Heterogeneous HPC changes alter context processing in MAM model of schizophrenia

异质 HPC 变化改变了精神分裂症 MAM 模型的上下文处理

• 批准号: 8969297
• 负责人: KATHRYN M GILL
• 金额: $ 7.16万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8969297
• 关键词: Amphetamines; Amygdaloid structure; Animal Model; Animals; Baclofen; Behavior; Behavioral; Brain region; Cell Nucleus; Cells; Cognitive; Development; Dimensions; Discrimination; Disease; Dissection; Emotional; Emotions; Exhibits; Failure; Frequencies; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Future; Glutamates; Goals; Hippocampus (Brain); Hyperactive behavior; Hypersensitivity; Impaired cognition; Individual; Infusion procedures; Laboratories; Lead; Learning; Lighting; Link; Measures; Mediating; Memory; Methylazoxymethanol Acetate; Modeling; Muscimol; Neural Pathways; Neurons; Odors; Output; Pathology; Pathway interactions; Patients; Pattern; Performance; Pharmacological Treatment; Pharmacotherapy; Procedures; Process; Property; Publishing; Rattus; Rodent; Rodent Model; Runaway; Saline; Schizophrenia; Shapes; Stimulus; Synaptic plasticity; Techniques; Testing; Thinking; Variant; Work; auditory stimulus; awake; conditioned fear; density; dopamine system; entorhinal cortex; extracellular; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; human subject; in vivo; information processing; neural circuit; neural patterning; offspring; optogenetics; prepulse inhibition; psychostimulant; public health relevance; relating to nervous system; research study; response; sensory input; sensory stimulus; skills

 DESCRIPTION (provided by applicant): Heterogeneous HPC changes alter context processing in MAM model of schizophrenia The primary goal of the proposed experiments is to establish a link between ventral hippocampal pathology, e.g. aberrant gating of afferent inputs arising from the basolateral amygdala, and pattern separation deficits in the methylazoxymethanol acetate neurodevelopmental model of schizophrenia. The planned studies involve a combination of in vivo extracellular electrophysiological recording techniques and optogenetic manipulations of specific neural pathways in awake behaving animals, both powerful procedures for the dissection of patterns of neural activation in specific neural circuits and their impact on pathological behaviors. In brief, the extracellular electrophysiological properties of the intrahippocampal, in CA3 and CA1 subregions, dysfunction resulting from MAM treatment will be measured. Specifically, alterations in the gating, and synaptic plasticity, of emotional context input from the basolateral nucleus of the amygdala (BLA) with processed sensory input from entorhinal cortex (EC) will be tested in pyramidal neurons of the CA1 and CA3 subregions of the ventral hippocampus (vHPC) in the MAM rat. In addition, the impact of optogenetic alterations of the BLA-CA3 circuitry on pattern separation, or spatial context discrimination, performance in the MAM rat, a cognitive dimension known to be impaired in schizophrenia, will be evaluated. In normal rats, inactivation of the BLA projections will determine whether this circuitry is required for performance of the spatial context discrimination task following fear conditioning. It is hypothesized that subregional specific, destabilization of afferent input arising from the BLA and EC in CA3 vs CA1 subregions of the vHPC, underlies a deficit in pattern separation performance in MAM rats. There are important implications of the intended studies in regards to the efficacy of pharmacotherapies in the treatment of cognitive impairments schizophrenia. The heterogeneous alteration of vHPC function along with the pattern of context deficits in the MAM rat substantiates the necessity of more targeted pharmacological treatments.

 描述（由申请人提供）：异质HPC变化改变精神分裂症MAM模型中的上下文处理所提出的实验的主要目标是建立腹侧海马病理（例如，由基底外侧杏仁核引起的传入输入的异常门控）与精神分裂症的甲基偶氮甲醇乙酸酯神经发育模型中的模式分离缺陷之间的联系。计划中的研究涉及体内细胞外电生理记录技术和清醒行为动物中特定神经通路的光遗传学操纵的组合，这两种方法都是解剖特定神经回路中神经激活模式的强大程序 及其对病理行为的影响。简而言之，将测量MAM治疗导致的海马内CA 3和CA 1亚区功能障碍的细胞外电生理特性。具体来说，将在腹侧海马CA 1和CA 3亚区的锥体神经元中测试来自杏仁核基底外侧核（BLA）的情感背景输入与来自内嗅皮质（EC）的经处理的感觉输入的门控和突触可塑性的变化（vHPC）在MAM大鼠中。此外，将评估BLA-CA 3电路的光遗传学改变对MAM大鼠中模式分离或空间背景辨别性能的影响，MAM大鼠是已知在精神分裂症中受损的认知维度。在正常大鼠中，BLA投射的失活将决定在恐惧条件反射后执行空间背景辨别任务是否需要该回路。据推测，次区域特定的，不稳定的传入输入所产生的BLA和EC在CA 3与CA 1亚区的vHPC，在MAM大鼠的模式分离性能的赤字的基础。关于药物治疗认知障碍精神分裂症的疗效，预期研究具有重要意义。MAM大鼠中vHPC功能的异质性改变沿着背景缺陷的模式证实了更有针对性的药物治疗的必要性。