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

基本信息

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
项目类别：
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

项目摘要

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（适用提供）：精神分裂症MAM模型中的异质HPC变化改变了上下文处理。拟议实验的主要目标是在腹侧海马病理学之间建立联系，例如由基底外侧杏仁核引起的传入输入的异常门控，模式分离定义了精神分裂症的乙酸乙酸甲酯神经发育模型。计划的研究涉及在醒着的动物中对特定神经病变的特定神经病变的体内电生理记录技术和光遗传学操纵，这是特定神经循环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，在CA3和CA1子区域中，将测量MAM治疗引起的功能障碍。具体而言，杏仁核（BLA）的基础外部核核的门控和合成可塑性的变化将在Hippocampus（Vhpocampus（Vhpocampus）的CA1和CA3子区域的锥体神经元中测试，并在thepralamid calmidal神经元中测试。此外，将评估BLA-CA3电路的光遗传学改变对模式分离或空间上下文歧视，MAM大鼠的表现，MAM大鼠的性能，一种已知在精神分裂症中受损的认知维度。在正常大鼠中，BLA投影的灭活将确定在恐惧调节后是否需要该电路才能执行空间上下文歧视任务。假设次区域特异性的，对VHPC CA3与CA1子区域中BLA和EC产生的传入输入的不稳定，这是MAM大鼠模式分离性能的不足。预期研究对药物治疗精神分裂症治疗的有效性具有重要意义。 VHPC函数的异质变化以及上下文模式定义了MAM大鼠中更靶向药物治疗的必要性。