2013 — 2017 |
Lin, Dayu |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Deconstruction of a Neural Circuit For Aggression @ New York University School of Medicine
DESCRIPTION (provided by applicant): Aggression is an innate social behavior prevalent among mammalian species including human. In the quest to comprehend the neural substrates underlying aggression, we use a genetically tractable model organism, namely mice, which show a high level of territorial aggression in the laboratory setting. Our recent studies found tha inactivation of ventromedial hypothalamus ventrolateral part (VMHvl) suppresses natural territory aggression while optogenetic activation of neurons in the VMHvl can induce appetitive approach as well as consummatory attack towards conspecific intruders. Under certain circumstances, the approach and attack can be induced independently. Furthermore, chronic in vivo recording reveals that many VMHvl cells begin to increase activity prior to any physical contact with an intruder, escalate during approach, and reach peaks during attack; a small fraction of cells are activated only during attack. Taken together, these results indicate that VMHvl may drive both appetitive approach and consummatory attack, and separate pathways may mediate these two aspects of aggression. This project will test this hypothesis and identify other relays extended from the VMHvl in the aggression circuit. As VMHvl contains cells with heterogeneous functions, we will first identify the synaptic targets of aggression related cells by examining the colocalization of fighting induced immediate early gene expression and retrogradely labeled signals from a candidate downstream region in the VMHvl. Once an anatomical area is identified as a synaptic target of VMHvl aggression cells, we will manipulate activity in the region using various pharmacological or pharmacogenetic means and examine changes in social approach and attack behaviors. Furthermore, we will manipulate the target region in tandem with VMHvl activation to examine whether the candidate area is an essential node between VMHvl output and motor execution. Finally, to understand how the VMHvl output is organized to drive downstream cells, we will relate the cell function to its connectivity by recording VMHvl cells with antidromically identified projection patterns in freely moving animals. At the output end, we will record cells in the downstream regions and examine how the VMHvl information is filtered and transformed along the aggression pathway. This project will not only address a basic question in neuroscience regarding how instinct behavior is generated but also provide a neural circuit diagram for developing potential treatments for pathological aggression.
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1 |
2016 — 2017 |
Lin, Dayu |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Understand the Neural Mechanism Underlying Aggressive Motivation @ New York University School of Medicine
? DESCRIPTION (provided by applicant): Aggression is an innate social behavior across invertebrate and vertebrate species. For most individuals, aggression is essential to protect their resources and ensure reproductive success when interference arises. However, for some individuals, aggression appears to be a source of pleasure. Many examples show that certain individuals across a range of species, from fish to primates, will voluntarily seek out the opportunity to engage in aggressive actions. For humans, bullying, stalking, and sexual predation are among the many forms of aggression-seeking behaviors that negatively affect our society. Treatments that suppress aggression-seeking behaviors would be especially useful given that they could prevent potential aggressive actions without compromising general social, cognitive, and motor abilities. Unfortunately, little is known about what brain activity promotes the aggression-seeking behavior and consequently no treatment is currently available to specifically suppress aggressive motivation. In response to this knowledge gap, our studies seek to understand how the aggressive impulses emerge in the brain. In our previous studies, we identified the ventrolateral part of the ventromedial hypothalamus (VMHvl) as being indispensable for inter-male attack. Whereas activation of the VMHvl induces acute attack towards both male and female conspecifics, suppression of the VMHvl reduces natural inter-male attack. However, it remains unclear whether the VMHvl only controls the motor expression of attack or also determines sensory-independent aggression- seeking behaviors. To address this question, we designed a self-initiated aggression (SIA) task that allows us to temporarily separate the seeking phase and the action phase of aggression. During the task, the animal learns to voluntarily nose poke to gain access to a weaker intruder that they can attack. Using this task, we found that the VMHvl activity can substantially modulate the aggressive motivation in mice. In this study we will follow up on these initial findings and examine the natural VMHvl cell activity during the SIA task at both the single-cell and population levels. Through this study we hope to shed some new light onto the neural origin of aggressive motivation.
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1 |
2018 |
Hires, Samuel Andrew [⬀] Lin, Dayu |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Administrative Supplement to Novel Fluorescent Sensors Based On Gpcrs For Imaging Neuromodulation @ University of Southern California
Neuromodulators are essential signaling molecules that regulate many neural processes, including cognition, mood, memory, and sleep, through their influence on brain circuits. Monitoring the release and distribution of neuromodulators in behaving animals is critical for understanding the diverse functions of these molecules. A major impediment to developing this understanding is the lack of tools that can monitor these compounds at the temporal, spatial and concentration scales relevant to these brain processes. Filling this technological gap is one of the most pressing needs in neuroscience research. Our proposal directly bridges this gap by developing a platform of new tools for chronic, non- invasive monitoring of neuromodulators at millisecond, subcellular, and nanomolar resolution. Genetically-encoded fluorescent indicators for calcium and glutamate have transformed investigation of dynamic brain processes in the major model systems, including worms, flies, rodents, and increasingly primates. Building on our prior experience in developing these tools, we now propose to build a new suite of GPCR-activation-based (GRAB) genetically-encoded fluorescent indicators for neuromodulators. Our preliminary data shows we can generate GRABs with >500% fluorescence change and nanomolar affinity in mammalian cells. We propose to further develop and validate these prototypes in cultured neurons, flies, rodent brain slices, anesthetized and behaving mice to maximize their utility. In Aim 1, we will develop GRAB indicators for acetylcholine, serotonin, and norepinephrine by iteratively screening libraries that systematically vary in insertion site, linkers, cpGFP sequence, and FP-GPCR protein surface interface. The dimensions of optimization will be dF/F, membrane surface expression, affinity, and non-disruption of endogenous signaling. Our targeted performance levels are >10x dF/F, nanomolar range affinity and <10 millisecond on-rates in vitro. In Aim 2, performance of top candidate GRAB indicators from the in vitro screen will be validated following long-term expression in drosophila olfactory system, in brain slice, in anesthetized and behaving mouse cortex. Feedback from these experiments will guide iterative optimization in Aim 1. Successful completion of our Aims will yield a suite of powerful molecular constructs, cell-type specific viral tools and technical approaches that will be broadly disseminated to the neuroscience community. The GRAB indicators can be easily integrated with existing mouse models of human mental disorders. Since these probes for neuromodulators are well-suited for a wide range of preparations, and a large number of investigators, they will have a multiplicative impact on our understanding of neural circuit function and dysfunction when combined with other advances supported by the BRAIN Initiative.
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0.954 |
2018 — 2021 |
Lin, Dayu |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Deconstruction of a Neural Circuit For Aggression - Renewal - 1 @ New York University School of Medicine
SUMMARY STATEMENT Aggression is an innate social behavior across vertebrate species. However, excessive aggression?ranging from school bullying to terrorist attacks?imposes a devastating risk to our society. Individuals with certain psychiatric disorders, such as bipolar disorder and post- traumatic stress disorder, are more likely to act violently, jeopardizing their own lives and those around them. While classic models of aggression have long-suggested that improper aggression results from dysfunction of ?top-down? executive control of aggression-relevant circuitry, there is little direct physiological or neural circuit evidence to support this. Here, we will take an alternative ?bottom-up? approach to investigate the inhibitory control impinged onto a neural locus with a clear role in aggression. We hypothesize that these inhibitory controls are essential to ensure aggression is expressed at the right time and towards the right target. We have identified the ventrolateral part of the ventromedial hypothalamus (VMHvl) as an essential locus for both ?reactive? and ?proactive? aggression. Whereas optogenetic activation of the VMHvl can promote both attack and aggression-seeking behavior, VMHvl inhibition has the opposite effect. In this study, we will address how local and long-range inhibitory inputs modulate responses of VMHvl cells, and consequently aggressive behaviors. Although neurons in the VMHvl are primarily excitatory, the VMHvl is directly and strongly inhibited by VMHvl ?shell? neurons that are situated lateral and ventral to the VMHvl core. Thus, we hypothesize that the VMHvl shell is well positioned to shape aggression-relevant activity in excitatory VMHvl neurons. In the first part of the study, we will employ in vivo recording, functional manipulation, channelrhodopsin-assisted circuit mapping, and viral tracing to define the relationship between this inhibitory shell and excitatory ?core? of the VMHvl. In the second part of the study, we will zoom out and examine the function of long-range inhibitory inputs to the VMHvl. Specifically, we will test the hypothesis that the inhibitory inputs from the medial preoptic area, a hypothalamic region critical for reproduction and parental care, is essential for suppressing VMHvl responses towards improper aggression targets and preventing misdirected attack. In summary, this study will provide a much needed framework to understand how inhibitory mechanisms control aggressive behavior, and pave the way for new types of circuit-level therapeutics for aggression control.
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1 |
2018 — 2021 |
Lin, Dayu |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Dissecting the Neural Circuits of Maternal Behaviors @ New York University School of Medicine
SUMMARY STATEMENT Across mammalian species, maternal behavior is an innate social behavior essential for the survival and success of the offspring. Decades of research has identified an evolutionarily conserved hypothalamic area, the medial preoptic area (MPOA), as being essential for the expression of maternal behavior. However, given that the MPOA contains heterogeneous and multifunctional cells, the identity of cells relevant for maternal behavior remains unclear. Recently, using a series of state-of-art functional manipulation and in vivo recording tools, we found that cells in the MPOA that express the estrogen receptor alpha (Esr1) are necessary, sufficient and naturally active during maternal behaviors. Our proposed study will expand on these essential findings by seeking to further investigate the neural circuits extended from the population. In Aim 1, we will combine retrograde and antegrade tracing and in vitro slice electrophysiology to identify the downstream targets of the MPOA Esr1+ cells in female mice. In Aim 2, we will employ optogenetic and pharmacogenetic tools to address the functional role of each MPOA pathway and its related downstream cells in driving various components of maternal behaviors. In Aim 3, we will use in vivo optical and electrophysiological recordings to examine the natural responses of cells in the MPOA downstream regions during maternal behaviors, and the principles that underlie the transfer of information from the MPOA to its downstream cells. This project addresses a basic question in neuroscience regarding how maternal behavior is generated and is relevant for understanding and treating a defective maternal circuit that causes abnormal maternal behaviors, such as child neglect and abuse.
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1 |
2018 — 2019 |
Lin, Dayu |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Investigating the Neural Mechanism of Maternal Motivation @ New York University School of Medicine
SUMMARY STATEMENT Across mammalian species, appropriate parental behavior is essential for the survival and success of the offspring. In humans, child neglect reportedly occurs in 15?20% of children and can have severe life-long physical and mental consequences. Possibly reflecting the fact that mothers are usually primary caregivers, approximately 70% of perpetrators of child neglect are reported to be the biological mother of the victim. In these cases, the mother?s limited interest, empathy, and interaction with the child can likely be attributed to low maternal motivation. Given that the neural substrates for maternal motivation remain unclear, options to improve maternal motivation are limited. To fill this knowledge gap, we have studied the neural bases of maternal behaviors in a genetically tractable model organism, namely mouse. Using a variety of functional manipulation approaches, we recently found that a genetically defined population of cells in the medial preoptic area (MPOA) is both necessary and sufficient for specific maternal behaviors. Our proposed study will expand on this preliminary finding by seeking to further investigate the natural responses and functions of this population in maternal behaviors. We are particularly interested in addressing whether the population carries information about maternal motivation and whether it mediates flexible pup-seeking behaviors in addition to species-specific innate maternal actions. Answers to these questions are important given that whereas maternal actions differ dramatically across mammalian species, the maternal motivation remains the same. In Aim 1, we will use in vivo recording to examine the natural responses of the cells during various pup-directed behaviors in virgin and lactating females and ask how the responses are influenced by the motivational state of the female towards the pups, which will be determined based on characteristic pup-directed behaviors (e.g. infanticide and pup retrieval). In Aim 2, we will use an operant responding task with pup reinforcement and various functional manipulation tools to address whether the activities of the cells signal the maternal motivation and drive flexible pup-seeking behaviors. This project will not only address a basic question in neuroscience regarding how instinct behavior is generated but also may reveal a key neural population that determines the level of maternal motivation. This knowledge will be essential for developing new strategies to improve maternal motivation and ultimately reduce the incidence of child maltreatment.
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1 |
2019 — 2021 |
Dan, Yang [⬀] Ding, Jun Li, Yulong (co-PI) [⬀] Lin, Dayu |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Novel Fluorescent Sensors For Imaging Neuromodulation @ University of California Berkeley
SUMMARY Animal behaviors are orchestrated by the sophisticated nervous system, which is dynamically regulated by neuromodulators including lipids and neuropeptides. Endocannabinoids (eCBs) are neurolipids exist broadly in the brain and regulate learning and memory, addiction, pain sensation, and food intake. Among neuropeptides, cholecystokinin (CCK) is involved in nutrient sensing, food intake, and sleep regulation, and oxytocin (OXT) and vasopressin (AVP) play important roles in various aspects of social behaviors. However, how and when lipid and neuropeptide transmission occur in the brain are largely unclear. Existing methods (e.g. microdialysis) that measures brain chemical content suffer from low temporal and spatial resolution. Additionally, since neurolipid and neuropeptide releases often require repetitive neuronal firing and can occur at both axonal and dendritic sites, activity of the neuromodulator- releasing neurons cannot reliably predict where and when neurolipids and neuropeptides are released. Here we propose to develop a set of new tools for long-term monitoring of neurolipids and neuropeptides. Our strategy taps into their natural receptors, human G protein-coupled receptors (GPCRs), which are coupled to GFP. In the presence of neurolipids or neuropeptides, these GPCR Activation-Based (GRAB) sensors transform ligand binding-induced conformational changes into rapid fluorescent signals. We aim to develop and optimize neurolipid and neuropeptide GRAB sensors with >500% fluorescence change (dF/F) and 10- nanomolar affinity in vitro and validate these novel tools in brain slices ex vivo and mouse behavioral paradigms in vivo. In Aim 1, we will develop GRAB sensors for endocannabinoids, CCK, vasopressin, and OXT by systematically varying key sites involved in ligand binding, conformational change, etc. In Aim 2, we will validate the performance of these sensors in brain slice following long-term expression using viral tools. In Aim 3, we will use three different imaging methods (fiber photometry, epifluorescence and 2-photon imaging coupled with GRIN lens) in different behavioral paradigms to test in vivo performance of the novel GRAB sensors in mice. Feedback from experiments in Aims 2-3 will guide iterative optimization in Aim 1. Successful completion of our proposal will yield a suite of powerful tools and technical approaches, which will greatly facilitate studies of neurolipids and neuropeptides under both physiological and pathological conditions, helping reveal disease mechanisms, providing therapeutic guidance, and eventually benefiting human health.
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0.954 |
2019 — 2021 |
Lin, Dayu |
U19Activity Code Description: To support a research program of multiple projects directed toward a specific major objective, basic theme or program goal, requiring a broadly based, multidisciplinary and often long-term approach. A cooperative agreement research program generally involves the organized efforts of large groups, members of which are conducting research projects designed to elucidate the various aspects of a specific objective. Substantial Federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of award. The investigators have primary authorities and responsibilities to define research objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations and conclusions of their studies. Each research project is usually under the leadership of an established investigator in an area representing his/her special interest and competencies. Each project supported through this mechanism should contribute to or be directly related to the common theme of the total research effort. The award can provide support for certain basic shared resources, including clinical components, which facilitate the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence. |
Oxytocin Modulation of Female Aggression @ New York University School of Medicine
Project Summary (Project 4, Co-PIs: Lin, Froemke, Buzsaki, Tsien) Social bonding refers to an intimate relationship formed among members of the same species. Across species, social bonding is often accompanied by increased aggressiveness towards perceived threats against the object of attachment. The neural process underlying the social bonding induced increase in aggression remains unclear. Oxytocin plays pivotal roles in the formation of social bonds. Coincidently, the ventrolateral part of the ventromedial hypothalamus (VMHvl), a hypothalamic region indispensable for both male and female aggression expresses high level of oxytocin receptor and a dense cluster of oxytocin neurons are found right next to the VMHvl. Thus, we hypothesize that oxytocin may play an important role in altering the VMHvl cell responses to potential threat to increase female aggression after mother-infant bonding. Here we will test this hypothesis through three aims. In Aim 1, we will test the functional role of local and distal oxytocin inputs to the VMHvl in increasing female aggression during lactation. In Aim 2, we will perform in vivo cell-type specific recording to address how VMHvl cells and their neighboring oxytocin neurons respond during natural female aggression. Additionally, we will employ a novel genetically encoded oxytocin sensor to address how oxytocin influences the activity of VMHvl cells in naïve and lactating females. In Aim 3, we will employ RNAseq and in vitro slice recording to investigate how the VMHvl cells change the molecular and electrophysiological properties during lactation. In summary, this project will combine the various tools developed in Projects 1-3 to provide new insight into the neuromodulatory mechanisms in hypothalamus that alter aggressive behavior during social bonding.
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1 |
2019 |
Lin, Dayu |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Research Supplement to Promote Diversity in Health-Related Research @ New York University School of Medicine
SUMMARY STATEMENT Aggression is an innate social behavior across vertebrate species. However, excessive aggression?ranging from school bullying to terrorist attacks?imposes a devastating risk to our society. Individuals with certain psychiatric disorders, such as bipolar disorder and post- traumatic stress disorder, are more likely to act violently, jeopardizing their own lives and those around them. While classic models of aggression have long-suggested that improper aggression results from dysfunction of ?top-down? executive control of aggression-relevant circuitry, there is little direct physiological or neural circuit evidence to support this. Here, we will take an alternative ?bottom-up? approach to investigate the inhibitory control impinged onto a neural locus with a clear role in aggression. We hypothesize that these inhibitory controls are essential to ensure aggression is expressed at the right time and towards the right target. We have identified the ventrolateral part of the ventromedial hypothalamus (VMHvl) as an essential locus for both ?reactive? and ?proactive? aggression. Whereas optogenetic activation of the VMHvl can promote both attack and aggression-seeking behavior, VMHvl inhibition has the opposite effect. In this study, we will address how local and long-range inhibitory inputs modulate responses of VMHvl cells, and consequently aggressive behaviors. Although neurons in the VMHvl are primarily excitatory, the VMHvl is directly and strongly inhibited by VMHvl ?shell? neurons that are situated lateral and ventral to the VMHvl core. Thus, we hypothesize that the VMHvl shell is well positioned to shape aggression-relevant activity in excitatory VMHvl neurons. In the first part of the study, we will employ in vivo recording, functional manipulation, channelrhodopsin-assisted circuit mapping, and viral tracing to define the relationship between this inhibitory shell and excitatory ?core? of the VMHvl. In the second part of the study, we will zoom out and examine the function of long-range inhibitory inputs to the VMHvl. Specifically, we will test the hypothesis that the inhibitory inputs from the medial preoptic area, a hypothalamic region critical for reproduction and parental care, is essential for suppressing VMHvl responses towards improper aggression targets and preventing misdirected attack. In summary, this study will provide a much needed framework to understand how inhibitory mechanisms control aggressive behavior, and pave the way for new types of circuit-level therapeutics for aggression control.
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1 |