Hippocampal Interneurons are Required for Trace Eyeblink Conditioning in Mice

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.

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.…”

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

“…Using a combination of multichannel recording and optogenetics, we revealed that the hippocampal PV-INs showed CSevoked firing activity during tEBC acquisition. In particular, the There is growing evidence indicating an involvement of hippocampal interneurons in associative learning (Fuchs et al, 2007;He et al, 2021;Zhang et al, 2021). However, the mechanisms by which the hippocampal interneurons participate in associative learning remain not fully understood.…”

“…Intriguingly, the hippocampus connects with several forebrain areas such as the prefrontal cortex (Jay and Witter, 1991;Cenquizca and Swanson, 2007) and the entorhinal cortex (Amaral and Witter, 1989;Rozov et al, 2020), which have been demonstrated to be critically involved in tEBC (Weible et al, 2000;Ryou et al, 2001;Siegel et al, 2015;Tanninen et al, 2015;Chen et al, 2016). Electrophysiological studies have documented that a number of hippocampal PYRs exhibited sustained excitatory activity in the CS-US interval during tEBC, whereas a larger number of hippocampal PYRs showed sustained inhibitory activity (McEchron and Disterhoft, 1997;Hattori et al, 2015;Zhang et al, 2021;Li et al, 2022). Likewise, both sparse excitatory and strong inhibitory activities were observed in the hippocampal PYRs during appetitive auditory trace conditioning (Klee et al, 2021).…”

“…The sustained and/or sequential firing of hippocampal PYRs enables the hippocampus to bridge the time gap between time-separated stimuli, which is hypothesized to support associative learning (Wallenstein et al, 1998;Kitamura et al, 2015;Kitamura, 2017). However, a recent study has shown that disinhibition of the hippocampal PYRs lead to great sustained activity but impairment in associative learning (Zhang et al, 2021). Likewise, overactivity of hippocampal PYRs has been demonstrated to produce adverse effects on associative learning (Koh et al, 2016).…”

“…Recently it has been demonstrated that a number of hippocampal interneurons show increased firing responses to the CS presentations, and optogenetic suppression of the increased firing of hippocampal interneurons impairs the acquisition of tEBC (Zhang et al, 2021). Moreover, there is an increase in the intrinsic excitability of hippocampal interneurons after tEBC training (McKay et al, 2013).…”