Mouse Models with Multi electrode arrays

单胺类物质在抑郁症中起主要作用。本提案将 通过评估各种抑郁症小鼠模型的神经反应来检验这一想法，它将 通过提供一种识别大脑区域的功能方法和 可能参与类似抑郁行为的神经回路。它还将补充人类 小鼠多电极靶向额叶皮质皮层的形态学实验 在抑郁症患者中被证明是改变的。为了更好地了解单胺类物质在抑郁症中的作用， 我们将使用多电极阵列来研究大脑皮质和皮质下神经元活动的变化。 具有去甲肾上腺素(NE)和/或5-羟色胺(5-HT)功能障碍的转基因小鼠。最近，我们 已经开发出一种方法，可以同时记录不同大脑中多个单一神经元的活动 自由活动的老鼠的区域。使用这种方法，将监测皮质和皮质下神经元的活动。 在几种抑郁的小鼠模型中，并在不同的行为和治疗条件下。简而言之，我们将研究囊泡单胺转运蛋白2(VMAT2)杂合子，糖原 合酶激酶3b(GSK)杂合子和携带TPH2基因多态的小鼠 在抑郁症患者中被发现。野生型(WT)和突变小鼠将植入多电极 靶向背内侧额叶和眼眶额叶皮质、伏隔核(NAC)和中央 和基底外侧杏仁核(AMY)--想象研究表明同样的部位也会受到影响 人类抑郁症患者。多个电极将同时定向到这些区域中的每个区域 在慢性暴露后，将在基线条件下评估行为自由的小鼠的神经活动 压力，以及在用抗抑郁药物治疗之后。此外，正如许多抑郁症患者所显示的那样 在觉醒-睡眠周期中的干扰，我们还将分析小鼠整个周期的大脑状态动态 在基线、压力和治疗条件下。我们提出的实验将第一次允许 分子、细胞、系统和行为数据在同一动物中的集成和这种方法 应该会导致对抑郁症潜在机制的更全面的理解。

Monoamines play a major role in depression. The present proposal will examine this idea by evaluating neural responses in the various mouse models of depression and it will complement the human imagining studies by providing a functional approach for identifying brain areas and neural circuits that may participate in depressive-like behaviors. It will also complement the human morphology experiments by targeting multi-electrodes in mice to cortical layers in frontal cortex that have been shown to change in depressed patients. To better understand the role of monoamines in depression, we will use multi-electrode arrays to investigate changes in cortical and subcortical neuronal activity in genetically-modified mice that have norepinephrine (NE) and/or serotonin (5-HT) dysfunction. Recently, we have developed a method to record activity simultaneously from multiple single neurons in various brain areas of freely-behaving mice. With this approach, cortical and subcortical neuronal activity will be monitored in several mouse models of depression and under different behavioral and treatment conditions. Briefly, we will study vesicular monoamine transporter 2 (VMAT2) heterozygotes, glycogen synthase kinase 3b (GSK) heterozygotes, and mice carrying a polymorphism in the Tph2 gene that has been identified in depressed patients. Wild type (WT) and mutant mice will be implanted with multi-electrode arrays targeted to the dorsomediofrontal and orbitofrontal cortices, nucleus accumbens (NAc), and central and basolateral amygdala (AMY) - the same sites that imagining studies have shown to be affected in human depressed patients. Multiple electrodes will be targeted to each of these areas simultaneously and neural activity will be assessed in freely-behaving mice under baseline conditions, after exposure to chronic stress, and following treatment with anti-depressants. In addition, as many depressed patients show disturbances in wake-sleep cycles, we will also analyze brain state dynamics throughout the cycle in mice under baseline, stress, and treatment conditions. The experiments we propose will allow for the first time the integration of molecular, cellular, systems, and behavioral data within the same animal and this approach should lead to a more complete understanding of the mechanisms underlying depression.