Associative Encoding and Retrieval Are Predicted by Functional Connectivity in Distinct Hippocampal Area CA1 Pathways

Abstract

Determining how the hippocampus supports the unique demands of memory encoding and retrieval is fundamental for understanding the biological basis of episodic memory. One possibility proposed by theoretical models is that the distinct computational demands of encoding and retrieval are accommodated by shifts in the functional interaction between the hippocampal CA1 subregion and its input structures. However, empirical tests of this hypothesis are lacking. To test this in humans, we used high-resolution fMRI to measure functional connectivity between hippocampal area CA1 and regions of the medial temporal lobe and midbrain during extended blocks of associative encoding and retrieval tasks. We found evidence for a double dissociation between the pathways supporting successful encoding and retrieval. Specifically, during the associative encoding task, but not the retrieval task, functional connectivity only between area CA1 and the ventral tegmental area predicted associative long-term memory. In contrast, connectivity between area CA1 and DG/CA3 was greater, on average, during the retrieval task compared with the encoding task, and, importantly, the strength of this connectivity significantly correlated with retrieval success. Together, these findings serve as an important first step toward understanding how the demands of fundamental memory processes may be met by changes in the relative strength of connectivity within hippocampal pathways.Key words: CA1; CA3; functional connectivity; high-resolution fMRI; hippocampus; VTA IntroductionIn everyday experience, memory encoding and retrieval appear seamlessly intertwined; encoding provides material that will later be retrieved, whereas retrieval supplies context to facilitate meaningful encoding. However, the neural mechanisms thought to underlie these processes have been hypothesized to place opposing demands on the episodic memory system (Marr, 1971;O'Reilly and McClelland, 1994). Specifically, the rapid formation of memory traces representing single episodes requires high levels of synaptic plasticity that, during retrieval, could lead to the overwriting of stored memories. Conversely, successful associative retrieval requires that cues reactivate related memory traces and thus benefits from a low threshold for memory reinstatement, but reinstating related memories at the time of encoding could lead to proactive interference (O'Reilly and McClelland, 1994).Although it is generally agreed that the hippocampus is critical for both encoding and retrieval (Scoville and Milner, 1957;Eichenbaum et al., 2007; Squire et al., 2007), it remains unknown how the hippocampus supports the complex demands of both processes. However, the unique pattern of afferent projections converging on area CA1, the major hippocampal output subregion, may provide an answer. On the one hand, inputs to CA1 might differentially support long-term memory encoding. Specifically, both late-phase long-term potentiation (LTP) at CA1 synapses and long-term memory formation have been demonstrated to be...

Complementary Roles of Human Hippocampal Subfields in Differentiation and Integration of Spatial Context

“…Furthermore, recent high-resolution imaging has also suggested that the CA1 subfield and neocortical-to-CA1 connectivity are important to memory retrieval success (Brown et al, 2014; Duncan et al, 2014). Because CA1 area receives input from parahippocampal cortex via entorhinal cortex and the temporoammonic pathway (Amaral & Insausti, 1990), one possibility is that CA1 may play a role in anchoring new visuospatial input onto existing templates (see also: J.…”

“…1). Entorhinal cortex (EC) was omitted from analyses due to imaging signal dropout, an issue present in other high-resolution imaging studies targeting the MTL using similar MRI acquisition sequences (e.g., Duncan, Tompary, & Davachi, 2014). In accordance with the methodology from other high-resolution fMRI projects, the “CA3/DG” ROI was defined to include subfields CA3, CA2 and DG because spatial resolution limitations prevent finer division (Chen, Olsen, Preston, Glover, & Wagner, 2011; Ekstrom et al, 2009; LaRocque et al, 2013; Zeineh et al, 2000).…”

Attentional modulation of background connectivity between ventral visual cortex and the medial temporal lobe

“…There are several approaches for dealing with this issue (Friston et al, 1997; Rissman et al, 2004). Here we adopt a “background connectivity” approach in which stimulus-evoked responses and noise sources are projected out of the data and correlations are calculated in the residuals during different experimental conditions (Al-Aidroos et al, 2012; Griffis et al, 2015; Norman-Haignere et al, 2012; Duncan et al, 2014; Tompary et al, 2015). The resulting connectivity reflects spontaneous, intrinsic interactions within the functional networks engaged by each condition.…”

High-resolution <em>In Vivo</em> Manual Segmentation Protocol for Human Hippocampal Subfields Using 3T Magnetic Resonance Imaging

“…Although images taken at a high field strength are able to offer detailed insight into hippocampal subfields, high-field scanners are not yet common in clinical or research settings, so 7T and 9.4T protocols currently have limited applicability. Similar protocols have been developed for images collected on 3T and 4T scanners 11,20,21,23,24,25,28,33 . Many of these protocols are based on images with sub-1mm voxels voxel dimensions in the coronal plane, but have large slice thicknesses (0.8-3 mm) 11,20,21,23,25,28,33 or large inter-slice distances 20,28 , both of which result in a significant measurement bias in the estimation of volumes of the individual subfields.…”

“…Many of these protocols are based on images with sub-1mm voxels voxel dimensions in the coronal plane, but have large slice thicknesses (0.8-3 mm) 11,20,21,23,25,28,33 or large inter-slice distances 20,28 , both of which result in a significant measurement bias in the estimation of volumes of the individual subfields. Additionally, many of the existing 3T protocols exclude subfields in all or part of the hippocampal head or tail 20,23,25,33 or do not provide detailed segmentations of important substructures (i.e., combine the DG with CA2/CA3 or do not include the strata radiatum/lacunosum/moleculare of the CA) 11,20,21,23,24,25,28,33 . There is therefore a need in the field for a detailed description of a protocol that can reliably identify relevant subfields throughout the head, body, and tail of the hippocampus that is based on a scanner commonly available in clinical and research settings.…”