The Hippocampal CA2 Ensemble Is Sensitive to Contextual Change

Abstract

Contextual learning involves associating cues with an environment and relating them to past experience. Previous data indicate functional specialization within the hippocampal circuit: the dentate gyrus (DG) is crucial for discriminating similar contexts, whereas CA3 is required for associative encoding and recall. Here, we used Arc/H1a catFISH imaging to address the contribution of the largely overlooked CA2 region to contextual learning by comparing ensemble codes across CA3, CA2, and CA1 in mice exposed to familiar, altered, and novel contexts. Further, to manipulate the quality of information arriving in CA2 we used two hippocampal mutant mouse lines, CA3-NR1 KOs and DG-NR1 KOs, that result in hippocampal CA3 neuronal activity that is uncoupled from the animal's sensory environment. Our data reveal largely coherent responses across the CA axis in control mice in purely novel or familiar contexts; however, in the mutant mice subject to these protocols the CA2 response becomes uncoupled from CA1 and CA3. Moreover, we show in wild-type mice that the CA2 ensemble is more sensitive than CA1 and CA3 to small changes in overall context. Our data suggest that CA2 may be tuned to remap in response to any conflict between stored and current experience.

Neural Population Evidence of Functional Heterogeneity along the CA3 Transverse Axis: Pattern Completion versus Pattern Separation

“…The mechanisms generating the CA2 temporal instability are currently unknown (see Mankin et al, 2015, for a discussion of possible mechanisms). CA2 representational plasticity has been studied with IEG expression (Wintzer et al, 2014), and interesting differences with CA3 have been reported. It will be important for future studies to concentrate on this long-neglected component of the hippocampal pyramidal layer to understand its precise computational roles in comparison with the differentiated roles of CA3 and CA1 that have begun to be unraveled in the past decade (Guzowski et al, 2004; Lee et al, 2004a; Lee et al, 2004b; Leutgeb et al, 2004).…”

Novel connection between newborn granule neurons and the hippocampal CA2 field

“…A widely accepted definition of the CA2 region also included the absence of mossy fiber innervation (de Nó, 1934;van Strien et al, 2009) and a prominent innervation from the supramammillary nucleus (Haglund et al, 1984). However, recent data obtained by novel optogenetic and electrophysiological tools have revealed unique features of this alternative circuit which is essential for social and contextual learning (Hitti and Siegelbaum, 2014;Kohara et al, 2014;Wintzer et al, 2014). It is possible that the singularity of this role is determined by the unusual and profuse connections received by the CA2 region.…”

“…Thus the question as to whether newborn neurons contribute to this connection is highly relevant, especially when taking into account that both the CA2 region and AHN are implicated in pattern separation. In fact, recent data point to remarkable functional similarities between the DG and CA2 region in detecting and encoding changes in patterns of similar inputs (Leutgeb et al, 2007;Wintzer et al, 2014). Not surprisingly, these two structures share a high degree of inhibitory tone (Mercer et al, 2007) and receive inputs from the supramammillary nucleus (Haglund et al, 1984), a region that plays a determinant role in reactions to novelty (Ito et al, 2009).…”

“…However, recent data point to the existence of an alternative trisynaptic circuit (Kohara et al, 2014) that involves the connection between mature granule neurons and CA2 pyramidal neurons. This alternative circuit is crucial for contextual and social memory (Hitti and Siegelbaum, 2014;Wintzer et al, 2014). However, whether newborn granule neurons contribute to this connection remains unknown.…”

Rediscovering area CA2: unique properties and functions

“…Using compartment analysis of temporal activity fluorescence in situ hybridization (catFISH) in mice 84 , the authors of this study found that when subtle contextual changes were made to a familiar environment, such as replacing an object with a new one, the cell ensembles in CA2 changed dramatically, whereas changes to cell ensembles in areas CA1 and CA3 were closer to being proportional to the magnitude of the contextual change 84 . These data suggest that CA2 neurons are more sensitive to subtle changes in contexts than neurons in areas CA1 and CA3 (REF.…”