Forebrain-Cerebellum Interactions in Trace Conditioning

描述(申请人提供)：各种行为通常被称为“海马体依赖”或“小脑依赖”。事实上，大脑功能在很大程度上涉及大脑系统之间的相互作用，尽管这些相互作用很难研究。前脑投射到小脑的丰富突显了前脑和小脑相互作用的中心突起。跟踪眼皮条件作用的实践和概念优势代表了一个在明确定义的学习行为的背景下研究前脑-小脑相互作用的机会。延迟性眼皮条件作用相对直接地与小脑接触，不需要前脑结构。相比之下，微量眼皮条件反射会受到小脑、海马体和内侧前额叶皮质(MPFC)损伤的干扰。一种著名的理论认为，小脑不能通过痕迹输入进行学习，前脑结构在沉默的痕迹间隔期间激活小脑输入，这些输入参与正常的小脑学习机制，以获得适当的跟踪反应。这一理论的关键测试-从苔藓纤维输入到小脑的记录由海马体和 MPFC-一直不可能，因为这些苔藓纤维还没有被识别出来。拟议的研究扩展了初步发现，1)证实了苔藓纤维刺激，小脑不能通过痕量输入学习，以及2)确定了苔藓纤维对痕迹条件作用至关重要。这些实验将作为在活体中记录痕迹条件作用所必需的苔藓纤维和由音调条件刺激直接激活的苔藓纤维的前奏。这些细胞的听觉反应和与痕量条件作用发展起来的学习依赖活动将被表征。然后，可以使用可逆性失活的海马体或mPFC来识别驱动学习依赖反应的基本输入来源。最后，使用苔藓纤维的刺激，将测试这些学习依赖反应的充分性，以支持小脑学习适当的痕迹反应。

DESCRIPTION (provided by applicant): Various behaviors are often referred to as "hippocampal dependent" or "cerebellar dependent." In reality, brain function largely involves interactions between brain systems, although these interactions are difficult to study. The abundance of forebrain projections to cerebellum highlights the central prominence of interactions between forebrain and cerebellum. The practical and conceptual advantages of trace eyelid conditioning represent an opportunity to study forebrain-cerebellum interactions in the context of a well-defined learned behavior. Delay eyelid conditioning engages the cerebellum relatively directly and does not require forebrain structures. In contrast, trace eyelid conditioning is disrupted by lesions of the cerebellum, hippocampus and medial prefrontal cortex (mPFC). A prominent theory asserts that cerebellum cannot learn with trace inputs, that forebrain structures activate cerebellar inputs during the silent trace-interval, and that these inputs engage normal cerebellar learning mechanisms to acquire appropriate trace responses. The key test of this theory - to record from the mossy fiber inputs to cerebellum activated by hippocampus and mPFC - has not been possible because these mossy fibers had not been identified. The proposed studies extend preliminary findings that have 1) confirmed with mossy fiber stimulation that cerebellum cannot learn with trace inputs, and 2) identified the mossy fibers essential for trace conditioning. The experiments will be completed as a prelude to recording in vivo from the mossy fibers essential for trace conditioning and from the mossy fibers activated directly by the tone conditioned stimulus. The auditory responses of these cells and the learning-dependent activity that develops with trace conditioning will be characterized. Reversible inactivation of hippocampus or mPFC can then be used to identify essential sources of input that drive the learning-dependent responses. Finally, using stimulation of mossy fibers, the sufficiency of these learning dependent responses to support cerebellar learning of appropriate trace responses will be tested.