CA2 beyond social memory: Evidence for a fundamental role in hippocampal information processing

Lehr, Andrew B.; Kumar, Arvind; Tetzlaff, Christian; Hafting, Torkel; Fyhn, Marianne; Stöber, Tristan M.

doi:10.1016/j.neubiorev.2021.03.020

Cited by 37 publications

(31 citation statements)

References 157 publications

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“…A strong control by CA2 of pathological hippocampal network activity such as temporal lobe seizures is consistent with recent investigations into the role of CA2 in healthy animals (Kay & Frank, 2019; Lehr et al, 2021). Thus, CA2 PCs play an important role in generating sharp wave ripples (SWRs), brief periods of synchronous firing observed during slow wave sleep.…”

Section: Discussionsupporting

confidence: 90%

“…Although relatively small, the CA2 subfield is of particular interest as it forms the nexus of a powerfully excitatory disynaptic circuit that directly links cortical input to hippocampal output (Chevaleyre & Siegelbaum, 2010; Srinivas et al, 2017). Furthermore, accumulating evidence suggests that CA2 may have a unique role regulating hippocampal network excitability and organizing population activity (Boehringer et al, 2017; He et al, 2021; Lehr et al, 2021; Oliva, Fernández-Ruiz, Buzsáki, & Berényi, 2016; Oliva, Fernández-Ruiz, Leroy, & Siegelbaum, 2020). Recordings from surgically-resected hippocampal tissue from patients with refractory TLE revealed spontaneous interictal-like spikes in CA2, but the study could not address whether CA2 activity contributes to spontaneous recurring seizures (Wittner et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Enhanced excitability of the hippocampal CA2 region and its contribution to seizure generation in a mouse model of temporal lobe epilepsy

Whitebirch

LaFrancois

Jain

et al. 2022

Preprint

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The hippocampal CA2 region, an area important for social memory, has been suspected to play a role in temporal lobe epilepsy (TLE) because of its resistance to the degeneration observed in neighboring CA1 and CA3 regions in both human and rodent models of TLE. However, little is known about whether alterations in CA2 properties serve to promote seizure generation or propagation. Here we have used the pilocarpine-induced status epilepticus (PILO-SE) model of TLE to explore the role of CA2. Ex vivo electrophysiological recordings from acute hippocampal slices revealed a set of coordinated changes that enhance CA2 intrinsic excitability, reduce CA2 local inhibitory input, and increase CA2 excitatory output to its major CA1 synaptic target. Moreover, selective silencing of CA2 pyramidal cells using a chemogenetic approach caused a significant decrease in the frequency of spontaneous seizures. These findings provide the first evidence that CA2 actively contributes to TLE seizure activity and may thus be a promising therapeutic target.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Enhanced excitability of the hippocampal CA2 region and its contribution to seizure generation in a mouse model of temporal lobe epilepsy

Whitebirch

LaFrancois

Jain

et al. 2022

Preprint

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“…The hippocampal CA2 region has been proven to be a crucial hub in SRM processing [ 9 , 13 ]. A host of neuromodulatory inputs have been suggested to converge on the CA2 subfield [ 40 , 41 ], among which OXT and its closely related neuropeptide arginine vasopressin have been received much more attention. We have previously reported that conditional deletion of CA2/CA3a OXTR impairs the persistence of long-term SRM [ 12 ], but no consensus has thus far emerged.…”

Section: Discussionmentioning

confidence: 99%

A dorsal CA2 to ventral CA1 circuit contributes to oxytocinergic modulation of long-term social recognition memory

et al. 2022

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Background Social recognition memory (SRM) is the ability to distinguish familiar from novel conspecifics and is crucial for survival and reproductive success across social species. We previously reported that oxytocin (OXT) receptor (OXTR) signaling in the CA2/CA3a of dorsal hippocampus is essential to promote the persistence of long-term SRM, yet how the endogenous OXT system influences CA2 outputs to regulate long-term SRM formation remains unclear. Methods To achieve a selective deletion of CA2 OXTRs, we crossed Amigo2-Cre mice with Oxtr-floxed mice to generate CA2-specific Oxtr conditional knockout (Oxtr−/−) mice. A three-chamber paradigm test was used for studying SRM in mice. Chemogenetic and optogenetic targeting strategies were employed to manipulate neuronal activity. Results We show that selective ablation of Oxtr in the CA2 suffices to impair the persistence of long-term SRM but has no effect on sociability and social novelty preference in the three-chamber paradigm test. We find that cell-type specific activation of OXT neurons within the hypothalamic paraventricular nucleus enhances long-term SRM and this enhancement is blocked by local application of OXTR antagonist L-368,899 into dorsal hippocampal CA2 (dCA2) region. In addition, chemogenetic neuronal silencing in dCA2 demonstrated that neuronal activity is essential for forming long-term SRM. Moreover, chemogenetic terminal-specific inactivation reveals a crucial role for dCA2 outputs to ventral CA1 (vCA1), but not dorsal lateral septum, in long-term SRM. Finally, targeted activation of the dCA2-to-vCA1 circuit effectively ameliorates long-term SRM deficit observed in Oxtr−/− mice. Conclusions These findings highlight the importance of hippocampal CA2 OXTR signaling in governing the persistence of long-term SRM and identify a hippocampal circuit linking dCA2 to vCA1 necessary for controlling long-term SRM formation.

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“…In hippocampal CA2, selective release of neuromodulators has been suggested to prioritize important experiences for replay via neuromodulator-dependent plasticity (dependent e.g. on vasopressin, oxytocin, or substance P; 70 , 71 ). Our results here suggest that widespread release coming after an experience can still selectively determine the neuronal subpopulation recruited to store a memory.…”

Section: Discussionmentioning

confidence: 99%

Neuromodulator-dependent synaptic tagging and capture retroactively controls neural coding in spiking neural networks

Lehr

Luboeinski

Tetzlaff

2022

Sci Rep

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Events that are important to an individual’s life trigger neuromodulator release in brain areas responsible for cognitive and behavioral function. While it is well known that the presence of neuromodulators such as dopamine and norepinephrine is required for memory consolidation, the impact of neuromodulator concentration is, however, less understood. In a recurrent spiking neural network model featuring neuromodulator-dependent synaptic tagging and capture, we study how synaptic memory consolidation depends on the amount of neuromodulator present in the minutes to hours after learning. We find that the storage of rate-based and spike timing-based information is controlled by the level of neuromodulation. Specifically, we find better recall of temporal information for high levels of neuromodulation, while we find better recall of rate-coded spatial patterns for lower neuromodulation, mediated by the selection of different groups of synapses for consolidation. Hence, our results indicate that in minutes to hours after learning, the level of neuromodulation may alter the process of synaptic consolidation to ultimately control which type of information becomes consolidated in the recurrent neural network.

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CA2 beyond social memory: Evidence for a fundamental role in hippocampal information processing

Cited by 37 publications

References 157 publications

Enhanced excitability of the hippocampal CA2 region and its contribution to seizure generation in a mouse model of temporal lobe epilepsy

Enhanced excitability of the hippocampal CA2 region and its contribution to seizure generation in a mouse model of temporal lobe epilepsy

A dorsal CA2 to ventral CA1 circuit contributes to oxytocinergic modulation of long-term social recognition memory

Neuromodulator-dependent synaptic tagging and capture retroactively controls neural coding in spiking neural networks

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