산전 발프론산 노출 자폐 백서 모델에서의 뇌 활성 및 연결성

Dept. of Medical Science/박사Autism spectrum disorder (ASD) is a severe lifelong neurodevelopmental disorder characterized by early-onset impairments in social communication and social interaction, and restrictive and repetitive behavior, interests, or activities. Currently no biological markers are available to make a reliable diagnosis of ASD. I used valproic acid (VPA) rat model to explore the possible alterations in metabolic brain activity and connectivity. Female Sprague Dawley rats were given a single intraperitoneal injection of sodium valproate or normal saline on embryonic day 12.5. To evaluate autistic-like behaviors in pups, social interaction was examined during postnatal weeks 4-6 using three-chamber social approach test. Resting-state 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scans were acquired at postnatal weeks 6 or 62. To assess the changes in metabolic brain activity by VPA treatment, Statistical Parametric Mapping (SPM) was performed. I also examined if change in metabolic brain connectivity was accompanied with alterations of regional metabolic activity. Metabolic connectivity was modeled using both conventional correlation analysis, and sparse inverse covariance estimation (SICE), a partial correlation analysis. VPA-treated rats exhibited impairments in social behaviors, and this difference was more pronounced in male than female rats. Preference for social novelty was impaired in VPA-treated male rats, while sociability was diminished in VPA-treated female rats. I found that metabolic activity and connectivity was significantly changed by VPA treatment. Changes in metabolic connectivity was revealed by SICE while conventional correlation analysis did not show any difference. VPA-treated male rats had significantly decreased metabolic activity in the olfactory bulb, and had decreased metabolic connectivity between the left insular cortex and left amygdala, which constitute the salience network. There were no brain regions with decreased metabolic activity in VPA-treated female rats. In contrast, VPA-treated female rats had reduced metabolic connectivity between the thalamus and midbrain, and between the right medial prefrontal cortex and left caudoputamen. Such alterations in metabolic activity and connectivity may represent neurobiological substrates of autistic-like behavior, particularly in males, and may serve as a pathognomonic sign in VPA rat models of ASD. As such this study supports the idea that non-invasive brain imaging may serve as an imaging endophenotype that could aid diagnosis of ASD, classification of severity, and possibly reveal insights to neurobiological underpinnings in autistic-like behavior. 자폐스펙트럼장애는 일생 동안 지속되는 심한 신경발생학적 장애로, 조기에 사회적 의사소통과 사회적 상호작용에 저하가 발생하고, 제한적이고 반복적인 행동이 나타나는 것이 특징이다. 현재 진단에 유용한 생물학적 표지자는 알려진 것이 없다. 발프론산 백서 모델을 사용하여 뇌 대사 및 연결성에 변화가 존재하는지 알아보았다. 암컷 백서(female Sprague Dawley rat)에 임신 후 12.5일에 발프론산 또는 생리 식염수를 복강 내에 주사하였다. 새끼 백서에서 자폐 행동을 평가하기 위하여 행동 검사(three-chamber social approach test)를 생후 4-6주에 시행하였다. 기저 상태 18F-FDG 양전자방출단층촬영(18F-fluorodeoxyglucose positron emission tomography)을 생후 6주 또는 62주에 시행하였고, 뇌 대사에 변화가 있는지 알아보기 위하여 SPM(Statistical Parametric Mapping)을 시행하였다. 또한 대사 연결성 변화가 동반되는지 확인하였다. 대사 연결성은 전통적인 상관 분석, 그리고 부분 상관 분석 기법인 SICE(sparse inverse covariance estimation)를 이용하여 분석하였다. 발프론산에 노출된 백서는 사회적 행동이 저하되었으며, 이 차이는 암컷 백서보다 수컷 백서에서 두드러지게 나타났다. 수컷 백서에서는 사회적 새로움 선호(preference for social novelty)가 감소하였고, 암컷 백서에서는 사회성(sociability)이 감소하였다. 발프론산에 노출된 백서에서 대사 활성도 및 대사 연결성에 변화가 나타나는 것을 확인하였다. 대사 연결성 변화는 전통적인 상관 분석으로는 확인할 수 없었고, SICE로 확인할 수 있었다. 발프론산에 노출된 수컷 백서에서 후각망울(olfactory bulb)에서 대사가 유의하게 감소하였고, 현저성 망(salience network)을 구성하는 좌도피질(left insular cortex)과 좌편도(amygdala) 사이에 대사 연결성이 감소하였다. 발프론산에 노출된 암컷 백서에서는 대사 활성도가 감소한 부분이 없었으나 시상(thalamus)과 중뇌(midbrain), 그리고 우내측전전두엽피질(right medial prefrontal cortex)과 꼬리조가비핵(caudoputamen) 사이의 대사적 연결성이 감소하였다. 이러한 대사 활성도 및 대사 연결성 변화는 특히 남성에서 자폐 유사 행동에 대한 신경생물학적인 기질을 대변할 수 있을 것으로 보이며, 발프론산 노출 자폐 모델에서 질병 특유 징후로서 가능성이 있음을 시사한다. 따라서 본 연구는 비침습적...ope

Glutamatergic stimulation of the left dentate gyrus abolishes depressive-like behaviors in a rat learned helplessness paradigm

BACKGROUND: Episodic experiences of stress have been identified as the leading cause of major depressive disorder (MDD). The occurrence of MDD is profoundly influenced by the individual's coping strategy, rather than the severity of the stress itself. Resting brain activity has been shown to alter in several mental disorders. However, the functional relationship between resting brain activity and coping strategies has not yet been studied. In the present study, we observed different patterns of resting brain activity in rats that had determined either positive (resilient to stress) or negative (vulnerable to stress) coping strategies, and examined whether modulation of the preset resting brain activity could influence the behavioral phenotype associated with negative coping strategy (i.e., depressive-like behaviors). METHODS: We used a learned helplessness paradigm-a well-established model of MDD-to detect coping strategies. Differences in resting state brain activity between animals with positive and negative coping strategies were assessed using 18F-fluorodeoxyglucose positron emission tomography (FDG-PET). Glutamatergic stimulation was used to modulate resting brain activity. RESULTS: After exposure to repeated uncontrollable stress, seven of 23 rats exhibited positive coping strategies, while eight of 23 rats exhibited negative coping strategies. Increased resting brain activity was observed only in the left ventral dentate gyrus of the positive coping rats using FDG-PET. Furthermore, glutamatergic stimulation of the left dentate gyrus abolished depressive-like behaviors in rats with negative coping strategies. CONCLUSION: Increased resting brain activity in the left ventral dentate gyrus helps animals to select positive coping strategies in response to future stress.restrictio