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

想象一下，如果你的世界不再有意义。你可能会看到和听到奇怪的事情。你可能会改变你所记得的，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。目前的药物在治疗某些症状方面是有效的-特别是听觉，视觉和信念的变化（“积极”症状）。然而，人们对决策、记忆和情绪（认知和“消极”症状）的问题知之甚少，因此治疗不力。我们的研究旨在了解认知症状的原因，并提出治疗建议。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，纹状体是一个控制动机和运动的大脑区域。SZ患者的前额叶皮层（PFC）和海马体也发生了变化，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中进行，但大鼠PFC不像人类PFC，因为它简单得多。介于老鼠和人类之间的是像绒猴这样的小猴子。我们可以测量绒猴的复杂行为（比如对所见事物的工作记忆）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，而这些变化无法在大鼠或人类身上进行。SZ患者还显示出一种称为神经元周网（PNN）的结构的改变，海马和PFC中脑细胞的支架。我们知道，去除海马PNN的大鼠显示出与SZ相似的DA变化。因此，可能是由PNN的丧失引起的海马变化，反过来又引起PFC的变化，这是SZ认知症状的原因。我们的初步数据支持这种联系。如果是这样的话，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降解酶来降解绒猴海马或PFC中的PNN。我们将测量这对PFC结构、化学（信号化学物质的水平）和功能的影响，我们将包括适当的控制条件（例如，确保注射本身并不重要）。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采样流体。我们将通过我们开发的任务来测量PFC区域的功能（和正在发展中的）依赖于特定的全氟化学品区域，比如工作记忆测试（这需要背外侧PFC）或当另一个更好地预测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PNN在背外侧PFC中降解的影响。然后，我们将把活性、结构和化学变化与行为变化联系起来。我们在这项研究中非常有经验。我们非常好地照顾我们的绒猴，不使用超过我们必须使用的量。我们预测海马PNN退化会影响PFC功能，然后我们将利用我们对PFC化学变化的了解来尝试治疗PNN退化引起的任何行为问题，首先直接给PFC“拯救”药物。这些研究可能会导致SZ认知症状的新片剂。

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.