Cortical pathways and local circuits mediating memory formation: electrophysiological studies.

记忆痕迹被认为是由同时激活的神经元组成的网络，形成新网络的一个主要机制是通过神经元之间突触连接强度的长期增加(或减少)。我的研究旨在了解新的记忆痕迹是如何通过脑细胞之间突触连接强度的长期变化形成的。在记忆的编码过程中，海马结构和周围的海马旁皮质区域被认为结合了不同类型的感觉输入，记忆的长期巩固被认为涉及大脑的其他部分，包括新皮质。我实验室的研究重点是有助于唤醒的调节性神经递质乙酰胆碱和多巴胺如何调节大鼠海马区正在进行的突触处理，并有助于诱导突触强度的长期变化。我使用电生理学和药理学技术来研究这些递质在海马区的作用。在清醒的大鼠中，通过监测由突触输入的短暂电刺激所诱发的突触场电位来评估突触连接强度的变化。脑组织切片中单个神经元的录音也被用来研究调节突触连接变化的细胞机制。 第一个主要研究方向是了解内嗅皮层(一个重要的海马区)是如何处理和编码感觉输入的。在这一系列研究中有三个系列的研究。第一个建立在我们发现乙酰胆碱的释放导致梨状(嗅觉)皮质输入到内嗅皮层的突触强度受到抑制的基础上，并将使用脑片记录来确定这种抑制的细胞机制。第二个系列的研究将通过描述梨状皮质和虹膜周围皮质的突触输入之间的相互作用，来检验内嗅觉皮质多模式感觉整合的细胞基础。第三个系列的研究将集中在从海马结构的小叶旁分裂到内嗅觉皮质的输入如何被乙酰胆碱调制。副小结参与空间加工，我们将研究乙酰胆碱如何在重复刺激过程中诱导突触反应的“相对易化”。这些结果将有助于发展关于这一途径在空间加工中的作用的理论。 第二条研究路线是关于多巴胺递质引起的内脏回路的变化，多巴胺被认为促进了与动机和奖励相关的刺激的认知处理。我们将研究多巴胺释放与对食物奖励的预期或对下丘脑的奖励电刺激如何导致内嗅皮层突触输入强度的变化。高浓度的多巴胺抑制突触输入，低浓度的多巴胺促进突触强度，实验将确定介导这些影响的细胞内信号。更多的实验将确定多巴胺如何阻断突触强度持续增加或减少的诱导。“光遗传”刺激技术也将被用来确定突触释放多巴胺对内嗅神经元谷氨酸能传递和放电行为的影响。这一系列研究将有助于表征多巴胺如何改变内嗅皮层的感觉处理和助记功能，并将阐明介导这些变化的基本神经机制。

Memory traces are thought to consist of networks of simultaneously activated neurons, and a major mechanism through which new networks can be formed is through long-lasting increases (or decreases) in the strength of synaptic connections between neurons. My research is aimed at understanding how new memory traces are formed through long-lasting changes in the strength of synaptic connections between brain cells. The hippocampal formation and surrounding parahippocampal cortical regions are thought to combine different types of sensory input during the encoding of memory, and the long-term consolidation of memory is thought to involve other parts of the brain including the neocortex. Research in my lab focusses on how the modulatory neurotransmitters acetylcholine and dopamine, that contribute to arousal, can modulate ongoing synaptic processing within the parahippocampal region of the rat and contribute to the induction of long-lasting changes in synaptic strength. I use electrophysiological and pharmacological techniques to investigate the role of these transmitters in the parahippocampal region. In the awake rat, changes in the strength of synaptic connections are assessed by monitoring synaptic field potentials that are evoked by brief electrical stimulation of synaptic inputs. Recordings from single neurons in slices of brain tissue are also used to investigate the cellular mechanisms that mediate changes in synaptic connections. The first major line of research is aimed at understanding how the entorhinal cortex (an important parahippocampal area) processes and encodes sensory input. There are three series of studies in this line of research. The first builds upon our finding that release of acetylcholine causes a suppression of synaptic strength in piriform (olfactory) cortex inputs to the entorhinal cortex, and will use brain-slice recordings to determine the cellular mechanisms of this suppression. A second series of studies will examine the cellular basis of multi-modal sensory integration in the entorhinal cortex by characterizing interactions between synaptic inputs from the piriform and perirhinal cortex. The third series of studies will focus on how inputs to the entorhinal cortex from the parasubicular division of the hippocampal formation are modulated by acetylcholine. The parasubiculum contributes to spatial processing and we will investigate how acetylcholine induces a “relative facilitation” of synaptic responses during repeated stimulation. Results will contribute to developing theories of the role of this pathway in spatial processing. The second general line of research is concerned with changes in entorhinal circuitry induced by the transmitter dopamine that is thought to promote cognitive processing of stimuli associated with motivation and reward. We will investigate how dopamine release associated with anticipation of food-reward, or rewarding electrical stimulation of the hypothalamus, leads to changes in the strength of synaptic inputs to the entorhinal cortex. High concentrations of dopamine suppress synaptic inputs, and low concentrations facilitate synaptic strength, and experiments will determine the intracellular signals that mediate these effects. Additional experiments will determine how dopamine can gate the induction of lasting increases or decreases in synaptic strength. “Optogenetic” stimulation techniques will also be used to determine the effects of synaptic release of dopamine on glutamatergic transmission and firing behaviour of entorhinal neurons. This line of research will help characterize how sensory processing and mnemonic function may be altered in the entorhinal cortex by dopamine, and will also clarify the fundamental neuronal mechanisms that mediate these changes.