Recruitment of Cerebellar Circuits with Balance Training for Cognitive Rehabilitation in a Mouse Model of Mild Traumatic Brain Injury

在轻度创伤性脑损伤小鼠模型中通过平衡训练募集小脑回路进行认知康复

• 批准号: 10753349
• 负责人: Erik Sean Carlson
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-10-01 至 2027-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753349
• 关键词: Acute; Affect; Affective; Affective Symptoms; Afghanistan; Age; Aging; Animals; Applications Grants; Area; Association Learning; Attention; Avoidance Learning; Balance training; Behavioral; Brain; Cell Nucleus; Cells; Cerebellar Diseases; Cerebellar Nuclei; Cerebellum; Clinical; Cognition; Cognitive; Cognitive deficits; Complex; Data; Dementia; Dentate nucleus; Disease; Effectiveness; Elderly; Environment; Episodic memory; Equilibrium; Etiology; Exercise; Exposure to; Family; Fright; Functional disorder; Gait speed; Genetic; Grant; Hand Strength; Health system; Human; Immunohistochemistry; Impaired cognition; Impulsivity; Incubated; Injury; Intervention; Iraq; Lateral; Learning; Longevity; Measures; Memory; Methods; Microglia; Midbrain structure; Modeling; Morbidity - disease rate; Morphology; Motivation; Motor; Movement; Mus; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Output; Parkinson Disease; Patients; Phenotype; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Pre-Clinical Model; Precision therapeutics; Proteins; Protocols documentation; Recovery of Function; Reporting; Rest; Rewards; Risk; Rodent; Role; Sensory; Severities; Short-Term Memory; Social Functioning; Stimulus; Stress; Stroke; Structure; Symptoms; TBI Patients; Techniques; Testing; Time; Training; Trauma; Traumatic Brain Injury; Ventral Tegmental Area; Veterans; War; cognitive function; cognitive performance; cognitive recovery; cognitive rehabilitation; cognitive task; cohort; cost; design; designer receptors exclusively activated by designer drugs; exercise intervention; falls; functional outcomes; genetic approach; immune cell infiltrate; improved; innovation; insight; interest; mild traumatic brain injury; motor disorder; mouse model; neuroinflammation; neuropathology; neuroprotection; neuropsychiatric disorder; neurotoxic; neurotoxicity; nonhuman primate; novel; preclinical study; recruit; response; sensory discrimination; single-cell RNA sequencing; stressor; therapeutic candidate; therapy design; way finding

Declines in cognitive and balance function are associated with numerous neuropsychiatric disorders affecting Veterans, including post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI). Both functions have overlap, in the form of functional activation, in the human cerebellum. TBI exposure is particularly relevant to Veterans and increases risk of cognitive dysfunction, disequilibrium and imbalance, and dementia. TBI is the signature injury of the wars in Iraq and Afghanistan and increases risk of both cognitive dysfunction and dementia. Across these disorders, these symptoms have a paucity of treatments. The burden of TBI on families and the US health system is enormous, so novel interventions are of great interest. Treatments that elicit improved balance in the young and elderly also improve cognitive symptoms. Studies in humans and non- human primates have identified a region of the dentate nucleus of the cerebellum (DCN), or lateral nucleus in rodents (LCN), which is activated during performance of cognitive tasks involving complex spatial and sequential planning. Posterior-lateral areas of the human cerebellum that are associated with cognitive function, grip strength, and gait speed overlap and project to the DCN. This locus in the brain is particularly promising, as there is evidence that the cerebellum ages more slowly than the rest of the brain and shows compensatory activation in stroke and neurodegenerative disease. We have previously begun to dissect the circuit components of this nucleus in mice and defined a role for specific LCN circuits in supporting cognitive functions in working memory, episodic memory, response inhibition, sensory discrimination, and social functions. We have also shown that this region directly wires to midbrain structures, such as the ventral tegmental area, involved in associative learning. In preliminary data, we show that a specific rotarod-based balance training protocol rescues several cognitive and affective symptoms, particularly with respect to associative learning in both reward learning and response to threat stimuli, in a mild TBI (mTBI) mouse model relevant to mTBI and PTSD in Veterans. In this grant proposal, we will behaviorally dissect specific contributions of exercise versus balance in this mTBI model and determine their effects on cognitive function. In other words, we will quantify levels of response inhibition and impulsivity, spatial navigation memory, and incubation of fear in mTBI mice treated with different balance and exercise interventions designed to isolate effects of balance training from exercise. This grant also aims to determine whether rotarod-based balance training 1) alter the subpopulations of neuroinflammatory cells called microglia so that they are more neuroprotective rather than neurotoxic, and 2) it can recruit a specific cognitive cerebellar circuit in the LCN. To accomplish this, we will use immunohistochemistry, protein quantification methods and single cell RNA Sequencing of microglia from the LCN. We will also use a chemogenetic circuit approach (inhibitory and excitatory DREADDs) to increase or decrease the excitability of a specific excitatory output population of cells in the lateral (dentate) nucleus of the cerebellum during balance training. Then, we will test the functional outcomes of these perturbations in the above tests of response inhibition and impulsivity, spatial navigation memory, and incubation of fear. Successful completion of our proposed aims will provide novel insight into a preclinical model of balance training in mice, circuits in the cerebellum that support cognitive and equilibrium functions, and establish a framework for novel, precision therapeutics to assist patients with TBI or neurodegenerative disease with cognitive and equilibrium dysfunction.

Declines in cognitive and balance function are associated with numerous neuropsychiatric disorders affecting Veterans, including post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI). Both functions have overlap, in the form of functional activation, in the human cerebellum. TBI exposure is particularly relevant to Veterans and increases risk of cognitive dysfunction, disequilibrium and imbalance, and dementia. TBI is the signature injury of the wars in Iraq and Afghanistan and increases risk of both cognitive dysfunction and dementia. Across these disorders, these symptoms have a paucity of treatments. The burden of TBI on families and the US health system is enormous, so novel interventions are of great interest. Treatments that elicit improved balance in the young and elderly also improve cognitive symptoms. Studies in humans and non- human primates have identified a region of the dentate nucleus of the cerebellum (DCN), or lateral nucleus in rodents (LCN), which is activated during performance of cognitive tasks involving complex spatial and sequential planning. Posterior-lateral areas of the human cerebellum that are associated with cognitive function, grip strength, and gait speed overlap and project to the DCN. This locus in the brain is particularly promising, as there is evidence that the cerebellum ages more slowly than the rest of the brain and shows compensatory activation in stroke and neurodegenerative disease. We have previously begun to dissect the circuit components of this nucleus in mice and defined a role for specific LCN circuits in supporting cognitive functions in working memory, episodic memory, response inhibition, sensory discrimination, and social functions. We have also shown that this region directly wires to midbrain structures, such as the ventral tegmental area, involved in associative learning. In preliminary data, we show that a specific rotarod-based balance training protocol rescues several cognitive and affective symptoms, particularly with respect to associative learning in both reward learning and response to threat stimuli, in a mild TBI (mTBI) mouse model relevant to mTBI and PTSD in Veterans. In this grant proposal, we will behaviorally dissect specific contributions of exercise versus balance in this mTBI model and determine their effects on cognitive function. In other words, we will quantify levels of response inhibition and impulsivity, spatial navigation memory, and incubation of fear in mTBI mice treated with different balance and exercise interventions designed to isolate effects of balance training from exercise. This grant also aims to determine whether rotarod-based balance training 1) alter the subpopulations of neuroinflammatory cells called microglia so that they are more neuroprotective rather than neurotoxic, and 2) it can recruit a specific cognitive cerebellar circuit in the LCN. To accomplish this, we will use immunohistochemistry, protein quantification methods and single cell RNA Sequencing of microglia from the LCN. We will also use a chemogenetic circuit approach (inhibitory and excitatory DREADDs) to increase or decrease the excitability of a specific excitatory output population of cells in the lateral (dentate) nucleus of the cerebellum during balance training. Then, we will test the functional outcomes of these perturbations in the above tests of response inhibition and impulsivity, spatial navigation memory, and incubation of fear. Successful completion of our proposed aims will provide novel insight into a preclinical model of balance training in mice, circuits in the cerebellum that support cognitive and equilibrium functions, and establish a framework for novel, precision therapeutics to assist patients with TBI or neurodegenerative disease with cognitive and equilibrium dysfunction.