Non human primate investigations into hippocampal-prefrontal interactions and cognitive dysfunction of relevance to schizophrenia

想象一下，如果你的世界失去了意义。你可能会看到和听到奇怪的事情。你可能会改变你的记忆，你所做的决定，以及你对事物的享受。这些都是精神分裂症（SZ）的症状，这是一种毁灭性的、无法治愈的精神疾病，影响了1%的人类。目前的药物对治疗某些症状有效，尤其是听觉、视觉和信念的变化（“阳性”症状）。然而，决策、记忆和情绪方面的问题（认知和“消极”症状）却知之甚少，因此治疗也很差。我们的研究旨在了解认知症状的原因，并提出治疗建议。SZ不容易在动物身上进行研究。很难知道动物是否产生了幻觉。然而，我们知道人类的“阳性”症状，我们可以在动物身上进行测试。例如，这些症状与纹状体中释放过多的多巴胺（DA）有关，纹状体是控制动机和运动的大脑区域。患有SZ的人的前额叶皮层（PFC）和海马体也有变化，这两个相连的结构可能导致一些认知症状。为了研究这些症状，我们可以测量SZ的错误行为。这些研究通常在大鼠身上进行，但大鼠的PFC不像人类的PFC，因为它要简单得多。介于老鼠和人类之间的是像狨猴这样的小猴子。我们可以测量狨猴的复杂行为（比如它们对所见事物的工作记忆），它们依赖于与人类相同的PFC亚区，我们还可以测量PFC中的神经递质，并在实验中引起大脑区域的变化，这在老鼠或人类身上是无法进行的。患有SZ的人也表现出被称为神经周围网（PNN）的结构的改变，PNN是海马和pfc中脑细胞的支架。我们知道，切除海马PNN的大鼠显示出与SZ相似的DA变化。因此，可能是海马的变化，由PNN的丧失引起，进而引起PFC的变化，而PFC的变化是导致SZ认知症状的原因。我们的初步数据支持这种联系。如果是这样，这可能会提出一种治疗这些症状的新方法。因此，我们计划通过注射PNN降解酶来降解狨猴海马或PFC中的PNN。我们将测量这对PFC结构，化学（信号化学物质水平）和功能的影响，并且我们将包括适当的控制条件（例如，确保注射本身不是重要的）。我们将使用成像技术，如磁共振成像，正电子发射断层扫描，并通过直接从PFC取样来测量PFC区域的功能。我们将通过我们已经开发（和正在开发）的任务来测量PFC区域的功能，这些任务依赖于特定的PFC区域，如工作记忆测试（这需要背侧PFC）或当另一个刺激来预测更好的奖励时放弃先前奖励刺激的能力（这需要眶额PFC）。为了比较，我们还将研究降解PNN在背外侧pfc中的影响。然后，我们将活性、结构和化学的变化与行为的变化联系起来。我们在这方面很有经验。我们对狨猴照顾得特别好，不会过度使用。我们预测海马PNN的降解将影响PFC的功能，然后我们将利用我们所了解的PFC化学变化来尝试治疗由PNN降解引起的任何行为问题，首先是直接向PFC注入“拯救”药物。这些研究可能会带来治疗SZ认知症状的新药片。

Imagine if your world stopped making sense. You might see and hear strange things. You might change what you remember, the decisions you make, and your enjoyment in things. These are all symptoms of schizophrenia (SZ), a devastating, incurable psychiatric illness affecting 1% of humans. Current medicines are effective at treating some symptoms - particularly the auditory, visual and belief changes (the "positive" symptoms). However the problems with decision making, memory and mood (the cognitive and "negative" symptoms) are poorly understood, and hence poorly treated. Our research aims to understand the causes of the cognitive symptoms, and to suggest treatments.SZ is not easy to study in animals. It is hard to know if an animal is hallucinating. However, we know things about "positive" symptoms in humans that we can test for in animals. For example, these symptoms are associated with the release of too much dopamine (DA) in the striatum, a brain region that governs motivation and movement. Humans with SZ also have changes in their prefrontal cortex (PFC) and hippocampus, two connected structures which may be responsible for some of the cognitive symptoms. To investigate these symptoms we can measure behaviours that go wrong in SZ.These studies are often performed in rats, but rat PFC isn't like human PFC as it's much simpler. In between rats and humans are small monkeys like marmosets. We can measure complex behaviours in marmosets (such as working memory for things they've seen) that depend on the same PFC subregions as in humans, and we can also measure neurotransmitters in the PFC, and cause changes to brain regions in experiments that couldn't be performed in rats or humans.Humans with SZ also show alterations in a structure called the perineuronal net (PNN), a scaffold for brain cells in both the hippocampus and the PFC. We know that rats who have their hippocampal PNN removed show changes in DA like those seen in SZ. Therefore it may be that hippocampal changes, caused by the loss of the PNN, in turn cause changes in the PFC that are responsible for the cognitive symptoms of SZ. Our preliminary data supports such a link. If so, this might suggest a new way of treating these symptoms. We therefore plan to degrade the PNN in the hippocampus or PFC of marmosets by injecting a PNN-degrading enzyme. We'll measure what this does to PFC structure, chemistry (levels of signalling chemicals), and function, and we will include appropriate control conditions (e.g. to make sure that an injection itself isn't what's important). We will do this using imaging techniques such as magnetic resonance imaging, positron emission tomography, and by sampling fluid directly from the PFC. We will measure the function of PFC regions through tasks we've developed (and are developing) that depend on specific PFC regions, like tests of working memory (which tax the dorsolateral PFC) or the ability to abandon a previously rewarded stimulus when another comes to predict reward better (which requires the orbitofrontal PFC). For comparison we will also investigate the effects of degrading the PNN in the dorsolateral PFC. We will then relate changes in activity, structure and chemistry to changes in behaviour. We are very experienced in this research. We look after our marmosets exceptionally well and don't use more than we have to.We predict that hippocampal PNN degradation will affect PFC function, and we will then use what we learn about the changes in PFC chemistry to try to treat any behavioural problems caused by PNN degradation, at first by giving "rescue" drugs into the PFC directly. These studies might lead to new tablets for cognitive symptoms in SZ.