Pre- and postsynaptic signatures in the prelimbic cortex associated with "alcohol use disorder" in the rat.

The transition to alcohol use disorder (AUD) involves persistent neuroadaptations in executive control functions primarily regulated by the medial prefrontal cortex. However, the neurophysiological correlates to behavioral manifestations of AUD are not fully defined. The association between cortical neuroadaptations and behavioral manifestations of addiction was studied using a multi-symptomatic operant model based on the DSM-5 diagnostic criteria for AUD.

Pharmacological blockage of NOP receptors decreases ventral tegmental area dopamine neuronal activity through GABA receptor-mediated mechanism.

The Nociceptin/Orphanin FQ (N/OFQ) peptide and its receptor NOP are highly expressed within several regions of the mesolimbic system, including the ventral tegmental area (VTA). Evidence indicates that the N/OFQ-NOP receptor system is involved in reward processing and historically it has been proposed that activation of NOP receptors attenuates the motivation for substances of abuse. However, recent findings demonstrated that drug self-administration and relapse to drug-seeking are also attenuated after administration of NOP receptor antagonists.

Acamprosate reduces ethanol intake in the rat by a combined action of different drug components.

Alcohol misuse accounts for a sizeable proportion of the global burden of disease, and Campral (acamprosate; calcium-bis-(N-acetylhomotaurinate)) is widely used as relapse prevention therapy. The mechanism underlying its effect has in some studies been attributed to the calcium moiety and not to the N-acetylhomotaurine part of the compound. We recently suggested that the dopamine elevating effect of acamprosate is mediated both by N-acetylhomotaurine and calcium in a glycine receptor dependent manner.

The development of compulsive coping behavior depends on dorsolateral striatum dopamine-dependent mechanisms.

Humans greatly differ in how they cope with stress, a natural behavior learnt through negative reinforcement. Some individuals engage in displacement activities, others in exercise or comfort eating, and others still in alcohol use. Across species, adjunctive behaviors, such as polydipsic drinking, are used as a form of displacement activity that reduces stress.

Nicotine but not saline self-administering or yoked control conditions produces sustained neuroadaptations in the accumbens shell.

Introduction: Using yoked animals as the control when monitoring operant drug-self-administration is considered the golden standard. However, instrumental learning recruits several neurocircuits that may produce distinct or overlapping neuroadaptations with drugs of abuse. The aim of this project was to assess if contingent responding for nicotine or saline in the presence of a light stimulus as a conditioned reinforcer is associated with sustained neurophysiological adaptations in the nucleus accumbens shell (nAcS), a brain region repeatedly associated with reward related behaviors.

Abstinence-Induced Nicotine Seeking Relays on a Persistent Hypoglutamatergic State within the Amygdalo-Striatal Neurocircuitry.

Nicotine robustly sustains smoking behavior by acting as a primary reinforcer and by enhancing the incentive salience of the nicotine-associated stimuli. The motivational effects produced by environmental cues associated with nicotine delivery can progressively manifest during abstinence resulting in reinstatement of nicotine seeking. However, how the activity in reward neuronal circuits is transformed during abstinence-induced nicotine seeking is not yet fully understood.

Viral delivery of a peptide-based immunomodulator enhances T cell priming during vaccination.

Modern, subunit-based vaccines have so far failed to induce significant T cell responses, contributing to ineffective vaccination against many pathogens. Importantly, while today's adjuvants are designed to trigger innate and non-specific immune responses, they fail to directly stimulate the adaptive immune compartment. Programmed cell death 1 (PD-1) partly regulates naïve-to-antigen-specific effector T cell transition and differentiation by suppressing the magnitude of activation.

An epigenetic mechanism for over-consolidation of fear memories.

Excessive fear is a hallmark of anxiety disorders, a major cause of disease burden worldwide. Substantial evidence supports a role of prefrontal cortex-amygdala circuits in the regulation of fear and anxiety, but the molecular mechanisms that regulate their activity remain poorly understood. Here, we show that downregulation of the histone methyltransferase PRDM2 in the dorsomedial prefrontal cortex enhances fear expression by modulating fear memory consolidation.

A single immunization with a modified vaccinia Ankara vectored vaccine producing Sudan virus-like particles protects from lethal infection.

A new vectored vaccine MVA-VLP-SUDV was generated against Sudan ebolavirus (SUDV) combining the advantages of the immunogenicity of a live attenuated vaccine vector (Modified Vaccinia Ankara, MVA) with the authentic conformation of virus-like particles (VLPs). The vaccine expresses minimal components to generate self-assembling VLPs in the vaccinee: the envelope glycoprotein GP and the matrix protein VP40. Guinea pigs vaccinated with one dose of MVA-VLP-SUDV generated SUDV-specific binding and neutralizing antibody responses as well as Fc-mediated protective effects.

The multitarget FAAH inhibitor/D3 partial agonist ARN15381 decreases nicotine self-administration in male rats.

Tobacco use disorder is a worldwide health problem for which available medications show limited efficacy. Nicotine is the psychoactive component of tobacco responsible for its addictive liability. Similar to other addictive drugs, nicotine enhances mesolimbic dopamine transmission.

Differential and long-lasting changes in neurotransmission in the amygdala of male Wistar rats during extended amphetamine abstinence.

Amphetamine addiction is associated with maladaptive actions that promotes continued use despite negative consequences, and a high risk of relapse even after protracted abstinence. Considering the role of the amygdala in regulating incentive motivation and reward-based behavior, the aim of this study was to assess neuroadaptations in subregions of the amygdala elicited by a brief period of discontinuous amphetamine exposure (2.0 mg/kg/day, 5 days) followed by abstinence (2 weeks, 1 month, 3 months) in male Wistar rats.

Vertebral Deformity Measurements at MRI, CT, and Radiography Using Deep Learning.

Purpose: To construct and evaluate the efficacy of a deep learning system to rapidly and automatically locate six vertebral landmarks, which are used to measure vertebral body heights, and to output spine angle measurements (lumbar lordosis angles [LLAs]) across multiple modalities.

Materials And Methods: In this retrospective study, MR ( = 1123), CT ( = 137), and radiographic ( = 484) images were used from a wide variety of patient populations, ages, disease stages, bone densities, and interventions ( = 1744 total patients, 64 years ± 8, 76.8% women; images acquired 2005-2020).

Microplastics in the abyss: a first investigation into sediments at 2443-m depth (Toulon, France).

Plastic and microplastic pollutions are known to be widespread across the planet in all types of environments. However, relatively little about microplastic quantities in the deeper areas of the oceans is known, due to the difficulty to reach these environments. In this work, we present an investigation of microplastic (<5 mm) distribution performed in the bottom sediments of the abyssal plain off the coast and the canyon of Toulon (France).

Astrocytes modulate extracellular neurotransmitter levels and excitatory neurotransmission in dorsolateral striatum via dopamine D2 receptor signaling.

Astrocytes provide structural and metabolic support of neuronal tissue, but may also be involved in shaping synaptic output. To further define the role of striatal astrocytes in modulating neurotransmission we performed in vivo microdialysis and ex vivo slice electrophysiology combined with metabolic, chemogenetic, and pharmacological approaches. Microdialysis recordings revealed that intrastriatal perfusion of the metabolic uncoupler fluorocitrate (FC) produced a robust increase in extracellular glutamate levels, with a parallel and progressive decline in glutamine.

NOP receptor antagonism attenuates reinstatement of alcohol-seeking through modulation of the mesolimbic circuitry in male and female alcohol-preferring rats.

In patients suffering from alcohol use disorder (AUD), stress and environmental stimuli associated with alcohol availability are important triggers of relapse. Activation of the nociceptin opioid peptide (NOP) receptor by its endogenous ligand Nociceptin/Orphanin FQ (N/OFQ) attenuates alcohol drinking and relapse in rodents, suggesting that NOP agonists may be efficacious in treating AUD. Intriguingly, recent data demonstrated that also blockade of NOP receptor reduced alcohol drinking in rodents.

Selective Inhibition of Phosphodiesterase 7 Enzymes Reduces Motivation for Nicotine Use through Modulation of Mesolimbic Dopaminergic Transmission.

Approximately 5 million people die from diseases related to nicotine addiction and tobacco use each year. The nicotine-induced increase of corticomesolimbic dopaminergic (DAergic) transmission and hypodopaminergic conditions occurring during abstinence are important for maintaining drug-use habits. We examined the notion of reequilibrating DAergic transmission by inhibiting phosphodiesterase 7 (PDE7), an intracellular enzyme highly expressed in the corticomesolimbic circuitry and responsible for the degradation of cyclic adenosine monophosphate (cAMP), the main second messenger modulated by DA receptor activation.

A deep learning system for automated, multi-modality 2D segmentation of vertebral bodies and intervertebral discs.

Purpose: Fractures in vertebral bodies are among the most common complications of osteoporosis and other bone diseases. However, studies that aim to predict future fractures and assess general spine health must manually delineate vertebral bodies and intervertebral discs in imaging studies for further radiomic analysis. This study aims to develop a deep learning system that can automatically and rapidly segment (delineate) vertebrae and discs in MR, CT, and X-ray imaging studies.

Neurobiology of alcohol seeking behavior.

Alcohol addiction is a chronic relapsing brain disease characterized by an impaired ability to stop or control alcohol use despite adverse consequences. A main challenge of addiction treatment is to prevent relapse, which occurs in more than >50% of newly abstinent patients with alcohol disorder within 3 months. In people suffering from alcohol addiction, stressful events, drug-associated cues and contexts, or re-exposure to a small amount of alcohol trigger a chain of behaviors that frequently culminates in relapse.

Targeting the Opioid Receptors: A Promising Therapeutic Avenue for Treatment in "Heavy Drinking Smokers".

Aims: Despite a general decline in tobacco use in the last decades, the prevalence of tobacco smoking in individuals with alcohol use disorder (AUD) remains substantial (45-50%). Importantly, the co-use of both substances potentiates the adverse effects, making it a significant public health problem. Substantial evidence suggests that AUD and Tobacco use disorder (TUD) may share common mechanisms.

Downregulation of Synaptotagmin 1 in the Prelimbic Cortex Drives Alcohol-Associated Behaviors in Rats.

Background: Alcohol addiction is characterized by persistent neuroadaptations in brain structures involved in motivation, emotion, and decision making, including the medial prefrontal cortex, the nucleus accumbens, and the amygdala. We previously reported that induction of alcohol dependence was associated with long-term changes in the expression of genes involved in neurotransmitter release. Specifically, Syt1, which plays a key role in neurotransmitter release and neuronal functions, was downregulated.

Modified vaccinia Ankara vaccine expressing Marburg virus-like particles protects guinea pigs from lethal Marburg virus infection.

We introduce a new vaccine platform against Marburg virus (MARV) combining the advantages of the immunogenicity of a highly attenuated vaccine vector (Modified Vaccinia Ankara, MVA) with the authentic conformation of virus-like particles (VLPs). Our vaccine, MVA-MARV-VLP, expresses the minimal components of MARV VLPs: the envelope glycoprotein GP and the matrix protein VP40. Electron microscopy confirmed self-assembly and budding of VLPs from infected cells.