Sustained Activity of Hippocampal Parvalbumin-Expressing Interneurons Supports Trace Eyeblink Conditioning in Mice

Abstract

Although recent studies have revealed an involvement of hippocampal interneurons in learning the association among time-separated events, its underlying cellular mechanisms remained not fully clarified. Here, we combined multichannel recording and optogenetics to elucidate how the hippocampal parvalbumin-expressing interneurons (PV-INs) support associative learning. To address this issue, we trained the mice (both sexes) to learn hippocampus-dependent trace eyeblink conditioning (tEBC) in which they associated a light flash conditioned stimulus (CS) with a corneal air puff unconditioned stimuli (US) separated by a 250 ms time interval. We found that the hippocampal PV-INs exhibited learning-associated sustained activity at the early stage of tEBC acquisition. Moreover, the PV-IN sustained activity was positively correlated with the occurrence of conditioned eyeblink responses at the early learning stage. Suppression of the PV-IN sustained activity impaired the acquisition of tEBC, whereas the PV-IN activity suppression had no effect on the acquisition of delay eyeblink conditioning, a hippocampus-independent learning task. Learning-associated augmentation in the excitatory pyramidal cell-to-PVIN drive may contribute to the formation of PV-IN sustained activity. Suppression of the PV-IN sustained activity disrupted hippocampal gamma but not theta band oscillation during the CS-US interval period. Gamma frequency (40 Hz) activation of the PV-INs during the CS-US interval period facilitated the acquisition of tEBC. Our current findings highlight the involvement of hippocampal PV-INs in tEBC acquisition and reveal insights into the PV-IN activity kinetics which are of key importance for the hippocampal involvement in associative learning.SIGNIFICANCE STATEMENTThe cellular mechanisms underlying associative learning have not been fully clarified. Previous studies focused on the involvement of hippocampal pyramidal cells in associative learning, whereas the activity and function of hippocampal interneurons were largely neglected. We herein demonstrated the hippocampal PV-INs exhibited learning-associated sustained activity, which was required for the acquisition of tEBC. Furthermore, we showed evidence that the PV-IN sustained activity might have arisen from the learning-associated augmentation in excitatory pyramidal cell-to-PVIN drive and contributed to learning-associated augmentation in gamma band oscillation during tEBC acquisition. Our findings provide more mechanistic understanding of the cellular mechanisms underlying the hippocampal involvement in associative learning.

The little brain and the seahorse: Cerebellar-hippocampal interactions

“…This is very similar to the tiling of time noted in the object-odor pairing task described above ( MacDonald et al, 2011 ). Two more recent studies have provided information also about the activity and role of hippocampal inhibitory interneurons during trace eyeblink conditioning – hippocampal interneurons actively increased their firing rates during the CS and the US ( Zhang et al, 2021 ; Li et al, 2022 ), and inhibition of broad ( Zhang et al, 2021 ) or specific ( Li et al, 2022 ) interneuron populations disrupted task acquisition. Taken together, these studies suggest that hippocampal time cells may bridge the temporal gap between the CS and US (during acquisition) and illustrate that the importance of inhibition to proper hippocampal functioning should not be ignored.…”