Memory Retrieval in Mice and Men

Abstract

Retrieval, the use of learned information, was until recently mostly terra incognita in the neurobiology of memory, owing to shortage of research methods with the spatiotemporal resolution required to identify and dissect fast reactivation or reconstruction of complex memories in the mammalian brain. The development of novel paradigms, model systems, and new tools in molecular genetics, electrophysiology, optogenetics, in situ microscopy, and functional imaging, have contributed markedly in recent years to our ability to investigate brain mechanisms of retrieval. We review selected developments in the study of explicit retrieval in the rodent and human brain. The picture that emerges is that retrieval involves coordinated fast interplay of sparse and distributed corticohippocampal and neocortical networks that may permit permutational binding of representational elements to yield specific representations. These representations are driven largely by the activity patterns shaped during encoding, but are malleable, subject to the influence of time and interaction of the existing memory with novel information.

Figure 1.

Memory retrieval induced by direct circuit reactivation. (A) System for introducing genes into neurons based on their natural, sensory-evoked activity patterns (Reijmers et al. 2007). The cfos-promoter drives tetracycline transactivator (tTA) in response to neural activity and the tTA then activates and gene of interest (GOI) that is linked to a TRE-promoter. Doxycycline (Dox-yellow shading) blocks the transcriptional activity of tTA providing temporal control over the time frame in which neural activity drives the GOI. (B) Experimental design for demonstrating the functional relevance of distributed neural ensembles. Neurons activated during learning in a fear-conditioning paradigm are genetically tagged with channelrhodopsin (ChR2). The subsequent light-induced firing of these ensembles is able to produce a fear response in a second, emotionally neutral, context.

Figure 2.

Brain correlates of retrieval of human declarative memory. (A) Brain network associated with recognition memory. The figure depicts a meta-analysis of areas that show old > new activation in recognition tests in 38 fMRI (functional magnetic resonance imaging) studies. The regions identified include the, angular gyrus, caudate nucleus, dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex, dorsal posterior parietal cortex, posterior cingulate cortex, and precuneus. (Based on data in Kim 2013; with permission from the author.) (B) Diagrams depicting the dynamics of brain network fast functional connectivity in memory retrieval revealed by electrocorticographical (ECoG) recording in patients undergoing seizure monitoring. The patients were engaged in retrieving spatial and temporal episodic contexts. Phase synchronization between brain areas was used as a measure of connectivity. The panels display the connectivity correlated with correct spatial and temporal retrieval in the 1–4 Hz and 7–10 Hz bands. PHG, Parahippocampal gyrus; MFG, middle frontal gyrus; SFG, superior frontal gyrus; IFG, inferior frontal gyrus; IPL, inferior parietal lobule; PCN, precuneus; SPL, superior parietal lobule. Successful retrieval was associated with greater global connectivity among the sites with the medial temporal lobe (MTL) acting as a hub for the interactions, but whereas correct spatial context retrieval was characterized by lower frequency interactions across the network, temporal context retrieval was characterized by faster frequency interactions. These results provide insight into how multiple contexts associated with a single event can be retrieved in the same network. (Based on data in Watrous et al. 2013; with permission from the authors.)