Hippocampal Interneurons are Required for Trace Eyeblink Conditioning in Mice

Qian-Hui Zhang,Hao Chen,Jie Zhang,Zhi-An Hu,Zhong-Xiang Yao,Rong-Rong Li,Bo Hu,Jie Yan,Wei-Wei Zhang

doi:10.1007/s12264-021-00700-0

Abstract

While the hippocampus has been implicated in supporting the association among time-separated events, the underlying cellular mechanisms have not been fully clarified. Here, we combined in vivo multi-channel recording and optogenetics to investigate the activity of hippocampal interneurons in freely-moving mice performing a trace eyeblink conditioning (tEBC) task. We found that the hippocampal interneurons exhibited conditioned stimulus (CS)-evoked sustained activity, which predicted the performance of conditioned eyeblink responses (CRs) in the early acquisition of the tEBC. Consistent with this, greater proportions of hippocampal pyramidal cells showed CS-evoked decreased activity in the early acquisition of the tEBC. Moreover, optogenetic suppression of the sustained activity in hippocampal interneurons severely impaired acquisition of the tEBC. In contrast, suppression of the sustained activity of hippocampal interneurons had no effect on the performance of well-learned CRs. Our findings highlight the role of hippocampal interneurons in the tEBC, and point to a potential cellular mechanism subserving associative learning.

Highlights

Learning to associate two events that occur separately in time is critical for animals to produce behavioral responses with appropriate timing and strength [1, 2]
We found that the hippocampal interneurons exhibited conditioned stimulus (CS)-evoked sustained activity, which predicted the performance of conditioned eyeblink responses (CRs) in the early acquisition of the trace eyeblink conditioning (tEBC)
We found that the mice receiving CS-unconditioned stimulus (US) paired presentations learned this task and exhibited adaptive CRs to the light CSs (Fig. 1A)

Summary

Introduction

Learning to associate two events that occur separately in time is critical for animals to produce behavioral responses with appropriate timing and strength [1, 2]. Lesions of the dorsal hippocampus before training prevents subsequent associative learning [5,6,7,8,9]. Blockade of NMDA receptors in the dorsal hippocampus severely impairs the learning of associations between time-separated stimuli [10, 11]. Consistent with these lesion and inactivation studies, in vivo electrophysiological recordings show that a group of hippocampal pyramidal cells exhibits elevated activity and encodes information about discontiguous sets of stimuli [12]. It has been hypothesized that the hippocampus functions to form associations between time-separated events, thereby supporting associative learning [2, 13]

Methods

Results

Conclusion