Temporal Association Memory Research Articles

Astrocytic α4-containing nAChR signaling in the hippocampus governs the formation of temporal association memory

Everyday episodic memories involve linking together related events that are temporally separated. However, the mechanisms of forming this temporal association have remained unclear. Here, using astrocyte-specific manipulations, we show that potentiating astrocyte Ca2+ signaling in the hippocampal cornu ammonis 1 (CA1) enhances the strength of such temporal association, in parallel with long-term potentiation (LTP) enhancement of temporoammonic pathway to CA1, whereas attenuation of astrocyte Ca2+ signaling has the opposite effect. Moreover, we identify that these effects are mediated by astrocytic α4 subunit-containing nicotinic acetylcholine receptors (α4-nAChRs) via mechanisms involving NMDAR co-agonist supply. Finally, astrocytic α4-nAChRs underlie the cognitive enhancer nicotine's physiological effects. Together, these findings highlight the importance of astrocyte Ca2+ signaling in cognitive behavior and reveal a mechanism in governing the temporal association of episodic memory formation that operates through α4-nAChRs on hippocampal astrocytes.

Extended Temporal Association Memory by Modulations of Inhibitory Circuits.

Hebbian learning of excitatory synapses plays a central role in storing activity patterns in associative memory models. Interstimulus Hebbian learning associates multiple items by converting temporal correlation to spatial correlation between attractors. Growing evidence suggests the importance of inhibitory plasticity in memory processing, but the consequence of such regulation in associative memory has not been understood. Noting that Hebbian learning of inhibitory synapses yields an anti-Hebbian effect, we show that the combination of Hebbian and anti-Hebbian learning can significantly increase the span of temporal association between correlated attractors as well as the sensitivity of these states to external input. Furthermore, these effects are regulated by changing the ratio of local and global recurrent inhibition after learning weights for excitation-inhibition balance. Our results suggest a nontrivial role of plasticity and modulation of inhibitory circuits in associative memory.

A behavioral defect of temporal association memory in mice that partly lack dopamine reuptake transporter.

Temporal association memory, like working memory, is a type of episodic memory in which temporally discontinuous elements are associated. However, the mechanisms that govern this association remain incompletely understood. Here, we identify a crucial role of dopaminergic action in temporal association memory. We used hemizygote hyperdopaminergic mutant mice with reduced dopamine transporter (DAT) expression, referred to as DAT+/− mice. We found that mice with this modest dopamine imbalance exhibited significantly impaired trace fear conditioning, which necessitates the association of temporally discontinuous elements, and intact delay auditory fear conditioning, which does not. Moreover, the DAT+/− mice displayed substantial impairments in non-matching-to-place spatial working-memory tasks. Interestingly, these temporal association and working memory deficits could be mimicked by a low dose of the dopamine D2 receptor antagonist haloperidol. The shared phenotypes resulting from either the genetic reduction of DAT or the pharmacological inhibition of the D2 receptor collectively indicate that temporal association memory necessitates precise regulation of dopaminergic signaling. The particular defect in temporal association memory due to partial lack of DAT provides mechanistic insights on the understanding of cognitive impairments in multiple neurodevelopmental disorders.

Island cells control temporal association memory.

Episodic memory requires associations of temporally discontiguous events. In the entorhinal-hippocampal network, temporal associations are driven by a direct pathway from layer III of the medial entorhinal cortex (MECIII) to the hippocampal CA1 region. However, the identification of neural circuits that regulate this association has remained unknown. In layer II of entorhinal cortex (ECII), we report clusters of excitatory neurons called island cells, which appear in a curvilinear matrix of bulblike structures, directly project to CA1, and activate interneurons that target the distal dendrites of CA1 pyramidal neurons. Island cells suppress the excitatory MECIII input through the feed-forward inhibition to control the strength and duration of temporal association in trace fear memory. Together, the two EC inputs compose a control circuit for temporal association memory.

Cholinergic receptor activation supports persistent firing in layer III neurons in the medial entorhinal cortex

Medial temporal lobe (MTL) areas are crucial for memory tasks such as spatial working memory and temporal association memory, which require an active maintenance of memory for a short period of time (a few hundred milliseconds to tens of seconds). Recent work has shown that the projection from layer III neurons in the medial entorhinal cortex (MEC) to hippocampal region CA1, the temporoammonic (TA) pathway, might be specially important for these memory tasks. In addition, lesions to the entorhinal cortex disrupt persistent firing in CA1 which is believed to support active maintenance of memory. Injection of cholinergic antagonists and group I mGlu receptor antagonists to the MEC impairs spatial working memory and temporal association memory. Consistent with this, we have shown that group I mGlu receptor activation supports persistent firing in principal cells of the MEC layer III in vitro (Yoshida et al. [39]). However, it still remains unknown whether cholinergic receptor activation also supports persistent firing in MEC layer III neurons. In this paper, we tested this in MEC layer III cells using both ruptured and perforated whole-cell recordings in vitro. We report that the majority of cells we recorded from in MEC layer III show persistent firing during perfusion of the cholinergic agonist carbachol (2–10μM). In addition, repeated stimulation gradually suppressed persistent firing. We further discuss the possible role of persistent firing in memory function in general.