraction and library preparation, we demonstrate confirmation of a hot-spot mutation (250x support) from tumor tissue in less than 30 minutes.

bioinformatics↗