Molecular and neural mechanisms associated with injury and recovery from traumatic brain injury
与创伤性脑损伤的损伤和恢复相关的分子和神经机制
基本信息
- 批准号:10693653
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAfghanistanAnimal ModelAnimalsAnxietyAreaAttentional deficitAutomobile DrivingAxonBehaviorBehavioralBehavioral inhibitionBilateralBiologicalBiological MarkersBrainBrain ConcussionBrain InjuriesBrain regionCentral Nervous SystemChronicClinical ResearchCognitionCognitiveCognitive deficitsCognitive remediationCommunicationContusionsCorpus striatum structureCouplingDecision MakingDiscriminationEffectivenessElectric StimulationEncephalitisFrequenciesGoalsHemorrhageHumanImpairmentImpulsivityInflammationInflammatoryInjuryInterruptionInterventionIraqKnowledgeLateralLearningLocationMeasuresMediatingMental DepressionMental disordersMethodsMilitary PersonnelMissionModelingMolecularMood DisordersMoodsNeurobehavioral ManifestationsNeuronal PlasticityOperative Surgical ProceduresOutcomePatient-Focused OutcomesPatientsPatternPeriodicalsPeriodicityPersonsPre-Clinical ModelPreclinical TestingPrefrontal CortexProceduresPsychological reinforcementRattusReproducibilityResearchReversal LearningRewardsRiskRodentRodent ModelRoleRunningSeveritiesSoldierStructureSymptomsTechniquesTestingTherapeutic InterventionTrainingTraumaTraumatic Brain InjuryTraumatic Brain Injury recoveryUnited StatesUpdateVeteransassociated symptombehavioral impairmentbrain basedclinically relevantcognitive functioncohortcontrolled cortical impactcraniumdisabling symptomeffectiveness testingelectrical potentialexperienceflexibilitygray matterimprovedinsightneuralneuromechanismneurophysiologyneuroregulationnew therapeutic targetnovelpersistent symptompre-clinicalprecision medicinepsychiatric symptomremediationtranslational potentialwhite matter
项目摘要
Optimal reward-guided behavior relies on intact connections between prefrontal cortex and striatum: circuitry
that is disrupted by frontal brain injury1,2. Sustaining a brain injury increases risk for developing depression,
anxiety, attention deficits, mood disorders and problems with impulse control3,4. The symptoms of frontal
traumatic brain injury (TBI) strongly resemble psychiatric disorders with regards to disruptions in reward-guided
behavior, and therefore may share common mechanisms driving behavioral impairments. Mechanisms may
include a combination of inflammatory, molecular, and cellular changes that are triggered by injury. Determining
which factors mediate persistent effects of behavior is necessary to understand chronic impacts of TBI and
develop treatments addressing the often debilitating symptoms enduring after injury. The proposed research will
examine how severe and mild frontal TBI impacts neural communication with its distributed striatal network to
influence reward-guided behavior. Identifying a neurophysiology signature associated with reward deficits would
provide a new target for brain-based treatment options. Neuromodulation, altering the electrical potentials of
the brain, may serve as a potential intervention to remediate behavioral deficits by restoring rhythmic brain
patterns and structural integrity of their underlying connections following injury. Preclinical testing in
translational animal models is critical to better understand the structural and functional mechanisms driving
behavioral impairments, and to test repetitive brain stimulation as a method to remediate effects of injury.
The first goal of this proposal is to quantify behavioral consequences of severe and mild frontal TBI made using
a controlled cortical impact (CCI) in rodents. TBI causes axonal shearing of white matter tracts and chronic
inflammation resulting in long-term changes to the brain’s microstructure. Abnormalities in corticostriatal
connectivity is being implicated in the onset of psychiatric-like symptoms, yet the relationship with TBI-induced
impairments remains unclear. As one of the most widely used injury models in animals, CCI produces focal
damage in rats that mirrors concussion, contusion, and hemorrhage in humans by driving an impactor directly
into the brain through a surgical opening in the skull30. The injury severity and location are controlled by the
experimenter and highly reproducible across animals. After injury, rats will perform a probabilistic reversal
learning task which requires reward-guided decision making, behavioral inhibition, flexible behavior, and
conditional discrimination: cognitive functions that all depend on intact prefrontal cortex. Reward-related
behavioral impairments on the reversal learning task will be related to microstructural changes.
To capture disturbances in the cortico-striatal network after TBI, brain activity will be recorded as rats run the
probabilistic reversal learning task. Neural activity is not random, it oscillates at periodic frequencies to coordinate
communication within and between distributed brain areas. Each of these frequency bands are predicted to
coordinate different aspects of behavior through long-range coupling in functional networks. Large-scale local
field potential probes will be used to record from 32 brain areas simultaneously capturing these oscillatory
dynamics during reward-guided behavior. Identifying frequency-specific activity that is disrupted by TBI, would
offer insight into the neural mechanisms of reward-guided behavior and point to a new therapeutic target.
Lastly, brain stimulation targeting the cortico-striatal network will be used to assess its effectiveness at inducing
neuroplasticity changes to remediate effects of TBI. We will follow neuromodulation procedures known to be
successful in humans with the goal of studying the structural and functional mechanisms associated with
restored reward-guided behavior. The proposal will examine if stimulation to lateral orbitofrontal cortex can
improve reward-guided behavior, restore cortico-striatal network activity, and induce long-term structural
changes. This research is critical to identify mechanisms of TBI and remediate reward-related impairments.
最佳的奖励引导行为依赖于前额皮质和纹状体之间完整的连接
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Miranda Francoeur Koloski其他文献
20. On-Demand Beta Frequency Stimulation Modulates Temporal Discounting Choice
- DOI:
10.1016/j.biopsych.2024.02.198 - 发表时间:
2024-05-15 - 期刊:
- 影响因子:
- 作者:
Miranda Francoeur Koloski;Morteza Salimi;Jonathan Mishler;Dhakshin Ramanathan - 通讯作者:
Dhakshin Ramanathan
P7. Beta Oscillatory Activity Reflects Value Representation in Cortico-Striatal Reward Networks
- DOI:
10.1016/j.biopsych.2022.02.242 - 发表时间:
2022-05-01 - 期刊:
- 影响因子:
- 作者:
Miranda Francoeur Koloski;Sidharth Hulyalkar;Jessica Cramer;Dhakshin Ramanathan - 通讯作者:
Dhakshin Ramanathan
Miranda Francoeur Koloski的其他文献
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