THEBRAININITIATIVE®

BrainResearchthroughAdvancingInnovativeNeurotechnologies® (BRAIN)

InitiativeJoshuaGordon,MD,PhDWalterKoroshetz,MD

BRAINMulti-CouncilWorkingGroupCo-Chairs

THEBRAININITIATIVE®

Goal:Elucidatecircuit structureandfunctiontounderstand:• Howthebrainmoves,plans,executes• Howtomonitor/manipulatecircuitsforimprovedfunction

• That disorderedbraincircuitscauseneuro/mental/substanceabusedisorders

Long-termgoal:Makecircuitabnormalitiesthebasisofdiagnostics, andnormalizationofcircuitfunction thetargetofintervention

Molecular/StructuralPathology

CircuitDysfunction

Neuro/Mental/SubstanceAbuseFunctionalDisability

FosterInnovation:FocusonBrainCircuits

Emphasizetechnologydevelopment

FIRSTFIVEYEARS

Emphasizediscovery

drivenscience

SECONDFIVEYEARS

THEBRAININITIATIVE®

1.Discoveringdiversity:Identifyandprovideexperimentalaccesstothedifferentbraincelltypestodeterminetheirrolesinhealthanddisease.

2.Mapsatmultiplescales:Generatecircuitdiagramsthatvaryinresolutionfromsynapsestothewholebrain.

3.Thebraininaction:Produceadynamicpictureofthefunctioningbrainbydevelopingandapplyingimprovedmethodsforlarge-scalemonitoringofneuralactivity.

4.Demonstratingcausality:Linkbrainactivitytobehaviorwithpreciseinterventionaltoolsthatchangeneuralcircuitdynamics.

SevenHighPriorityResearchAreasBrainCellTypes

ToolsforCircuit

Diagrams

Tech.toMonitorNeuralActivity

PreciseInter-

ventionalTools

THEBRAININITIATIVE®

5.Identifyingfundamentalprinciples:Produceconceptualfoundationsforunderstandingthebiologicalbasisofmentalprocessesthroughdevelopmentofnewtheoreticalanddataanalysistools.

6.Advancinghumanneuroscience:Developinnovativetechnologiestounderstandthehumanbrainandtreatitsdisorders;createandsupportintegratedhumanbrainresearchnetworks.

7.FromBRAINInitiativetothebrain:Integratenewtechnologicalandconceptualapproachesproducedingoals#1-6todiscoverhowdynamicpatternsofneuralactivityaretransformedintocognition,emotion,perception,andactioninhealthanddisease.

TheoryandDataAnalysisTools

AdvanceHumanNeuro-science

IntegrateApproaches

SevenHighPriorityResearchAreas

THEBRAININITIATIVE®

Training/Dissemination?Theory

*AllFY17informationisanestimate,aswedonotknowtheFY17budget.President’sbudget~$195M

ScientificStewardship:NIHBRAINInvestment

ScientificgoalsandoverarchingprinciplesoftheBRAIN2025reportandtheBRAINMulti-CouncilWorkingGroup(MCWG)continuetoguideNIHfundingdecisionsBRAINMCWGassessedprogressinFeb.2017,recognizedinvestmentstowards65/74short-termgoals

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20

40

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80

100

120

140

160

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200

Millions

Training/Dissemination

HumanImaging/Modulation

UnderstandingCircuits

NeuralRecording/Modulation

Cell/CircuitTools

CellTypes

Theory/Training/Dissemination

*

THEBRAININITIATIVE®

• Blueprint• NCCIH• NEI• NIA• NIAAA• NIBIB• NICHD• NIDA• NIDCD• NIMH• NINDS• OBSSR• OD• ORWH

FiscalYear

ActualBudget

#New BRAINAwards

21st CenturyCures

ACDWGRecommendation

FY14 $46.1M 58

FY15 $85M 67 $100M

FY16 $154M 108 $190M

FY17 TBD $10M $300M

FY18 TBD $86M $400M

FY19 TBD $115M $500M

NIHBRAINInvestment

THEBRAININITIATIVE®BRAIN21st CenturyCures

InnovationFunds

$0

$50

$100

$150

$200

$250

$300

$350

$400

$450

$500

FY17 FY18 FY19 FY20 FY21 FY22 FY23 FY24 FY25 FY26

DollarsinMillions

21st CenturyCuresActauthorizes$1.511billiontobetransferredfromtheBeauBidenCancerMoonshot&NIHInnovationAccountforBRAINresearchthrough2026

Fundsneedtobeappropriatedeachyear,nottoexceed theseamounts:• FY17:$10,000,000• FY18:$86,000,000• FY19:$115,000,000• FY20:$140,000,000• FY21:$100,000,000• FY22:$152,000,000• FY23:$450,000,000• FY24:$172,000,000• FY25:$91,000,000• FY26:$195,000,000

THEBRAININITIATIVE®InnovationFund Budget

ScenarioFYYear

OriginalCuresFund Competing Noncompeting MultiYear

Funded Total

2017 10,000,000 10,000,000 - 10,000,000

2018 86,000,000 38,000,000 10,000,000 38,000,000 86,000,000

2019 115,000,000 33,500,000 48,000,000 33,500,000 115,000,000

2020 140,000,000 _________ 81,500,000 58,500,000 140,000,000

2021 100,000,000 28,500,000 71,500,000 100,000,000

2022 152,000,000** 45,000,000 62,000,000 45,000,000 152,000,000

2023 450,000,000** 45,000,000 73,500,000 331,500,000 450,000,000

2024 172,000,000** 118,000,000 54,000,000 172,000,000

2025 91,000,000 89,500,000 1,500,000 91,000,000

2026 195,000,000 89,500,000 105,500,000 195,000,000

Total 1,511,000,000 200,000,000 598,500,000 712,500,000 1,511,000,000

**Potentialtimeframetotakeadvantageofemergingscientificopportunitiesand/ortousefundstoadvancedisseminationofnewtools/technologiesordevelopnewdatasharingplatforms.

THEBRAININITIATIVE®

SCAPE:Novel3Dmicroscopymethodforhigh-speed,volumetricimagingoflivingtissuevisualizesspontaneousneuronalfiringinwhole-brainofawake,behavingmiceandDrosophilalarvae

Diamondelectrodescanmeasurestimulation-drivenmonoaminetransmitterreleaseinbasalgangliaofhumanswithgreaterlongevityandstrength

Two-PhotonHolographicStimulationofred-shiftedopsin,ReaChR:Red-shiftedopsins reacttolongerwavelengthsoflight,mayreachdeepbrainstructures

Bouchardetal.,NaturePhotonics, 2015

Bennet etal.,FrontiersinHumanNeuroscience, 2016

Chaigneau etal.,FrontiersinCellularNeuroscience, 2016

BRAIN-supportedTechnologyLeapstoCatalyzeNeuroscience

THEBRAININITIATIVE®

MaintainflexibilitytoallowustotakeadvantageofemergingscientificopportunitiesUtilizeavarietyoffundingapproachestoensuresustainedfundingBalanceregularandmulti-yearfundingofgrants• Abilitytospreadfundsovermorethanoneyeartoprovideamoresteadystreamofresources

• Leverageadministrativeandcompetitivesupplements• Ensurefullfundingofallgrantsby2026

21st CenturyCuresInnovationFunds:StrategiesforBRAIN

THEBRAININITIATIVE®

$150

$150

$150

$100

$75$386

$500

BrainCellTypes

ToolsforCircuit

Diagrams

Tech.toMonitorNeuralActivity

PreciseInter-

ventionalTools

TheoryandDataAnalysisTools

AdvanceHumanNeuro-science

IntegrateApproaches&Principles

HighlevelestimateofpotentialdistributionofInnovationFundsoverthenext9yearsFY2022,2023,2024largefundingincreasesmaybeopportunitytotakeadvantageofscientificopportunitytorapidlyadvanceanareaand/ordevoteadditionalfundstooneoftheBRAINinitiativepriorities,particularlycostlygoalse.g.:• Humanstudies• Disseminationofnew

technologies/training• Infrastructurefordatascienceandnew

datasharingplatforms

21st CenturyCuresInnovationFunds:PotentialDistribution

Dollarsinmillions

THEBRAININITIATIVE®

BRAIN…mappingbrainactivityatthe

speedofthought

THEBRAININITIATIVE®

Mission:TocoordinateandfacilitatecommunicationsfromitsmembersrelatedtotheBRAINInitiative

Websiteprovidesplatformforfundingopportunities,news,achievements,resources,andmoregatheredfromacrossthefederalandnon-federalparticipantsoftheBRAINInitiative

www.braininitative.org

AdvancingResearchthroughPartnerships:BRAINInitiativeAlliance

THEBRAININITIATIVE®RecruitingOutstandingWorkforce:

EngagingManyDisciplinesDepartmentCategory(forContactandMultiPIs) FY15 ~FY16Biochemistry 11 12Biology/cellbiology/Microbiology/Pathology/Immunology 43 36Chemistry 17 11Genetics 4 3Biostatistics/math/computerscience 12 33Physics 16 14Engineering(allcategories) 119 141Neuroscience/Neurology 146 141Neurosurgery 14 47Psychiatry/Psychology 17 69Radiology/Radiation-Diagnostic 31 61Bioimaging/Imaging 15 8

THEBRAININITIATIVE®

0%

10%

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30%

40%

Applications Scored ScoreBetterthan40 Awarded

NewInvestigator(NI):EligibleContactApplicants

FY14-16R01 FY14 FY15 FY16

RecruitingOutstandingWorkforce:New,EarlyStageInvestigators

ControlisneuroscienceacrossallICs.

0%

5%

10%

15%

20%

Applications Scored ScoreBetterthan40 Awarded

EarlyStageInvestigator(ESI):EligibleContactApplicants

FY14-16R01 FY14 FY15 FY16

• TheBRAINInitiativeisreachingearlystageinvestigatorsandtheirapplicationsaredoingspectacularlywell

• NewBRAINFOAsattractbothNIandESIapplicants.SourceoftheincreaseinFY15andFY16

• TheR21FundingopportunityforlargescalerecordingcontinuestoattractNIandESIapplicants

THEBRAININITIATIVE®

Novelmethodforclassifyingcelltypesusinghighthroughputgeneticsequencingallowedcomprehensiveclassificationofretinalbipolarneurons

Genomeeditingofsynthetictargetarraysforlineagetracing(GESTALT)trackscellfateinwholecomplex,multicellularorganisms

Thezebrafish optomotor response:Integrationofwhole-brainimaging,behavioralanalysis,functionalperturbations,andnetworkmodelingtobuildabrain-scalecircuitmodelofanorientingbehavior

3Dmapofmotorcortextractpathwaysinmicerevealasystematicallyorganizedconnectome ofmotoroutputprojections

BRAIN-supportedTechnologyLeapstoCatalyzeNeuroscience

Shekhar etal.,Cell, 2016

McKennaetal.,Science, 2016

Naumann etal.,Cell 2016

Jeong etal., ScientificReports 2016

THEBRAININITIATIVE®

Dr.ArnoldKriegstein andcolleaguesidentifycandidateentryreceptorforZika virusinneuralstemcells

SinglecellRNA-seq analysisofdifferentcelltypesduringearlydevelopment(CellStemCell)• Examinedexpressionofseveral

candidateentryreceptorsforZika virus

• CandidateAXLishighlyexpressedinseveralcelltypes,includinghumanradialglialcells• Lossofradialgliafounderpopulationsleadstomicrocephaly

• AXLexpressionpatternisconservedinmice,ferrets,andhumaniPSCs – modelsforinfectivityanddevelopmentaleffectsofZika virus

ScientificAdvancements:CellTypes