Classics in Chemical Neuroscience: Deliriant Antihistaminic Drugs.

Antihistaminic drugs are widely used clinically and have long been primarily known for their use to treat severe allergic conditions caused by histamine release. Antihistaminic drugs also exert central nervous system (CNS) effects, acting as anxiolytics, hypnotics, and neuroleptics. However, these drugs also have multiple serious neuropharmacological side-effects, inducing delirium, hyperarousal, disorganized behavior, and hallucinations. Due to their robust CNS effects, antihistamines are also increasingly abused, with occasional overdoses and life-threatening toxicity. Here, we discuss chemical and neuropharmacological aspects of antihistaminic drugs in both human and animal (experimental) models and outline their current societal and mental health importance as neuroactive substances.

Ketamine modulates the exploratory dynamics and homebase-related behaviors of adult zebrafish.

Anxiety is a protective behavior when animals face aversive conditions, but commonly associated with various neuropsychiatric disorders when exacerbated. Drug repurposing has emerged as a valuable strategy to use existing pharmaceuticals for new therapeutic purposes. Ketamine, traditionally used as an anesthetic, acts as a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, and evidence has shown potential anxiolytic and antidepressant effects at subanesthetic doses. However, the influence of ketamine on multiple behavioral domains in vertebrates is not completely understood. Here, we evaluated the potential modulatory effect of ketamine on the spatio-temporal exploratory dynamics and homebase-related behaviors in adult zebrafish using the open field test (OFT). Animals were exposed to subanesthetic concentrations of ketamine (0, 2, 20, and 40 mg/L) for 20 min and locomotion- exploration- and homebase-related behaviors were assessed in a single 30-min trial. Our data revealed that ketamine (20 and 40 mg/L) induced hyperlocomotion, as verified by the increased total distance traveled. All concentrations tested elicited circling behavior, a stereotyped-like response which gradually reduced across the periods of test. We also observed modulatory effects of ketamine on the spatio-temporal exploratory pattern, in which the reduced thigmotaxis and homebase activity, associated with the increased average length of trips were suggestive of anxiolytic-like effects. Collectively, our novel findings support the modulatory effects of ketamine on the spatio-temporal exploratory activity, as well as the utility of homebase-related measurements to evaluate the behavioral dynamics of zebrafish.

Minocycline reduces neurobehavioral deficits evoked by chronic unpredictable stress in adult zebrafish.

Chronic stress-related brain disorders are widespread and debilitating, and often cause lasting neurobehavioral deficits. Minocycline, a common antibiotic and an established inhibitor of microglia, emerges as potential treatment of these disorders. The zebrafish (Danio rerio) is an important emerging model organism in translational neuroscience and stress research. Here, we evaluated the potential of minocycline to correct microglia-mediated behavioral, genomic and neuroimmune responses induced by chronic unpredictable stress (CUS) in adult zebrafish. We demonstrated that CUS evoked overt behavioral deficits in the novel tank, light-dark box and shoaling tests, paralleled by elevated stress hormones (CRH, ACTH and cortisol), and upregulated brain expression of the 'neurotoxic M1' microglia-specific biomarker gene (MHC-2) and pro-inflammatory cytokine genes (IL-1ß, IL-6 and IFN-γ). CUS also elevated peripheral (whole-body) pro-inflammatory (IL-1ß, IFN-γ) and lowered anti-inflammatory cytokines (IL-4 and IL-10), as well as reduced whole-brain serotonin, dopamine and norepinephrine levels, and increased brain dopamine and serotonin turnover. In contrast, minocycline attenuated most of these effects, also reducing CUS-elevated peripheral levels of IL-6 and IFN-γ. Collectively, this implicates microglia in zebrafish responses to chronic stress, and suggests glial pathways as potential evolutionarily conserved drug targets for treating stress-evoked neuropathogenesis. Our findings also support the growing translational value of zebrafish models for understanding complex molecular mechanisms of brain pathogenesis and its therapy.

A novel open-access artificial-intelligence-driven platform for CNS drug discovery utilizing adult zebrafish.

BACKGROUND: Although zebrafish are increasingly utilized in biomedicine for CNS disease modelling and drug discovery, this generates big data necessitating objective, precise and reproducible analyses. The artificial intelligence (AI) applications have empowered automated image recognition and video-tracking to ensure more efficient behavioral testing. NEW METHOD: Capitalizing on several AI tools that most recently became available, here we present a novel open-access AI-driven platform to analyze tracks of adult zebrafish collected from in vivo neuropharmacological experiments. For this, we trained the AI system to distinguish zebrafish behavioral patterns following systemic treatment with several well-studied psychoactive drugs - nicotine, caffeine and ethanol. RESULTS: Experiment 1 showed the ability of the AI system to distinguish nicotine and caffeine with 75 % and ethanol with 88 % probability and high (81 %) accuracy following a post-training exposure to these drugs. Experiment 2 further validated our system with additional, previously unexposed compounds (cholinergic arecoline and varenicline, and serotonergic fluoxetine), used as positive and negative controls, respectively. COMPARISON WITH EXISTING METHODS: The present study introduces a novel open-access AI-driven approach to analyze locomotor activity of adult zebrafish. CONCLUSIONS: Taken together, these findings support the value of custom-made AI tools for unlocking full potential of zebrafish CNS drug research by monitoring, processing and interpreting the results of in vivo experiments.

Zebrafish models for studying cognitive enhancers.

Cognitive decline is commonly seen both in normal aging and in neurodegenerative and neuropsychiatric diseases. Various experimental animal models represent a valuable tool to study brain cognitive processes and their deficits. Equally important is the search for novel drugs to treat cognitive deficits and improve cognitions. Complementing rodent and clinical findings, studies utilizing zebrafish (Danio rerio) are rapidly gaining popularity in translational cognitive research and neuroactive drug screening. Here, we discuss the value of zebrafish models and assays for screening nootropic (cognitive enhancer) drugs and the discovery of novel nootropics. We also discuss the existing challenges, and outline future directions of research in this field.

Decoding Molecular Bases of Rodent Social Hetero-Grooming Behavior Using in Silico Analyses and Bioinformatics Tools.

Highly prevalent in laboratory rodents, 'social' hetero-grooming behavior is translationally relevant to modeling a wide range of neuropsychiatric disorders. Here, we comprehensively evaluated all known to date mouse genes linked to aberrant hetero-grooming phenotype, and applied bioinformatics tools to construct a network of their established protein-protein interactions (PPI). We next identified several distinct molecular clusters within this complex network, including neuronal differentiation, cytoskeletal, WNT-signaling and synapsins-associated pathways. Using additional bioinformatics analyses, we further identified 'central' (hub) proteins within these molecular clusters, likely key for mouse hetero-grooming behavior. Overall, a more comprehensive characterization of intricate molecular pathways linked to aberrant rodent grooming may markedly advance our understanding of underlying cellular mechanisms and related neurological disorders, eventually helping discover novel targets for their pharmacological or gene therapy interventions.

In silico analysis of non-structural protein 12 sequences from SARS-COV-2 found in Manaus, Amazonas, Brazil, reveals mutations linked to higher transmissibility.

The disease coronavirus COVID-19 has been the cause of millions of deaths worldwide. Among the proteins of SARS-CoV-2, non-structural protein 12 (NSP12) plays a key role during COVID infection and is part of the RNA-dependent RNA polymerase complex. The monitoring of NSP12 polymorphisms is extremely important for the design of new antiviral drugs and monitoring of viral evolution. This study analyzed the NSP12 mutations detected in circulating SARS-CoV-2 during the years 2020 to 2022 in the population of the city of Manaus, Amazonas, Brazil. The most frequent mutations found were P323L and G671S. Reports in the literature indicate that these mutations are related to transmissibility efficiency, which may have contributed to the extremely high numbers of cases in this location. In addition, two mutations described here (E796D and R914K) are close and have RMSD that is similar to the mutations M794V and N911K, which have been described in the literature as influential on the performance of the NSP12 enzyme. These data demonstrate the need to monitor the emergence of new mutations in NSP12 in order to better understand their consequences for the treatments currently used and in the design of new drugs.

Rapid Prototyping of Anomalous Reflective Metasurfaces Using Spray-Coated Liquid Metal.

Reconfigurable intelligent surfaces (RISs) have the potential to improve wireless communication links by dynamically redirecting signals to dead spots. Although a reconfigurable surface is best suited for environments in which the reflected signal must be dynamically steered, there are cases where a static, non-reconfigurable anomalous reflective metasurface can suffice. In this work, spray-coated liquid metal is used to rapidly prototype an anomalous reflective metasurface. Using a pressurized air gun and a plastic thin-film mask, a metasurface consisting of a 6 × 4 array of Galinstan liquid-metal elements is sprayed within minutes. The metasurface produces a reflected wave at an angle of 28° from normal in response to a normal incident 3.5-GHz electromagnetic plane wave. The spray-coated liquid-metal metasurface shows comparable results to an anomalous reflective metasurface with copper elements of the same dimensions, demonstrating that this liquid-metal fabrication process is a viable solution for the rapid prototyping of anomalous reflective metasurfaces.

Developing Peripheral Biochemical Biomarkers of Brain Disorders: Insights from Zebrafish Models.

High prevalence of human brain disorders necessitates development of the reliable peripheral biomarkers as diagnostic and disease-monitoring tools. In addition to clinical studies, animal models markedly advance studying of non-brain abnormalities associated with brain pathogenesis. The zebrafish (Danio rerio) is becoming increasingly popular as an animal model organism in translational neuroscience. These fish share some practical advantages over mammalian models together with high genetic homology and evolutionarily conserved biochemical and neurobehavioral phenotypes, thus enabling large-scale modeling of human brain diseases. Here, we review mounting evidence on peripheral biomarkers of brain disorders in zebrafish models, focusing on altered biochemistry (lipids, carbohydrates, proteins, and other non-signal molecules, as well as metabolic reactions and activity of enzymes). Collectively, these data strongly support the utility of zebrafish (from a systems biology standpoint) to study peripheral manifestations of brain disorders, as well as highlight potential applications of biochemical biomarkers in zebrafish models to biomarker-based drug discovery and development.

Chronic Behavioral and Neurochemical Effects of Four Novel N-Benzyl-2-phenylethylamine Derivatives Recently Identified as "Psychoactive" in Adult Zebrafish Screens.

Potently affecting human and animal brain and behavior, hallucinogenic drugs have recently emerged as potentially promising agents in psychopharmacotherapy. Complementing laboratory rodents, the zebrafish (Danio rerio) is a powerful model organism for screening neuroactive drugs, including hallucinogens. Here, we tested four novel N-benzyl-2-phenylethylamine (NBPEA) derivatives with 2,4- and 3,4-dimethoxy substitutions in the phenethylamine moiety and the -F, -Cl, and -OCF3 substitutions in the ortho position of the phenyl ring of the N-benzyl moiety (34H-NBF, 34H-NBCl, 24H-NBOMe(F), and 34H-NBOMe(F)), assessing their behavioral and neurochemical effects following chronic 14 day treatment in adult zebrafish. While the novel tank test behavioral data indicate anxiolytic-like effects of 24H-NBOMe(F) and 34H-NBOMe(F), neurochemical analyses reveal reduced brain norepinephrine by all four drugs, and (except 34H-NBCl) - reduced dopamine and serotonin levels. We also found reduced turnover rates for all three brain monoamines but unaltered levels of their respective metabolites. Collectively, these findings further our understanding of complex central behavioral and neurochemical effects of chronically administered novel NBPEAs and highlight the potential of zebrafish as a model for preclinical screening of small psychoactive molecules.

Can we gain translational insights into the functional roles of cerebral cortex from acortical rodent and naturally acortical zebrafish models?

Cerebral cortex is found only in mammals and is particularly prominent and developed in humans. Various rodent models with fully or partially ablated cortex are commonly used to probe the role of cortex in brain functions and its multiple subcortical projections, including pallium, thalamus and the limbic system. Various rodent models are traditionally used to study the role of cortex in brain functions. A small teleost fish, the zebrafish (Danio rerio), has gained popularity in neuroscience research, and albeit (like other fishes) lacking cortex, its brain performs well some key functions (e.g., memory, consciousness and motivation) with complex, context-specific and well-defined behaviors. Can rodent and zebrafish models help generate insights into the role of cortex in brain functions, and dissect its cortex-specific (vs. non-cortical) functions? To address this conceptual question, here we evaluate brain functionality in intact vs. decorticated rodents and further compare it in the zebrafish, a naturally occurring acortical species. Overall, comparing cortical and acortical rodent models with naturally acortical zebrafish reveals both distinct and overlapping contributions of neocortex and 'precortical' zebrafish telencephalic regions to higher brain functions. Albeit morphologically different, mammalian neocortex and fish pallium may possess more functional similarities than it is presently recognized, calling for further integrative research utilizing both cortical and decorticated/acortical vertebrate model organisms.

A smoking cessation intervention for rural veterans tailored to individual risk factors: A multicenter randomized clinical trial.

INTRODUCTION: Rates of cigarette use remain elevated among those living in rural areas. Depressive symptoms, risky alcohol use, and weight concerns frequently accompany cigarette smoking and may adversely affect quitting. Whether treatment for tobacco use that simultaneously addresses these issues affects cessation outcomes is uncertain. METHODS: The study was a multicenter, two-group, randomized controlled trial involving mostly rural veterans who smoke (N = 358) receiving treatment at one of five Veterans Affairs Medical Centers. The study randomly assigned participants to a tailored telephone counseling intervention or referral to their state tobacco quitline. Both groups received guideline-recommended smoking cessation pharmacotherapy, selected using a shared decision-making approach. The primary outcome was self-reported seven-day point prevalence abstinence (PPA) at three and six months. The study used salivary cotinine to verify self-reported quitting at six months. RESULTS: Self-reported PPA was significantly greater in participants assigned to Tailored Counseling at three (OR = 1.66; 95 % CI: 1.07-2.58) but not six (OR = 1.35; 95 % CI: 0.85-2.15) months. Post hoc subgroup analyses examining treatment group differences based on whether participants had a positive screen for elevated depressive symptoms, risky alcohol use, and/or concerns about weight gain indicated that the cessation benefit of Tailored Counseling at three months was limited to those with ≥1 accompanying concern (OR = 2.02, 95 % CI: 1.20-3.42). Biochemical verification suggested low rates of misreporting. CONCLUSIONS: A tailored smoking cessation intervention addressing concomitant risk factors enhanced short-term abstinence but did not significantly improve long-term quitting. Extending the duration of treatment may be necessary to sustain treatment effects.

Experimental models of human cortical malformations: from mammals to 'acortical' zebrafish.

Human neocortex controls and integrates cognition, emotions, perception and complex behaviors. Aberrant cortical development can be triggered by multiple genetic and environmental factors, causing cortical malformations. Animal models, especially rodents, are a valuable tool to probe molecular and physiological mechanisms of cortical malformations. Complementing rodent studies, the zebrafish (Danio rerio) is an important model organism in biomedicine. Although the zebrafish (like other fishes) lacks neocortex, here we argue that this species can still be used to model various aspects and brain phenomena related to human cortical malformations. We also discuss novel perspectives in this field, covering both advantages and limitations of using mammalian and zebrafish models in cortical malformation research. Summarizing mounting evidence, we also highlight the importance of translationally-relevant insights into the pathogenesis of cortical malformations from animal models, and discuss future strategies of research in the field.

Telemedicine-based inspiratory muscle training and walking promotion with lung cancer survivors following curative intent therapy: a parallel-group pilot randomized trial.

PURPOSE: Following curative-intent therapy of lung cancer, many survivors experience dyspnea and physical inactivity. We investigated the feasibility, acceptability, safety, and potential efficacy of inspiratory muscle training (IMT) and walking promotion to disrupt a postulated "dyspnea-inactivity" spiral. METHODS: Between January and December 2022, we recruited lung cancer survivors from Kaiser Permanente Colorado who completed curative-intent therapy within 1-6 months into a phase-IIb, parallel-group, pilot randomized trial (1:1 allocation). The 12-week intervention, delivered via telemedicine, consisted of exercise training (IMT + walking), education, and behavior change support. Control participants received educational materials on general exercise. We determined feasibility a priori: enrollment of ≥ 20% eligible patients, ≥ 75% retention, study measure completion, and adherence. We assessed acceptability using the Telemedicine-Satisfaction-and-Usefulness-Questionnaire and safety events that included emergency department visits or hospitalizations. Patient-centered outcome measures (PCOMs) included dyspnea (University-of-California-San-Diego-Shortness-of-Breath-Questionnaire), physical activity (activPAL™ steps/day), functional exercise capacity (mobile-based-six-minute-walk-test), and health-related quality of life (HRQL, St.-George's-Respiratory-Questionnaire). We used linear mixed-effects models to assess potential efficacy. RESULTS: We screened 751 patients, identified 124 eligible, and consented 31 (25%) participants. Among 28 participants randomized (14/group), 22 (11/group) completed the study (79% retention). Intervention participants returned > 90% of self-reported activity logs, completed > 90% of PCOMs, and attended > 90% of tele-visits; 75% of participants performed IMT at the recommended dose. Participants had high satisfaction with tele-visits and found the intervention useful. There was no statistically significant difference in safety events between groups. Compared to control participants from baseline to follow-up, intervention participants had statistically significant and clinically meaningful improved HRQL (SGRQ total, symptom, and impact scores) (standardized effect size: -1.03 to -1.30). CONCLUSIONS: Among lung cancer survivors following curative-intent therapy, telemedicine-based IMT + walking was feasible, acceptable, safe, and had potential to disrupt the "dyspnea-inactivity" spiral. Future efficacy/effectiveness trials are warranted and should incorporate IMT and walking promotion to improve HRQL. TRIAL REGISTRATION: ClinicalTrials.gov NCT05059132.

The emerging complexity of molecular pathways implicated in mouse self-grooming behavior.

Rodent self-grooming is an important complex behavior, and its deficits are translationally relevant to a wide range of neuropsychiatric disorders. Here, we analyzed a comprehensive dataset of 227 genes whose mutations are known to evoke aberrant self-grooming in mice. Using these genes, we constructed the network of their established protein-protein interactions (PPI), yielding several distinct molecular clusters related to postsynaptic density, the Wnt signaling, transcription factors, neuronal cell cycle, NOS neurotransmission, microtubule regulation, neuronal differentiation/trafficking, neurodevelopment and mitochondrial function. Utilizing further bioinformatics analyses, we also identified novel central ('hub') proteins within these clusters, whose genes may also be implicated in aberrant self-grooming and other repetitive behaviors in general. Untangling complex molecular pathways of this important behavior using in silico approaches contributes to our understanding of related neurological disorders, and may suggest novel potential targets for their pharmacological or gene therapy.

Molecular signature of excessive female aggression: study of stressed mice with genetic inactivation of neuronal serotonin synthesis.

Aggression is a complex social behavior, critically involving brain serotonin (5-HT) function. The neurobiology of female aggression remains elusive, while the incidence of its manifestations has been increasing. Yet, animal models of female aggression are scarce. We previously proposed a paradigm of female aggression in the context of gene x environment interaction where mice with partial genetic inactivation of tryptophan hydroxylase-2 (Tph2+/- mice), a key enzyme of neuronal 5-HT synthesis, are subjected to predation stress resulting in pathological aggression. Using deep sequencing and the EBSeq method, we studied the transcriptomic signature of excessive aggression in the prefrontal cortex of female Tph2+/- mice subjected to rat exposure stress and food deprivation. Challenged mutants, but not other groups, displayed marked aggressive behaviors. We found 26 genes with altered expression in the opposite direction between stressed groups of both Tph2 genotypes. We identified several molecular markers, including Dgkh, Arfgef3, Kcnh7, Grin2a, Tenm1 and Epha6, implicated in neurodevelopmental deficits and psychiatric conditions featuring impaired cognition and emotional dysregulation. Moreover, while 17 regulons, including several relevant to neural plasticity and function, were significantly altered in stressed mutants, no alteration in regulons was detected in stressed wildtype mice. An interplay of the uncovered pathways likely mediates partial Tph2 inactivation in interaction with severe stress experience, thus resulting in excessive female aggression.

Towards experimental models of delirium utilizing zebrafish.

Delirium is an acute neuropsychiatric condition characterized by impaired behavior and cognition. Although the syndrome has been known for millennia, its CNS mechanisms and risk factors remain poorly understood. Experimental animal models, especially rodent-based, are commonly used to probe various pathogenetic aspects of delirium. Complementing rodents, the zebrafish (Danio rerio) emerges as a promising novel model organism to study delirium. Zebrafish demonstrate high genetic and physiological homology to mammals, easy maintenance, robust behaviors in various sensitive behavioral tests, and the potential to screen for pharmacological agents relevant to delirium. Here, we critically discuss recent developments in the field, and emphasize the developing utility of zebrafish models for translational studies of delirium and deliriant drugs. Overall, the zebrafish represents a valuable and promising aquatic model species whose use may help understand delirium etiology, as well as develop novel therapies for this severely debilitating disorder.

Lung cancer survivors' views on telerehabilitation following curative intent therapy: a formative qualitative study.

OBJECTIVES: To inform personalised home-based rehabilitation interventions, we sought to gain in-depth understanding of lung cancer survivors' (1) attitudes and perceived self-efficacy towards telemedicine; (2) knowledge of the benefits of rehabilitation and exercise training; (3) perceived facilitators and preferences for telerehabilitation; and (4) health goals following curative intent therapy. DESIGN: We conducted semi-structured interviews guided by Bandura's Social Cognitive Theory and used directed content analysis to identify salient themes. SETTING: One USA Veterans Affairs Medical Center. PARTICIPANTS: We enrolled 20 stage I-IIIA lung cancer survivors who completed curative intent therapy in the prior 1-6 months. Eighty-five percent of participants had prior experience with telemedicine, but none with telerehabilitation or rehabilitation for lung cancer. RESULTS: Participants viewed telemedicine as convenient, however impersonal and technologically challenging, with most reporting low self-efficacy in their ability to use technology. Most reported little to no knowledge of the potential benefits of specific exercise training regimens, including those directed towards reducing dyspnoea, fatigue or falls. If they were to design their own telerehabilitation programme, participants had a predominant preference for live and one-on-one interaction with a therapist, to enhance therapeutic relationship and ensure correct learning of the training techniques. Most participants had trouble stating their explicit health goals, with many having questions or concerns about their lung cancer status. Some wanted better control of symptoms and functional challenges or engage in healthful behaviours. CONCLUSIONS: Features of telerehabilitation interventions for lung cancer survivors following curative intent therapy may need to include strategies to improve self-efficacy and skills with telemedicine. Education to improve knowledge of the benefits of rehabilitation and exercise training, with alignment to patient-formulated goals, may increase uptake. Exercise training with live and one-on-one therapist interaction may enhance learning, adherence, and completion. Future work should determine how to incorporate these features into telerehabilitation.