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Identifying behavioral links to neural dynamics of multifiber photometry recordings in a mouse social behavior network

Chen, Yibo; Chien, Jonathan; Dai, Bing; Lin, Dayu; Chen, Zhe Sage
Distributed hypothalamic-midbrain neural circuits help orchestrate complex behavioral responses during social interactions. Given rapid advances in optical imaging, it is a fundamental question how population-averaged neural activity measured by multi-fiber photometry (MFP) for calcium fluorescence signals correlates with social behaviors is a fundamental question. This paper aims to investigate the correspondence between MFP data and social behaviors. 
Approach: We propose a state-space analysis framework to characterize mouse MFP data based on dynamic latent variable models, which include a continuous-state linear dynamical system (LDS) and a discrete-state hidden semi-Markov model (HSMM). We validate these models on extensive MFP recordings during aggressive and mating behaviors in male-male and male-female interactions, respectively. 
Main Results: Our results show that these models are capable of capturing both temporal behavioral structure and associated neural states, and produce interpretable latent states. Our approach is also validated in computer simulations in the presence of known ground truth.
Significance: Overall, these analysis approaches provide a state-space framework to examine neural dynamics underlying social behaviors and reveals mechanistic insights into the relevant networks. 
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PMID: 38861996
ISSN: 1741-2552
CID: 5668992

Monitoring norepinephrine release in vivo using next-generation GRABNE sensors

Feng, Jiesi; Dong, Hui; Lischinsky, Julieta E; Zhou, Jingheng; Deng, Fei; Zhuang, Chaowei; Miao, Xiaolei; Wang, Huan; Li, Guochuan; Cai, Ruyi; Xie, Hao; Cui, Guohong; Lin, Dayu; Li, Yulong
Norepinephrine (NE) is an essential biogenic monoamine neurotransmitter. The first-generation NE sensor makes in vivo, real-time, cell-type-specific and region-specific NE detection possible, but its low NE sensitivity limits its utility. Here, we developed the second-generation GPCR-activation-based NE sensors (GRABNE2m and GRABNE2h) with a superior response and high sensitivity and selectivity to NE both in vitro and in vivo. Notably, these sensors can detect NE release triggered by either optogenetic or behavioral stimuli in freely moving mice, producing robust signals in the locus coeruleus and hypothalamus. With the development of a novel transgenic mouse line, we recorded both NE release and calcium dynamics with dual-color fiber photometry throughout the sleep-wake cycle; moreover, dual-color mesoscopic imaging revealed cell-type-specific spatiotemporal dynamics of NE and calcium during sensory processing and locomotion. Thus, these new GRABNE sensors are valuable tools for monitoring the precise spatiotemporal release of NE in vivo, providing new insights into the physiological and pathophysiological roles of NE.
PMID: 38547869
ISSN: 1097-4199
CID: 5645192

Brain-wide multi-fiber recording of neuronal activity in freely moving mice

Dai, Bing; Guo, Zhichao; Lin, Dayu
While brain regions function in coordination to mediate diverse behaviors, techniques allowing simultaneous monitoring of many deep brain regions remain limited. Here, we present a multi-fiber recording protocol that enables simultaneous recording of fluorescence signals from multiple brain regions in freely behaving mice. We describe steps for assembling a multi-fiber array and patch cord, implantation, and recording. We then detail procedures for data extraction and visualization. This protocol enables a comprehensive view of the neural activity at the network level. For complete details on the use and execution of this protocol, please refer to Guo et al.1.
PMID: 38340320
ISSN: 2666-1667
CID: 5632202

A dedicated hypothalamic oxytocin circuit controls aversive social learning

Osakada, Takuya; Yan, Rongzhen; Jiang, Yiwen; Wei, Dongyu; Tabuchi, Rina; Dai, Bing; Wang, Xiaohan; Zhao, Gavin; Wang, Clara Xi; Liu, Jing-Jing; Tsien, Richard W; Mar, Adam C; Lin, Dayu
To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks1. Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOROXT) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvlOXTR) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvlOXTR cells minimally respond to aggressor cues. During defeat, aVMHvlOXTR cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvlOXTR cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity.
PMID: 38267576
ISSN: 1476-4687
CID: 5625042

Identifying behavioral links to neural dynamics of multifiber photometry recordings in a mouse social behavior network

Chen, Yibo; Chien, Jonathan; Dai, Bing; Lin, Dayu; Chen, Zhe Sage
Distributed hypothalamic-midbrain neural circuits orchestrate complex behavioral responses during social interactions. How population-averaged neural activity measured by multi-fiber photometry (MFP) for calcium fluorescence signals correlates with social behaviors is a fundamental question. We propose a state-space analysis framework to characterize mouse MFP data based on dynamic latent variable models, which include continuous-state linear dynamical system (LDS) and discrete-state hidden semi-Markov model (HSMM). We validate these models on extensive MFP recordings during aggressive and mating behaviors in male-male and male-female interactions, respectively. Our results show that these models are capable of capturing both temporal behavioral structure and associated neural states. Overall, these analysis approaches provide an unbiased strategy to examine neural dynamics underlying social behaviors and reveals mechanistic insights into the relevant networks.
PMCID:10793434
PMID: 38234793
CID: 5631482

A dedicated hypothalamic oxytocin circuit controls aversive social learning

Osakada, Takuya; Yan, Rongzhen; Jiang, Yiwen; Wei, Dongyu; Tabuchi, Rina; Dai, Bing; Wang, Xiaohan; Zhao, Gavin; Wang, Clara Xi; Liu, Jing Jing; Tsien, Richard W.; Mar, Adam C.; Lin, Dayu
To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks1. Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOROXT) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvlOXTR) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvlOXTR cells minimally respond to aggressor cues. During defeat, aVMHvlOXTR cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvlOXTR cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity.
SCOPUS:85182997082
ISSN: 0028-0836
CID: 5629362

Transcriptionally defined amygdala subpopulations play distinct roles in innate social behaviors

Lischinsky, Julieta E; Yin, Luping; Shi, Chenxi; Prakash, Nandkishore; Burke, Jared; Shekaran, Govind; Grba, Maria; Corbin, Joshua G; Lin, Dayu
Social behaviors are innate and supported by dedicated neural circuits, but the molecular identities of these circuits and how they are established developmentally and shaped by experience remain unclear. Here we show that medial amygdala (MeA) cells originating from two embryonically parcellated developmental lineages have distinct response patterns and functions in social behavior in male mice. MeA cells expressing the transcription factor Foxp2 (MeAFoxp2) are specialized for processing male conspecific cues and are essential for adult inter-male aggression. By contrast, MeA cells derived from the Dbx1 lineage (MeADbx1) respond broadly to social cues, respond strongly during ejaculation and are not essential for male aggression. Furthermore, MeAFoxp2 and MeADbx1 cells show differential anatomical and functional connectivity. Altogether, our results suggest a developmentally hardwired aggression circuit at the MeA level and a lineage-based circuit organization by which a cell's embryonic transcription factor profile determines its social information representation and behavioral relevance during adulthood.
PMID: 37946049
ISSN: 1546-1726
CID: 5603032

A tool kit of highly selective and sensitive genetically encoded neuropeptide sensors

Wang, Huan; Qian, Tongrui; Zhao, Yulin; Zhuo, Yizhou; Wu, Chunling; Osakada, Takuya; Chen, Peng; Chen, Zijun; Ren, Huixia; Yan, Yuqi; Geng, Lan; Fu, Shengwei; Mei, Long; Li, Guochuan; Wu, Ling; Jiang, Yiwen; Qian, Weiran; Zhang, Li; Peng, Wanling; Xu, Min; Hu, Ji; Jiang, Man; Chen, Liangyi; Tang, Chao; Zhu, Yingjie; Lin, Dayu; Zhou, Jiang-Ning; Li, Yulong
Neuropeptides are key signaling molecules in the endocrine and nervous systems that regulate many critical physiological processes. Understanding the functions of neuropeptides in vivo requires the ability to monitor their dynamics with high specificity, sensitivity, and spatiotemporal resolution. However, this has been hindered by the lack of direct, sensitive, and noninvasive tools. We developed a series of GRAB (G protein-coupled receptor activation‒based) sensors for detecting somatostatin (SST), corticotropin-releasing factor (CRF), cholecystokinin (CCK), neuropeptide Y (NPY), neurotensin (NTS), and vasoactive intestinal peptide (VIP). These fluorescent sensors, which enable detection of specific neuropeptide binding at nanomolar concentrations, establish a robust tool kit for studying the release, function, and regulation of neuropeptides under both physiological and pathophysiological conditions.
PMID: 37972184
ISSN: 1095-9203
CID: 5608072

Hypothalamic control of innate social behaviors

Mei, Long; Osakada, Takuya; Lin, Dayu
Sexual, parental, and aggressive behaviors are central to the reproductive success of individuals and species survival and thus are supported by hardwired neural circuits. The reproductive behavior control column (RBCC), which comprises the medial preoptic nucleus (MPN), the ventrolateral part of the ventromedial hypothalamus (VMHvl), and the ventral premammillary nucleus (PMv), is essential for all social behaviors. The RBCC integrates diverse hormonal and metabolic cues and adjusts an animal's physical activity, hence the chance of social encounters. The RBCC further engages the mesolimbic dopamine system to maintain social interest and reinforces cues and actions that are time-locked with social behaviors. We propose that the RBCC and brainstem form a dual-control system for generating moment-to-moment social actions. This Review summarizes recent progress regarding the identities of RBCC cells and their pathways that drive different aspects of social behaviors.
PMID: 37883550
ISSN: 1095-9203
CID: 5607582

Neural dynamics in the limbic system during male social behaviors

Guo, Zhichao; Yin, Luping; Diaz, Veronica; Dai, Bing; Osakada, Takuya; Lischinsky, Julieta E; Chien, Jonathan; Yamaguchi, Takashi; Urtecho, Ashley; Tong, Xiaoyu; Chen, Zhe S; Lin, Dayu
Sexual and aggressive behaviors are vital for species survival and individual reproductive success. Although many limbic regions have been found relevant to these behaviors, how social cues are represented across regions and how the network activity generates each behavior remains elusive. To answer these questions, we utilize multi-fiber photometry (MFP) to simultaneously record Ca2+ signals of estrogen receptor alpha (Esr1)-expressing cells from 13 limbic regions in male mice during mating and fighting. We find that conspecific sensory information and social action signals are widely distributed in the limbic system and can be decoded from the network activity. Cross-region correlation analysis reveals striking increases in the network functional connectivity during the social action initiation phase, whereas late copulation is accompanied by a "dissociated" network state. Based on the response patterns, we propose a mating-biased network (MBN) and an aggression-biased network (ABN) for mediating male sexual and aggressive behaviors, respectively.
PMCID:10592239
PMID: 37586365
ISSN: 1097-4199
CID: 5606582