Enhanced social motivation in briefly isolated male rats.

Loneliness and anxiety are associated with psychiatric disorders in humans. Although brief social isolation in adult rats and mice has been proposed as a rodent model of loneliness, its socioemotional characteristics are not well known. In this study, we evaluated the social and emotional behaviors of adult male rats subjected to brief social isolation. Isolated rats frequently showed sniffing behavior toward empty cylinders where conspecifics had previously existed, as well as conspecifics themselves. Furthermore, social motivation correlated with anxiety levels, as indicated by the elevated plus-maze test performance in isolated but not in non-isolated rats. These results suggest that high social motivation is associated with anxiety in briefly isolated rats.

Clinical and molecular delineation of classical-like Ehlers-Danlos syndrome through a comprehensive next-generation sequencing-based screening system.

Classical-like Ehlers-Danlos syndrome (clEDS) is an autosomal recessive disorder caused by complete absence of tenascin-X resulting from biallelic variation in TNXB. Thus far, 50 patients from 43 families with biallelic TNXB variants have been identified. Accurate detection of TNXB variants is challenging because of the presence of the pseudogene TNXA, which can undergo non-allelic homologous recombination. Therefore, we designed a genetic screening system that is performed using similar operations to other next-generation sequencing (NGS) panel analyses and can be applied to accurately detect TNXB variants and the recombination of TNXA-derived sequences into TNXB. Using this system, we identified biallelic TNXB variants in nine unrelated clEDS patients. TNXA-derived variations were found in >75% of the current cohort, comparable to previous reports. The current cohort generally exhibited similar clinical features to patients in previous reports, but had a higher frequency of gastrointestinal complications (e.g., perforation, diverticulitis, gastrointestinal bleeding, intestinal obstruction, rectal/anal prolapse, and gallstones). This report is the first to apply an NGS-based screening for TNXB variants and represents the third largest cohort of clEDS, highlighting the importance of increasing awareness of the risk of gastrointestinal complications.

Factors influencing acceptability of final disposal of incinerated ash and decontaminated soil from TEPCO's Fukushima Daiichi nuclear power plant accident.

TEPCO's Fukushima Daiichi nuclear power plant accident prompted extensive decontamination work. The decontaminated soil and incinerated ash generated by the process are scheduled for final disposal by March 2045 outside Fukushima Prefecture. The final disposal is unprecedented worldwide. Clarifying their acceptability will contribute to the final disposal of decontaminated soil and incinerated ash, as well as add knowledge about the perceived risk of low-concentration radioactive waste. A questionnaire survey was conducted to assess the psychological factors influencing final disposal acceptability. The results of the structural equation modeling demonstrated stable results, with risk perception decreasing acceptability, social benefits increasing acceptability, and personal benefits having limited impact. The initiative for the final disposal of decontaminated soil and incinerated ash can facilitate the reconstruction of Fukushima Prefecture after the disaster. Trust and intergenerational expectations are critical factors influencing the acceptability of this disposal. The responses were classified based on the relevance of moral norms using cluster analysis and moral foundations. The influence of each element on acceptability varied depending on the cluster. Trust was identified as the most influential factor in acceptability, regardless of the level of importance placed on moral norms.

Secular trends and features of thalamic hemorrhages compared with other hypertensive intracerebral hemorrhages: an 18-year single-center retrospective assessment.

Introduction: Trends regarding the locations of hypertensive cerebral hemorrhages are unclear. To clarify hypertensive hemorrhage trends, we investigated intracerebral hemorrhages (ICHs) over an 18-year period, focusing on thalamic hemorrhages compared with other sites of hemorrhages. Methods: We reviewed the cases of patients hospitalized for hypertensive ICH in 2004-2021 at our hospital; 1,320 eligible patients were registered with a primary ICH/intraventricular hemorrhage. After exclusion criteria were applied, we retrospectively analyzed 1,026 hypertensive ICH cases. Results: The proportions of thalamic and subcortical hemorrhages increased over the 18-year period, whereas putaminal hemorrhage decreased. Multivariate logistic regression analyses revealed that for thalamic hemorrhage, ≥200 mmHg systolic blood pressure (p = 0.031), bleeding <15 mL (p = 0.001), and higher modified Rankin scale (mRS) score ≥ 4 at discharge (p = 0.006) were significant variables in the late period (2013-2021) versus the early period (2004-2012), whereas for putaminal hemorrhage, significant factors in the late period were triglyceride <150 mg/dL (p = 0.006) and mRS score ≥ 4 at discharge (p = 0.002). Among the features of the thalamic hemorrhages in the late period revealed by our group comparison with the putaminal and subcortical hemorrhages, the total and subcortical microbleeds were more notable in the thalamic hemorrhages than in the other two types of hemorrhage, whereas cerebellar microbleeds were more prominent when compared only with subcortical hemorrhages. Discussion: Our findings revealed an increasing trend for thalamic hypertensive hemorrhage and a decreasing trend for putaminal hemorrhage. The thalamic hemorrhage increase was observed in both young and older patients, regardless of gender. The main features of thalamic hemorrhage in the late period versus the early period were decrease in larger hemorrhage (≥15 mL) and an increase in cases with higher systolic blood pressure (at least partially involved a small number of untreated hypertensive patients who developed major bleeding). The total and subcortical microbleeds were more notable in the thalamic hemorrhages of the late period than in the putaminal and subcortical hemorrhages. These results may contribute to a better understanding of the recent trends of hypertensive ICHs and may help guide their appropriate treatments for this condition.

Odors associated with neonatal experiences with the dam have enhanced anxiolytic effects in rat.

Odor stimuli are widely reported to promote relaxation and reduce anxiety in humans and rodents. However, it remains unclear if this anxiolytic efficacy can be further enhanced by association with positive experiences. Therefore, we compared the effects of a novel odor to a familiar odor previously paired with a positive experience on anxiety-like behaviors in rats. One group of Wistar-Imamichi female and male pups was exposed to an odor stimulus with their dams during postnatal days (PNDs) 8-12, whereas another control group was exposed to perfused air during the same period. Starting on PND 42, all animals were examined in the open field test (OFT) and elevated plus maze (EPM) test during exposure to scent-free air (vehicle), a novel odor, or the positive-familiar odor from postnatal exposure. In the EPM, female rats entered open arms with all 4 paws (complete entry) more frequently and spent more time on open arms during exposure to the positive-familiar odor than during exposure to air or a novel odor, whereas partial open arm entries with forepaws only were increased during exposure to both novel and positive-familiar odors compared to air. In contrast, male rats demonstrated no significant increase in open arm activity during positive-familiar odor exposure, but did show equally reduced grooming frequency during novel and familiar-positive odor exposure in the OFT. Exposure to positive-familiar odors may be an effective and safe method for anxiety reduction, especially in females.

COL1A1 expression induced by overexpression of both a 15­amino acid peptide from the fibrinogen domain of tenascin­X and integrin α11 in LX­2 cells.

Extracellular matrix tenascin­X (TNX) is the largest member of the tenascin family. Our previous study demonstrated that TNX was involved in hepatic dysfunction, including fibrosis, in mice that were administered a high­fat and high­cholesterol diet with high levels of phosphorus and calcium. The present study investigated whether overexpression of both the fibrinogen domain of TNX (TNX­FG) and integrin α11, one of the TNX cell surface receptors, induces in vitro fibrosis in LX­2 human hepatic stellate cells. Overexpression of both a 15­amino acid peptide (hTNX­FGFFFF) derived from the TNX­FG domain and integrin α11 induced the expression of type I collagen α1 chain (COL1A1). Treatment with verteporfin [YAP (Yes­associated protein) inhibitor] attenuated the elevated COL1A1 expression elicited by overexpression of both hTNX­FGFFFF and integrin α11. In addition, small interfering RNA­mediated knockdown of YAP1 resulted in a decrease in COL1A1 expression induced by overexpression of both hTNX­FGFFFF and integrin α11. These results indicated that overexpression of both hTNX­FGFFFF and integrin α11 induced COL1A1 expression via the YAP signaling pathway.

Socially Transferred Stress Experience Modulates Social Affective Behaviors in Rats.

Social communication of affective states between individuals, as well as actual experiences, influences their internal states and behaviors. Although prior stress experiences promote empathy-like behaviors, it remains unclear whether the social transmission of stress events modulates these behaviors. Here, we provide evidence that transferred stress experiences from cage mates modulate socioaffective approach-avoidance behaviors in rats. Male Wistar-Imamichi rats were assigned to one of five experimental groups (Control (n = 15); no shock with shocked cage mates (n = 15); low (0.1 mA, n = 15), middle (0.5 mA, n = 14), and high shock (1.0 mA, n = 14)). Except for the naïve and housed with stressed mate groups, rats received two foot-shocks (5 s for each). The next day, the subjects were allowed to explore two unfamiliar conspecifics; one was a naïve, while the other was a distressed conspecific that received two foot-shocks (1.0 mA, 5 s) immediately before the test. Rats that were housed with stressed mates, as well as those that experienced a higher intensity of foot-shocks, were more likely to approach, while naïve rats avoided, a distressed conspecific. These results suggest that socially transferred stress shifts socioaffective response styles from avoidance to approach toward a stressed conspecific in rats.

Caffeine facilitates extinction of auditory fear conditioning in rats.

Caffeine is the most widely consumed psychostimulant drug which could affect learning and memory acting through central adenosine receptors. Although caffeine has been suggested to impair the acquisition and the expression of auditory fear conditioning, its effect on the extinction has not been elucidated. To address this issue, in the present study, we investigated whether caffeine affects the extinction of conditioned fear in an auditory fear conditioning paradigm. During conditioning, rats received pairings of auditory cues (conditioned stimulus, CS) and foot shocks (unconditioned stimulus). On the next day, the rats were intraperitoneally administrated saline or caffeine (5 or 10 mg/kg) and then subjected to the extinction training, in which CSs were repeatedly presented without the foot shocks. Twenty-four hours later, the rats were re-exposed to the presentations of CSs (retrieval test). We found an acute caffeine administration dose-dependently decreased freezing rates during the presentations of CS in the extinction training. Furthermore, caffeine-treated animals showed lower conditioned freezing responses in the retrieval test. These findings suggest that caffeine facilitates the extinction of conditioned fear.

Important factors for public acceptance of the final disposal of contaminated soil and wastes resulting from the Fukushima Daiichi nuclear power station accident.

Large-scale decontamination work has been carried out in the aftermath of the Fukushima Daiichi nuclear power station accident in Japan in 2011. The soil that was removed and the wastes that were generated during the decontamination will be finally disposed of outside Fukushima Prefecture by 2045. To ensure successful and socially acceptable implementation of this final disposal process, it is essential to have a good understanding of what is considered important by the public. We used a choice-based conjoint analysis in the form of a web-based questionnaire to examine the relative importance of several factors in the choice of the final disposal sites of the removed soil and incinerated ash of the wastes. The questionnaires covered four attributes and 12 levels, namely the distance between the disposal site and a person's residential area, procedural fairness (decision process), distributive fairness (direct mitigation of inequity through multiple siting locations), and the volume and radioactivity of the substances to be disposed. Responses were received from 4000 people nationwide, excluding Fukushima residents. The results showed that the respondents gave high importance to choosing sites that were far from residential areas and to the two types of fairness, especially distributive fairness. The respondents showed no preference for the volume and radioactivity. This indicates that the public cares about the fairness of the siting for the final disposal sites and feels uncomfortable with plans for a final disposal site located close to them. Distributive fairness is necessary to pursue consensus in addition to procedural fairness.

Effects of repetitive transcranial magnetic stimulation on cerebral glucose metabolism.

OBJECTIVE: To investigate the mechanisms underlying the effect of repetitive transcranial magnetic stimulation (rTMS) on post-stroke hemiplegia, we assessed alterations in cerebral glucose metabolism. METHODS: Five post-stroke hemiplegic patients (three targeted for upper limb impairment and two targeted for lower limb impairment) aged 62.6 ± 6.1 years (mean ± standard deviation) with a duration since stroke onset of 3.5 ± 3.8 years participated in this preliminary study. Cerebral glucose metabolism was measured twice-before and after rTMS with intensive rehabilitation-using positron emission tomography with [18F]fluorodeoxyglucose. The Asymmetry Index (AI) was calculated to assess laterality of metabolism between the lesional and contralesional motor areas. The alteration rates of AI (%ΔAI) were compared between participants in whom rTMS was effective and ineffective. RESULTS: Two of the three upper-limb-targeted patients and one of the two lower-limb-targeted patients showed motor function improvements following rTMS treatment. All three patients who responded to rTMS had improved laterality of cerebral glucose metabolism in motor areas, commonly in the precentral gyrus, with an %ΔAI of approximately 10%. In contrast, the two patients who did not respond to rTMS had no improvements in laterality. CONCLUSIONS: These results suggest for the first time that improved glucose metabolism is associated with improved motor function after a combination of rTMS and intensive rehabilitation.

Prior stress experience modulates social preference for stressed conspecifics in male rats.

Adult male rats tend to avoid adult conspecifics in distress. In this study, we asked whether prior stress experience would modulate social preference for a stressed conspecific using a social affective preference (SAP) test. Male Long-Evans adult rats were assigned to the shocked and non-shocked groups. In the shocked group, rats were acutely subjected to foot shocks (1.0 mA, 5 s duration × 2) 24 h before the SAP test. During the SAP test, the experimental rats were placed in an arena where two adult conspecific stimuli, one of which received the foot shocks immediately before the SAP test, were presented at both ends and allowed to explore freely for 5 min. We measured sniffing behavior toward each conspecific as an index of social preference. Non-shocked adult rats avoided, while shocked rats approached, the stressed conspecifics more than the non-stressed ones. These results suggest that prior stress promotes social preference for a stressed conspecific in adult male rats.

Kleptomania Induced by Venlafaxine.

Introduction. Kleptomania is an impulse-control disorder that results in an irresistible urge to steal. It is often observed as a comorbidity in patients undergoing pharmacological treatment for Parkinson's disease. Recurrent shopliftings are also observed in the clinical course of frontotemporal dementia. Case Presentation. After successful treatment of severe depression with venlafaxine at a dose of 225 mg/day, a 54-year-old euthymic female patient exhibited recurrent stealing behavior. After the diagnostic exclusion of frontotemporal dementia, kleptomania induced by venlafaxine administration was suspected. The symptoms of kleptomania disappeared with the gradual decrease in the venlafaxine dosage to 37.5 mg/day. Discussion. Venlafaxine is a dual serotonin-norepinephrine reuptake inhibitor. We considered two possible mechanisms to explain the pathophysiology of kleptomania in the present case: (1) increased dopaminergic neural transmission due to the inhibited dopamine reuptake by the norepinephrine transporter with a high dose of venlafaxine or (2) enhanced serotonergic neural transmission by the inhibition of serotonin reuptake by venlafaxine. In past studies, five cases of impulse-control disorder induced by selective serotonin reuptake inhibitors have been reported. This is the fourth report of venlafaxine-induced kleptomania and highlights the importance of considering the possibility of a rare side effect of kleptomania induced by antidepressant.

Pharmacologically induced N-methyl-D-aspartate receptor hypofunction impairs goal-directed food seeking in rats.

AIM: Acute N-methyl-D-aspartate (NMDA) receptor antagonism is an important pharmacological animal model of schizophrenia. In previous studies, schizophrenia patients show impaired goal-directed behavior in an outcome-specific devaluation procedure. In this study, we investigated whether the rat model of the NMDA receptor blockade also showed altered goal-directed behavior in a satiety-induced outcome devaluation paradigm. METHODS: In experiments 1 and 2, we aimed to establish the satiety-induced outcome devaluation test using sucrose and lipid rewards in operant conditioning and free consumption paradigms. In experiment 3, we tested the effect of MK-801 (0.1 mg/kg, i.p.) on outcome-specific devaluation. RESULTS: Experiments 1 and 2 demonstrated that 1-h ad libitum food consumption is sufficient to induce outcome-specific devaluation in both lever-press and free consumption tests in rats. Experiment 3 showed that the administration of MK-801 impaired satiety-induced devaluation in the lever-press test but not in the subsequent free consumption test. CONCLUSIONS: Our results suggest that acute pharmacological NMDA receptor antagonism in rats is a useful animal model for impaired goal-directed behavior in schizophrenia.

Water Dissolved in a Variety of Polymers Studied by Molecular Dynamics Simulation and a Theory of Solutions.

The performance of a polymer medium as a separation membrane is determined by the dissolution free energy ΔG and diffusion coefficient D of the permeant. In this work, ΔG and D of water are investigated with all-atom molecular dynamics simulation in a wide variety of polymer species in the amorphous state. The computed ΔG is shown to agree well with the experimental value for linear homopolymers, and the degrees of polymerization of the homopolymers do not affect ΔG when they are beyond ∼10. The copolymers of ethylene-vinylidene difluoride, ethylene-vinyl acetate, and ethylene-acrylamide are then examined by changing the repeating patterns of the constituent monomers in both the periodic and graft forms. It is found that ΔG is determined primarily by the overall compositions of the monomers and is not affected by the copolymerization topology (periodic or graft). The hydrophobicity of the copolymer is enhanced, furthermore, when the hydrophobicity and hydrophilicity of the ethylene and non-ethylene parts are well contrasted and those parts are fragmented along the polymer chain. According to the computed D, the diffusivity of water tends to be larger when the (co)polymer is more hydrophobic and ΔG is more positive. D is actually seen to vary by orders of magnitude with the polymer structures, while the effect of the polymer species on the water permeation is stronger for ΔG than for D.

Long-term associative memory in rats: Effects of familiarization period in object-place-context recognition test.

Spontaneous recognition tests, which utilize rodents' innate tendency to explore novelty, can evaluate not only simple non-associative recognition memory but also more complex associative memory in animals. In the present study, we investigated whether the length of the object familiarization period (sample phase) improved subsequent novelty discrimination in the spontaneous object, place, and object-place-context (OPC) recognition tests in rats. In the OPC recognition test, rats showed a significant novelty preference only when the familiarization period was 30 min but not when it was 5 min or 15 min. In addition, repeated 30-min familiarization periods extended the significant novelty preference to 72 hours. However, the rats exhibited a successful discrimination between the stayed and replaced objects under 15 min and 30 min familiarization period conditions in the place recognition test and between the novel and familiar objects under all conditions of 5, 15 and 30 min in the object recognition test. Our results suggest that the extension of the familiarization period improves performance in the spontaneous recognition paradigms, and a longer familiarization period is necessary for long-term associative recognition memory than for non-associative memory.

CRISPR/Cas9-engineered Gad1 elimination in rats leads to complex behavioral changes: implications for schizophrenia.

GABAergic dysfunctions have been implicated in the pathogenesis of schizophrenia, especially the associated cognitive impairments. The GABA synthetic enzyme glutamate decarboxylase 67-kDa isoform (GAD67) encoded by the GAD1 gene is downregulated in the brains of patients with schizophrenia. Furthermore, a patient with schizophrenia harboring a homozygous mutation of GAD1 has recently been discovered. However, it remains unclear whether loss of function of GAD1 leads to the symptoms observed in schizophrenia, including cognitive impairment. One of the obstacles faced in experimental studies to address this issue is the perinatal lethality of Gad1 knockout (KO) mice, which precluded characterization at the adult stage. In the present study, we successfully generated Gad1 KO rats using CRISPR/Cas9 genome editing technology. Surprisingly, 33% of Gad1 KO rats survived to adulthood and could be subjected to further characterization. The GABA concentration in the Gad1 KO cerebrum was reduced to ~52% of the level in wild-type rats. Gad1 KO rats exhibited impairments in both spatial reference and working memory without affecting adult neurogenesis in the hippocampus. In addition, Gad1 KO rats showed a wide range of behavioral alterations, such as enhanced sensitivity to an NMDA receptor antagonist, hypoactivity in a novel environment, and decreased preference for social novelty. Taken together, the results suggest that Gad1 KO rats could provide a novel model covering not only cognitive deficits but also other aspects of the disorder. Furthermore, the present study teaches an important lesson: differences between species should be considered when developing animal models of human diseases.

Dopaminergic function in spinocerebellar ataxia type 6 patients with and without parkinsonism.

BACKGROUND: Although pure cerebellar ataxia is usually emphasized as the characteristic clinical feature of spinocerebellar ataxia type 6 (SCA6), parkinsonism has been repeatedly described in patients with genetically confirmed SCA6. METHODS: We conducted a positron emission tomography study using a combination of [18F]fluoro-L-dopa for dopamine synthesis and [11C]raclopride for dopamine D2 receptor function on six genetically confirmed SCA6 patients, both with and without parkinsonism. To the best of our knowledge, this is the first dopamine receptor imaging study of patients with SCA6. RESULTS: Most patients had somewhat decreased dopaminergic function, and this decrease was significant in the caudate nucleus. In addition, one SCA6 patient with parkinsonism had whole striatal dysfunction of both dopamine synthesis and dopamine D2 receptor function. CONCLUSIONS: The pathology of SCA6 may not be restricted to the cerebellum, but may also be distributed across various regions, including in both presynaptic and postsynaptic dopaminergic neurons to some degree. Patients with SCA6 may show apparent parkinsonism after the progression of neurodegeneration.