Ventro-dorsal Hippocampal Pathway Gates Novelty-Induced Contextual Memory Formation

Fredes, Felipe; Silva, Maria Alejandra; Koppensteiner, Peter; Kobayashi, Kenta; Joesch, Maximilian; Shigemoto, Ryuichi

doi:10.1016/j.cub.2020.09.074

Cited by 51 publications

(64 citation statements)

References 75 publications

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“…As sections progressed to more caudal and ventral regions, the number of GFP+ hilar cells increased significantly (Figure 3b5–b10). A very small number of weakly‐labeled GFP+ cells were observed in the CA3c region of some sections (Figure 3b7–b9), consistent with previous reports (Fredes et al, 2020; Yeh et al, 2018). Importantly, the GFP+ axon was largely restricted to the IML of the DG throughout the entire septotemporal axis of the DG.…”

Section: Resultssupporting

confidence: 91%

Dorsal and ventral mossy cells differ in their axonal projections throughout the dentate gyrus of the mouse hippocampus

et al. 2021

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Glutamatergic hilar mossy cells (MCs) have axons that terminate both near and far from their cell body but stay within the DG, making synapses primarily in the molecular layer. The long‐range axons are considered the primary projection, and extend throughout the DG ipsilateral to the soma, and project to the contralateral DG. The specificity of MC axons for the inner molecular layer (IML) has been considered to be a key characteristic of the DG. In the present study, we made the surprising finding that dorsal MC axons are an exception to this rule. We used two mouse lines that allow for Cre‐dependent viral labeling of MCs and their axons: dopamine receptor D2 (Drd2‐Cre) and calcitonin receptor‐like receptor (Crlr‐Cre). A single viral injection into the dorsal DG to label dorsal MCs resulted in labeling of MC axons in both the IML and middle molecular layer (MML). Interestingly, this broad termination of dorsal MC axons occurred throughout the septotemporal DG. In contrast, long‐range axons of ventral MCs terminated in the IML, consistent with the literature. Taken together, these results suggest that dorsal and ventral MCs differ significantly in their axonal projections. Since MC projections in the ML are thought to terminate primarily on GCs, the results suggest a dorsal–ventral difference in MC activation of GCs. The surprising difference in dorsal and ventral MC projections should therefore be considered when evaluating dorsal–ventral differences in DG function.

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Section: Resultssupporting

confidence: 91%

Dorsal and ventral mossy cells differ in their axonal projections throughout the dentate gyrus of the mouse hippocampus

et al. 2021

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“…It thus may not be sufficient to extrapolate findings from dMCs to all MCs across the HPC longitudinal axis. Of note, an elegant recent study using in vivo microscopy showed increased vMC activity in novel versus familiar environments that was not due to locomotion differences (72), in line with our fiber photometry findings.…”

Section: Discussionsupporting

confidence: 90%

“…Less attention has been devoted to the role of MCs, especially vMCs, in behavior relevant to neuropsychiatric disease including learning, memory, novelty, and anxiety, however there is growing research interest in these topics. Distinctions between vMCs and dMCs are supported by physiological (69-72), biochemical (27, 28), and anatomical (49, 72, 73) evidence. It thus may not be sufficient to extrapolate findings from dMCs to all MCs across the HPC longitudinal axis.…”

Section: Discussionmentioning

confidence: 94%

“…Fredes et al . showed that vMC activation prior to shock-context pairing enhanced fear conditioning when the conditioning occurred in a familiar context (72), an important finding because contextual fear conditioning is markedly stronger in novel versus familiar contexts. Another study reported that vMC chemogenetic activation did not significantly impair encoding in an object location memory task in which the delay between encoding and retrieval sessions was only one hr (74) as opposed to the 24 hr delay used in the present study and that of Bui et al .…”

Section: Discussionmentioning

confidence: 99%

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Modeling intrahippocampal effects of anterior hippocampal hyperactivity relevant to schizophrenia using chemogenetic excitation of long axis-projecting mossy cells in the mouse dentate gyrus

Bauer

Rader

Joffe

et al. 2020

Preprint

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Background: The anterior hippocampus of individuals with early psychosis or schizophrenia is hyperactive, as is the ventral hippocampus in rodent models for schizophrenia risk. Hyperactive ventral hippocampal projections to extrahippocampal brain regions contribute to schizophrenia symptoms, but less is known about the functional effects of hyperactive projections within the hippocampal formation long axis. We approached this question by testing whether hyperactivation of ventral dentate gyrus (DG) mossy cells (MCs), which densely project intrahippocampally to the dorsal DG, influences spatial memory, a cognition dependent on intact dorsal DG function. Methods: In CD-1 mice, we targeted dorsal DG-projecting ventral DG MCs using an adeno-associated virus intersectional strategy. In vivo fiber photometry recording of ventral DG MCs was performed during exploratory behaviors. We targeted excitatory chemogenetic constructs to ventral DG MCs and tested whether their hyperactivation impaired encoding in a spatial memory task. Results: Ventral DG MCs were activated during behavior related to environmental information gathering (rearing) but not during non-exploratory motor behaviors. Ventral DG MCs made functional monosynaptic inputs to dorsal DG granule cells, with chemogenetic activation of ventral DG MCs leading to increased activity of dorsal DG granule cells. Finally, chemogenetic activation of ventral DG MCs during the encoding phase of an object location memory task impaired retrieval 24 hours later, without effects on locomotion or other exploratory behaviors. Conclusions: These data suggest that localized hippocampal hyperactivity may have longitudinal intrahippocampal functional consequences, supporting study of longitudinal circuits as targets to mitigate cognitive deficits associated with schizophrenia.

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“…Activity levels in granule cell populations have been shown to decrease over the time course of several minutes and more as the animal familiarizes itself with a novel environment 10,69,71 . However, how the population activity changes at the moment when the animal transitions into a novel environment is unclear.…”

Section: Discussionmentioning

confidence: 99%

A synaptic novelty signal to switch hippocampal attractor networks from generalization to discrimination

Gómez-Ocádiz

Trippa

Posani

et al. 2021

Preprint

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Episodic memory formation and recall are complementary processes that put conflicting requirements on neuronal computations in the hippocampus. How this challenge is resolved in hippocampal circuits is unclear. To address this question, we obtained in vivo whole-cell patch-clamp recordings from dentate gyrus granule cells in head-fixed mice navigating in familiar and novel virtual environments. We find that granule cells consistently show a small transient depolarization of their membrane potential upon transition to a novel environment. This synaptic novelty signal is sensitive to local application of atropine, indicating that it depends on metabotropic acetylcholine receptors. A computational model suggests that the observed transient synaptic response to novel environments may lead to a bias in the granule cell population activity, which can in turn drive the downstream attractor networks to a new state, thereby favoring the switch from generalization to discrimination when faced with novelty. Such a novelty-driven cholinergic switch may enable flexible encoding of new memories while preserving stable retrieval of familiar ones.

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Ventro-dorsal Hippocampal Pathway Gates Novelty-Induced Contextual Memory Formation

Cited by 51 publications

References 75 publications

Dorsal and ventral mossy cells differ in their axonal projections throughout the dentate gyrus of the mouse hippocampus

Dorsal and ventral mossy cells differ in their axonal projections throughout the dentate gyrus of the mouse hippocampus

Modeling intrahippocampal effects of anterior hippocampal hyperactivity relevant to schizophrenia using chemogenetic excitation of long axis-projecting mossy cells in the mouse dentate gyrus

A synaptic novelty signal to switch hippocampal attractor networks from generalization to discrimination

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