Biology subjects

Grella, S. L.

Publications and source records attributed to Grella, S. L..

9 recordsLinked to original sources

bioRxiv2026

Chemogenetic Inhibition of the Ventrolateral Orbitofrontal Cortex Disrupts Prediction Error and Salience-Guided Memory-Updating at the Hippocampal Engram Level

RationaleAdaptive behavior requires revising memories when outcomes deviate from expectations. The orbitofrontal cortex (OFC) is implicated in representing outcome expectancies, but its role in memory-updating, beyond value-based learning, remains unclear. ObjectivesWe tested whether the ventrolateral OFC (VLO) contributes to hippocampal-dependent memory-updating in the Objects in Updated Locations (OUL) task, where novelty-driven exploration provides a behavioral readout consistent with successful updating of spatial information MethodsUsing inhibitory DREADDs, in male and female (Swiss Webster and C57BL/6) mice, we suppressed VLO activity during the Updating session, when new object-location information was introduced. ResultsControl mice preferentially explored the updated object-location configuration during Updating and discriminated between updated and novel object-location configurations at Test, whereas VLO-inhibited mice did not. VLO inhibition when no updating demand was present did not alter exploration of novel object-location configurations or memory for the original spatial configuration at Test. ConclusionsThese results indicate that VLO activity is selectively required when novelty must be interpreted relative to prior experience, implicating this region in evaluating change rather than detecting it. To assess hippocampal ensemble dynamics, we tagged neuronal ensembles, in the dorsal dentate gyrus (dDG) recruited during Updating, followed by quantification of overlap between Updating-tagged cells and ensembles reactivated at Test. We found that VLO inhibition reduced reactivation of Updating-tagged dDG ensembles, paralleling the behavioral impairments observed in the OUL task. These findings support a role for the VLO in hippocampal-dependent memory-updating and extend OFC models beyond reward contexts to include predictive updating of spatial memory representations. Significance StatementUsing a spatial paradigm that distinguishes detection of changed information from incorporation of that information into an updated hippocampal representation, we found that ventrolateral orbitofrontal cortex (VLO) activity is required for memory-updating when new information is present. We found behavioral deficits accompanied by impairments in hippocampal ensemble representations, indicating VLO activity is necessary for memory-updating at the hippocampal engram level. Through this mechanism, the OFC supports the flexible updating of expected outcomes when environmental conditions shift, allowing for the re-evaluation of previously learned associations. These findings extend models of orbitofrontal cortex function beyond reward-guided behavior and identify a cortical contribution to predictive spatial memory processes. Disruption of this computation may contribute to the cognitive rigidity observed in neuropsychiatric disorders.

neuroscience↗

bioRxiv2026

Artificial Reactivation of a Cocaine-Associated Engram in the Dorsal Dentate Gyrus Attenuates Cocaine Prime-Induced Reinstatement of Drug-Seeking

Relapse-prevention strategies aimed at reducing relapse following abstinence, primarily focus on reducing cravings that lead to drug-seeking triggered by stress, drug-related cues, or re-exposure to the drug. Because addictive drugs form persistent associative contextual memories, we investigated how reactivation of cocaine-related hippocampal memories influences subsequent drug-seeking. Here, we tagged dorsal dentate gyrus (dDG) memory ensembles involved in encoding either a first or fourth cocaine exposure (15mg/kg, i.p) in male and female c57BL/6 mice using a TetTag approach. Mice underwent cocaine conditioned place preference (CPP), extinction, and reinstatement. We assessed whether optical reactivation of tagged cocaine-related ensembles could substitute for a cocaine priming injection to reinstate CPP, whether reactivation altered cocaine-induced reinstatement, and if these effects differed depending on stage of drug exposure. We also compared these effects to reactivation of saline-associated ensembles. Cocaine produced robust locomotor activation during conditioning, and sensitization developed across repeated drug exposures. Reactivation of a cocaine-related engram alone did not reinstate CPP. However, reactivation of the first cocaine exposure engram attenuated cocaine-induced reinstatement. In contrast, reactivation of the fourth exposure engram did not confer this protective effect. Interestingly, reactivation of saline-associated ensembles also reduced cocaine-induced reinstatement specifically in females, suggesting dDG ensemble reactivation may modulate relapse-related behavior through interference or neuromodulatory disruption of cocaine-associated representations, consistent with our prior work. These findings raise the possibility that early contextual experiences form competing or destabilizing representations that interfere with later cocaine-seeking when reactivated. Females also displayed greater sensitivity to locomotor-inducing effects of cocaine memory reactivation, although this was dissociated from CPP. Together, these findings show that cocaine memories are distinct across drug experience and selective reactivation of dDG engrams can differentially influence drug-seeking.

animal behavior and cognition↗

bioRxiv2021

Reactivating Hippocampal-Mediated Memories to Disrupt the Reconsolidation of Fear

Memories are stored in the brain as cellular ensembles activated during learning and reactivated during retrieval. Using the Tet-tag system in mice, we label dorsal dentate gyrus neurons activated by positive, neutral or negative experiences with channelrhodopsin-2. Following fear-conditioning, these cells are artificially reactivated during fear memory recall. Optical stimulation of a competing positive memory is sufficient to update the memory during reconsolidation, thereby reducing conditioned fear acutely and enduringly. Moreover, mice demonstrate operant responding for reactivation of a positive memory, confirming its rewarding properties. These results show that interference from a rewarding experience can counteract negative affective states. While memory-updating, induced by memory reactivation, involves a relatively small set of neurons, we also find that activating a large population of randomly labeled dorsal dentate gyrus neurons is effective in promoting reconsolidation. Importantly, memory-updating is specific to the fear memory. These findings implicate the dorsal dentate gyrus as a potential therapeutic node for modulating memories to suppress fear.

neuroscience↗

bioRxiv2020

Hippocampal cells multiplex positive and negative engrams

The hippocampus is involved in processing a variety of mnemonic computations specifically the spatiotemporal components and emotional dimensions of contextual memory.1-3 Recent studies have demonstrated vast structural and functional heterogeneity along the dorsal-ventral axis1, 5 of the hippocampus. The ventral hippocampus has been shown to be important in the processing of emotion and valence.6-9 Here, we combine transgenic and all-virus based activity-dependent tagging strategies to visualize multiple valence-specific engrams in the vHPC and demonstrate two partially segregated cell populations and projections that respond to appetitive and aversive experiences. Next, using RNA sequencing and DNA methylation sequencing approaches, we find that vHPC appetitive and aversive engram cells display distinct transcriptional programs and DNA methylation landscapes compared to a neutral engram population. Additionally, while optogenetic manipulation of tagged cell bodies in vHPC is not sufficient to drive appetitive or aversive behavior in real-time place preference, stimulation of tagged vHPC terminals projecting to the amygdala and nucleus accumbens (NAc), but not the prefrontal cortex (PFC), had the capacity drive preference and avoidance. These terminals can also undergo a "switch" or "reset" in their capacity to drive either, thereby demonstrating their adaptable contributions to behavior. We conclude that the vHPC contains genetically, cellularly, and behaviorally distinct populations of cells processing appetitive and aversive memory engrams. Together, our findings provide a novel means by which to visualize multiple engrams within the same brain and point to their unique genetic signatures as reference maps for the future development of new therapeutic strategies. One sentence summaryThe hippocampus contains neurons that correspond to positive and negative engrams, which are segregated by their molecular, cellular, and projection-specific features.

neuroscience↗

bioRxiv2020

Chronic activation of fear engrams induces extinction-like behavior in ethanol-exposed mice

Alcohol withdrawal directly impacts the brains stress and memory systems, which may underlie individual susceptibility to persistent drug and alcohol-seeking behaviors. Numerous studies demonstrate that forced alcohol abstinence, which may lead to withdrawal, can impair fear-related memory processes in rodents such as extinction learning, however the underlying neural circuits mediating these impairments remain elusive. Here, we tested an optogenetic strategy aimed at mitigating fear extinction impairments in male c57BL/6 mice following exposure to alcohol (i.e., ethanol) and forced abstinence. In the first experiment, extensive behavioral extinction training in a fear-conditioned context was impaired in ethanol-exposed mice compared to controls. In the second experiment, neuronal ensembles processing a contextual fear memory in the dorsal hippocampus were tagged and optogenetically reactivated repeatedly in a distinct context in ethanol-exposed and control mice. Chronic activation of these cells resulted in a context-specific, extinction-like reduction in fear responses in both control and ethanol-exposed mice. These findings suggest that while ethanol can impair fear extinction learning, optogenetic manipulation of a fear engram is sufficient to induce an extinction-like reduction in fear responses.

neuroscience↗

bioRxiv2020

Norepinephrine as a Memory Reset Signal: Switching the System from Retrieval to Encoding During a Spatial Memory Task can be Both Adaptive and Maladaptive

Contextual information is represented in the hippocampus (HPC) partially through the recruitment of distinct neuronal ensembles. It is believed that reactivation of these ensembles underlies memory retrieval processes. Recently, we showed that norepinephrine (NE) input from phasic locus coeruleus (LC) activation induces hippocampal plasticity resulting in the recruitment of new neurons and a disengagement from previously established representations. We hypothesize that NE may provide a neuromodulatory, mnemonic switch signaling the HPC to move from a state of retrieval to encoding in the presence of novelty, and therefore, plays a role in memory updating. Here, we tested whether bilateral dorsal dentate gyrus (DG) infusions of the {beta}-adrenergic receptor (BAR) agonist isoproterenol (ISO), administered prior to encoding or retrieval, would impair spatial working and reference memory by reverting the system to encoding (thereby recruiting new neurons) potentially interfering with retrieval of the previously established spatial ensemble. We also investigated whether dDG infusions of ISO could promote cognitive flexibility by switching the system to encoding when it is adaptive (i.e. when new information is presented e.g. reversal learning). We found that intra-dDG infusions of ISO given prior to retrieval caused deficits in working and reference memory which was blocked by pre-treatment with the BAR-antagonist, propranolol (PRO). In contrast, ISO administered prior to reversal learning led to improved performance. These data support our hypothesis that NE serves as a novelty signal to update HPC contextual representations via BAR activation-facilitated recruitment of new neurons. This can be both maladaptive and adaptive depending on the situation. SIGNIFICANCE STATEMENTThe current work highlights the involvement of hippocampal BARs in determining the flexibility of contextual representations to promote new learning in a way that supports adaptive behavior. This work builds upon previous work showing that noradrenergic input to the hippocampus is involved in recruiting new neurons resulting in new contextual representations and may be involved in the underlying neural mechanisms that support memory updating. These data suggest targets for anxiety disorders such as PTSD, which are characterized by noradrenergic dysregulation, and may also involve impairments in memory updating mechanisms where the incorporation of new information is not effectively encoded. The further understanding of the neurobiological mechanisms involved in updating memories may provide insight into novel treatment strategies.

animal behavior and cognition↗

bioRxiv2020

Chronic optogenetic stimulation of hippocampal engrams variably modulates social behaviors in mice

The hippocampus processes both spatial-temporal information and emotionally salient experiences. To test the functional properties of discrete sets of cells in the dorsal dentate gyrus (dDG), we examined whether chronic optogenetic reactivation of these ensembles was sufficient to modulate social behaviors in mice. We found that chronic reactivation of dDG cells in male mice was sufficient to enhance social behaviors in a female exposure task when compared to pre-stimulation levels. However, chronic reactivation of these cells was not sufficient to modulate group differences in a separate subset of social behaviors, and multi-region analysis of neural activity did not yield detectable differences in immediate-early gene expression or neurogenesis, suggesting a dissociation between our chronic stimulation-induced behavioral effects and underlying neural responses. Together, our results demonstrate that chronic optogenetic stimulation of cells processing valent experiences enduringly and unidirectionally modulates social interactions between male and female mice.

neuroscience↗

bioRxiv2019

Hippocampus and amygdala fear memory engrams re-emerge after contextual fear reinstatement

The formation and extinction of fear memories represent two forms of learning that each engage the hippocampus and amygdala. How cell populations in these areas contribute to fear relapse, however, remains unclear. Here, we demonstrate that, in male mice, cells active during fear conditioning in the dentate gyrus of hippocampus exhibit decreased activity during extinction and are re-engaged after contextual fear relapse. In vivo calcium imaging reveals that relapse drives population dynamics in the basolateral amygdala to revert to a network state similar to the state present during fear conditioning. Finally, we find that optogenetic inactivation of neuronal ensembles active during fear conditioning in either the hippocampus or amygdala is sufficient to disrupt fear expression after relapse. These results suggest that fear relapse triggers a partial re-emergence of the original fear memory representation, providing new insight into the neural substrates of fear relapse.

neuroscience↗

bioRxiv2019

Odor Modulates the Temporal Dynamics of Fear Memory Consolidation

Systems consolidation (SC) theory proposes that recent, contextually rich memories are stored in the hippocampus (HPC). As these memories become remote, they are believed to rely more heavily on cortical structures within the prefrontal cortex (PFC), where they lose much of their contextual detail and become schematized. Odor is a particularly evocative cue for intense remote memory recall and despite these memories being remote, they are highly contextual. In instances such as post-traumatic stress disorder (PTSD), intense remote memory recall can occur years after trauma, which seemingly contradicts SC. We hypothesized that odor may shift the organization of salient or fearful memories such that when paired with an odor at the time of encoding, they are delayed in the de-contextualization process that occurs across time, and retrieval may still rely on the HPC, where memories are imbued with contextually rich information, even at remote time points. We investigated this by tagging odor- and non-odor-associated fear memories in male c57BL/6 mice and assessed recall and c-Fos expression in the dorsal CA1 (dCA1) and prelimbic cortex (PL) 1 d or 21 d later. In support of SC, our data showed that recent memories were more dCA1-dependent whereas remote memories were more PL-dependent. However, we also found that odor influenced this temporal dynamic biasing the memory system from the PL to the dCA1 when odor cues were present. Behaviorally, inhibiting the dCA1 with activity-dependent DREADDs had no effect on recall at 1 d and unexpectedly caused an increase in freezing at 21 d. Together, these findings demonstrate that odor can shift the organization of fear memories at the systems level.

neuroscience↗