developing zebrafish models of complex phenotypes relevant to human brain disorders
DESCRIPTION
Dissertation Defense Presentation Jan 2013 - Tulane University, Neuroscience Graduate Program Jonathan M. Cachat Committee: Allan V. Kalueff, Ph.D. Jill Daniel, Ph.D. David Corey, Ph.D Benjamin Hall, Ph.D.TRANSCRIPT
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DEVELOPING ZEBRAFISH MODELS OF COMPLEX PHENOTYPES RELEVANT TO
HUMAN BRAIN DISORDERS
Jonathan M. Cachat, MS
CommitteeAllan V. Kalueff, Ph.D., Director
Jill Daniel, Ph.D.David Corey, Ph.D
Benjamin Hall, Ph.D.
Neuroscience ProgramSchool of Science and Engineering
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Outline• Challenges in Neurobehavioral Research
• Zebrafish (Danio rerio)
• Problem Statement
• Central Hypothesis, Research Strategy and Specific Aims
• Results
• Conclusions
• Translational Value
• Future Directions of Research
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Challenges in Neurobehavioral Research
Use models to elucidate etiological and pathologicalmechanisms of human brain disorders
(Gerlai, 2012; Burne et al., 2011; Morris, 2009; Sison et al., 2006)
• Developing sensitive, high-throughput, cost effective in-vivoscreening assays
• Standardizing and enhancing methodologies for objective acquisition and analysis of behavioral data
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Zebrafish (Danio rerio)
(Cachat et al., 2010)
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Zebrafish Genome• Genome duplication event
• Paralogous genes & sub-functionalization
• Advantageous (i.e. Sonic hedgehog knockdown)
• Zebrafish possess high nucleotide sequence homology (70-80%) with that of human genes.
• Functionally relevant as the amino acid sequence of zebrafish proteins (60-90% sequence homology) especially at the functionally relevant catalytic or ligand binding domains (approaching 100% sequence homology).
(Dooley, 2000; Renier et al., 2007; Reimers et al., 2004; Gerlai, 2011; Lillesaar, 2011)
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Central Nervous System & HPI-Axis
(Lillesar, 2011; Mueller, 2012; Panula, 2010; Alsop, 2009; Cachat, 2010)
Homologous Brain Regions Relevant to Affective Research• Amygdala – Dm, medial zone of dorsal telencephalon• Hippocampus
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Problem Statement
Adult zebrafish behavioral phenotypes are largely uncharacterized due to a lack of available, validated behavioral test paradigms
(Agid et al., 2007; Blaser et al., 2012; Luca et al., 2012; Savio et al., 2012; Sison et al., 2006)
The overarching goal of this dissertation is to advance the characterization of adult zebrafish behaviors, and progress comprehensive quantification of phenotypic profiles translationally relevant to
neuropsychiatric disorders.
Dissecting adult zebrafish behavior is a necessary process before targeted genetic or molecular high-throughput screens can be confidently hypothesized and performed
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Research Approach
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Central Hypothesis• Zebrafish represent a sensitive, highly translational, evolutionarily related
organisms that can be used to model endophenotypes of human brain disorders
I expect that
• A integrative approach to quantify behavioral and physiological phenotypes in zebrafish following several psychotropic treatments result profiles analogous to those observed in rodents and humans
• Using automated video-tracking technologies will enable objective detection and dissection of behavioral profiles in adult zebrafish, as well as 3D reconstructions of swim paths
• Increasing the granularity, data density collected per fish will enable application of data-mining and detection of new dependent variables that could potentially be used to predict the mechanism of action in novel or poorly characterized psychotropic compounds
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Design of Behavioral Tests
Specific Aim 1Characterize and Quantify Behavioral Phenotypes of Zebrafish exposed to Experimental Treatments in Affective, Social and Cognitive Domains
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Specific Aim 2
Specific Aim 1Characterize and Quantify Behavioral Phenotypes exposed to Experimental Treatments Modifying Affective, Social and Cognitive Domains
Develop Automated Quantification Techniques of Behavioral Endpoints
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Specific Aim 3
Specific Aim 1Characterize and Quantify Behavioral Phenotypes exposed to Experimental Treatments Modifying Affective, Social and Cognitive Domains
Specific Aim 2Develop Automated Behavioral Quantification of Phenotypic Measures
Identify New Phenotypic Features
Evaluating 3D Trajectory
Reconstructions
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Modeling Affective Phenotypes
Ethologically Relevant Stimuli
• Alarm Pheromone Exposure
• Predator Exposure
How do zebrafish display anxiety/fear-like behaviors?
Novel Tank Test • Manual (observation, event-based) and automated behavioral quantification• Analysis of behavior in 3D trajectory reconstructions
Approach: Behavior
Big Question:
Pharmacological Treatments
• Putative Anxiogenic and Anxiolytic Drugs
Physiology
Whole-body Cortisol Concentrations
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Primary Endpoints
Novel Tank Test
• Latency to Upper Half, s
• Transitions to Upper Half
• Time Spent in Upper Half
• Erratic Movements
• Freezing Bouts
• Freezing Duration, s
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Predator Exposure
(Cachat et al., 2010)
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Alarm Pheromone
Representative 2D Swim Traces
(Cachat et al., 2011)
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Summary of Results I
Establishing Anxiogenic Profile in Novel Tank Test
Pharmacological Treatments
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Pharmacological Treatments
• Caffeine
• Fluoxetine
• Ethanol
• Nicotine
• Cocaine
• Morphine
• Ethanol Withdrawal
• Caffeine Withdrawal
• Morphine Withdrawal
• Known to evoke anxiogenic or anxiolytic behavioral responses in humans and rodents
• Can zebrafish be used to model phenotypes relevant to pharmacogenic anxiety and drug abuse related syndromes?
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Caffeine
Representative 2D Swim Traces
(Cachat et al., 2011)
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3D Trajectory Reconstructions
Wild-Type Control
Alarm Pheromone
Caffeine
(Cachat et al., 2011)
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Fluoxetine
Representative
2D Swim Traces
(Cachat et al., 2011)
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Ethanol
(Egan et. al., 2009; Cachat et al., 2011)
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Nicotine
Representative
2D Swim Traces
(Cachat et al., 2011)
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Wild-Type Control
Chronic Ethanol
Acute Nicotine
Chronic Fluoxetine
(Cachat et al., 2011)
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Summary of Results II
Establishing an Anxiolytic Profilein Novel Tank Test
Reproducing Anxiogenic Profile in Novel Tank Test
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Pharmacological Treatments
Latency to upper half, s
Transitions to upper half
Erratic movements
Freezing bouts
Freezing duration, s
Cortisol Concentration
Time in upper half, s
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Chronic Morphine
Representative
2D Swim Traces
(Cachat et al., 2011)
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Withdrawal
(Cachat et al., 2011)
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Wild-Type Control
Ethanol Withdrawal
Chronic Morphine
Repeated Morphine Withdrawal
(Cachat et al., 2011)
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Summary of Results III
Reproducing Anxiolytic & Anxiogenic Profile in Novel Tank Test
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Drug WithdrawalDrugs of Abuse
Freezing bouts
Freezing duration, s
Cortisol Concentration
Latency to upper half, s
Transitions to upper half
Time in upper half, s
Erratic movements
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Modeling Affective Phenotypes
How do zebrafish display anxiety/fear-like behaviors?
Results: In the Novel Tank Test,
Question:
A high anxiety behavioral profile in zebrafish is represented by:• Decreased exploration throughout environment• Increase in freezing throughout novel tank test• Short-lived, erratic movements • Stress-axis activation as measured by cortisol concentrations
A low anxiety profile is reflected by an inverse of this behavioral profile
3D Trajectory Reconstructions reveal the spatial and temporal dynamics of these responses
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Translational Value
Zebrafish behavioral response following ethological and pharmacological treatments paralleled the changes observed in the affective domain of rodents and humans.
• Including dose and duration specific effects
Primary endpoints of novel tank are able to reliably distinguish between strong anxiogenic and anxiolytic phenotypes
Can detection of these phenotypes be automated for NTT?
Automation
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Specific Aim 2
Distance, m Velocity, m/s TurnAngle, ° TurnBias, °/s
Control 0.0015 0.0460 0.0268 0.80
Anxiogenic 0.0011 0.0321 0.0776 2.33
Anxiolytic 0.0011 0.0319 0.2509 7.52
Average 0.0012 0.0367 0.1184 3.55
Control 0.0034 0.1019 5.0300 150.75
Anxiogenic 0.0023 0.0677 3.0255 90.67
Anxiolytic 0.0016 0.0493 0.8654 25.94
Average 0.0024 0.0730 2.9736 89.12
Control 0.0000 0.0004 -0.1433 -4.29
Anxiogenic 0.0001 0.0025 0.3319 9.95
Average 0.0000 0.0014 0.0943 2.83
Erratic
Freezing
Automated Movement Parameter
Swimming
Behavioral State (Manually Recorded)
Behavioral tests designed precisely integrate manual (observation, event-based scoring) and automated
quantification within individual spatiotemporal data
Manual, Event based & Automated
Manual Observation & Manual, Event-Based
Develop Automated Quantification Techniques of Behavioral Endpoints
(Cachat et al., 2011)
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Correlation Observable in 3D Reconstructions
(Cachat et al., 2011)
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Automated Detection of Complex Behavior(Cachat et al., 2011)
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Using 3D Reconstructions to Optimize Automated Techniques
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Modeling Hallucinogenic Phenotypes
Are zebrafish sensitive to hallucinogenic compounds? How do these drugs alter behaviors in affective, social and cognitive domains?
Novel Tank Test, Open Field Test, Light-Dark Box, Shoaling, Social Preference Tests• Manual (observational, event-based) and automated behavioral quantification• Analysis of behavior in 3D trajectory reconstructions
Approach: Behavior
Big Question:
Physiology
Whole-body Cortisol Concentrations
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Hallucinogenic Treatments• Lysergic acid diethylamide (LSD)
• 3, 4-Methylenedioxymethylamphetamine (MDMA)
• Ibogaine
• LSD = 1.0964
• MDMA = 1.1293
• Most profound effects on rodents and humans
• Never been examined before in zebrafish
• Recent resurgence of interest in hallucinogenic drug action for use in clinical therapy
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Novel Tank Test
MDMA
(Grossman et al., 2010; Stewart, 2011; Cachat, 2013)
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Light-Dark Box and Open-Field Test(Grossman et al., 2010; Cachat, 2013)
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Shoaling and Social Preference
(Grossman et al., 2010; Cachat, 2013)
LSD (250 µg/L, 20 min) Ibogaine (10, 20 mg/L, 20 min)
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Modeling Hallucinogenic Phenotypes
Are zebrafish sensitive to hallucinogenic compounds? How do these drugs alter behaviors in affective, social and cognitive domains?
Answer:
Big Question:
Novel Tank Test – mixed behavioral & physiological profile, largely insignificant
Light-Dark Box – increase preference for white chamber compared to matched controls, with LSD increasing cortisol
Open Field Test – primary endpoints insignificantly altered in LSD and Ibogaine treated fish compared to controls
Social Domains – no effects on social preference, decreased shoal cohesion
3D Trajectories – strong modifications on zebrafish exploration and movement
Zebrafish are sensitive to hallucinogenic compounds, but phenotypic domains unclear with primary endpoints in behavioral tests – however trajectories illustrate evident differences, suggesting that novel measures are necessary to provide detailed characterization.
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Identify New Phenotypic Features using 3D Trajectory ReconstructionsSpecific Aim 3
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Reveal Phenotypic Differences
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Identification of Novel Phenotypes
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Fractal d
Fractal d = 1.163
Fractal d = 1.169
Fractal d = 1.94
Segmentation
Smoothed Data
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Arena Segmentation
Preliminary results suggest that feature sets based on new arena segmentations could be used to
discriminate between treatments
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Future Directions of Research
• Zebrafish Movement Database
• Application of Trajectory & Movement Pattern Analysis Techniques• Customized Analysis Intrinsic Thresholds
• Multi-Scale Straightness Index (MSSI)
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Summary of Dissertation• Validated Zebrafish as Translationally Relevant Model for Neurobehavioral
Research• Replicating Previous Findings
• Enhancing Phenotypic Characterization
• Paralleling Rodent and Clinical Profiles
• Introduced Zebrafish as model for Hallucinogenic Drug Action
• Established Approaches to Achieve Automate Analysis of Zebrafish Behavior
• Developed Innovative 3D Trajectory Reconstructions and New Endpoints with potential to Distinguishing Experimental Treatments
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Acknowledgements• Kalueff Lab
• Members of Dissertation Committee• Dr. Jill Daniel
• Dr. David Corey
• Dr. Benjamin Hall
• Tulane University Neuroscience Program• Dr. Jeffery Tasker
• Sherrie Calogero
• Collaborators• Noldus Information Technologies
• University of Zurich –GIS Department
• Dr. Ramgopal Mettu, TU Comp Sci
• Grants• NIH
• Louisiana Board of Regents
• Tulane University
• NIDA
• Fellowships/Awards• NSF
• SfN GNOSN Chapter Travel Award