Memory retrieval along the proximodistal axis of CA1

Abstract

The proximal and distal segments of CA1 are thought to perform distinct computations. Neurons in proximal CA1 are reciprocally connected with the medial entorhinal cortex (MEC) and exhibit precise spatial firing. In contrast, cells in distal CA1 communicate with the lateral entorhinal cortex (LEC), exhibit more diffuse spatial firing and are affected by the presence of objects in the environment. To determine if these segments make unique contributions to memory retrieval, we examined cellular activity along the proximodistal axis of CA1 using transgenic reporter mice. Neurons tagged during context learning in proximal CA1 were more likely to be reactivated during testing than those in distal CA1. This was true following context fear conditioning and after exposure to a novel environment. Reactivation was also higher in brain regions connected to proximal CA1 (MEC, distal CA3) than those connected to the distal segment (LEC, proximal CA3). To examine contributions to memory retrieval, we performed neurotoxic lesions of proximal or distal CA1 after training. Lesions of the proximal segment significantly impaired memory retrieval while damage to distal CA1 had no effect. These data suggest that context memories are retrieved by a hippocampal microcircuit that involves the proximal but not distal segment of CA1.

Proximodistal Heterogeneity of Hippocampal CA3 Pyramidal Neuron Intrinsic Properties, Connectivity, and Reactivation during Memory Recall

“…Using a genetic memory trace strategy (Cazzulino et al, 2016; Denny et al, 2014; Josselyn et al, 2015), we demonstrated variations in the engagement of CA3 neurons in memory recall along the CA3 transverse axis. Our findings support the results of a recent study in showing that CA3c has weaker reactivation compared to more distal regions of CA3 (Nakazawa et al, 2016). By distinguishing between CA3a and CA3b, we find that cellular reactivation efficiency peaks in CA3b.…”

“…A functional divergence along the proximodistal axis has also been observed in CA1 (Henriksen et al, 2010; Igarashi et al, 2014; Masurkar et al, 2017; Nakazawa et al, 2016). The distinctive behavioral roles and physiological properties of distal versus proximal CA1 are primarily attributed to differences in the sources of synaptic input.…”

“…A number of studies support the view that hippocampal CA3 neurons have distinct anatomical (Ishizuka et al, 1990, 1995; Li et al, 1994; Turner et al, 1995) and molecular properties (Thompson et al, 2008) along the transverse axis. In addition the CA3 subregions may differentially participate in encoding spatial and contextual representations (Lee et al, 2015; Lu et al, 2015) and play different roles in learning and memory (Hunsaker et al, 2008; Nakamura et al, 2013) and memory recall (Nakazawa et al, 2016). However, there had been no systematic exploration of the circuit-based mechanisms that enable the distinct CA3 subregions to carry out their specific functions.…”

“…Imaging of immediate early gene Arc expression revealed a proximodistal gradient of activation during pattern separation, with proximal CA3 showing the greatest sensitivity to different environments and distal CA3 the least (Marrone et al., 2014). In addition, a proximodistal gradient of increasing reactivation of CA3 during retrieval of fear memory has recently been reported based on c-fos driven transgene expression (Nakazawa et al, 2016). These data are consistent with a functional gradient of place cell properties along the proximodistal axis, with distal CA3 more strongly involved in pattern completion and proximal CA3 more strongly involved in pattern separation (Lee et al, 2015; Lu et al., 2015).…”

Nonspatial sequence coding varies along the CA1 transverse axis

“…Relative to distal CA1 cells, place cells in proximal CA1 are more spatially selective, carry more spatial information, show higher rate remapping following changes to the environment, and exhibit stronger theta phase-coupling with spatially tuned MEC cells (Henriksen et al, 2010;Hartzell et al, 2013;Oliva et al, 2016). Relative to distal CA1, proximal CA1 also shows higher immediate early gene (c-fos) activation during memory retrieval for spatially-cued contextual fear, and proximal (but not distal) CA1 lesions abolish such memory retrieval (Nakazawa et al, 2016).…”