MICA: Optogenetic dissection of homeostatic and Hebbian components of cortical plasticity

大脑皮层是大脑中至关重要的一部分；它在人类中最为发达，并赋予我们许多独特的人类品质。当大脑皮层在精神分裂症和自闭症等精神疾病中出现故障，或在阿尔茨海默病等疾病中退化时，这些独特的人类品质就会丧失或退化。多年来，关于我们如何应对这些使人衰弱的疾病的想法发生了变化。正如美国国家心理健康研究所所长所指出的那样，我们过去将精神健康障碍理解为“化学失衡”或“社会结构”的方式似乎奇怪地过时了，并且在一系列发现中让位于将精神健康状况理解为由遗传风险因素和环境影响共同引起的“大脑回路”障碍的新观点(1)。也许这并不完全令人惊讶，我们目前仍然只是在一个非常初级的水平上了解皮层“大脑回路”的运作，毕竟它是极其复杂的。然而，现在有许多强大的分子和光遗传学工具可以解开这个复杂的结(2)。我们的方法是观察皮层中一个相对简单的部分，即桶状皮层，在那里，皮层的基本结构可以通过简单的组织化学染色或生理成像方法看到，并试图了解涉及的皮层回路。构成皮层的基本模块被称为皮层柱，它由一组相互连接的神经元组成，这些神经元排列在六层中。具有更复杂皮层的高级动物比低级动物有更多的脑柱，但这两种动物脑柱的基本结构是相似的。因此，我们可以通过分析老鼠的桶状皮质回路，对人类的皮质回路有更深入的了解。我们想知道信息是如何在这些回路中被处理的，并了解允许回路通过突触可塑性机制对改变的经验做出反应的分子机制。我们目前对这个系统的回路和可塑性的研究已经让我们对精神分裂症和艾滋病相关的痴呆有了深入的了解。在目前的工作中，我们将光遗传通路刺激，树突脊柱成像和突触光学操作的新技术与我们对桶状皮质操作的丰富知识和经验相结合，以了解皮质回路。我们近期的计划包括测试我们的发现是否适用于视觉皮层。我们最近有了一个突破性的发现，发现第5层细胞的两个主要细分，即规则峰值细胞（RS）和内在破裂细胞（IB），表现出根本不同的可塑性。这些细胞是皮层的主要输出细胞。在一阶分析中，RS细胞表现为抑制而非增强，IB细胞表现为增强而非抑制。在二级分析中，RS细胞显示皮层下输入增强，而不是皮层内输入增强。我们现在在分子水平上发现了进一步的差异：RS细胞在对抑郁的反应中表现出稳态（tnfalpha依赖）可塑性，而IB细胞表现出Hebbian CaMKII依赖性增强。我们需要知道这些可塑性差异是如何产生的，它们是否适用于其他皮层区域，以及它们如何适应皮层回路对感觉输入变化的一般反应。1. 把科学机会转化为公共卫生影响：精神疾病研究的战略计划。Arch Gen Psychiatry 66,128 （2009）L. Madisen等。用于光诱导激活和沉默的cree依赖性光遗传转基因小鼠工具箱。Nat. Neurosci 15,793 （2012）

The cerebral cortex is a vitally important part of the brain; it is most highly developed in humans and endows us with many of our uniquely human qualities. When the cortex malfunctions in psychiatric conditions such as schizophrenia and autism, or degenerates in conditions such as Alzheimer's disease, those uniquely human qualities are lost or degraded. Ideas about how we might tackle these debilitating conditions have changed over the years. As pointed out by the head of the US National Institute for Mental Health, the way we used to understand mental health disorders as "chemical imbalances" or as "social constructs" seem strangely outdated and have given way amidst a flurry of discoveries to the newer ideas of mental health conditions as disorders of "brain circuits" arising from a combination of genetic risk factors and environmental effects(1). Perhaps it is not entirely surprising that we still only understand the operation of the cortical "brain circuit" at a very rudimentary level at present, after all it is extremely complex. However, a number of powerful molecular and optogenetic tools are now available for unpicking this complicated knot (2) . Our approach is to look at a relatively simple part of the cortex known as the barrel cortex, where the basic architecture of the cortex can be seen using simple histochemical stains or physiological imaging methods, and to try to understand the cortical circuits involved. The elementary modules that make up the cortex are known as cortical columns and consist of groups of interconnected neurones arranged in six layers. Higher order animals with more complicated cortex have more columns than lower order animals, but the basic architecture of the columns are similar in both cases. We can therefore understand a great deal about the human cortical circuitry by analysing the mouse barrel cortex circuitry. We want to know how information is processed within these circuits and to understand the molecular mechanisms that allow the circuits to change in response to altered experience via their synaptic plasticity mechanisms. Our present work on the circuitry and plasticity of this system has already yielded insights into schizophrenia and AIDS-related dementia. In the present work we combine the new technologies of optogenetic pathway stimulation, dendritic spine imaging and optical manipulation of synapses with our substantial knowledge and experience of the operation of the barrel cortex to understand the cortical circuit. Our immediate plan includes provision to test whether our findings generalise to visual cortex.We recently made a ground breaking discovery in finding that two major subdivisions of the layer 5 cells, the regular spiking (RS) and intrinsic bursting (IB) cells show fundamentally different plasticity. These cells are the major output cells in the cortex. To a first order analysis, RS cells show depression but not potentiation while IB cells show potentiation but not depression. To a second order analysis, RS cells showed potentiation to subcortical but not intracortical input. We have now discovered a further difference at the molecular level: RS cells exhibit homeostatic (TNFalpha-dependent) plasticity in response to depression, while IB cells show Hebbian CaMKII dependent potentiation. We need to know how these plasticity differences arise, whether they are general to other cortical areas and how they fit into the general response of the cortical circuit to changes in sensory input. 1. T.R.Insel Translating scientific opportunity into public health impact: a strategic plan for research on mental illness. Arch Gen Psychiatry 66,128 (2009)2. L. Madisen et al. A toolboox of cre-dependent optogenetic transgenic mice for light induced activation and silencing. Nat. Neurosci 15,793 (2012)