The Reinforcing Properties of Drugs of Abuse are Attenuated by Naltrexone in Caenorhabditis elegans

poster abstractDrug addiction is a chronic, relapsing disease premised on compulsive drug seeking. Previous work from our lab demonstrated that the nematode Caenorhabditis elegans (C. elegans) can be used to examine the reinforcing properties of drugs of abuse. A successful model for studying the reinforcing effects of drugs in C. elegans would greatly aid efforts to discover potential therapeutic interventions for drug addiction. The present study examined preference for morphine, ethanol, cocaine, and a cannabinoid agonist (CB agonist) in C. elegans and the effect of naltrexone, an opioid antagonist, on this behavior. Six-well agar test plates were utilized to test drug preference. Each well had two circular target zones equidistant from the center; 4μl of the targeted drug or water were placed in the center of one of the two target zones within each well. Worms in one group were pre-treated with 10mM naltrexone, while controls were pre-treated with 0.97 mM HCl for 30 min prior to testing. Worms in each treatment group were then placed in the center of each well and allowed to move freely for 30 minutes-images were captured at 10 and 30 minutes. Animals treated with vehicle displayed a significant preference for the aforementioned drugs relative to controls; naltrexone pretreatment significantly ameliorated this effect. Naltrexone had no effect on food or chemoatractant preference, indicating that the effects of naltrexone on drug preference are selective and not due to disruption in general behaviors. These findings suggest that the reinforcing properties of drugs of abuse can be examined in C. elegans and this model may be useful for screening potential pharmacotherapies for drug abuse

Caenorhabditis elegans as a model system to identify therapeutics for alcohol use disorders

Alcohol use disorders (AUDs) cause serious problems in society and few effective treatments are available. Caenorhabditis elegans (C. elegans) is an excellent invertebrate model to study the neurobiological basis of human behavior with a conserved, fully tractable genome, and a short generation time for fast generation of data at a fraction of the cost of other organisms. C. elegans demonstrate movement toward, and concentration-dependent self-exposure to various psychoactive drugs. The discovery of opioid receptors in C. elegans provided the impetus to test the hypothesis that C. elegans may be used as a medications screen to identify new AUD treatments. We tested the effects of naltrexone, an opioid antagonist and effective treatment for AUDs, on EtOH preference in C. elegans. Six-well agar test plates were prepared with EtOH placed in a target zone on one side and water in the opposite target zone of each well. Worms were treated with naltrexone before EtOH preference testing and then placed in the center of each well. Wild-type worms exhibited a concentration-dependent preference for 50, 70 and 95% EtOH. Naltrexone blocked acute EtOH preference, but had no effect on attraction to food or benzaldehyde in wild-type worms. Npr-17 opioid receptor knockout mutants did not display a preference for EtOH. In contrast, npr-17 opioid receptor rescue mutants exhibited significant EtOH preference behavior, which was attenuated by naltrexone. Chronic EtOH exposure induced treatment resistance and compulsive-like behavior. These data indicate that C. elegans can serve as a model system to identify compounds to treat AUDs

Immunoregulatory Potential of Exosomes Derived from Cancer Stem Cells.

Head and neck squamous cell carcinomas (HNSCCs) are malignancies that originate in the mucosal lining of the upper aerodigestive tract. Despite advances in therapeutic interventions, survival rates among HNSCC patients have remained static for years. Cancer stem cells (CSCs) are tumor-initiating cells that are highly resistant to treatment, and are hypothesized to contribute to a significant fraction of tumor recurrences. Consequently, further investigations of how CSCs mediate recurrence may provide insights into novel druggable targets. A key element of recurrence involves the tumor's ability to evade immunosurveillance. Recent published reports suggest that CSCs possess immunosuppressive properties, however, the underlying mechanism have yet to be fully elucidated. To date, most groups have focused on the role of CSC-derived secretory proteins, such as cytokines and growth factors. Here, we review the established immunoregulatory role of exosomes derived from mixed tumor cell populations, and propose further study of CSC-derived exosomes may be warranted. Such studies may yield novel insights into new druggable targets, or lay the foundation for future exosome-based diagnostics

Single-molecule super-resolution imaging of chromosomes and in situ haplotype visualization using Oligopaint FISH probes

Fluorescence in situ hybridization (FISH) is a powerful single-cell technique for studying nuclear structure and organization. Here we report two advances in FISH-based imaging. We first describe the in situ visualization of single-copy regions of the genome using two single-molecule super-resolution methodologies. We then introduce a robust and reliable system that harnesses single-nucleotide polymorphisms (SNPs) to visually distinguish the maternal and paternal homologous chromosomes in mammalian and insect systems. Both of these new technologies are enabled by renewable, bioinformatically designed, oligonucleotide-based Oligopaint probes, which we augment with a strategy that uses secondary oligonucleotides (oligos) to produce and enhance fluorescent signals. These advances should substantially expand the capability to query parent-of-origin-specific chromosome positioning and gene expression on a cell-by-cell basis

Assessment of ground deformation and seismicity in two areas of intense hydrocarbon production in the Argentinian Patagonia

The exploitation of both conventional and unconventional hydrocarbons may lead to still not well-known environmental consequences such as ground deformation and induced/triggered seismicity. Identifying and characterizing these effects is fundamental for prevention or mitigation purposes, especially when they impact populated areas. Two case studies of such effects on hydrocarbon-producing basins in Argentina, the Neuquén and the Golfo de San Jorge, are presented in this work. The intense hydrocarbon production activities in recent years and their potential link with the occurrence of two earthquakes of magnitude 4.9 and 5 near the operating well fields is assessed. A joint analysis of satellite radar interferometry and records of fluid injection and extraction demonstrate that, between 2017 and 2020, vertical ground displacements occurred in both study areas over active well fields that might indicate a correlation to hydrocarbon production activities. Coseismic deformation models of the two earthquakes constrain source depths to less than 2 km. The absence of seismicity before the beginning of the hydrocarbon activities in both areas, and the occurrence of the two largest and shallow earthquakes in the vicinity of the active well fields just after intensive production periods, points towards the potential association between both phenomena.Fil: Tamburini Beliveau, Guillermo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia de Santa Cruz. Universidad Tecnológica Nacional. Facultad Regional Santa Cruz. Centro de Investigaciones y Transferencia de Santa Cruz. Universidad Nacional de la Patagonia Austral. Centro de Investigaciones y Transferencia de Santa Cruz; ArgentinaFil: Grosso Heredia, Javier A.. Universidad Nacional del Comahue; ArgentinaFil: Béjar Pizarro, Marta. Instituto Geológico y Minero de España; EspañaFil: Pérez López, Raúl. Instituto Geológico y Minero de España; EspañaFil: Portela, Juan. Universidad Politécnica de Madrid; EspañaFil: Cismondi Duarte, Martín. Universidad Nacional de Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación y Desarrollo en Ingeniería de Procesos y Química Aplicada; ArgentinaFil: Monserrat, Oriol. Centre Tecnològic de Telecomunicacions de Catalunya; Españ

New Zealand secondary school teachers’ perspectives on teaching Relationships and Sexuality Education

Best practice relationships and sexuality education (RSE) increases young people’s knowledge, critical thinking, and positive attitudes related to sexual and reproductive health and relationships (UNESCO, 2018). The Ministry of Education (2020a) asserts that a comprehensive approach to RSE begins early in a child’s life and progresses throughout the years of formal schooling. The Ministry of Education’s guidance (2020a) as well as the statement of National Educational and Learning Priorities (NELP) coming into effect in 2023, make it clear that expectations for RSE go beyond solely health education teaching and link to a whole school approach for the promotion of student wellbeing. Research literature from New Zealand generally highlights the inadequacies, gaps, and inconsistencies in RSE practice (Classification Office, 2020; Education Review Office, 2018; Family Planning, 2019; O’Neill, 2017). This research base has primarily been informed by young people’s perspectives and the evaluative work of the Education Review Office and reveals a gap in understanding of teachers’ perspectives of teaching RSE in New Zealand. The purpose of this research project, therefore, was to gain a contemporary view of the experiences of secondary school teachers in New Zealand in relation to relationships and sexuality education (RSE)

Caenorhabditis elegans Show Preference for Stimulants and Potential as a Model Organism for Medications Screening

The nematode Caenorhabditis elegans (C. elegans) is a popular invertebrate model organism to study neurobiological disease states. This is due in part to the intricate mapping of all neurons and synapses of the entire animal, the wide availability of mutant strains, and the genetic and molecular tools that can be used to manipulate the genome and gene expression. We have shown that, C. elegans develops a conditioned preference for cues that had previously been paired with either cocaine or methamphetamine exposure that is dependent on dopamine neurotransmission, similar to findings using place conditioning with rats and mice. In the current study, we show C. elegans also display a preference for, and self-exposure to, cocaine and nicotine. This substance of abuse (SOA) preference response can be selectively blocked by pretreatment with naltrexone and is consistent with the recent discovery of an opioid receptor system in C. elegans. In addition, pre-exposure to the smoking cessation treatment varenicline also inhibits self-exposure to nicotine. Exposure to concentrations of treatments that inhibit SOA preference/self-exposure did not induce any significant inhibition of locomotor activity or affect food or benzaldehyde chemotaxis. These data provide predictive validity for the development of high-throughput C. elegans behavioral medication screens. These screens could enable fast and accurate generation of data to identify compounds that may be effective in treating human addiction. The successful development and validation of such models would introduce powerful and novel tools in the search for new pharmacological treatments for substance use disorders, and provide a platform to study the mechanisms that underlie addictions

Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin

What is the level of consciousness of the psychedelic state? Empirically, measures of neural signal diversity such as entropy and Lempel-Ziv (LZ) complexity score higher for wakeful rest than for states with lower conscious level like propofol-induced anesthesia. Here we compute these measures for spontaneous magnetoencephalographic (MEG) signals from humans during altered states of consciousness induced by three psychedelic substances: psilocybin, ketamine and LSD. For all three, we find reliably higher spontaneous signal diversity, even when controlling for spectral changes. This increase is most pronounced for the single-channel LZ complexity measure, and hence for temporal, as opposed to spatial, signal diversity. We also uncover selective correlations between changes in signal diversity and phenomenological reports of the intensity of psychedelic experience. This is the first time that these measures have been applied to the psychedelic state and, crucially, that they have yielded values exceeding those of normal waking consciousness. These findings suggest that the sustained occurrence of psychedelic phenomenology constitutes an elevated level of consciousness - as measured by neural signal diversity

Nanotools for Neuroscience and Brain Activity Mapping

Neuroscience is at a crossroads. Great effort is being invested into deciphering specific neural interactions and circuits. At the same time, there exist few general theories or principles that explain brain function. We attribute this disparity, in part, to limitations in current methodologies. Traditional neurophysiological approaches record the activities of one neuron or a few neurons at a time. Neurochemical approaches focus on single neurotransmitters. Yet, there is an increasing realization that neural circuits operate at emergent levels, where the interactions between hundreds or thousands of neurons, utilizing multiple chemical transmitters, generate functional states. Brains function at the nanoscale, so tools to study brains must ultimately operate at this scale, as well. Nanoscience and nanotechnology are poised to provide a rich toolkit of novel methods to explore brain function by enabling simultaneous measurement and manipulation of activity of thousands or even millions of neurons. We and others refer to this goal as the Brain Activity Mapping Project. In this Nano Focus, we discuss how recent developments in nanoscale analysis tools and in the design and synthesis of nanomaterials have generated optical, electrical, and chemical methods that can readily be adapted for use in neuroscience. These approaches represent exciting areas of technical development and research. Moreover, unique opportunities exist for nanoscientists, nanotechnologists, and other physical scientists and engineers to contribute to tackling the challenging problems involved in understanding the fundamentals of brain function