Associations of the immune system in aggression traits and the role of microglia as mediators.

There is an important relationship between the immune system and aggressive behavior. Aggressive encounters acutely increase the levels of proinflammatory cytokines, and there are positive correlations between aggressive traits and peripheral proinflammatory cytokines. Endotoxin lipopolysaccharide (LPS) treatment, which results in peripheral immune activation, decreases aggressive behavior as one of the sickness behavioral symptoms. In contrast, certain brain infections and chronic interferon treatment are associated with increased aggression. Indeed, the effects of proinflammatory cytokines on the brain in aggressive behavior are bidirectional, depending on the type and dose of cytokine, target brain region, and type of aggression. Some studies have suggested that microglial activation and neuroinflammation influence intermale aggression in rodent models. In addition, pathological conditions as well as physiological levels of cytokines produced by microglia play an important role in social and aggressive behavior in adult animals. Furthermore, microglial function in early development is necessary for the establishment of the social brain and the expression of juvenile social behaviors, including play fighting. Overall, this review discusses the important link between the immune system and aggressive traits and the role of microglia as mediators of this link.

Toward understanding the neural mechanisms involved in early life stress-induced aggression: A Highlight for "Maternal separation early in life induces excessive activity of the central amygdala related to abnormal aggression".

Early life stress, such as childhood abuse and neglect, is one of the major risk factors for the development of antisocial behavior. In rat models, repeated maternal separation (MS) stress, in which the pups are separated from the dams for a few hours each day during the first 2-3 weeks of life, increases aggressive behavior in adult males. This Editorial highlights an article in the current issue of the Journal of Neurochemistry that demonstrates the involvement of the central nucleus of the amygdala (CeA) in the escalation of aggressive behavior in the MS model. The authors show that MS rats exhibit higher c-Fos expression in the CeA during an aggressive encounter compared to non-isolated control rats. Unexpectedly, other amygdala subnuclei did not show differential activation between MS and control groups. Using optogenetics, they provide direct evidence that activation of CeA neurons increases intermale aggressive behavior and that bilateral CeA activation shifts behavioral patterns toward more qualitatively intense aggressive behavior than unilateral CeA activation. These findings highlight the important role of the CeA in the development of abnormal aggression and indicate that this region may be an important therapeutic target for human aggression induced by early life stress.

Aggression modulator: Understanding the multifaceted role of the dorsal raphe nucleus.

Aggressive behavior is instinctively driven behavior that helps animals to survive and reproduce and is closely related to multiple behavioral and physiological processes. The dorsal raphe nucleus (DRN) is an evolutionarily conserved midbrain structure that regulates aggressive behavior by integrating diverse brain inputs. The DRN consists predominantly of serotonergic (5-HT:5-hydroxytryptamine) neurons and decreased 5-HT activity was classically thought to increase aggression. However, recent studies challenge this 5-HT deficiency model, revealing a more complex role for the DRN 5-HT system in aggression. Furthermore, emerging evidence has shown that non-5-HT populations in the DRN and specific neural circuits contribute to the escalation of aggressive behavior. This review argues that the DRN serves as a multifaceted modulator of aggression, acting not only via 5-HT but also via other neurotransmitters and neural pathways, as well as different subsets of 5-HT neurons. In addition, we discuss the contribution of DRN neurons in the behavioral and physiological aspects implicated in aggressive behavior, such as arousal, reward, and impulsivity, to further our understanding of DRN-mediated aggression modulation.

Evaluating the feasibility of batteries for second-life applications using machine learning.

This article presents a combination of machine learning techniques to enable prompt evaluation of retired electric vehicle batteries as to either retain those batteries for a second-life application and extend their operation beyond the original and first intent or send them to recycling facilities. The proposed algorithm generates features from available battery current and voltage measurements with simple statistics, selects and ranks the features using correlation analysis, and employs Gaussian process regression enhanced with bagging. This approach is validated over publicly available aging datasets of more than 200 with slow and fast charging cells, with different cathode chemistries, and for diverse operating conditions. Promising results are observed based on multiple training-test partitions, wherein the mean of Root Mean Squared Percent Error and Mean Percent Error performance errors are found to be less than 1.48% and 1.29%, respectively, in the worst-case scenarios.

Prenatal asfotase alfa-mediated enzyme replacement therapy restores delayed calcification in a severe infantile form of hypophosphatasia model mice.

Hypophosphatasia (HPP) is a congenital disorder caused by mutations in the tissue-nonspecific alkaline phosphatase (TNALP) gene. The pathogenesis of HPP varies, ranging from severe cases in which there is total absence of fetal bone calcification, which leads to stillbirth, to relatively mild cases in which the effects are confined to the teeth, such as early loss of the primary teeth. In recent years, the establishment of enzyme supplementation as a treatment method has prolonged survival in patients; however, this approach does not provide sufficient improvement for failed calcification. Furthermore, the effects of enzyme replacement therapy on the jawbone and periodontal tissues have not yet been studied in detail. Therefore, in this study, we investigated the therapeutic effects of enzyme replacement therapy on jawbone hypocalcification in mice. Recombinant TNALP was administered to mothers before birth and newborns immediately after birth, and the effect of treatment was evaluated at 20 days of age. The treated HPP mice had improved mandible (mandibular length and bone quality) and tooth quality (root length of mandibular first molar, formation of cementum), as well as improved periodontal tissue structure (structure of periodontal ligament). Furthermore, prenatal treatment had an additional therapeutic effect on the degree of mandible and enamel calcification. These results suggest that enzyme replacement therapy is effective for the treatment of HPP, specifically in the maxillofacial region (including the teeth and mandible), and that early initiation of treatment may have additional beneficial therapeutic effects.

Psychological Adjustment and Related Factors in Patients with Recurrence/Metastatic Lung Cancer after Curative Surgery.

The purpose of study was to clarify the psychological adjustment and related factors in lung cancer patients with recurrence/metastasis after curative surgery. Forty-one with lung cancer who were informed of a recurrence/metastasis after curative surgery completed a questionnaire comprised of the Mental Adjustment to Cancer Scale (MAC), Psychological Adjustment scale for Cancer Survivors (PACS), and information pertaining to demographic variables. When healthcare providers intervene in patients with lung cancer that has recurred/metastasized after curative surgery, it is necessary to assess patients' psychological adjustment based on demographic information, such as age, sex, marital status, and employment status, and to provide effective support promptly. Factors associated with psychological adjustment with recurrent/metastatic lung cancer after curative surgery were 1) female, 2) having a job, 3) over 65 years of age, 4) having a spouse, and 5) advanced-stage cancer. There was no difference in psychological adjustment between treatment and the period from cancer incidence to recurrence/metastatic. J. Med. Invest. 70 : 200-207, February, 2023.

The role of social isolation stress in escalated aggression in rodent models.

Anti-social behavior and violence are major public health concerns. Globally, violence contributes to more than 1.6 million deaths each year. Previous studies have reported that social rejection or neglect exacerbates aggression. In rodent models, social isolation stress is used to demonstrate the adverse effects of social deprivation on physiological, endocrinological, immunological, and behavioral parameters, including aggressive behavior. This review summarizes recent rodent studies on the effect of social isolation stress during different developmental periods on aggressive behavior and the underlying neural mechanisms. Social isolation during adulthood affects the levels of neurosteroids and neuropeptides and increases aggressive behavior. These changes are ethologically relevant for the adaptation to changes in local environmental conditions in the natural habitats. Chronic deprivation of social interaction after weaning, especially during the juvenile to adolescent periods, leads to the disruption of the development of appropriate social behavior and the maladaptive escalation of aggressive behavior. The understanding of neurobiological mechanisms underlying social isolation-induced escalated aggression will aid in the development of therapeutic interventions for escalated aggression.

Lateral habenula glutamatergic neurons projecting to the dorsal raphe nucleus promote aggressive arousal in mice.

The dorsal raphe nucleus (DRN) is known to control aggressive behavior in mice. Here, we found that glutamatergic projections from the lateral habenula (LHb) to the DRN were activated in male mice that experienced pre-exposure to a rival male mouse ("social instigation") resulting in heightened intermale aggression. Both chemogenetic and optogenetic suppression of the LHb-DRN projection blocked heightened aggression after social instigation in male mice. In contrast, inhibition of this pathway did not affect basal levels of aggressive behavior, suggesting that the activity of the LHb-DRN projection is not necessary for the expression of species-typical aggressive behavior, but required for the increase of aggressive behavior resulting from social instigation. Anatomical analysis showed that LHb neurons synapse on non-serotonergic DRN neurons that project to the ventral tegmental area (VTA), and optogenetic activation of the DRN-VTA projection increased aggressive behaviors. Our results demonstrate that the LHb glutamatergic inputs to the DRN promote aggressive arousal induced by social instigation, which contributes to aggressive behavior by activating VTA-projecting non-serotonergic DRN neurons as one of its potential targets.

Neuromodulatory effect of interleukin 1ß in the dorsal raphe nucleus on individual differences in aggression.

Heightened aggressive behavior is considered as one of the central symptoms of many neuropsychiatric disorders including autism, schizophrenia, and dementia. The consequences of aggression pose a heavy burden on patients and their families and clinicians. Unfortunately, we have limited treatment options for aggression and lack mechanistic insight into the causes of aggression needed to inform new efforts in drug discovery and development. Levels of proinflammatory cytokines in the periphery or cerebrospinal fluid were previously reported to correlate with aggressive traits in humans. However, it is still unknown whether cytokines affect brain circuits to modulate aggression. Here, we examined the functional role of interleukin 1ß (IL-1ß) in mediating individual differences in aggression using a resident-intruder mouse model. We found that nonaggressive mice exhibit higher levels of IL-1ß in the dorsal raphe nucleus (DRN), the major source of forebrain serotonin (5-HT), compared to aggressive mice. We then examined the effect of pharmacological antagonism and viral-mediated gene knockdown of the receptors for IL-1 within the DRN and found that both treatments consistently increased aggressive behavior of male mice. Aggressive mice also exhibited higher c-Fos expression in 5-HT neurons in the DRN compared to nonaggressive mice. In line with these findings, deletion of IL-1 receptor in the DRN enhanced c-Fos expression in 5-HT neurons during aggressive encounters, suggesting that modulation of 5-HT neuronal activity by IL-1ß signaling in the DRN controls expression of aggressive behavior.

Impact of a web-based educational program on Japanese nurses tobacco cessation practice and attitudes in oncology settings.

PURPOSE: To evaluate the effects of a short web-based educational program on Japanese nurses' self-reported attitudes toward tobacco cessation and their use of interventions to help smokers to quit. DESIGN: Prospective, single-group design with a pre-educational survey, a short web-based educational program, and a follow-up survey at 3 months. METHODS: Clinical nurses were asked to view two prerecorded webcasts about helping smokers quit. They completed two online surveys, one at baseline and one at a 3-month follow-up. Generalized linear models were used to determine changes in nurses' self-reported routine practice after the study intervention. FINDINGS: A total of 1401 nurses responded to the baseline survey, 678 of whom completed the follow-up survey. Compared with baseline, nurses at follow-up were more likely to advise smokers to quit (odds ratio [OR] = 1.45, 95% confidence interval [CI: 1.15, 1.82]), assess patients' interest in quitting (OR = 1.46, 95% CI [1.01, 1.04]), and assist patients with smoking cessation (OR = 1.34, 95% CI [1.04, 1.72]). However, the proportion of nurses who consistently recommended resources for tobacco cessation did not significantly improve at follow-up. CONCLUSIONS: This study provides preliminary evidence that a web-based educational program can increase nurses' implementation of tobacco dependence interventions in cancer care practice. Sustaining these educational efforts could increase nurses' involvement in providing these interventions, encourage nurses to refer patients to cessation resources, and support nurses' attitudes towards their role in smoking cessation. CLINICAL RELEVANCE: Our short web-based educational program can increase nurses' use of tobacco-dependence interventions in cancer care practice. This role can be enhanced with additional information about existing cessation resources that nurses could use to refer patients for support post-discharge. Japanese nurses, when properly educated, are willing and significant contributors to promote tobacco use cessation for cancer patients. The contribution can be facilitated through nursing care protocol that integrate tobacco use cessation interventions within evidence-based cancer care approaches.

Social Stress and Aggression in Murine Models.

Throughout life, animals engage in a variety of social interactions ranging from the affiliative mother-offspring interaction and juvenile play to aggressive conflict. Deprivation of the appropriate social interaction during early development is stressful and disrupts the development of appropriate social behaviors and emotional responses later in life. Additionally, agonistic encounters can induce stress responses in both dominant and subordinate individuals. This review focuses on the social stress that escalates aggressive behavior of animals and discusses the known neurobiological and physiological mechanisms underlying the link between social stress and aggression. Social instigation, a brief exposure to a rival without physical contact, induces aggressive arousal in dominant animals and escalates aggressive behaviors in the following agonistic encounter. Furthermore, the experience of winning an aggressive encounter is known to be as rewarding as addictive drugs, and the experience of repeatedly winning induces addiction-like behavioral and neurobiological changes and leads to abnormal aggressive behaviors. Social isolation stress in early development from neonatal to juvenile and adolescent periods also affects aggressive behavior, but these effects largely depend on the strain, sex, and species as well as the stage of development in which isolation stress is experienced. In conclusion, understanding neurobiological mechanisms underlying the link between social stress and aggression will provide an important insight for the development of more effective and tolerable treatments for maladaptive aggression in humans.

A new mouse model of Ehlers-Danlos syndrome generated using CRISPR/Cas9-mediated genomic editing.

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is caused by generalized depletion of dermatan sulfate (DS) due to biallelic pathogenic variants in CHST14 encoding dermatan 4-O-sulfotransferase 1 (D4ST1) (mcEDS-CHST14). Here, we generated mouse models for mcEDS-CHST14 carrying homozygous mutations (1 bp deletion or 6 bp insertion/10 bp deletion) in Chst14 through CRISPR/Cas9 genome engineering to overcome perinatal lethality in conventional Chst14-deleted knockout mice. DS depletion was detected in the skeletal muscle of these genome-edited mutant mice, consistent with loss of D4ST1 activity. The mutant mice showed common pathophysiological features, regardless of the variant, including growth impairment and skin fragility. Notably, we identified myopathy-related phenotypes. Muscle histopathology showed variation in fiber size and spread of the muscle interstitium. Decorin localized diffusely in the spread endomysium and perimysium of skeletal muscle, unlike in wild-type mice. The mutant mice showed lower grip strength and decreased exercise capacity compared to wild type, and morphometric evaluation demonstrated thoracic kyphosis in mutant mice. The established CRISPR/Cas9-engineered Chst14 mutant mice could be a useful model to further our understanding of mcEDS pathophysiology and aid in the development of novel treatment strategies.

Myopathy Associated With Dermatan Sulfate-Deficient Decorin and Myostatin in Musculocontractural Ehlers-Danlos Syndrome: A Mouse Model Investigation.

Carbohydrate sulfotransferase 14 (CHST14) encodes dermatan 4-O-sulfotransferase 1, a critical enzyme for dermatan sulfate (DS) biosynthesis. Musculocontractural Ehlers-Danlos syndrome (mcEDS) is associated with biallelic pathogenic variants of CHST14 and is characterized by malformations and manifestations related to progressive connective tissue fragility. We identified myopathy phenotypes in Chst14-deficient mice using an mcEDS model. Decorin is a proteoglycan harboring a single glycosaminoglycan chain containing mainly DS, which are replaced with chondroitin sulfate (CS) in mcEDS patients with CHST14 deficiency. We studied the function of decorin in the skeletal muscle of Chst14-deficient mice because decorin is important for collagen-fibril assembly and has a myokine role in promoting muscle growth. Although decorin was present in the muscle perimysium of wild-type (Chst14+/+ ) mice, decorin was distributed in the muscle perimysium as well as in the endomysium of Chst14-/- mice. Chst14-/- mice had small muscle fibers within the spread interstitium; however, histopathological findings indicated milder myopathy in Chst14-/- mice. Myostatin, a negative regulator of protein synthesis in the muscle, was upregulated in Chst14-/- mice. In the muscle of Chst14-/- mice, decorin was downregulated compared to that in Chst14+/+ mice. Chst14-/- mice showed altered cytokine/chemokine balance and increased fibrosis, suggesting low myogenic activity in DS-deficient muscle. Therefore, DS deficiency in mcEDS causes pathological localization and functional abnormalities of decorin, which causes disturbances in skeletal muscle myogenesis.

Prenatal enzyme replacement therapy for Akp2 -/- mice with lethal hypophosphatasia.

Hypophosphatasia (HPP) is a congenital skeletal disease. Impairment of bone mineralization and seizures are due to a deficiency of tissue-nonspecific alkaline phosphatase (TNAP). Enzyme replacement therapy (ERT) is available as a highly successful treatment for pediatric-onset HPP. However, the potential for prenatal ERT has not been fully investigated to date. In this study, we assessed outcomes and maternal safety using a combinational approach with prenatal and postnatal administration of recombinant TNAP in Akp2 -/- mice as a model of infantile HPP. For the prenatal ERT, we administered subcutaneous injections of recombinant TNAP to pregnant mice from embryonic day 11.5-14.5 until delivery, and then sequentially to Akp2 -/- pups from birth to day 18. For the postnatal ERT, we injected Akp2 -/- pups from birth until day 18. Prenatal ERT did not cause any ectopic mineralization in heterozygous maternal mice. Both prenatal and postnatal ERT preserved growth, survival rate and improved bone calcification in Akp2 -/- mice. However, the effects of additional prenatal treatment to newborn mice appeared to be minimal, and the difference between prenatal and postnatal ERT was subtle. Further improvement of the prenatal ERT schedule and long-term observation will be required. The present paper sets a standard for such future studies.

Toward Understanding the Sex Differences in the Biological Mechanism of Social Stress in Mouse Models.

Significant sex differences in terms of prevalence, symptomatic profiles, severity, and comorbidities of psychiatric disorders are quite common. Women have been shown to be more vulnerable to stress and are nearly twice as likely as men to develop stress-related disorders such as depression and anxiety. Therefore, understanding sex differences with respect to the neurobiological mechanisms underlying stress-related disorders is important for developing more efficient pharmacological interventions for women. However, most preclinical studies on stress-related disorders have focused heavily on male rodents. Here, recent developments in the study of repeated social defeat stress models in female mice are summarized. Our findings suggest that a variety of factors need to be considered when employing this model.

Orexin signaling in GABAergic lateral habenula neurons modulates aggressive behavior in male mice.

Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have various negative effects on patients, their families and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, domination of subordinate social targets is reinforcing. In this study, we showed that, in male mice, orexin neurons in the lateral hypothalamus activated a small population of glutamic acid decarboxylase 2 (GAD2)-expressing neurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2) and that activation of these GAD2 neurons promoted male-male aggression and conditioned place preference for aggression-paired contexts. Moreover, LHb GAD2 neurons were inhibitory within the LHb and dampened the activity of the LHb as a whole. These results suggest that the orexin system is important for the regulation of inter-male aggressive behavior and provide the first functional evidence of a local inhibitory circuit within the LHb.

Tissue-nonspecific alkaline phosphatase promotes the osteogenic differentiation of osteoprogenitor cells.

Tissue-nonspecific alkaline phosphatase (TNAP) is expressed in the calcification sites of the skeletal tissue. It promotes hydroxyapatite crystal formation by degrading inorganic pyrophosphate (PPi) and increasing inorganic phosphate (Pi) concentration. However, abnormalities in Alpl-/- mouse-derived osteoblasts are poorly understood, and the involvement of TNAP in osteoblast differentiation remains unclear. Therefore, in this study, we aimed to investigate the precise role of TNAP in osteoblast differentiation. TNAP inhibition by levamisole, a reversible TNAP inhibitor, suppressed the expression of osteoblast differentiation marker genes in wild-type osteoblastic cells. Alpl overexpression increased the expression of master osteoblast transcription factor genes runt-related transcription factor 2 (Runx2) and Sp7 and the mature osteoblast and osteocyte marker genes, bone γ-carboxyglutamate protein 2 (Bglap2) and dentin matrix protein 1 (Dmp1), respectively in Alpl-deficient osteoblastic cells. TNAP regulated Runx2 expression, which in turn regulated the expression of all other osteoblast markers, except Dmp1. Dmp1 expression was independent of RUNX2 but was dependent on extracellular Pi concentration in Runx2-deficient osteogenic cells. These results suggest that TNAP functions as an osteogenic differentiation regulator either by regulating Runx2 expression or by controlling extracellular Pi concentration.

High-Level Expression of Alkaline Phosphatase by Adeno-Associated Virus Vector Ameliorates Pathological Bone Structure in a Hypophosphatasia Mouse Model.

Hypophosphatasia (HPP) is a systemic skeletal disease caused by mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNALP). We recently reported that survival of HPP model mice can be prolonged using an adeno-associated virus (AAV) vector expressing bone-targeted TNALP with deca-aspartate at the C terminus (TNALP-D10); however, abnormal bone structure and hypomineralization remained in the treated mice. Here, to develop a more effective and clinically applicable approach, we assessed whether transfection with TNALP-D10 expressing virus vector at a higher dose than previously used would ameliorate bone structure defects. We constructed a self-complementary AAV8 vector expressing TNALP driven by the chicken beta-actin (CBA) promoter (scAAV8-CB-TNALP-D10). The vector was injected into both quadriceps femoris muscles of newborn HPP mice at a dose of 4.5 × 1012 vector genome (v.g.)/body, resulting in 20 U/mL of serum ALP activity. The 4.5 × 1012 v.g./body-treated HPP mice grew normally and displayed improved bone structure at the knee joints in X-ray images. Micro-CT analysis showed normal trabecular bone structure and mineralization. The mechanical properties of the femur were also recovered. Histological analysis of the femurs demonstrated that ALP replacement levels were sufficient to promote normal, growth plate cartilage arrangement. These results suggest that AAV vector-mediated high-dose TNALP-D10 therapy is a promising option for improving the quality of life (QOL) of patients with the infantile form of HPP.

Erratum to "Relationship between sensory-processing sensitivity and age in a large cross-sectional Japanese sample" [Heliyon 5, (10), (October 2019), e02508].

[This corrects the article DOI: 10.1016/j.heliyon.2019.e02508.].

Relationship between sensory-processing sensitivity and age in a large cross-sectional Japanese sample.

Sensory-processing sensitivity is a trait involving inherent individual differences that typically manifest in the brain's handling of sensory information (Aron and Aron, 1997). Studies regarding sensory-processing sensitivity have focused on specific age ranges; however, developmental changes in sensory-processing sensitivity have not been studied. This study aimed to examine the relationship between sensory-processing sensitivity and age in Japanese adults (N = 1,983, 1,078 men). Participants ranging in age from 20-69 completed the Japanese version of the 19-item Highly Sensitive Person Scale (Takahashi, 2016). Results of hierarchical multiple regression analysis indicated that low sensory threshold and ease of excitation decrease linearly with age, whereas aesthetic sensitivity increases linearly with age. In contrast, age-related changes in sensory-processing sensitivity do not differ by sex. Thus, the status of age-related changes differs slightly based on sensory-processing sensitivity factors.