Modulation of eyeblink conditioning through sensory processing of conditioned stimulus by cortical and subcortical regions.

Classical eyeblink conditioning (EBC) is one of the simplest forms of associative learning that depends critically on the cerebellum. Using delay EBC (dEBC), a standard paradigm in which the unconditioned stimulus (US) is delayed and co-terminates with the conditioned stimulus (CS), converging lines of evidence has been accumulated and shows that the essential neural circuit mediating EBC resides in the cerebellum and brainstem. In addition to this essential circuit, multiple cerebral cortical and subcortical structures are required to modulate dEBC with suboptimal training parameters, and trace EBC (tEBC) in which a trace-interval separates the CS and US. However, it remains largely unclear why and how so many brain regions are involved for modulation of EBC. Previous research has suggested that the forebrain regions, such as medial prefrontal cortex (mPFC) and hippocampus, may be required to process weak CSs, or to realize temporal overlap between the CS and US signal inputs when the two stimuli were separated in time (i.e. during tEBC). Here, we proposed a multi-level network model for EBC modulation which focuses on sensory processing of CS. The model explains how different neural pathways projecting to pontine nucleus (PN) are involved to amplify or extend CS through heterosynaptic facilitation mechanism or "substitution effect" under different circumstances to achieve EBC. As such, our model can serve as a general framework to explain the modulating mechanism of EBC in a variety of conditions and to help understand the interaction among cerebellum, brainstem, cortical and subcortical regions in EBC modulation.