Role of dorsomedial prefrontal cortex astrocytes in mouse dominance and depressive behavior

학위논문 (박사) -- 서울대학교 대학원 : 치의학대학원 치의과학과, 2020. 8. 이성중.사회 서열에 직접적으로 관여하는 서열행동은 대부분의 동물들이 기본적으로 가지고 있는 본능행동이다. 보다 높은 사회적 위치를 달성하고 이를 유지하고자 하는 행동은 생존을 위해서 필수적이다. 최근 연구들은 뇌의 전전두엽 영역의 피라미드 신경세포가 높은 사회적 지위에 도달하고 이를 유지하는 데에 직접적인 역할을 한다는 것으로 보고하고 있다. 한편 사회적 서열과 정신 건강 사이에는 깊은 상관 관계가 있는 것으로 알려져 있는데, 낮은 사회 경제적 위치가 우울증 발병의 많은 원인 중 하나라는 연구 결과가 그 대표적이다. 뇌 전전두엽 영역의 성상교세포가 항우울제에 대한 반응에 관여하는 핵심세포로 기능하고 있는 점으로 볼 때, 성상교세포가 서열행동과 더불어 낮은 서열로 인한 우울증에 동시에 관여할 가능성이 있다. 본 연구에서는 생쥐의 서열행동과 우울증에 대한 뇌 전전두엽 성상교세포의 역할을 밝히고자 한다. 이 논문의 첫 장에서는 사회적 서열이 낮은 생쥐의 뇌 전전두엽 성상교세포를 화학 및 광유전학적으로 자극함으로써 성상교세포의 활성이 서열행동에 미치는 영향을 분석하였다. 전전두엽 성상교세포의 화학 및 광유전학적 자극은 생쥐의 저항 행동을 유발하였고, 이는 하위 서열에 있는 생쥐의 서열 상승을 크게 유도하였다. 나아가 전전두엽 성상교세포의 광유전학적 활성은 세포 밖 글루타메이트 농도를 증가 시켰으며, 이는 피라미드 신경세포로 흥분성 시냅스 입력을 증가시키는 데에 기여하였다. 더불어 서열행동을 유발하는 성상교세포와 신경세포의 차이를 확인하기 위해 성상교세포와 피라미드 신경세포를 광유전학적으로 각각 자극한 생쥐를 서로 경쟁시켰다. 그 결과 두 생쥐간의 승률은 차이가 없었지만 승리하기 위한 행동 방식이 서로 다른 것으로 나타났다. 제 2 장에서는 성상교세포 활성에 의해 유발된 서열행동이 항우울 효과를 보임을 밝혀냈다. 3 주간의 구속 스트레스를 받은 생쥐는 우울 행동을 보였을 뿐 만 아니라 급격히 저하된 서열행동을 보였다. 그러나 스트레스를 받은 생쥐의 전전두엽 성상교세포를 화학유전학적 방법으로 자극하면, 자극을 받은 생쥐는 스트레스를 받지 않은 정상 생쥐에 대하여 강한 저항 행동을 보이고, 이를 통한 반복적인 승리 이후에는 밀어내기 행동을 보였다. 이러한 행동 변화는 만성 스트레스에 의해 유발된 우울 행동을 빠르게 개선시켰는데, 피라미드 신경세포를 자극하였을 경우에는 항우울 효과가 나타나지 않았다. 본 연구에서는 생쥐의 지속적인 저항 행동으로 인한 경쟁에서의 승리가 전전두엽의 성상교세포 활성과 직접 관련이 있으며, 빠른 항우울 효과를 보인다는 것을 밝혀냈다. 이는 낮은 사회적 지위로 인해 발병하게 되는 만성 스트레스성 우울증에 대해 전전두엽의 성상교세포가 새로운 치료 타겟이 될 수 있음을 시사한다.Dominance behavior is a fundamental organizing mechanism for most animal societies. Achieving and remaining at a high social status are essential for survival. Recent studies have identified that pyramidal neurons in dorsomedial prefrontal cortex (dmPFC) region have a key role for remaining and maintaining at high social status. There is also a correlation between social status and mental health such as depression. In human, individuals with low socio-economic status (SES) are vulnerable to depression. Furthermore, astrocytes in dmPFC region are also involved in mouse depression and the response to anti-depressant drugs. Here, in this study, I suggest that dmPFC astrocytes in mice are directly involved in both dominance and depressive-like behaviors. In the first part of this thesis, I applied both chemogenetic and optogenetic manipulation of dmPFC astrocytes into low social ranked mice. Both chemogenetic and optogenetic stimulation of dmPFC astrocyte successfully induced hierarchical rank graduation of subordinate mice by showing resistance behavior rather than pushing behavior during social competition. Optogenetic stimulation of dmPFC astrocytes increased extracellular glutamate level leading to the increase of excitatory synaptic inputs into layer V pyramidal neurons. I next compared astrocyte stimulation-induced dominance behavior with the results of neuron stimulation, and both mouse groups showed comparable winning rates in the tube test with different behavioral mode to achieve dominancy. In the second part, I investigated the relationship between dominance behavior and depression. After 3 weeks of restraint stress (RS), the RS-received mice (RS mice) showed depressive-like behavior, and they also showed reduced dominance behavior compared with that of control mice. However, after chemogenetic stimulation of dmPFC astrocyte into RS mice, they showed increased resistance behavior against control mice during the tube test, and RS mice started to push, which was not observed during the basal behavior. This behavioral shift may be due to the prior winning experience obtained by resistance action, which might confer a winning effect. Furthermore, repetitive winning experience abrogated depressive-like behavior of RS mice. However, neuron-stimulated RS mice did not show anti-depressive behavior although they obtained winning experience by pushing action. This result suggests that rapid anti-depressive effect can be obtained by astrocyte-derived winning experience in mice. In conclusion, dmPFC astrocyte activation enhances mouse dominance behavior by persistent resistance behavior. Moreover, depressive-like phenotype shown in chronic RS mice can be rapidly reversed by repetitive winning experience. This result suggests that the association between dominancy and depression through dmPFC astrocyte activity provides a clinical implication in treating depression due to low social status.Chapter I. The role of dmPFC astrocytes in mouse dominance behavior 13 Abstract 14 Introduction 15 Materials and Methods 18 Results 30 Discussion 55 Chapter II. The effects of dmPFC astrocyte activation-induced dominancy on depression 59 Abstract 60 Introduction 62 Materials and Methods 65 Results 71 Discussion 87 Conclusion 90 References 91 Abstract in Korean 102Docto

Octopamine Neuromodulatory Effects on a Social Behavior Decision-Making Network in Drosophila Males

Situations requiring rapid decision-making in response to dynamic environmental demands occur repeatedly in natural environments. Neuromodulation can offer important flexibility to the output of neural networks in coping with changing conditions, but the contribution of individual neuromodulatory neurons in social behavior networks remains relatively unknown. Here we manipulate the Drosophila octopaminergic system and assay changes in adult male decision-making in courtship and aggression paradigms. When the functional state of OA neural circuits is enhanced, males exhibit elevated courtship behavior towards other males in both behavioral contexts. Eliminating the expression of the male form of the neural sex determination factor, Fruitless (FruM), in three OA suboesophageal ganglia (SOG) neurons also leads to increased male-male courtship behavior in these same contexts. We analyzed the fine anatomical structure through confocal examination of labeled single neurons to determine the arborization patterns of each of the three FruM-positive OA SOG neurons. These neurons send processes that display mirror symmetric, widely distributed arbors of endings within brain regions including the ventrolateral protocerebra, the SOG and the peri-esophageal complex. The results suggest that a small subset of OA neurons have the potential to provide male selective modulation of behavior at a single neuron level

Socially driven changes in neural and behavioural plasticity in zebrafish

Tese de doutoramento, Biologia (Etologia), Universidade de Lisboa, Faculdade de Ciências, 2015Social competence, the ability of individuals to regulate the expression of their social behaviour in order to optimize their social relationships in a group, is especially benefic for individuals living in complex social environments, and implies the ability to perceive social cues and produce appropriate behavioural output responses (Social Plasticity). Numerous examples of social competence can be found in nature, where individuals extract social information from the environment, and change their behavioural response based on the collected information. At the neuronal level, two major plasticity mechanisms have been proposed to underlie social plasticity, structural reorganization and biochemical switching of the neuronal networks underlying behaviour. The neural substrate for behavioural plasticity has been identified as the social decision-making (SDM) network, such that the same neural circuitry may underlie the expression of different behaviours depending on social context. The goal of this work is to study the proximate mechanism underlying behavioural flexibility in the context of experience-dependent behavioural shifts, in an integrative framework. For this purpose we exposed male zebrafish to two types of social interactions: (1) real-opponent interactions, from which a Winner and Loser emerged; and (2) Mirror-elicited interactions, that produced individuals that did not experience a change in social status, despite expressing similar levels of aggressive behaviour to those participating in real-opponent fights. In a first set of experiments, we studied the influence of neuromodulators on social plasticity mechanisms, by characterizing the endocrine response to social challenges, as well as the social modulation of brain monoamines and nonapeptides. Next we tested the SDM network hypothesis by contrasting changes in functional localization vs. connectivity across this network. Finally we characterized changes in expression of key genes for different neuroplasticity mechanisms in response to changes in social status. Our research suggests different social plasticity mechanisms underlying Winners and Losers both at physiological and molecular levels, for Mirror-fighters, where the experience of winning or losing was decoupled for the fighting experience, few changes were detected. This, by itself suggests a pivotal role of social perception in triggering shifts between socially driven behavioural states

Advances in Solid State Circuit Technologies

This book brings together contributions from experts in the fields to describe the current status of important topics in solid-state circuit technologies. It consists of 20 chapters which are grouped under the following categories: general information, circuits and devices, materials, and characterization techniques. These chapters have been written by renowned experts in the respective fields making this book valuable to the integrated circuits and materials science communities. It is intended for a diverse readership including electrical engineers and material scientists in the industry and academic institutions. Readers will be able to familiarize themselves with the latest technologies in the various fields

Reservoir computing based on delay-dynamical systems

Today, except for mathematical operations, our brain functions much faster and more efficient than any supercomputer. It is precisely this form of information processing in neural networks that inspires researchers to create systems that mimic the brain’s information processing capabilities. In this thesis we propose a novel approach to implement these alternative computer architectures, based on delayed feedback. We show that one single nonlinear node with delayed feedback can replace a large network of nonlinear nodes. First we numerically investigate the architecture and performance of delayed feedback systems as information processing units. Then we elaborate on electronic and opto-electronic implementations of the concept. Next to evaluating their performance for standard benchmarks, we also study task independent properties of the system, extracting information on how to further improve the initial scheme. Finally, some simple modifications are suggested, yielding improvements in terms of speed or performanc

VLSI Design

This book provides some recent advances in design nanometer VLSI chips. The selected topics try to present some open problems and challenges with important topics ranging from design tools, new post-silicon devices, GPU-based parallel computing, emerging 3D integration, and antenna design. The book consists of two parts, with chapters such as: VLSI design for multi-sensor smart systems on a chip, Three-dimensional integrated circuits design for thousand-core processors, Parallel symbolic analysis of large analog circuits on GPU platforms, Algorithms for CAD tools VLSI design, A multilevel memetic algorithm for large SAT-encoded problems, etc

Competition between visual stimuli in the monkey parietal cortex

We live in a complicated visual world where stimuli are constantly clamoring for our limited attentional resources. We use our eyes to explore the world and our brain must make moment-to-moment decisions about which points of space contain the most information or which points are associated with rewarding outcomes. In our neural representation of the visual world, stimuli are locked in a constant battle for spatial priority and a single winner must emerge each time an eye movement is to be made, though the mechanisms by which this winner emerges are unclear. In this thesis we explore how competition between neural representations of visual stimuli in the parietal cortex may be implemented by changes in the activity and reliability of neural signals. The macaque lateral intraparietal area (LIP) is part of an oculomotor attentional network and its activity represents the relative priority of spatial locations. We demonstrate how neurons in LIP use surround suppressive mechanisms to resolve conflict between spatial locations and explore the role of shared variability in the priority map network. We manipulate the cognitive state of the monkey by changing his expected reward and show that the activity, reliability, and noise correlation are affected by the context of the monkeys' choice. Finally, we demonstrate how behavioral variables such as the monkeys' performance and saccade latency are modulated during competitive choice

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SciTech News Volume 71, No. 2 (2017)

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Behavioral and Neuroendocrine Correlates of Sex Change in the Gilthead Seabream (Sparus aurata)

Sequential hermaphroditism is the most radical form of environmental sex determination observed in fish: functional adult males or females retain their ability to change sex even as adults. Among the factors that affect sex change in these species, the least understood is the social environment. Here, I studied the influences of social context on sex change in the Gilthead Seabream, Sparus aurata, by using the individual‟s dominance rank as an indicator of social status. To understand the role that the brain might play in sex change, I also studied the two main neuroendocrine factors that serve as the sexually differentiated axes of neural plasticity in most teleost species: AVT and GnRH. To do this, I first developed a set of tools designed to address the challenges associated with observing the behavior of aquacultured species. Using these tools, I provide the first in-depth study of seabream captive behavior, including the results of size-matched and sex-matched paired encounters. I found that females are more aggressive than males, but this difference is influenced by gonadal developmental status. I also showed that small but young males are more aggressive than bigger but older females. I cloned the AVT mRNA in seabream, and validated a quantitative assay to measure total brain AVT levels together with GnRH-1, GnRH-2, and GnRH-3 levels. I found that AVT and GnRH-3 levels rise during the onset of the hypothesized sex-change window, and drop to pre-quiescent levels until spawning, when all of these factors seem to increase their expression levels again. I also show for the first time, that GnRH-2 and dominance rank are strongly correlated in seabream during the spawning season but not during quiescence. GnRH-1 was strongly correlated to rank during quiescence but not during spawning. Finally, neither dominance rank nor size were a good predictor of the outcome of sex change, which seems to contradict what has been documented in sequential hermaphrodite reef fishes. I provide a model that accounts for this apparent contradiction and conclude that the Gilthead seabream remains true to the size-advantage hypothesis of sex allocation theory, if size and dominance are seen as proximate, rather than ultimate, factors