In vivo magnetogenetics for cell-type-specific targeting and modulation of brain circuits.

Neuromodulation technologies are crucial for investigating neuronal connectivity and brain function. Magnetic neuromodulation offers wireless and remote deep brain stimulations that are lacking in optogenetic- and wired-electrode-based tools. However, due to the limited understanding of working principles and poorly designed magnetic operating systems, earlier magnetic approaches have yet to be utilized. Furthermore, despite its importance in neuroscience research, cell-type-specific magnetic neuromodulation has remained elusive. Here we present a nanomaterials-based magnetogenetic toolbox, in conjunction with Cre-loxP technology, to selectively activate genetically encoded Piezo1 ion channels in targeted neuronal populations via torque generated by the nanomagnetic actuators in vitro and in vivo. We demonstrate this cell-type-targeting magnetic approach for remote and spatiotemporal precise control of deep brain neural activity in multiple behavioural models, such as bidirectional feeding control, long-term neuromodulation for weight control in obese mice and wireless modulation of social behaviours in multiple mice in the same physical space. Our study demonstrates the potential of cell-type-specific magnetogenetics as an effective and reliable research tool for life sciences, especially in wireless, long-term and freely behaving animals.

The novel psychoactive substance 25E-NBOMe induces reward-related behaviors via dopamine D1 receptor signaling in male rodents.

Novel psychoactive substances (NPSs) are new psychotropic drugs designed to evade substance regulatory policies. 25E-NBOMe (2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine) has recently been identified as an NPS, and its recreational misuse has been reported to be rapidly increasing. However, the psychopharmacological effects and mechanisms of 25E-NBOMe have not been studied. We examined the abuse potential of 25E-NBOMe using the conditioned place preference in male mice and self-administration paradigms in male rats. Additionally, immunoblot assay, enzyme-linked immunosorbent assay, and microdialysis were used to determine the molecular effects of 25E-NBOMe in the nucleus accumbens (NAc). Our data demonstrated that 25E-NBOMe induces conditioned place preference, and the dopaminergic signaling in the NAc mediates these. Following 25E-NBOMe administration, expression of dopamine transporter and dopamine D1 receptor (D1DR) were enhanced in the NAc of male mice, and NAc dopamine levels were reduced in both male mice and rats. Induction of intracellular dopaminergic pathways, DARPP32, and phosphorylation of CREB in the NAc of male mice was also observed. Significantly, pharmacological blockade of D1DR or chemogenetic inhibition of D1DR-expressing medium spiny neurons in the NAc attenuated 25E-NBOMe-induced conditioned place preference in male mice. We also examined the hallucinogenic properties of 25E-NBOMe using the head twitch response test in male mice and found that this behavior was mediated by serotonin 2A receptor activity. Our findings demonstrate that D1DR signaling may govern the addictive potential of 25E-NBOMe. Moreover, our study provides new insights into the potential mechanisms of substance use disorder and the improvement of controlled substance management.

Adinazolam, a Benzodiazepine-Type New Psychoactive Substance, Has Abuse Potential and Induces Withdrawal Symptoms in Rodents.

Adinazolam (ADZ) is a benzodiazepine-type new psychoactive substance (NPS) with anxiolytic, anticonvulsant, and antidepressant effects. High ADZ doses have been reported to impair psychomotor performance and memory; however, the abuse potential and drug dependence of ADZ have not yet been fully investigated. In this study, we evaluated whether ADZ has abuse potential and leads to drug dependence and withdrawal symptoms. The intravenous self-administration (IVSA) test revealed that ADZ (0.01, 0.03, and 0.1 mg/kg/infusion) was self-administered significantly above vehicle levels, suggesting the reinforcing effect of ADZ. Furthermore, we revealed that treatment discontinuation following chronic ADZ administration (3 and 6 mg/kg) caused several somatic withdrawal symptoms in mice, including body tremor. Moreover, it induced motivational withdrawal signs, such as anxiety-related behavior in the elevated plus maze (EPM) test and memory deficits in the Y-maze test. After the IVSA test, an enzyme-linked immunosorbent assay (ELISA) showed that ADZ administration significantly increased the dopamine contents in the thalamus, nucleus accumbens (NAc), and ventral tegmental area (VTA). This finding was also supported by the results of the Western blot. Taken together, our results suggest that ADZ has abuse potential and can lead to drug dependence and withdrawal syndrome.

Designer Drug, 25D-NBOMe, Has Reinforcing and Rewarding Effects through Change of a Dopaminergic Neurochemical System.

2-(2,5-Dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)_ethanamine (25D-NBOMe), an analogue of the 2C family, is a newly synthesized psychoactive substance. It acts as an agonist at the 5-HT2A receptor and has a similar mechanism to that of NBOMe compounds. However, the pharmacological mechanism for its rewarding and reinforcing effects has not been revealed. In the present study, intravenous self-administration (IVSA) test and conditioned place preference (CPP) test were performed to investigate whether 25D-NBOMe has abuse potential. We also evaluated the effects of 25D-NBOMe on neurochemical changes using western blot analysis and microdialysis. The IVSA test revealed increased self-administration in 25D-NBOMe (0.03 mg/kg)-treated rats. In addition, the CPP test revealed rewarding effects in 25D-NBOMe (1 mg/kg)-treated mice. In the neurochemical studies, 25D-NBOMe treatment affected the expression of dopamine (DA) receptor D1 (DRD1), DA receptor D2 (DRD2), tyrosine hydroxylase, DA transporter (DAT), and phospho-DAT (p-DAT) in the nucleus accumbens (NAc). In addition, microdialysis revealed that treatment with progressively increasing doses (1, 3, and 10 mg/kg) of 25D-NBOMe increased the extracellular levels of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the rat NAc. Taken together, our results show the abuse potential and neurochemical changes related to addictive behavior after administration of 25D-NBOMe.

Efficacy of a Mobile-Based Multidomain Intervention to Improve Cognitive Function and Health-Related Outcomes Among Older Korean Adults with Subjective Cognitive Decline.

BACKGROUND: Subjective cognitive decline (SCD) is a self-reported experience of declining cognitive function showing normal performance in cognitive assessments, which is a known risk factor for dementia. Recent studies highlight the importance of nonpharmacological multidomain interventions that can target multiple risk factors of dementia in older adults. OBJECTIVE: This study investigated the efficacy of the Silvia program, a mobile-based multidomain intervention, to improve cognitive function and health-related outcomes of older adults with SCD. We compare its effects to a conventional paper-based multidomain program on various health indicators related to risk factors of dementia. METHODS: This prospective randomized controlled trial involved 77 older adults with SCD recruited from the Dementia Prevention and Management Center in Gwangju, South Korea during May to October 2022. Participants were randomly assigned to either the mobile- or paper-based group. Interventions were administered for 12 weeks, where pre- and post-assessments were conducted. RESULTS: The K-RBANS total score did not show significant differences between groups. The mobile group showed better improvement in K-PRMQ scores and PSS scores than the paper group. Differences within groups showed that mobile-based interventions significantly improved K-PRMQ, STAI-X-1, PSS, and EQ-5D-5 L scores, while paper-based interventions significantly improved PSS, and EQ-5D-5 L scores. Patient adherence rate was 76.6%. CONCLUSION: Overall, the Silvia program was effective for improving self-reported memory failures, stress, anxiety, and health-related quality of life in older adults with SCD. However, longer periods of administration for more than 12 weeks may be needed to achieve significant improvements in cognitive function by objective measures.

Effects of Physical Exercise Program for Older Family Caregivers of Persons With Dementia.

Self-efficacy plays a major role in improving health behaviors. The purpose of this study was to examine the effects of a physical activity program that utilized four self-efficacy resources in older family caregivers of persons with dementia. Quasi-experimental pretest-posttest design with control group was used. Study participants were 64 family caregivers aged 60 years or older. The intervention included a 60-minute group session per week for 8 weeks along with individual counseling and text messages. The experimental group showed significantly higher self-efficacy than the control group. In addition, physical function, quality of life related to health, caregiving burden, and depressive symptoms were significantly improved in the experimental group in comparison with those of control group. These findings suggest that a physical activity program with a focus on the resources of self-efficacy may be not only feasible but also effective for older family caregivers of persons with dementia.

Synthesis and Characterization of Zinc(II), Cadmium(II), and Palladium(II) Complexes with the Thiophene-Derived Schiff Base Ligand.

Zn(II), Pd(II), and Cd(II) complexes, [L TH MCl 2 ] (M = Zn, Pd; X = Br, Cl) and [L TH Cd(µ-X)X] n (X = Cl, Br; n = n, 2), supported by the (E)-N 1,N 1-dimethyl-N 2-(thiophen-2-ylmethylene)ethane-1,2-diamine (L TH ) ligand are synthesized and structurally characterized. Density functional theory (DFT) electronic structure calculations and variable-temperature NMR support the presence of two conformers and a dynamic interconversion process of the minor conformer to the major one in solution. It is found that the existence of two relevant complex conformers and their respective ratios in solution depend on the central metal ions and counter ions, either Cl- or Br-. Among the two relevant conformers, a single conformer is crystallized and X-ray diffraction analysis revealed a distorted tetrahedral geometry for Zn(II) complexes, and a distorted square planar and square pyramidal geometry for Pd(II) and Cd(II) complexes, respectively. It is shown that [L TH MCl 2 ]/LiO i Pr (M = Zn, Pd) and [L TH Cd(µ-Cl)Cl] n /LiO i Pr can effectively catalyze the ring-opening polymerization (ROP) reaction of rac-lactide (rac-LA) with 94% conversion within 30 s with [L TH ZnCl 2 ]/LiO i Pr at 0 °C. Overall, hetero-enriched poly(lactic acid)s (PLAs) were provided by these catalytic systems with [L TH ZnCl 2 ]/LiO i Pr producing PLA with higher heterotactic bias (P r up to 0.74 at 0 °C).

Mepirapim, a novel synthetic cannabinoid, induces Parkinson's disease-related behaviors by causing maladaptation of the dopamine system in the brain.

Mepirapim is a novel synthetic cannabinoid that first appeared on the illicit drug market in 2013. In recent years, recreational abuse of Mepirapim has caused serious emergencies, posing a threat to public health. However, there are no legal regulations to prohibit the use of Mepirapim, as there is no scientific evidence for the dangerous pharmacological effects of the drug. In the present study, we investigated the dangerous neurotoxic effects of Mepirapim through behavioral and molecular experiments in mice (ICR/CD1, male, 25-30 g). In particular, based on a previous study that Mepirapim activates the dopamine system, we evaluated whether high-dose Mepirapim [single (15, 30, or 60 mg·kg-1, i.p.) or multiple (8, 15, or 30 mg·kg-1, i.p. × 4 at 2 h intervals)] treatment causes Parkinson's disease-related symptoms through damage to the dopamine system. In the result, we found that Mepirapim treatment caused comprehensive Parkinson's disease-related symptoms, including motor impairment, cognitive deficits and mood disorders. Furthermore, we confirmed the maladaptation in dopamine-related neurochemicals, including decreased dopamine levels, decreased tyrosine hydroxylase expression, and increased α-synuclein expression, in the brains of mice treated with Mepirapim. Taken together, these results indicate that Mepirapim has dangerous neurotoxic effects that induces Parkinson's disease-related behaviors by causing maladaptation of the dopamine system in the brain. Based on these findings, we propose the strict regulation of recreational abuse and therapeutic misuse of Mepirapim.

Mepirapim, a Novel Synthetic Cannabinoid, Induces Addiction-Related Behaviors through Neurochemical Maladaptation in the Brain of Rodents.

Mepirapim is a synthetic cannabinoid that has recently been abused for recreational purposes. Although serious side effects have been reported from users, the dangerous pharmacological effects of Mepirapim have not been scientifically demonstrated. In this study, we investigated the addictive potential of Mepirapim through an intravenous self-administration test and a conditioned place preference test in rodents. Moreover, to determine whether the pharmacological effects of Mepirapim are mediated by cannabinoid receptors, we investigated whether Mepirapim treatment induces cannabinoid tetrad symptoms in mice. Lastly, to identify Mepirapim induced neurochemical maladaptation in the brains of mice, we performed microdialysis, western blots and neurotransmitter enzyme-linked immunosorbent assays. In the results, Mepirapim supported the maintenance of intravenous self-administration and the development of conditioned place preference. As a molecular mechanism of Mepirapim addiction, we identified a decrease in GABAeric signalling and an increase in dopaminergic signalling in the brain reward circuit. Finally, by confirming the Mepirapim-induced expression of cannabinoid tetrad symptoms, we confirmed that Mepirapim acts pharmacologically through cannabinoid receptor one. Taken together, we found that Mepirapim induces addiction-related behaviours through neurochemical maladaptation in the brain. On the basis of these findings, we propose the strict regulation of recreational abuse of Mepirapim.

Factors associated with eHealth literacy focusing on digital literacy components: A cross-sectional study of middle-aged adults in South Korea.

Background: Digital technology has dramatically changed the world in which we live, and the ability to access and understand information through these new technologies is becoming increasingly important. eHealth literacy is closely related to digital literacy, and some concepts may overlap to a certain extent. Identifying personal and digital-related factors related to eHealth literacy levels in middle-aged adults would be useful for planning tailored interventions and health promotion strategies. Objective: We aimed to identify the differences in digital literacy and eHealth literacy levels according to demographic features, and to elucidate the factors associated with eHealth literacy in the middle-aged population. Methods: We conducted a cross-sectional, observational study from 4th to 8th February 2021. A total of 320 South Korean participants aged 40-64 years were recruited and completed an online questionnaire, where demographic features, chronic disease status, frequency of Internet use, digital skills, digital competence, and eHealth literacy were measured. eHealth literacy was measured with the eHEALS. We used multiple regression analysis to elucidate the factors associated with eHealth literacy. Results: Multiple regression analysis revealed that digital competence was the highest contributor to an individual's eHealth literacy (ß = 0.330, P < 0.001), while digital skills was not significantly associated with eHealth literacy (ß = 0.086, P = 0.267). In addition, eHealth literacy was positively associated with increasing age (ß = 0.258, P < 0.001), female gender (ß = -0.118, P = 0.022), and higher education levels (ß = 0.114, P = 0.041), while marital state, chronic disease, and frequency of internet use were not significantly associated with eHealth literacy. Conclusions: Our study provides valuable information on digital literacy and eHealth literacy in middle-aged adults and may be used to guide tailored interventions for improving eHealth literacy. Future studies should consider the differences in digital literacy levels across generations when assessing eHealth literacy or planning digital health interventions.

Factors Associated With the Experience of Cognitive Training Apps for the Prevention of Dementia: Cross-sectional Study Using an Extended Health Belief Model.

BACKGROUND: The prevalence and economic burden of dementia are increasing dramatically. Using information communication technology to improve cognitive functions is proven to be effective and holds the potential to serve as a new and efficient method for the prevention of dementia. OBJECTIVE: The aim of this study was to identify factors associated with the experience of mobile apps for cognitive training in middle-aged adults. We evaluated the relationships between the experience of cognitive training apps and structural variables using an extended health belief model. METHODS: An online survey was conducted on South Korean participants aged 40 to 64 years (N=320). General characteristics and dementia knowledge were measured along with the health belief model constructs. Statistical analysis and logistic regression analysis were performed. RESULTS: Higher dementia knowledge (odds ratio [OR] 1.164, P=.02), higher perceived benefit (OR 1.373, P<.001), female gender (OR 0.499, P=.04), and family history of dementia (OR 1.933, P=.04) were significantly associated with the experience of cognitive training apps for the prevention of dementia. CONCLUSIONS: This study may serve as a theoretical basis for the development of intervention strategies to increase the use of cognitive training apps for the prevention of dementia.

Galectin-1 accelerates high-fat diet-induced obesity by activation of peroxisome proliferator-activated receptor gamma (PPARγ) in mice.

Galectin-1 contains a carbohydrate-recognition domain (CRD) as a member of the lectin family. Here, we investigated whether galectin-1 regulates adipogenesis and lipid accumulation. Galectin-1 mRNA is highly expressed in metabolic tissues such as the muscle and adipose tissues. Higher mRNA expression of galectin-1 was detected in white adipose tissues (WATs) of mice that were fed a high-fat diet (HFD) than in those of mice fed a normal-fat diet (NFD). Protein expression of galectin-1 also increased during adipocyte differentiation. Galectin-1 silencing inhibited the differentiation of 3T3-L1 cells and the expression of lipogenic factors, such as PPARγ, C/EBPα, FABP4, and FASN at both mRNA and protein levels. Lactose, an inhibitor by the binding with CRD of galectin-1 in extracellular matrix, did not affect adipocyte differentiation. Galectin-1 is localized in multiple cellular compartments in 3T3-L1 cells. However, we found that DMI (dexamethasone, methylisobutylxanthine, insulin) treatment increased its nuclear localization. Interestingly, galectin-1 interacted with PPARγ. Galectin-1 overexpression resulted in increased PPARγ expression and transcriptional activity. Furthermore, we prepared galectin-1-knockout (Lgals1-/-) mice and fed a 60% HFD. After 10 weeks, Lgals1-/- mice exhibited lower body weight and gonadal WAT (gWAT) mass than wild-type mice. Fasting glucose level was also lower in Lgals1-/-mice than that in wild-type mice. Moreover, lipogenic genes were significantly downregulated in the gWATs and liver tissues from Lgals1-/- mice. Pro-inflammatory cytokines, such as CCL2, CCL3, TNFα, and F4/80, as well as macrophage markers, were also drastically downregulated in the gWATs and liver tissues of Lgals1-/- mice. In addition, Lgals1-/-mice showed elevated expression of genes involved in thermogenesis in the brown adipose tissue. Collectively, galectin-1 exacerbates obesity of mice fed HFD by increment of PPARγ expression and activation. Our findings suggest that galectin-1 could be a potential therapeutic target for obesity and needed further study for clinical application.

Stereoselective polymerization of methyl methacrylate and rac-lactide mediated by iminomethylpyridine based Cu(ii) complexes.

Iminomethylpyridine based copper(ii) complexes [LnCuCl2] (Ln = LA, LC-LF) and [LBCu(µ-Cl)Cl]2 have been synthesized and characterized. [LCCuCl2] and [LECuCl2] were identified to possess distorted square pyramidal geometries obtained via N,N'-bidentate coordination, whereas [LFCuCl2] showed N,N',N''-coordination of the corresponding ligand (LF). [LBCu(µ-Cl)Cl]2 was found to be dimeric with a distorted square pyramidal geometry around the Cu(ii) center. The catalytic properties of dimethyl derivatives, generated in situ, towards the ring opening polymerization (ROP) of rac-LA were investigated. All the complexes efficiently polymerized rac-LA and yielded heterotactic poly(lactide) (PLA) (P r up to 0.88 at -25 °C). Further, these complexes could effectively polymerize methyl methacrylate (MMA) at 60 °C in the presence of modified methylaluminoxane (MMAO), to furnish syndio-enriched PMMA. The catalytic efficacies of synthesized complexes can be correlated to the suitable complexity of the substituents attached to the ligand architecture. Thus, both the steric and electronic properties as well as the orientation of the various substituents relative to the xy plane of the pyridyl moiety and metal center play an influential role in steering catalytic activities, whereas the selectivities remain unaffected.