Mouse Models with Multi electrode arrays

单胺在抑郁症中起着重要作用。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， 通过提供识别大脑区域的功能方法来补充人类想象研究， 可能参与抑郁样行为的神经回路。它也将补充人类 通过将小鼠中的多个电极靶向到额叶皮质中的皮质层进行形态学实验， 在抑郁症患者中的变化。为了更好地了解单胺在抑郁症中的作用， 我们将使用多电极阵列来研究皮层和皮层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）功能障碍的遗传修饰小鼠。最近我们 已经开发了一种方法，可以同时记录不同大脑中多个单个神经元的活动 自由活动的老鼠区域。通过这种方法，将监测皮层和皮层下神经元的活动 在不同的行为和治疗条件下，在几种抑郁症小鼠模型中。简单地说，我们将研究囊泡单胺转运蛋白2（VMAT 2）杂合子，糖原 合成酶激酶3b（GSK）杂合子，以及携带Tph 2基因多态性的小鼠， 在抑郁症患者中发现。野生型（WT）和突变小鼠将植入多电极 针对背内侧额叶和眶额叶皮质、中脑核（NAc）和中央的阵列 和基底外侧杏仁核（AMY）-想象研究表明， 人类抑郁症患者多个电极将同时瞄准这些区域中的每一个， 将在基线条件下，在暴露于慢性 压力，以及抗抑郁药治疗后。此外，正如许多抑郁症患者所显示的那样， 我们还将分析小鼠在整个周期中的大脑状态动力学 在基线、压力和治疗条件下。我们提出的实验将首次允许 在同一动物内整合分子、细胞、系统和行为数据， 应该会让我们更全面地了解抑郁症的潜在机制。

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.