Contextual Memory Formation Research Articles

Cellular and circuit features distinguish dentate gyrus semilunar granule cells and granule cells activated during contextual memory formation.

Evaluation of semilunar granule cell involvement in dentate gyrus contextual memory processing supports recruitment based on intrinsic and input characteristics while revealing limited contribution to ensemble refinement.

Activation of Gs Signaling in Cortical Astrocytes Does Not Influence Formation of a Persistent Contextual Memory Engram.

Formation and retrieval of remote contextual memory depends on cortical engram neurons that are defined during learning. Manipulation of astrocytic Gq and Gi associated G-protein coupled receptor (GPCR) signaling has been shown to affect memory processing, but little is known about the role of cortical astrocytic Gs-GPCR signaling in remote memory acquisition and the functioning of cortical engram neurons. We assessed this by chemogenetic manipulation of astrocytes in the medial prefrontal cortex (mPFC) of male mice, during either encoding or consolidation of a contextual fear memory, while simultaneously labeling cortical engram neurons. We found that stimulation of astrocytic Gs signaling during memory encoding and consolidation did not alter remote memory expression. In line with this, the size of the mPFC engram population and the recall-induced reactivation of these neurons was unaffected. Hence, our data indicate that activation of Gs-GPCR signaling in cortical astrocytes is not sufficient to alter memory performance and functioning of cortical engram neurons.

Hippocampal cholecystokinin-expressing interneurons regulate temporal coding and contextual learning

Cholecystokinin-expressing interneurons (CCKIs) are hypothesized to shape pyramidal cell-firing patterns and regulate network oscillations and related network state transitions. To directly probe their role in the CA1 region, we silenced their activity using optogenetic and chemogenetic tools in mice. Opto-tagged CCKIs revealed a heterogeneous population, and their optogenetic silencing triggered wide disinhibitory network changes affecting both pyramidal cells and other interneurons. CCKI silencing enhanced pyramidal cell burst firing and altered the temporal coding of place cells: theta phase precession was disrupted, whereas sequence reactivation was enhanced. Chemogenetic CCKI silencing did not alter the acquisition of spatial reference memories on the Morris water maze but enhanced the recall of contextual fear memories and enabled selective recall when similar environments were tested. This work suggests the key involvement of CCKIs in the control of place-cell temporal coding and the formation of contextual memories.

Developmental and molecular contributions to contextual fear memory emergence in mice

Cognitive impairment is a common phenotype of neurodevelopmental disorders, but how these deficits arise remains elusive. Determining the onset of discrete cognitive capabilities facilitates studies in probing mechanisms underlying their emergence. The present study analyzed the emergence of contextual fear memory persistence (7-day memory retention) and remote memory (30-day memory retention). There was a rapid transition from postnatal day (P) 20 to P21, in which memory persistence emerged in C57Bl/6 J male and female mice. Remote memory was present at P23, but expression was not robust compared to pubertal and adult mice. Previous studies reported that following deletion of the MET receptor tyrosine kinase (MET), there are fear memory deficits in adult mice and the timing of critical period plasticity is altered in the developing visual cortex, positioning MET as a regulator for onset of contextual fear memory. Sustaining Met past the normal window of peak cortical expression or deleting Met, however, did not alter the timing of emergence of persistence or remote memory capabilities during development. Fear memory in young adults, however, was disrupted. Remarkably, compared to homecage controls, the number of FOS-expressing infragranular neurons in medial prefrontal cortex (mPFC) did not increase from contextual memory formation recall of fear conditioning at P35 but exhibited enhanced activation at P90 in male and female mice. Additionally, MET-expressing neurons were preferentially recruited at P90 compared to P35 during fear memory expression. The studies demonstrate a developmental profile of contextual fear memory capabilities. Further, developmental disruption of Met leads to a delayed functional deficit that arises in young adulthood, correlated with an increase of mPFC neuron activation during fear memory recall.

On the effect of social cue valence in contextual memory persistence

Social cues are valuable sensorial stimuli to the acquisition and retrieval of contextual memories. Here, we asked whether the valence of social cues would impact the formation of contextual memories. Adult male C57/BL6 mice were exposed to either conditioned place preference (CPP) or avoidance (CPA). As positive stimuli we used social interaction with a female (IF), while interaction with a male CD1 mice (IM) was used as negative stimulus. Contextual memory was tested 24 h and 7 days after conditioning. Aggressive behavior of CD1, as well as interaction with the female were quantified along the conditioning sessions. IM, but not IF, was salient enough to induce contextual memory estimated by the difference between the time in the conditioned context during test and habituation. Next, we chose two odors with innate behavioral responses and opposite valence to narrow down the sociability to one of its sensorial sources of information – the olfaction. We used urine from females in proestrus (U) and 2,4,5-trimethyl thiazoline (TMT), a predator odor. TMT decreased and U increased the time in the conditioned context during the test performed 24 h and 7 days after conditioning. Taken together, our results suggest that contextual memories conditioned to social encounters are difficult to stablish in mice, specially the one with positive valence. On the other hand, using odors with ecological relevance is a promising strategy to study long-term contextual memories with opposite valences. Ultimately, the behavioral protocol proposed here offers the advantage of studying contextual memories with opposite valences using unconditioned stimulus from the same sensorial category such as olfaction.

Memory discrimination is promoted by the expression of the transcription repressor WT1 in the dentate gyrus.

The hippocampus is critical for the precise formation of contextual memories. Overlapping inputs coming from the entorhinal cortex are processed by the trisynaptic pathway to form distinct memories. Disruption in any step of the circuit flow can lead to a lack of memory precision, and to memory interference. We have identified the transcriptional repressor Wilm's Tumor 1 (WT1) as an important regulator of synaptic plasticity involved in memory discrimination in the hippocampus. In male mice, using viral and transgenic approaches, we showed that WT1 deletion in granule cells of the dentate gyrus (DG) disrupts memory discrimination. With electrophysiological methods, we then identified changes in granule cells' excitability and DG synaptic transmission indicating that WT1 knockdown in DG granule cells disrupts the inhibitory feedforward input from mossy fibers to CA3 by decreasing mIPSCs and shifting the normal excitatory/inhibitory (E/I) balance in the DG → CA3 circuit in favor of excitation. Finally, using a chemogenetic approach, we established a causal link between granule cell hyperexcitability and memory discrimination impairments. Our results suggest that WT1 enables a circuit-level computation that drives pattern discrimination behavior.

A locus coeruleus-dorsal CA1 dopaminergic circuit modulates memory linking

Individual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and this is known to depend on a temporary increase in excitability that drives the overlap between dorsal CA1 (dCA1) hippocampal ensembles that encode the linked memories. Here, we show that locus coeruleus (LC) cells projecting to dCA1 have a key permissive role in contextual memory linking, without affecting contextual memory formation, and that this effect is mediated by dopamine. Additionally, we found that LC-to-dCA1-projecting neurons modulate the excitability of dCA1 neurons and the extent of overlap between dCA1 memory ensembles as well as the stability of coactivity patterns within these ensembles. This discovery of a neuromodulatory system that specifically affects memory linking without affecting memory formation reveals a fundamental separation between the brain mechanisms modulating these two distinct processes.

Dose-dependent suppression of hippocampal contextual memory formation, place cells, and spatial engrams by the NMDAR antagonist (R)-CPP

We recently reported that the competitive NMDAR antagonist (R,S)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) does not suppress NMDAR-mediated field EPSPs (fEPSPNMDA) or long-term potentiation (LTP) in vitro at concentrations that block contextual conditioning in vivo. Here we tested one possible explanation for the mismatch – that the hippocampus is relatively resistant to CPP compared to other brain structures engaged in contextual fear conditioning. Using the context pre-exposure facilitation effect (CPFE) paradigm to separate the hippocampal and extra-hippocampal components of contextual learning, we found that the active enantiomer (R)-CPP suppressed the hippocampal component with an IC50 of 3.1 mg/kg, a dose that produces brain concentrations below those required to block fEPSPNMDA or LTP. Moreover, using in-vivo calcium imaging of place cells and spatial engrams to directly assess hippocampal spatial coding, we found that (R)-CPP dose-dependently reduced the development of place cells and interfered with the formation of stable spatial engrams when it was administered prior to exposing mice to a novel context. Both effects occurred at doses that interfered with freezing to context in CPFE experiments. We conclude that (R)-CPP blocks memory formation by interfering with hippocampal function, but that it does so by modulating NMDARs at sites that are not engaged in vitro in the same manner that they are in vivo – perhaps through interneuron circuits that do not contribute to fEPSPs and are not required to elicit LTP using standard induction protocols in vitro, but are essential for successful mnemonic function in vivo.

β Bursting in the Retrosplenial Cortex Is a Neurophysiological Correlate of Environmental Novelty Which Is Disrupted in a Mouse Model of Alzheimer's Disease.

The retrosplenial cortex (RSC) plays a significant role in spatial learning and memory and is functionally disrupted in the early stages of Alzheimer's disease (AD). In order to investigate neurophysiological correlates of spatial learning and memory in this region we employed in vivo electrophysiology in awake and freely moving male mice, comparing neural activity between wild-type and J20 mice, a transgenic model of AD-associated amyloidopathy. To determine the response of the RSC to environmental novelty local field potentials (LFPs) were recorded while mice explored novel and familiar recording arenas. In familiar environments we detected short, phasic bursts of β (20-30 Hz) oscillations (β bursts), which arose at a low but steady rate. Exposure to a novel environment rapidly initiated a dramatic increase in the rate, size and duration of β bursts. Additionally, θ-α/β cross-frequency coupling was significantly higher during novelty, and spiking of neurons in the RSC was significantly enhanced during β bursts. Finally, excessive β bursting was seen in J20 mice, including increased β bursting during novelty and familiarity, yet a loss of coupling between β bursts and spiking activity. These findings support the concept that β bursting may be responsible for the activation and reactivation of neuronal ensembles underpinning the formation and maintenance of cortical representations, and that disruptions to this activity in J20 mice may underlie cognitive impairments seen in these animals.SIGNIFICANCE STATEMENT The retrosplenial cortex (RSC) is thought to be involved in the formation, recall and consolidation of contextual memory. The discovery of bursts of β oscillations in this region, which are associated with increased neuronal spiking and strongly upregulated while mice explore novel environments, provides a potential mechanism for the activation of neuronal ensembles, which may underlie the formation of cortical representations of context. Excessive β bursting in the RSC of J20 mice, a mouse model of Alzheimer's disease (AD), alongside the disassociation of β bursting from neuronal spiking, may underlie spatial memory impairments previously shown in these mice. These findings introduce a novel neurophysiological correlate of spatial learning and memory, and a potentially new form of AD-related cortical dysfunction.

Retrosplenial Cortex Effects Contextual Fear Formation Relying on Dysgranular Constituent in Rats.

Animal contextual fear conditioning (CFC) models are the most-studied forms used to explore the neural substances of posttraumatic stress disorder (PTSD). In addition to the well-recognized hippocampal–amygdalar system, the retrosplenial cortex (RSC) is getting more and more attention due to substantial involvement in CFC, but with a poor understanding of the specific roles of its two major constituents—dysgranular (RSCd) and granular (RSCg). The current study sought to identify their roles and underlying brain network mechanisms during the encoding processing of the rat CFC model. Rats with pharmacologically inactivated RSCd, RSCg, and corresponding controls underwent contextual fear conditioning. [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scanning was performed for each animal. The 5-h and 24-h retrieval were followed to test the formation of contextual memory. Graph theoretic tools were used to identify the brain metabolic network involved in encoding phase, and changes of nodal (brain region) properties linked, respectively, to disturbed RSCd and RSCg were analyzed. Impaired retrieval occurred in disturbed RSCd animals, not in RSCg ones. The RSC, hippocampus (Hip), amygdala (Amy), piriform cortex (Pir), and visual cortex (VC) are hub nodes of the brain-wide network for contextual fear memory encoding in rats. Nodal degree and efficiency of hippocampus and its connectivity with amygdala, Pir, and VC were decreased in rats with disturbed RSCd, while not in those with suppressed RSCg. The RSC plays its role in contextual fear memory encoding mainly relying on its RSCd part, whose condition would influence the activity of the hippocampal–amygdalar system.

Neuronal Ensembles Organize Activity to Generate Contextual Memory.

Contextual learning is a critical component of episodic memory and important for living in any environment. Context can be described as the attributes of a location that are not the location itself. This includes a variety of non-spatial information that can be derived from sensory systems (sounds, smells, lighting, etc.) and internal state. In this review, we first address the behavioral underpinnings of contextual memory and the development of context memory theory, with a particular focus on the contextual fear conditioning paradigm as a means of assessing contextual learning and the underlying processes contributing to it. We then present the various neural centers that play roles in contextual learning. We continue with a discussion of the current knowledge of the neural circuitry and physiological processes that underlie contextual representations in the Entorhinal cortex-Hippocampal (EC-HPC) circuit, as the most well studied contributor to contextual memory, focusing on the role of ensemble activity as a representation of context with a description of remapping, and pattern separation and completion in the processing of contextual information. We then discuss other critical regions involved in contextual memory formation and retrieval. We finally consider the engram assembly as an indicator of stored contextual memories and discuss its potential contribution to contextual memory.

Sex-dependent and long-lasting effects of bisphenol AF exposure on emotional behaviors in mice

We recently reported that maternal exposure to bisphenol AF (BPAF), an environmental endocrine disruptor (EED), induced significant alterations in emotional behaviors in offspring mice during adolescence in a sex-dependent manner. However, the effects of adult BPAF exposure and the potential long-lasting effects of maternal exposure to BPAF on offspring mice are still unknown. The present study aimed to investigate the neurobehavioral effects of adult and maternal exposure to BPAF, intragastrically (0.4, 4 mg•kg−1, i.g.), by using a series of classic emotional behavioral tests, mainly referring to depression, anxiety, and memory. The results showed that adult BPAF exposure significantly attenuated anxiety- and depression-like behaviors in adult male mice, while increasing anxiety-like behaviors, promoting novel object recognition memory formation, and impairing contextual fear conditioning memory formation in adult female mice. Maternal exposure to BPAF induced anxiety-like effects and anti-depression-like effects in male offspring mice during adulthood, while maternal BPAF exposure increased anxiety- and depression-like behaviors in female offspring mice during adulthood. Our present findings indicate that BPAF exposure significantly affects emotional behaviors in adult/offspring mice in a sex-dependent manner and that female adult mice are more likely to have adverse consequences to BPAF exposure during adulthood, even during early life stages.

Diversity of learning-induced synaptic plasticity at dorsal CA1 synapses: a possible underlying mechanism of contextual memory formation

We expose various kinds of context in our everyday lives and hence contextual memory is critically important for us. Since hippocampus is a major area for processing contextual memory, it needs to encode different components of various contexts such as ‘what’, ‘where’ and ‘when’, etc. However, the underlying mechanism by which the hippocampus differentially encodes various kinds of contextual information is interesting but not yet revealed completely. Since long-term potentiation (LTP) had been discovered and believed to be mechanism of learning, many studies were conducted to investigate the underlying detailed mechanism of memory formation by using various LTP induction protocols. By combining HSV-mediated in vivo gene delivery with in vitro patch-clamp recordings, it was found that LTP can induce plastic changes such as delivery of GluA1-containing AMPA receptor to the dorsal CA1 synapses of the hippocampus and also the causal relationship between this AMPA receptor delivery and learning was discovered. Then it was found that learning induced synaptic plasticity with diverse pattern highlighting the importance of this diversity in contextual memory formation. Here, we mostly review the studies which used hippocampal-dependent learning paradigm (inhibitory avoidance task) for better comparison and mapping of the concept about how learning induced diversity of synaptic plasticity at dorsal hippocampal CA1 synapses and how this diversity may become responsible as an underlying mechanism of contextual memory formation. We found that contextual learning induces synaptic plasticity at CA1 neurons with synapse-specific diversity, input-specific diversity, subregion- or subfield-specific diversity, episode-specific diversity but only a few studies revealed their functional significance. For complete understanding of learning-induced diversity of synaptic plasticity, it demands further studies for investigation of their functional correlation to learning performance by using new highly promising approaches like optogenetic techniques and cell-specific self-entropy analysis, etc.

Gradual decorrelation of CA3 ensembles associated with contextual discrimination learning is impaired by Kv1.2 insufficiency.

The associative network of hippocampal CA3 is thought to contribute to rapid formation of contextual memory from one-trial learning, but the network mechanisms underlying decorrelation of neuronal ensembles in CA3 is largely unknown. Kv1.2 expressions in rodent CA3 pyramidal cells (CA3-PCs) are polarized to distal apical dendrites, and its downregulation specifically enhances dendritic responses to perforant pathway (PP) synaptic inputs. We found that haploinsufficiency of Kv1.2 (Kcna2+/-) in CA3-PCs, but not Kv1.1 (Kcna1+/-), lowers the threshold for long-term potentiation (LTP) at PP-CA3 synapses, and that the Kcna2+/- mice are normal in discrimination of distinct contexts but impaired in discrimination of similar but slightly distinct contexts. We further examined the neuronal ensembles in CA3 and dentate gyrus (DG), which represent the two similar contexts using in situ hybridization of immediate early genes, Homer1a and Arc. The size and overlap of CA3 ensembles activated by the first visit to the similar contexts were not different between wild type and Kcna2+/- mice, but these ensemble parameters diverged over training days between genotypes, suggesting that abnormal plastic changes at PP-CA3 synapses of Kcna2+/- mice is responsible for the impaired pattern separation. Unlike CA3, DG ensembles were not different between two genotype mice. The DG ensembles were already separated on the first day, and their overlap did not further evolve. Eventually, the Kcna2+/- mice exhibited larger CA3 ensemble size and overlap upon retrieval of two contexts, compared to wild type or Kcna1+/- mice. These results suggest that sparse LTP at PP-CA3 synapse probably supervised by mossy fiber inputs is essential for gradual decorrelation of CA3 ensembles.

The role of hippocampal mossy cells in novelty detection

At the encounter with a novel environment, contextual memory formation is greatly enhanced, accompanied with increased arousal and active exploration. Although this phenomenon has been widely observed in animal and human daily life, how the novelty in the environment is detected and contributes to contextual memory formation has lately started to be unveiled. The hippocampus has been studied for many decades for its largely known roles in encoding spatial memory, and a growing body of evidence indicates a differential involvement of dorsal and ventral hippocampal divisions in novelty detection. In this brief review article, we discuss the recent findings of the role of mossy cells in the ventral hippocampal moiety in novelty detection and put them in perspective with other novelty-related pathways in the hippocampus. We propose a mechanism for novelty-driven memory acquisition in the dentate gyrus by the direct projection of ventral mossy cells to dorsal dentate granule cells. By this projection, the ventral hippocampus sends novelty signals to the dorsal hippocampus, opening a gate for memory encoding in dentate granule cells based on information coming from the entorhinal cortex. We conclude that, contrary to the presently accepted functional independence, the dorsal and ventral hippocampi cooperate to link the novelty and contextual information, and this dorso-ventral interaction is crucial for the novelty-dependent memory formation.

Activity-induced secretion of semaphorin 3A mediates learning.

The semaphorin family is a well‐characterized family of secreted or membrane‐bound proteins that are involved in activity‐independent neurodevelopmental processes, such as axon guidance, cell migration, and immune functions. Although semaphorins have recently been demonstrated to regulate activity‐dependent synaptic scaling, their roles in Hebbian synaptic plasticity as well as learning and memory remain poorly understood. Here, using a rodent model, we found that an inhibitory avoidance task, a hippocampus‐dependent contextual learning paradigm, increased secretion of semaphorin 3A in the hippocampus. Furthermore, the secreted semaphorin 3A in the hippocampus mediated contextual memory formation likely by driving AMPA receptors into hippocampal synapses via the neuropilin1–plexin A4–semaphorin receptor complex. This signaling process involves alteration of the phosphorylation status of collapsin response mediator protein 2, which has been characterized as a downstream molecule in semaphorin signaling. These findings implicate semaphorin family as a regulator of Hebbian synaptic plasticity and learning.

Accelerated long-term forgetting is a BACE1 inhibitor-reversible incipient cognitive phenotype in Alzheimer's disease model mice.

AimAfter the continued failure of β‐secretase (BACE1) inhibitor clinical trials in prodromal as well as mild‐to‐moderate Alzheimer's disease (AD), they are shifting to further earlier or asymptomatic stages. The aim of this study is to explore a cognitive paradigm that allows us to more sensitively detect beneficial effects of BACE1 inhibitors in presymptomatic AD.MethodsGRL‐8234 (33.4 mg/kg, ip), a small‐molecule BACE1 inhibitor, was administered once daily for 28 days to the 5XAFD transgenic mouse model of AD. The contextual fear conditioning was used to evaluate the effects of GRL‐8234 on memory deficits in 5XFAD mice at different ages.ResultsChronic administration of GRL‐8234 to 5XFAD mice rescued their contextual memory deficits, when tested 1 day after training at 6‐8 months but not at 12 months of age. Importantly, 4‐month‐old 5XFAD mice retain the ability to form contextual memory equivalent to wild‐type controls, demonstrating that the standard method of 1‐day memory assessment is not suitable for evaluating BACE1 inhibitor efficacy in ameliorating cognitive declines during earlier disease stages. Despite normal contextual memory formation, young 5XFAD mice showed faster forgetting when a longer delay (28 days) intervened between training and memory testing. Notably, GRL‐8234 administered to 4‐month‐old 5XFAD mice during the 28‐day delay reversed accelerated long‐term forgetting almost completely back to wild‐type control levels.ConclusionThe results provide experimental evidence that accelerated long‐term forgetting represents more sensitive memory testing that can help evaluate BACE1 inhibitor therapy in presymptomatic AD populations.

Systemic nicotine enhances opioid self-administration and modulates the formation of opioid-associated memories partly through actions within the insular cortex

Habitual use of nicotine containing products increases propensity to misuse prescription opioids and its prevalence is substantially increased in individuals currently involved in opioid-treatment programs. Nicotine enhances self-administration of many classes of drugs in rodents, though evidence for direct effects on opioids is lacking. We sought to measure the effects of nicotine pretreatment on the reinforcing efficacy of opioids in both self-administration and contextual conditioning paradigms. First, we measured the effect of systemic nicotine pretreatment on self-administration of two opioids. Additionally, we measured the degree to which systemic nicotine pretreatment impacts the formation of morphine-associated contextual memories in conditioned taste avoidance and place preference paradigms. Given the involvement of the insula in the maintenance of substance abuse, its importance in nicotine addiction, and findings that insular inactivation impairs contextual drug conditioning, we examined whether nicotine administered directly to the insula could recapitulate the effects of systemic nicotine. We demonstrate that systemic nicotine pretreatment significantly enhances opioid self-administration and alters contextual conditioning. Furthermore, intra-insula nicotine similarly altered morphine contextual conditioning by blocking the formation of taste avoidance at all three morphine doses tested (5.0, 10, and 20 mg/kg), while shifting the dose–response curve of morphine in the place preference paradigm rightward. In conclusion, these data demonstrate that nicotine facilitates opioid intake and is partly acting within the insular cortex to obfuscate aversive opiate memories while potentiating approach to morphine-associated stimuli at higher doses.

Astroglial adrenoreceptors modulate synaptic transmission and contextual fear memory formation in dentate gyrus

Astrocytes perform various supporting functions, including ion buffering, metabolic supplying and neurotransmitter clearance. They can also sense neuronal activity owing to the presence of specific receptors for neurotransmitters. In turn, astrocytes can regulate synaptic activity through the release of gliotransmitters. Evidence has shown that astrocytes are very sensitive to the locus coeruleus (LC) afferents. However, little is known about how LC neuromodulatory norepinephrine (NE) modulates synaptic transmission through astrocytic activity. In mouse dentate gyrus (DG), we demonstrated an increase in the frequency of miniature excitatory postsynaptic currents (mEPSC) in response to NE, which required the release of glutamate from astrocytes. The rise in glutamate release probability is likely due to the activation of presynaptic GluN2B-containing NMDA receptors. Moreover, we showed that the activation of NE signaling in DG is necessary for the formation of contextual learning memory. Thus, NE signaling activation during fear conditioning training contributed to enduring changes in the frequency of mEPSC in DG. Our results strongly support the physiological neuromodulatory role of NE signaling, which is derived from activation of astrocytes.

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

SummaryNovelty facilitates memory formation and is detected by both the dorsal and ventral hippocampus. Although dentate granule cells (GCs) in the dorsal hippocampus are known to mediate the formation of novelty-induced contextual memories, the required pathways and mechanisms remain unclear. Here we demonstrate that a powerful excitatory pathway from mossy cells (MCs) in the ventral hippocampus to dorsal GCs is necessary and sufficient for driving dorsal GC activation in novel environment exploration. In vivo Ca2+ imaging in freely moving mice indicated that this pathway relays environmental novelty. Furthermore, manipulation of ventral MC activity bidirectionally regulates novelty-induced contextual memory acquisition. Our results show that ventral MC activity gates contextual memory formation through an intra-hippocampal interaction activated by environmental novelty.