一般口演
社会行動
Social Behavior 1
座長：渡部 文子（東京慈恵会医科大学総合医科学研究センター臨床医学研究所） |
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| 2022年6月30日 14:00～14:15 沖縄コンベンションセンター 会議場B2 第5会場
1O05a1-01
Early life trauma leads to sex specific long lasting violent behaviour by impairing thyroid hormone availability in brain
*Arpita Konar(1)
1. CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
Keyword: Aggression, stress
Violent behavior is an aberrant form of aggression that has detrimental impact on health and society. Epidemiological studies suggest remarkable influences of early life traumatic experiences on adulthood behavioral abnormalities increasing vulnerability to neuropsychiatric disorders. In particular, stressful experiences around puberty have been linked with long lasting escalated and aberrant aggressive behavior referred to as “pathological” that can even lead to violent and criminal incidences, though biological culprits are still obscure. In our laboratory, we used peripubertal stress (PPS) induced mouse model of pathological aggression and investigated the molecular roots in vulnerable brain regions of prefrontal cortex and hypothalamus. We observed drastic sex differences in behavioral responses as PPS exposed male mice exhibited pathological aggression in adulthood while females were resilient and did not show any sign of aggression. Such abnormal behavioral phenotype was also inherited in next generation as F1male progenies of F0 violent father were also hyper-aggressive despite being unexposed to PPS. Further, brain region and sex specific transcriptome profiling identified transthyretin (TTR) as a key regulator of PPS induced violent behavior and its sex differences. TTR mediated long-term perturbation in hypothalamic thyroid hormone (TH) availability contributed to male violent behavior without affecting circulating hormone. Further, we deciphered Ttr promoter hyper methylation in hypothalamus of violent males as compared to control counterparts. Our findings reveal that trauma during puberty trigger lasting violent behavior by epigenetic programming of TTR and consequent impaired thyroid availability in brain. TTR-TH signaling in hypothalamus can serve as potential target in reversal of violent behavior. | | 2022年6月30日 14:15～14:30 沖縄コンベンションセンター 会議場B2 第5会場
1O05a1-02
Ablating oxytocin receptor (Oxtr) reduces empathetic consoling and correlated brain activity in male, but not female, prairie voles (Microtus ochrogaster).
*Kengo Horie(1), Larry J. Young(1,2)
1. Center for Translational Social Neuroscience, Emory University, 2. Center for Social Neural Networks, University of Tsukuba
Keyword: Empathy, Oxytocin receptor, Prairie vole, Social behavior
Empathy is the ability to process the emotional states of others. Autism spectrum disorder (ASD) is associated with disrupted empathy-related processes. Recent data suggests that empathy is conserved across mammalian species, including monogamous prairie voles. Prairie vole display enduring pair bonding between mates, biparental care, and empathetic consoling (allogrooming) behavior towards distressed partners. These social behaviors are associated with oxytocin receptor (OXTR) signaling in specific areas of a social neural network. For example, pharmacologically blocking OXTR in anterior cingulate cortex (ACC) suppresses male consoling behaviors toward distressed partners. The role of OXTR in female consoling, or the involvement of other brain regions in OXTR dependent consoling have not been investigated. Here, we first assessed consoling behaviors in male and female Oxtr wildtype (WT) and knockout (KO) prairie voles. Subjects (observers) were paired with opposite sex WT partners (demonstrators) for 24 hours to establish a pair bond. Demonstrators were then removed and either distressed with foot shock or separated without foot shock (control). After 30 min, the pair were reunited and allowed to interact freely. The duration of allogrooming behavior of observers toward demonstrators was analyzed. Brains were collected 90 min after reunion for analysis of neural activity in the paradigm using c-Fos immunofluorescence. A 3-way ANOVA revealed a main effect of genotype, condition (shocked vs control), and a genotype x sex x condition interaction (ps<0.05). Male, but not female, Oxtr KO observers showed reduced consoling behaviors toward distressed partners (p<0.05). Analysis of c-FOS revealed no genotype or sex differences in neural activity across brain regions in a social neural network in this paradigm. We then assessed network coordinated activity using Pearson's correlation coefficients. Surprisingly, we found male, but not female, Oxtr KO exposed to distressed partners displayed hyper-correlated activity in the neural network (male WT vs KO; p<0.05). The hyper-correlations were highest amongst ACC, nucleus accumbens, insular cortex, basolateral amygdala, bed nucleus of stria terminalis, and anterior olfactory nucleus. These results suggest a sex-specific role for OXTR signaling in coordinating neural activity and facilitating empathy-based consoling behavior, which may have implications for male biased social deficits observed in ASD. | | 2022年6月30日 14:30～14:45 沖縄コンベンションセンター 会議場B2 第5会場
1O05a1-03
ミクログリア由来キヌレニン-3-モノオキシゲナーゼの発現低下に関連したキヌレン酸の増加は慢性予測不能軽度ストレスによるうつ様行動およびHPA系の調節不全に関与する
Increase of kynurenic acid associated with decrease of microglia-derived kynurenine-3-monooxygenase is involved in depressive-like behavior and dysregulation of hypothalamic-pituitary-adrenal axis induced by the chronic unpredictable mild stress
*長谷川 眞也(1)、毛利 彰宏(1,4)、國澤 和生(1)、窪田 悠力(1)、倉橋 仁美(1)、小菅 愛加(1)、山本 康子(2)、齋藤 邦明(2,3,4)、鍋島 俊隆(3,4)
1. 藤田医科大学大学院保健学研究科レギュラトリーサイエンス分野、2. 藤田医科大学大学院保健学研究科病態制御解析学分野、3. 藤田医科大学大学院保健学研究科先進診断システム探索研究部門、4. NPO法人医薬品適正使用推進機構
*Masaya Hasegawa(1), Akihiro Mouri(1,4), Kazuo Kunisawa(1), Hisayoshi Kubota(1), Hitomi Kurahashi(1), Aika Kosuge(1), Yasuko Yamamoto(2), Kuniaki Saito(2,3,4), Toshitaka Nabeshima(3,4)
1. Dept. Regulatory Sci., Grad. Sch. Health Sci., Fujita Health Univ., 2. Dept. Disease Control & Prevention., Grad. Sch. Health Sci., Fujita Health Univ., 3. Adv. Diagnostic. Syst. Res. Lab., Grad. Sch. Health Sci., Fujita Health Univ, 4. NPO.J-DO.
Keyword: Depression, Hypothalamic-pituitary-adrenal axis , Microglia-derived kynurenine-3-monooxygenase, α7 nicotinic acetylcholine receptor
Chronic stress is a risk factor in the development of major depressive disorder (MDD). Neuronal inflammation is suggested to be involved in the pathophysiology of MDD. Inflammation and stress activate kynurenine (KYN) synthesis. KYN is metabolized to 3-hydroxykynurenine (3-HK) by kynurenine 3-monooxygenase (KMO) and to kynurenic acid (KA) by kynurenine aminotransferase. We investigated the involvement of KYN metabolism in depressive-like behaviors induced by chronic unpredictable mild stress (CUMS) in mice. Mice were randomly exposed to CUMS for 4 weeks. In the expression of proinflammatory cytokines, interleukin-6 (IL-6) mRNA in the hippocampus (HIP) was increased immediately after CUMS for 2 days, but IL-1b mRNA was decreased for 4 weeks. KMO and Iba1 mRNA were decreased, but KA contents were increased immediately after CUMS for 4 weeks. Iba1 is a marker of microglia, and KMO is predominantly localized in microglia. CUMS decreased the number and soma area of microglia in the HIP. Further, serum corticosterone levels were elevated immediately after CUMS for 4 weeks. Interestingly, corticosterone administration for 4 weeks decreased Iba1 and KMO mRNA. These data suggested that the decrease of KMO was associated with the decrease of microglia induced by elevated corticosterone in CUMS. The decrease of KMO changed KYN metabolism from 3-HK to KA, an endogenous α7 nicotinic acetylcholine receptor (α7nAChR) antagonist. Administration of nicotine (Nic) and galantamine (Gal: α7nAChR allosteric modulator) under exposure stress improved decrease of sociability induced by CUMS. Nic not only attenuated sustained elevation of serum corticosterone levels, but also suppressed an increase of corticotropin-releasing hormone (CRH) expression in the hypothalamus of CUMS mice. These data suggested that the increase of KA associated with the decrease of microglia-derived KMO was involved in depressive-like behavior of mice induced by CUMS via the dysregulation of hypothalamic-pituitary-adrenal axis. | | 2022年6月30日 14:45～15:00 沖縄コンベンションセンター 会議場B2 第5会場
1O05a1-04
アストロサイトCD38は社会性記憶とSPARCL1を介したシナプス形成を制御する
Astroglial CD38 regulates social memory and synapse formation through SPARCL1 in the postnatal brain
*服部 剛志(1)、Stanislav Cherepanov(2)、坂賀 綾(1)、石井 宏史(1)、宝田 美佳(1)、東田 陽博(2)、堀 修(1)
1. 金沢大学医薬保健研究域医学系、2. 金沢大学子どものこころ研究セ
*Tsuyoshi Hattori(1), Stanislav M Cherepanov(2), Ryo Sakaga(1), Ishii hiroshi(1), Mika Takarada-Iemata(1), Haruhiro Higashida(2), Osamu Hori(1)
1. Grad Sch Med Sci, Kanazawa Univ, Ishikawa, Japan, 2. Res Cent Child Ment Dev, Kanazawa Univ, Ishikawa, Japan
Keyword: astrocyte, social behavior, synapse formation, prefrontal cortex
Social behavior is essential for the health, survival and reproduction of animals, yet the role of astrocytes, a kind of glial cells, in social behavior is largely unknown. CD38 is a multifunctional transmembrane protein that possesses ADP-ribosyl cyclase activity, which produces cyclic ADP-ribose (cADPR) from nicotinamide adenine dimucleotide (NAD+), and releases Ca2+ from intracellular stores. CD38 is critical for social behaviors by regulating oxytocin release from hypothalamic neurons. On the other hand, CD38 is most abundantly expressed in astrocytes especially in the postnatal cortex, and is important for astroglial development.
Here, we demonstrate that astroglial CD38 plays a pivotal role in the social behavior. Selective deletion of CD38 in postnatal astrocytes, but not in adult astrocytes, specifically impaired social memory without any other behavioral abnormalities. Morphological analysis revealed reductions in spine numbers, mature spines and excitatory synapse numbers in the pyramidal neurons of the medial prefrontal cortex (mPFC) due to deletion of astroglial CD38 in the postnatal brain. Astrocyte-conditioned medium (ACM) of CD38 KO astrocytes reduced synaptogenesis of cortical neurons by reducing extracellular SPARCL1, a synaptogenic protein. Finally, the release of SPARCL1 from astrocytes is regulated by CD38/cADPR/calcium signaling. Our data indicate that astroglial CD38 developmentally regulates social memory and neural circuit formation in the developing brain by promoting synaptogenesis through SPARCL1. | |
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