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.

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.

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.

Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility.

Behavioral coping strategies are critical for active resilience to stress and depression; here we describe a role for neuroligin-2 (NLGN-2) in the nucleus accumbens (NAc). Neuroligins (NLGN) are a family of neuronal postsynaptic cell adhesion proteins that are constituents of the excitatory and inhibitory synapse. Importantly, NLGN-3 and NLGN-4 mutations are strongly implicated as candidates underlying the development of neuropsychiatric disorders with social disturbances such as autism, but the role of NLGN-2 in neuropsychiatric disease states is unclear. Here we show a reduction in NLGN-2 gene expression in the NAc of patients with major depressive disorder. Chronic social defeat stress in mice also decreases NLGN-2 selectively in dopamine D1-positive cells, but not dopamine D2-positive cells, within the NAc of stress-susceptible mice. Functional NLGN-2 knockdown produces bidirectional, cell-type-specific effects: knockdown in dopamine D1-positive cells promotes subordination and stress susceptibility, whereas knockdown in dopamine D2-positive cells mediates active defensive behavior. These findings establish a behavioral role for NAc NLGN-2 in stress and depression; provide a basis for targeted, cell-type specific therapy; and highlight the role of active behavioral coping mechanisms in stress susceptibility.

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.

Cell-Type-Specific Role of ΔFosB in Nucleus Accumbens In Modulating Intermale Aggression.

A growing number of studies implicate the brain's reward circuitry in aggressive behavior. However, the cellular and molecular mechanisms within brain reward regions that modulate the intensity of aggression as well as motivation for it have been underexplored. Here, we investigate the cell-type-specific influence of ΔFosB, a transcription factor known to regulate a range of reward and motivated behaviors, acting in the nucleus accumbens (NAc), a key reward region, in male aggression in mice. We show that ΔFosB is specifically increased in dopamine D1 receptor (Drd1)-expressing medium spiny neurons (D1-MSNs) in NAc after repeated aggressive encounters. Viral-mediated induction of ΔFosB selectively in D1-MSNs of NAc intensifies aggressive behavior without affecting the preference for the aggression-paired context in a conditioned place preference (CPP) assay. In contrast, ΔFosB induction selectively in D2-MSNs reduces the time spent exploring the aggression-paired context during CPP without affecting the intensity of aggression per se. These data strongly support a dissociable cell-type-specific role for ΔFosB in the NAc in modulating aggression and aggression reward.SIGNIFICANCE STATEMENT Aggressive behavior is associated with several neuropsychiatric disorders and can be disruptive for affected individuals as well as their victims. Studies have shown a positive reinforcement mechanism underlying aggressive behavior that shares many common features with drug addiction. Here, we explore the cell-type-specific role of the addiction-associated transcription factor ΔFosB in the nucleus accumbens in aggression. We found that ΔFosB expression promotes aggressive behavior, effects that are dissociable from its effects on aggression reward. This finding is a significant first step in identifying therapeutic targets for the reduction of aggressive behavior across a range of neuropsychiatric illnesses.

Glutamate input in the dorsal raphe nucleus as a determinant of escalated aggression in male mice.

Although the dorsal raphe nucleus (DRN) has long been linked to neural control of aggression, little is known about the regulatory influences of the DRN when an animal engages in either adaptive species-typical aggressive behavior or escalated aggression. Therefore it is important to explore which neurotransmitter inputs into the DRN determine the escalation of aggression in male mice. Previously, we observed that microinjection of the GABAB receptor agonist baclofen into the DRN escalates aggressive behavior in male mice. Here, we used a serotonin (5-HT) neuron-specific GABAB receptor knock-out mouse to demonstrate that baclofen acts on nonserotonergic neurons to escalate aggression. Intra-DRN baclofen administration increased glutamate release, but did not alter GABA release, within the DRN. Microinjection of l-glutamate into the DRN escalated dose-dependently attack bites toward an intruder. In vivo microdialysis showed that glutamate release increased in the DRN during an aggressive encounter, and the level of glutamate was further increased when the animal was engaged in escalated aggressive behavior after social instigation. Finally, 5-HT release was increased within the DRN and also in the medial prefrontal cortex when animals were provoked by social instigation, and during escalated aggression after social instigation, but this increase in 5-HT release was not observed when animals were engaged in species-typical aggression. In summary, glutamate input into the DRN is enhanced during escalated aggression, which causes a phasic increase of 5-HT release from the DRN 5-HT neurons.

Sex Differences in Nucleus Accumbens Transcriptome Profiles Associated with Susceptibility versus Resilience to Subchronic Variable Stress.

Depression and anxiety disorders are more prevalent in females, but the majority of research in animal models, the first step in finding new treatments, has focused predominantly on males. Here we report that exposure to subchronic variable stress (SCVS) induces depression-associated behaviors in female mice, whereas males are resilient as they do not develop these behavioral abnormalities. In concert with these different behavioral responses, transcriptional analysis of nucleus accumbens (NAc), a major brain reward region, by use of RNA sequencing (RNA-seq) revealed markedly different patterns of stress regulation of gene expression between the sexes. Among the genes displaying sex differences was DNA methyltransferase 3a (Dnmt3a), which shows a greater induction in females after SCVS. Interestingly, Dnmt3a expression levels were increased in the NAc of depressed humans, an effect seen in both males and females. Local overexpression of Dnmt3a in NAc rendered male mice more susceptible to SCVS, whereas Dnmt3a knock-out in this region rendered females more resilient, directly implicating this gene in stress responses. Associated with this enhanced resilience of female mice upon NAc knock-out of Dnmt3a was a partial shift of the NAc female transcriptome toward the male pattern after SCVS. These data indicate that males and females undergo different patterns of transcriptional regulation in response to stress and that a DNA methyltransferase in NAc contributes to sex differences in stress vulnerability. SIGNIFICANCE STATEMENT: Women have a higher incidence of depression than men. However, preclinical models, the first step in developing new diagnostics and therapeutics, have been performed mainly on male subjects. Using a stress-based animal model of depression that causes behavioral effects in females but not males, we demonstrate a sex-specific transcriptional profile in brain reward circuitry. This transcriptional profile can be altered by removal of an epigenetic mechanism, which normally suppresses DNA transcription, creating a hybrid male/female transcriptional pattern. Removal of this epigenetic mechanism also induces behavioral resilience to stress in females. These findings shed new light onto molecular factors controlling sex differences in stress response.

Enhanced prepulse inhibition and low sensitivity to a dopamine agonist in HESR1 knockout mice.

Transcription factor Hesr family genes are important in neuronal development. We demonstrated previously that HESR1 and HESR2 modified expression of the dopamine transporter (DAT) reporter gene. HESR-family genes have been investigated in development, but their functions, especially in relation to behaviors regulated by dopamine, in adult animals remain unclear. In the present study, we investigated the effects of Hesr1 and Hesr2 on behavior. A behavioral test battery to examine spontaneous activity, anxiety-like behavior, aggressive behavior, pain sensitivity, and sensorimotor gating was conducted in Hesr1 and Hesr2 knockout (KO) mice. Enhanced prepulse inhibition (PPI), which is a form of sensorimotor gating, was observed in only Hesr1 KO mice; other behavioral traits were mostly comparable to wild-type animals in both the Hesr1 and the Hesr2 KO lines. Next, we used a dopamine agonist, apomorphine, to confirm the involvement of the dopaminergic system. Injection of apomorphine reduced the enhanced PPI in Hesr1 KO mice. Additionally, dose-dependent sensitivity to the agonist was lower in the Hesr1 KO mice than in wild-type mice, suggesting that the enhanced PPI resulted from this alteration in dopamine sensitivity. Furthermore, DAT mRNA was downregulated in Hesr1 KO mice, whereas the dopamine D1 and D2 receptors were comparable. These findings suggest Hesr1 to be a novel factor that affects dopamine sensitivity and the sensorimotor gating system.

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.

Ectopic pregnancy: MRI findings and clinical utility.

PURPOSE: To assess the utility of magnetic resonance imaging (MRI) in patients with clinically suspected ectopic pregnancy (EP). METHODS: We retrospectively reviewed MRIs of 26 consecutive patients who were clinically suspected of having an EP. The diagnostic utility of MRI features of EP was analyzed retrospectively as follows: (1) Direct sign detection of ectopic gestational sac (GS); (2) Indirect signs tubal dilatation with hemosalpinx, adnexal hematoma, and hemorrhagic ascites. The diagnostic accuracy of each sign and their combination was compared to surgical records. The MRI findings of an ectopic GS were reviewed as follows: size, shape, signal intensity, and enhancement pattern. RESULTS: Of 26 patients, 24 had a tubal pregnancy; 22 of these 24 patients (92%) had a direct sign (sensitivity: 91.3%; specificity: 100%; positive predictive value: 100%). The diagnostic accuracy of the direct sign was 92%; this was more accurate than that of any single indirect sign (39%, 54%, and 50%, respectively). However, the diagnostic accuracy of EP increased to 100% when diagnostic criteria required the presence of a direct sign or at least two indirect signs. CONCLUSIONS: MRI is an effective modality for diagnosing EP with a high detection rate of extrauterine GSs. The combination of direct and indirect signs is useful for establishing the correct diagnosis.

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.

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.

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.

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.

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.

GABA(B) receptor modulation of serotonin neurons in the dorsal raphé nucleus and escalation of aggression in mice.

The serotonin (5-HT) system in the brain has been studied more than any other neurotransmitter for its role in the neurobiological basis of aggression. However, which mechanisms modulate the 5-HT system to promote escalated aggression is not clear. We here explore the role of GABAergic modulation in the raphé nuclei, from which most 5-HT in the forebrain originates, on escalated aggression in male mice. Pharmacological activation of GABA(B), but not GABA(A), receptors in the dorsal raphé nucleus (DRN) escalated aggressive behaviors. In contrast, GABA agonists did not escalate aggressive behaviors after microinjection into the median raphé nucleus. The aggression-heightening effect of the GABA(B) agonist baclofen depended on the activation of 5-HT neurons in the DRN because it was blocked by coadministration of the 5-HT(1A) agonist 8-OH-DPAT [((+/-)-8-hydroxy-2-(di-n-propylamino)tetralin) hydrobromide] (DPAT), which acts on autoreceptors and inhibits 5-HT neural activity. In vivo microdialysis showed that GABA(B) activation in the DRN increased extracellular 5-HT level in the medial prefrontal cortex. This may be attributable to an indirect action via presynaptic GABA(B) receptors. The presynaptic GABA(B) receptors suppress Ca(2+) channel activity and inhibit neurotransmission, and the coadministration of N-type Ca(2+) channel blocker facilitated the effect of baclofen. These findings suggest that the indirect disinhibition of 5-HT neuron activity by presynaptic GABA(B) receptors on non-5-HT neurons in the DRN is one of the neurobiological mechanisms of escalated aggression.