Entorhinal–hippocampal neuronal circuits bridge temporally discontiguous events

Abstract

The entorhinal cortex (EC) -hippocampal (HPC) network plays an essential role for episodic memory, which preserves spatial and temporal information about the occurrence of past events. Although there has been significant progress toward understanding the neural circuits underlying the spatial dimension of episodic memory, the relevant circuits subserving the temporal dimension are just beginning to be understood. In this review, we examine the evidence concerning the role of the EC in associating events separated by time-or temporal associative learning-with emphasis on the function of persistent activity in the medial entorhinal cortex layer III (MECIII) and their direct inputs into the CA1 region of HPC. We also discuss the unique role of Island cells in the medial entorhinal cortex layer II (MECII), which is a newly discovered direct feedforward inhibitory circuit to CA1. Finally, we relate the function of these entorhinal cortical circuits to recent findings concerning hippocampal time cells, which may collectively activate in sequence to bridge temporal gaps between discontiguous events in an episode.

Hippocampal network reorganization underlies the formation of a temporal association memory

“…Episodic memory recapitulates the sequential structure of events that unfold in space and time [Eichenbaum, 2017]. In the brain, the hippocampal network is critical for binding the representations of discontiguous events [Kitamura et al, 2015, Eichenbaum, 2017]. These findings are corroborated by recent evidence that the hippocampus generates sequences of neural activity that bridge the gap between sensory experiences [Pastalkova et al, 2008, MacDonald et al, 2011, Wang et al, 2015, Robinson et al, 2017], and that these dynamics are critical for memory [Wang et al, 2015, Robinson et al, 2017].…”

“…Pavlovian fear conditioning provides an attractive framework to study the neuronal correlates and mechanisms of associative learning in the brain [Letzkus et al, 2015, Grundemann and Luthi, 2015, Maddox et al, 2019, Grewe et al, 2017]. Classical “trace” fear conditioning (tFC) has long been used as a model behavior in the hippocampal literature for studying temporal association learning [Raybuck and Lattal, 2014, Kitamura et al, 2015]. In this paradigm, subjects learn that a neutral conditioned stimulus (CS) predicts an aversive, unconditioned stimulus (US), which follows the CS by a considerable time delay (the “trace” period).…”

“…Previous work has proposed that persistent activity mechanisms enable the hippocampus to connect representations of events in time, bridging time gaps on the order of tens of seconds. In particular, theories suggest that representation of the neutral CS and aversive US are linked through the generation of stereotyped, sequential activity in CA1 [Kitamura et al, 2015, Sellami et al, 2017], even when animals are immobilized [MacDonald et al, 2013]. Alternatively, hippocampal activity could generate a sustained response to the CS in order to maintain a static representation of the sensory cue in working memory over the trace interval, such as in attractor models of neocortical delay period activity [Amit and Brunel, 1997, Barak and Tsodyks, 2014, Takehara-Nishiuchi and McNaughton, 2008] and recently in the human hippocampus [Kaminski et al, 2017] during working memory tasks.…”

Dendrites, deep learning, and sequences in the hippocampus

“…Several years ago, it was proposed that sequential activity in the hippocampus “fills in” the interval between discontiguous events (Wallenstein, Hasselmo, & Eichenbaum, ), and more recently this idea has been extended to include the EC (Kitamura, Macdonald, & Tonegawa, ). This could be a mechanism for maintaining a neural trace of a conditioning event so that it can be associated with a later unconditioned stimulus.…”

Adolescent transitions in reflexive and non-reflexive behavior: Review of fear conditioning and impulse control in rodent models

“…Trace conditioning involves the hippocampus (Czerniawski et al, 2012; Kitamura et al, 2015; McEchron et al, 1998; Misane et al, 2005; Quinn et al, 2002, 2005; Rodriguez & Levy, 2001), as well as the mPFC (Beeman et al, 2013; Gilmartin & McEchron, 2005; Kalmbach et al, 2009; McLaughlin et al, 2002; Raybuck & Gould, 2010; Runyan et al, 2004; Song et al, 2015) for acquisition and retention. The procedure is very similar to delay conditioning, except that the US is presented sometime after the offset of the CS.…”