Biology subjects

Vachez, Y. M.

Publications and source records attributed to Vachez, Y. M..

5 recordsLinked to original sources

bioRxiv2023

Pramipexole restores behavioral inhibition in highly impulsive rats through a paradoxical modulation of frontostriatal networks

Impulse control disorders (ICDs), a wide spectrum of maladaptive behaviors which includes pathological gambling, hypersexuality and compulsive buying, have been recently suggested to be triggered or aggravated by treatments with dopamine D2/3 receptor agonists, such as pramipexole (PPX). Despite evidence showing that impulsivity is associated with functional alterations in corticostriatal networks, the neural basis of the exacerbation of impulsivity by PPX has not been elucidated. Here we used a hotspot analysis to assess the functional recruitment of several corticostriatal structures by PPX in male rats identified as highly (HI), moderately impulsive (MI) or with low levels of impulsivity (LI) in the 5-choice serial reaction time task (5-CSRTT). PPX dramatically reduced impulsivity in HI rats. Assessment of the expression pattern of the two immediate early genes C-fos and Zif268 by in situ hybridization subsequently revealed that PPX resulted in a decrease in Zif268 mRNA levels in different striatal regions of both LI and HI rats accompanied by a high impulsivity specific reduction of Zif268 mRNA levels in prelimbic and cingulate cortices. PPX also decreased C-fos mRNA levels in all striatal regions of LI rats, but only in the dorsolateral striatum and nucleus accumbens core (NAc Core) of HI rats. Structural equation modelling further suggested that the anti-impulsive effect of PPX was mainly attributable to the specific downregulation of Zif268 mRNA in the NAc Core. Altogether, our results show that PPX restores impulse control in highly impulsive rats by modulation of limbic frontostriatal circuits.

neuroscience↗

bioRxiv2022

Oral oxycodone self-administration leads to features of opioid addiction in male and female mice

Use of prescription opioids, particularly oxycodone is an initiating factor driving the current opioid epidemic. There are several challenges with modeling oxycodone abuse. First, prescription opioids including oxycodone are orally self-administered and have different pharmacokinetics and dynamics than morphine or fentanyl which have been more commonly used in rodent research. This oral route of administration determines the pharmacokinetic profile, which then influences the establishment of drug-reinforcement associations in animals. Moreover, the pattern of intake and the environment in which addictive drugs are self-administered are critical determinants of the levels of drug intake, of behavioral sensitization, and of propensity to relapse behavior. These are all important considerations when modeling prescription opioid use, which is characterized by continuous drug access in familiar environments. Thus, to model features of prescription opioid use and the transition to abuse, we designed an oral, homecage-based oxycodone self-administration paradigm. Mice voluntarily self-administer oxycodone in this paradigm without any taste modification such as sweeteners, and the majority exhibit preference for oxycodone, escalation of intake, physical signs of dependence, and reinstatement of seeking after withdrawal. In addition, a subset of animals demonstrate drug taking that is resistant to aversive consequences. This model is therefore translationally relevant and useful for studying the neurobiological substrates of prescription opioid abuse.

neuroscience↗

bioRxiv2022

Enhanced food motivation in obese mice is controlled by D1R expressing spiny projection neurons in the nucleus accumbens.

Obesity is a chronic relapsing disorder that is caused by an excess of caloric intake relative to energy expenditure. In addition to homeostatic feeding mechanisms, there is growing recognition of the involvement of food reward and motivation in the development of obesity. However, it remains unclear how brain circuits that control food reward and motivation are altered in obese animals. Here, we tested the hypothesis that signaling through pro-motivational circuits in the core of the nucleus accumbens (NAc) is enhanced in the obese state, leading to invigoration of food seeking. Using a novel behavioral assay that quantifies physical work during food seeking, we confirmed that obese mice work harder than lean mice to obtain food, consistent with an increase in the relative reinforcing value of food in the obese state. To explain this behavioral finding, we recorded neural activity in the NAc core with both in vivo electrophysiology and cell-type specific calcium fiber photometry. Here we observed greater activation of D1-receptor expressing NAc spiny projection neurons (NAc D1SPNs) during food seeking in obese mice relative to lean mice. With ex vivo slice physiology we identified both pre- and post-synaptic mechanisms that contribute to this enhancement in NAc D1SPN activity in obese mice. Finally, blocking synaptic transmission from D1SPNs decreased physical work during food seeking and attenuated high-fat diet-induced weight gain. These experiments demonstrate that obesity is associated with a selective increase in the activity of D1SPNs during food seeking, which enhances the vigor of food seeking. This work also establishes the necessity of D1SPNs in the development of diet-induced obesity, establishing these neurons as a potential therapeutic target for preventing obesity.

neuroscience↗

bioRxiv2021

Modeling features of addiction with an oral oxycodone self-administration paradigm

Prescription opioid use is an initiating factor driving the current opioid epidemic. There are several challenges with modeling prescription opioid addiction. First, prescription opioids such as oxycodone are orally self-administered and have different pharmacokinetics and dynamics than morphine or fentanyl. This oral route of administration determines the pharmacokinetic profile, which is critical for establishing reliable drug-reinforcement associations in animals. Moreover, the pattern of intake and environment in which addictive drugs are self-administered intake are critical determinants of the levels of drug intake, sensitization and relapse behavior. This is an important consideration with prescription opioid use, which is characterized by continuous drug access in familiar environments. Thus, to model features of prescription opioid use and the transition to abuse, we present an oral oxycodone self-administration paradigm that is administered in the home cage. Mice voluntarily self-administer oxycodone in this paradigm without any taste modification such as sweeteners, and exhibit preference for oxycodone, escalation of intake, physical signs of dependence, reinstatement of seeking after withdrawal, and a subset of animals demonstrate drug taking that is resistant to aversive consequences. This model could be useful for studying the neurobiological substrates specifically relevant to prescription opioid abuse.

neuroscience↗

bioRxiv2020

Ventral arkypallidal neurons modulate accumbal firing to promote reward consumption.

A pause in firing of nucleus accumbens shell (NAcSh) neurons is critical for reward consumption; however, the substrate driving this pause is unknown. While ventral pallidal (VP) activity encodes reward value, the specific roles of VP subpopulations in computation and expression of this value are poorly understood. Here, we establish that inhibitory input from the VP is crucial for reward-related inhibition of NAc firing. A sparse, non-canonical subpopulation of VP neurons, the so-called "ventral arkypallidal (vArky)" neurons makes inhibitory synaptic contacts throughout the NAcSh, and drives inhibition of NAcSh neurons in vivo. Moreover, endogenous calcium activity of vArky neurons predicted subsequent reward consumption behavior, while optogenetically activating this pathway increased reward consumption by amplifying hedonic value of reward. Classically, the VP is considered downstream of the NAc; however, our results challenge this view and establish that vArky neurons in the VP promote reward consumption via potent modulation of NAcSh firing.

neuroscience↗