Fear Memory Retrieval Research Articles

Tumor necrosis factor α negatively regulates the retrieval and reconsolidation of hippocampus-dependent memory

Neural inflammation is associated with cognitive decline, especially learning and memory. Tumor necrosis factor α (TNFα) is a major cytokine generated during neuroinflammation. Previous studies indicated that TNFα impairs hippocampus-dependent memory including contextual fear and spatial memories. However, it is unknown which memory processes are impaired by TNFα. Here, we show that TNFα blocked the retrieval and reconsolidation of contextual fear and spatial memories. Micro-infusion of TNFα into the dorsal hippocampus at 6–18 h before retrieval impaired the retrieval of contextual fear memory, although micro-infusion before contextual fear conditioning had no effect on memory formation. Interestingly, hippocampal TNFα micro-infusion before memory retrieval decreased freezing responses, even at 24 h after retrieval, suggesting that TNFα impairs the reconsolidation of contextual fear memory. Similarly, hippocampal TNFα micro-infusion impaired the retrieval and reconsolidation of spatial memory in the Morris water maze. Consistent with these observations, hippocampal TNFα micro-infusion before retrieval blocked the induction of c-fos expression in the hippocampus, which is a marker of neural activation, in response to the retrieval of contextual fear memory. Collectively, our findings indicate that TNFα negatively regulates the retrieval and reconsolidation of hippocampus-dependent memory.

The 4-(Phenylsulfanyl) butan-2-one Improves Impaired Fear Memory Retrieval and Reduces Excessive Inflammatory Response in Triple Transgenic Alzheimer's Disease Mice.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by an excessive inflammatory response and impaired memory retrieval, including spatial memory, recognition memory, and emotional memory. Acquisition and retrieval of fear memory help one avoid dangers and natural threats. Thus, it is crucial for survival. AD patients with impaired retrieval of fear memory are vulnerable to dangerous conditions. Excessive expression of inflammatory markers is known to impede synaptic transmission and reduce the efficiency of memory retrieval. In wild-type mice, reducing inflammation response can improve fear memory retrieval; however, this effect of this approach is not yet investigated in 3xTg-AD model mice. To date, no satisfactory drug or treatment can attenuate the symptoms of AD despite numerous efforts. In the past few years, the direction of therapeutic drug development for AD has been shifted to natural compounds with anti-inflammatory effect. In the present study, we demonstrate that the compound 4-(phenylsulfanyl) butan-2-one (4-PSB-2) is effective in enhancing fear memory retrieval of wild-type and 3xTg-AD mice by reducing the expression of TNF-α, COX-2, and iNOS. We also found that 4-PSB-2 helps increase dendritic spine density, postsynaptic density protein-95 (PSD-95) expression, and long-term potentiation (LTP) in the hippocampus of 3xTg-AD mice. Our study indicates that 4-PSB-2 may be developed as a promising therapeutic compound for treating fear memory impairment of AD patients.

Lack of drug-induced post-retrieval amnesia for auditory fear memories in rats

BackgroundLong-term memory formation is generally assumed to involve the permanent storage of recently acquired memories, making them relatively insensitive to disruption, a process referred to as memory consolidation. However, when retrieved under specific circumstances, consolidated fear memories are thought to return to a labile state, thereby opening a window for modification (e.g., attenuation) of the memory. Several interventions during a critical time frame after this destabilization seem to be able to alter the retrieved memory, for example by pharmacologically interfering with the restabilization process, either by direct protein synthesis inhibition or indirectly, using drugs that can be safely administered in patients (e.g., propranolol). Here, we find that, contrary to expectations, systemic pharmacological manipulations in auditory fear-conditioned rats do not lead to drug-induced post-retrieval amnesia.ResultsIn a series of well-powered auditory fear conditioning experiments (four with propranolol, 10 mg/kg, two with rapamycin, 20–40 mg/kg, one with anisomycin, 150 mg/kg and cycloheximide, 1.5 mg/kg), we found no evidence for reduced cued fear memory expression during a drug-free test in adult male Sprague-Dawley rats that had previously received a systemic drug injection upon retrieval of the tone fear memory. All experiments used standard fear conditioning and reactivation procedures with freezing as the behavioral read-out (conceptual or exact replications of published reports) and common pharmacological agents. Additional tests confirmed that the applied drug doses and administration routes were effective in inducing their conventional effects on expression of fear (propranolol, acutely), body weight (rapamycin, anisomycin, cycloheximide), and consolidation of extinction memories (cycloheximide).ConclusionsIn contrast with previously published studies, we did not find evidence for drug-induced post-retrieval amnesia, underlining that this effect, as well as its clinical applicability, may be considerably more constrained and less readily reproduced than what the current literature would suggest.

Bidirectional regulation by the endocannabinoid in retrieval of fear memory using the fear conditioning task in mice

Bidirectional regulation by the endocannabinoid in retrieval of fear memory using the fear conditioning task in mice

Anodal tDCS applied to the left frontal cortex abrogates scopolamine-induced fear memory deficit via the dopaminergic system

Evidence suggests that transcranial direct current stimulation (tDCS) modulates conditioned fear memories and has effects on cognitive flexibility via the dopaminergic system. This study examines whether modulation of scopolamine‑induced fear memory deficit by anodal tDCS could be mediated by the dopaminergic system. The male NMRI mice received scopolamine, 30 min before fear conditioning, and showed impaired contextual memory retention. Mice subjected to left frontal anodal stimulation for 20 or 30 min, before fear conditioning, impaired fear memory retrieval. Anodal application for 20 min significantly decreased scopolamine response on fear retention, while the one applied for 30 min did not alter. Moreover, anodal stimulation for 30 min abolished scopolamine‑induced fear memory deficit. Dopaminergic antagonists SCH23390 and sulpiride, alone or in combination, prevented the abolishment effect of anodal stimulation on scopolamine‑induced fear memory deficit, whereas they did not alter the impairing effect of scopolamine at the dose of 2 mg/kg. Our data suggest that anodal stimulation for 30 min abrogates the impairing effect of scopolamine on fear memory retention. This influence could be prevented by dopaminergic antagonists, indicating the involvement of the dopaminergic system in the effect of anodal stimulation on scopolamine‑induced fear memory deficit.

An activity-dependent local transport regulation via degradation and synthesis of KIF17 underlying cognitive flexibility.

Synaptic weight changes among postsynaptic densities within a single dendrite are regulated by the balance between localized protein degradation and synthesis. However, the molecular mechanism via these opposing regulatory processes is still elusive. Here, we showed that the molecular motor KIF17 was locally degraded and synthesized in an N-methyl-d-aspartate receptor (NMDAR)-mediated activity-dependent manner. Accompanied by the degradation of KIF17, its transport was temporarily dampened in dendrites. We also observed that activity-dependent local KIF17 synthesis driven by its 3' untranslated region (3'UTR) occurred at dendritic shafts, and the newly synthesized KIF17 moved along the dendrites. Furthermore, hippocampus-specific deletion of Kif17 3'UTR disrupted KIF17 synthesis induced by fear memory retrieval, leading to impairment in extinction of fear memory. These results indicate that the regulation of the KIF17 transport is driven by the single dendrite-restricted cycle of degradation and synthesis that underlies cognitive flexibility.

Active Transition of Fear Memory Phase from Reconsolidation to Extinction through ERK-Mediated Prevention of Reconsolidation.

The retrieval of fear memory induces two opposite memory process, i.e., reconsolidation and extinction. Brief retrieval induces reconsolidation to maintain or enhance fear memory, while prolonged retrieval extinguishes this memory. Although the mechanisms of reconsolidation and extinction have been investigated, it remains unknown how fear memory phases are switched from reconsolidation to extinction during memory retrieval. Here, we show that an extracellular signal-regulated kinase (ERK)-dependent memory transition process after retrieval regulates the switch of memory phases from reconsolidation to extinction by preventing induction of reconsolidation in an inhibitory avoidance (IA) task in male mice. First, the transition memory phase, which cancels the induction of reconsolidation, but is insufficient for the acquisition of extinction, was identified after reconsolidation, but before extinction phases. Second, the reconsolidation, transition, and extinction phases after memory retrieval showed distinct molecular and cellular signatures through cAMP responsive element binding protein (CREB) and ERK phosphorylation in the amygdala, hippocampus, and medial prefrontal cortex (mPFC). The reconsolidation phase showed increased CREB phosphorylation, while the extinction phase displayed several neural populations with various combinations of CREB and/or ERK phosphorylation, in these brain regions. Interestingly, the three memory phases, including the transition phase, showed transient ERK activation immediately after retrieval. Most importantly, the blockade of ERK in the amygdala, hippocampus, or mPFC at the transition memory phase disinhibited reconsolidation-induced enhancement of IA memory. These observations suggest that the ERK-signaling pathway actively regulates the transition of memory phase from reconsolidation to extinction and this process functions as a switch that cancels reconsolidation of fear memory.SIGNIFICANCE STATEMENT Retrieval of fear memory induces two opposite memory process; reconsolidation and extinction. Reconsolidation maintains/enhances fear memory, while extinction weakens fear memory. It remains unknown how memory phases are switched from reconsolidation to extinction during retrieval. Here, we identified an active memory transition process functioning as a switch that inhibits reconsolidation. This memory transition phase showed a transient increase of extracellular signal-regulated kinase (ERK) phosphorylation in the amygdala, hippocampus and medial prefrontal cortex (mPFC). Interestingly, inhibition of ERK in these regions at the transition phase disinhibited the reconsolidation-mediated enhancement of inhibitory avoidance (IA) memory. These findings suggest that the transition memory process actively regulates the switch of fear memory phases of fear memory by preventing induction of reconsolidation through the activation of the ERK-signaling pathway.

A coral‐derived compound suppresses hippocampal inflammation and improved memory retrieval in triple transgenic Alzheimer’s mice

AbstractBackgroundThe relationship between neuronal inflammation and impairment of memory retrieval is not well established, partially because of the lack of appropriate compound to test this hypothesis. Here we investigated effects of a novel coral‐derived compound on hippocampal inflammation markers and contextual fear memory retrieval using a triple‐transgenic AD (3xTg‐AD) mouse modelMethodThe coral‐derived compound was administered to mice with intraperitoneal injection before subjected to trace fear conditioning. Expression of inflammation markers were measured by western blot analysis or flourescent immunihistochemijcal staining.ResultResults indicate that coral‐derived compound is effective on reducing expression levels of inflammatory markers including TNF‐α, COX‐2, and iNOS in the hippocamapal region, and increased expression of postsynaptic density protein‐95 (PSD‐95) in the hippocampus of 3xTg‐AD mice. It also increased dendritic spine density in hippocampus. Phenotypically, this compound enhanced hippocampadependent retrieval of contextual memory after trace fear conditioning.ConclusionOur results suggest the strong linkage between hippocampal inflammation and memory retrieval in AD, and that the coral‐derived compound may serve as a drug leading for a hippocampal anti‐inflammatory treatment to improve memory retrieval in AD patients.

DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation.

Numerous studies have shown that following retrieval, a previously consolidated memory requires increased transcriptional regulation in order to be reconsolidated. Previously, it was reported that histone H3 lysine-4 trimethylation (H3K4me3), a marker of active transcription, is increased in the hippocampus after the retrieval of contextual fear memory. However, it is currently unknown how this epigenetic mark is regulated during the reconsolidation process. Furthermore, though recent evidence suggests that neuronal activity triggers DNA double-strand breaks (DSBs) in some early-response genes, it is currently unknown if DSBs contribute to the reconsolidation of a memory following retrieval. Here, using chromatin immunoprecipitation (ChIP) analyses, we report a significant overlap between DSBs and H3K4me3 in area CA1 of the hippocampus during the reconsolidation process. We found an increase in phosphorylation of histone H2A.X at serine 139 (H2A.XpS139), a marker of DSB, in the Npas4, but not c-fos, promoter region 5 min after retrieval, which correlated with increased H3K4me3 levels, suggesting that the two epigenetic marks may work in concert during the reconsolidation process. Consistent with this, in vivo siRNA-mediated knockdown of topoisomerase II β, the enzyme responsible for DSB, prior to retrieval, reduced Npas4 promoter-specific H2A.XpS139 and H3K4me3 levels and impaired long-term memory, indicating an indispensable role of DSBs in the memory reconsolidation process. Collectively, our data propose a novel mechanism for memory reconsolidation through increases in epigenetic-mediated transcriptional control via DNA double-strand breaks.

Habenula kisspeptin retrieves morphine impaired fear memory in zebrafish

The habenula is an evolutionarily conserved brain structure, which has recently been implicated in fear memory. In the zebrafish, kisspeptin (Kiss1) is predominantly expressed in the habenula, which has been implicated as a modulator of fear response. Hence, in the present study, we questioned whether Kiss1 has a role in fear memory and morphine-induced fear memory impairment using an odorant cue (alarm substances, AS)-induced fear avoidance paradigm in adult zebrafish, whereby the fear-conditioned memory can be assessed by a change of basal place preference (= avoidance) of fish due to AS-induced fear experience. Subsequently, to examine the possible role of Kiss1 neurons-serotonergic pathway, kiss1 mRNA and serotonin levels were measured. AS exposure triggered fear episodes and fear-conditioned place avoidance. Morphine treatment followed by AS exposure, significantly impaired fear memory with increased time-spent in AS-paired compartment. However, fish administered with Kiss1 (10–21 mol/fish) after morphine treatment had significantly lower kiss1 mRNA levels but retained fear memory. In addition, the total brain serotonin levels were significantly increased in AS- and Kiss1-treated groups as compared to control and morphine treated group. These results suggest that habenular Kiss1 might be involved in consolidation or retrieval of fear memory through the serotonin system.

Evaluation of an angiotensin Type 1 receptor blocker on the reconsolidation of fear memory

Inhibition of the angiotensin type 1 receptor (AT1R) has been shown to decrease fear responses in both humans and rodents. These effects are attributed to modulation of extinction learning, however the contribution of AT1R to alternative memory processes remains unclear. Using classic Pavlovian conditioning combined with radiotelemetry and whole-genome RNA sequencing, we evaluated the effects of the AT1R antagonist losartan on fear memory reconsolidation. Following the retrieval of conditioned auditory fear memory, animals were given a single intraperitoneal injection of losartan or saline. In response to the conditioned stimulus (CS), losartan-treated animals exhibited significantly less freezing at 24 h and 1 week; an effect that was dependent upon memory reactivation and independent of conditioned cardiovascular reactivity. Using an unbiased whole-genome RNA sequencing approach, transcriptomic analysis of the basolateral amygdala (BLA) identified losartan-dependent differences in gene expression during the reconsolidation phase. These findings demonstrate that post-retrieval losartan modifies behavioral and transcriptomic markers of conditioned fear memory, supporting an important regulatory role for this receptor in reconsolidation and as a potential pharmacotherapeutic target for maladaptive fear disorders such as PTSD.

МЕХАНИЗМЫ ПАМЯТИ ПСИХОЛОГИЧЕСКОГО СТРЕССА И ВОЗДЕЙСТВИЯ НА НИХ В ЛЕЧЕНИИ СИНДРОМА ПОСТТРАВМАТИЧЕСКОГО СТРЕССА И БОЛЬШОГО ДЕПРЕССИВНОГО РАССТРОЙСТВА

Стресс, особенно его психологический компонент, связанный с невозможностью управлять им, или избежать его воздействия, вызывает тревожные или депрессивные расстройства в виде синдрома посттравматического стресса и большого депрессивного расстройства. В формировании этих заболеваний существенную роль играют формирование, воспроизведение и генерализация памяти страха и памяти отчаяния, которые нарушают деятельность синапсов, нейронов, нейронных сетей и поведения.В этом обзоре рассмотрены механизмы формирования и воспроизведения памяти контекстуального условного страха и отчасти памяти не избегаемого психологического стресса (памяти отчаяния). Проанализировано влияние традиционных и быстродействующих антидепрессантов на эти формы памяти, как одно из направлений фармакотерапии указанных аффективных расстройств.

Experience-dependent resonance in amygdalo-cortical circuits supports fear memory retrieval following extinction

Learned fear and safety are associated with distinct oscillatory states in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC). To determine if and how these network states support the retrieval of competing memories, we mimicked endogenous oscillatory activity through optogenetic stimulation of parvalbumin-expressing interneurons in mice during retrieval of contextual fear and extinction memories. We found that exogenously induced 4 Hz and 8 Hz oscillatory activity in the BLA exerts bi-directional control over conditioned freezing behavior in an experience- and context-specific manner, and that these oscillations have an experience-dependent ability to recruit distinct functional neuronal ensembles. At the network level we demonstrate, via simultaneous manipulation of BLA and mPFC, that experience-dependent 4 Hz resonance across BLA-mPFC circuitry supports post-extinction fear memory retrieval. Our findings reveal that post-extinction fear memory retrieval is supported by local and interregional experience-dependent resonance, and suggest novel approaches for interrogation and therapeutic manipulation of acquired fear circuitry.

Propranolol failed to prevent severe stress-induced long-term behavioral changes in male rats

Memories of adverse events can be maladaptive when they lead to exaggerated fear, as observed in post-traumatic stress disorder (PTSD). Fear conditioning and fear sensitization are learning processes thought to play a role in fear-related disorders, and only few animal studies have evaluated the relationship between the associative and non-associative fear memory components on the development and maintenance of PTSD-like behavioral changes. Here we assessed the effects of a single dose of propranolol (10 mg/kg) or saline after fear memory retrieval on the long-term behavioral responses induced by severe stress in male rats. Animals were submitted to contextual fear conditioning (delayed shock group) or not (non-shock group) and underwent fear memory retrieval followed by propranolol or saline administration two weeks later. Rats were then evaluated in different behavioral tests to assess the expression of the conditioned fear response, anxiety-like and exploratory behaviors, and fear response after the presentation of unknown acoustic stimulus. Post-retrieval propranolol did not disrupt the subsequent expression of neither conditioned fear response nor the exploratory deficit and fear sensitization response, indicating that propranolol failed to mitigate long-term behavioral changes induced by severe stress in rats.

Deletion of NRXN1\u03b1 impairs long-range and local connectivity in amygdala fear circuit

Neurexins are a family of presynaptic cell adhesion proteins that regulate synaptic structure and maintain normal synaptic transmission. Mutations in the α-isoform of neurexin1-gene (NRXN1α) are linked with cognitive and emotional dysregulation, which are heavily dependent on the amygdala and medial prefrontal cortex (mPFC). It is however not known whether deletion of NRXN1α gene affect specific synaptic elements within the amygdala microcircuit and connectivity with mPFC. In this study, we show that NRXN1α deletion impairs synaptic transmission between the dorsal medial prefrontal cortex (dmPFC) and basal amygdala (BA) principal neurons. Stimulation of dmPFC fibers resulted in reduced paired pulse ratio (PPR) and AMPA/NMDA ratio at dmPFC to BA synapses in NRXN1α-knockout (KO) (NRXN1α KO) mice suggestive of pre- and postsynaptic deficits but there was no change at the lateral amygdala (LA) to BA synapses following LA stimulation. However, feedforward inhibition from either pathway was significantly reduced, suggestive of input-independent deficit in GABAergic transmission within BA. We further analyzed BA inhibitory network and found reduced connectivity between BA GABAergic and glutamatergic neurons in NRXN1α KO mice. As this circuit is tightly linked with fear regulation, we subjected NRXN1α KO and WT mice to discriminative fear conditioning and found a deficit in fear memory retrieval in NRXN1α KO mice compared with WT mice. Together, we provide novel evidence that deletion of NRNX1α disrupts amygdala fear circuit.

Contextual fear memory retrieval by correlated ensembles of ventral CA1 neurons

Ventral hippocampal CA1 (vCA1) projections to the amygdala are necessary for contextual fear memory. Here we used in vivo Ca2+ imaging in mice to assess the temporal dynamics by which ensembles of vCA1 neurons mediate encoding and retrieval of contextual fear memories. We found that a subset of vCA1 neurons were responsive to the aversive shock during context conditioning, their activity was necessary for memory encoding, and these shock-responsive neurons were enriched in the vCA1 projection to the amygdala. During memory retrieval, a population of vCA1 neurons became correlated with shock-encoding neurons, and the magnitude of synchronized activity within this population was proportional to memory strength. The emergence of these correlated networks was disrupted by inhibiting vCA1 shock responses during memory encoding. Thus, our findings suggest that networks of cells that become correlated with shock-responsive neurons in vCA1 are essential components of contextual fear memory ensembles.

Contextual processing elicits sex differences in dorsal hippocampus activation following footshock and context fear retrieval

Establishing a contextual representation of an environment places specific spatial-temporal processing demands on the mammalian hippocampus, a region showing sex-differences in processing capabilities. However, evidence for sex differences in these processing demands during contextual fear learning remains limited. Here, we examined the relationship among contextual processing, timing of footshock, and activation of the dorsal hippocampus and basolateral amygdalar nuclei (BLA) in male and female mice (C57Bl/6 J). We modified the initial exposure time to the conditioning context prior to administration, or not, of a single footshock. We then quantified Fos- ir neurons activated by acquisition or retrieval of contextual fear memories in the rostral half of the dorsal CA1 (proximal – distal regions), CA3, Dentate Gyrus and basolateral amygdalar nuclei corresponding to atlas levels of the Allen Reference Atlas. In experiment 1, we found that sex differences in context elicited freezing were evident at the longest context placement-to-shock interval and that context fear retrieval with increasing contextual exposure periods increased CA1 Fos-ir in males, but not females. In experiment 2, we observed that an aversive footshock in males potentiated CA1 activation, while it downregulated CA1 activation in females. We also found that an aversive footshock independent of sex moderated Dentate Gyrus activation that normally showed increased activation with greater context exposure periods. Lastly, we identified a heightened responsiveness in BLA neurons to both footshock and length of context exposure in females compared to males. Overall, our findings suggest that sex differences in contextual fear conditioning may arise from marked sex differences in the contextual processing demands of the dorsal hippocampus subfields largely modulated by aversive outcomes.

CaMKII inhibitor 1 (CaMK2N1) mRNA is upregulated following LTP induction in hippocampal slices.

CaMK2N1 and CaMK2N2 (also known as CaMKIINα and β) are endogenous inhibitors of calcium/calmodulin-dependent kinase II (CaMKII), an enzyme critical for memory and long-term potentiation (LTP), a form of synaptic plasticity thought to underlie learning. CaMK2N1/2 mRNAs are rapidly and differentially upregulated in the hippocampus and amygdala after acquisition or retrieval of fear memory. Moreover, CaMK2N2 protein levels increase after contextual fear conditioning. Therefore, it was proposed that CaMK2N1/2 genes (Camk2n1/2) could be immediate-early genes transcribed promptly (30-60min) after training. As a first approach to explore a role in synaptic plasticity, we assessed a possible regulation of Camk2n1/2 during the expression phase of LTP in hippocampal CA3-CA1 connections in rat brain slices. Quantitative PCR revealed that Camk2n1, but not Camk2n2, is upregulated 60min after LTP induction by Schaffer collaterals high-frequency stimulation. We observed a graded, significant positive correlation between the magnitude of LTP and Camk2n1 change in individual slices, suggesting a coordinated regulation of these properties. If mRNA increment actually resulted in the protein upregulation in plasticity-relevant subcellular locations, CaMK2N1 may be involved in CaMKII fine-tuning during LTP maintenance or in the regulation of subsequent plasticity events (metaplasticity).

Evaluation of an Angiotensin Type 1 Receptor Blocker on the Reconsolidation of Fear Memory

Inhibition of the angiotensin type 1 receptor (AT1R) has been shown to decrease fear responses in both humans and rodents. These effects are attributed to modulation of extinction learning, however the contribution of AT1R to alternative memory processes remains unclear. Using classic Pavlovian conditioning combined with radiotelemetry and whole-genome RNA sequencing, we evaluated the effects of the AT1R antagonist losartan on fear memory reconsolidation. Following the retrieval of conditioned auditory fear memory, animals were given a single intraperitoneal injection of losartan or saline. In response to the conditioned stimulus (CS), losartan-treated animals exhibited significantly less freezing at 24 h and 1 week; an effect that was dependent upon memory reactivation and independent of conditioned cardiovascular reactivity. Using an unbiased whole-genome RNA sequencing approach, transcriptomic analysis of the basolateral amygdala (BLA) identified losartan-dependent differences in gene expression during the reconsolidation phase. These findings demonstrate that post-retrieval losartan modifies behavioral and transcriptomic markers of conditioned fear memory, supporting an important regulatory role for this receptor in reconsolidation and as a potential pharmacotherapeutic target for maladaptive fear disorders such as PTSD.

Molecularly Defined Hippocampal Inputs Regulate Population Dynamics in the Prelimbic Cortex to Suppress Context Fear Memory Retrieval

BackgroundContext fear memory dysregulation is a hallmark symptom of several neuropsychiatric disorders, including generalized anxiety disorder and posttraumatic stress disorder. The hippocampus (HC) and prelimbic (PrL) subregion of the medial prefrontal cortex have been linked with context fear memory retrieval in rodents, but the mechanisms by which HC-PrL circuitry regulates this process remain poorly understood. MethodsSpatial and genetic targeting of HC-PrL circuitry was used for RNA sequencing (n = 31), chemogenetic stimulation (n = 44), in vivo calcium imaging (n = 20), ex vivo electrophysiology (n = 8), and molecular regulation of plasticity cascades during fear behavior (context fear retrieval) (n = 16). ResultsWe showed that ventral HC (vHC) neurons with projections to the PrL cortex (vHC-PrL projectors) are a transcriptomically distinct subpopulation compared with adjacent nonprojecting neurons, and we showed complementary enrichment for diverse neuronal processes and central nervous system–related clinical gene sets. We further showed that stimulation of this population of vHC-PrL projectors suppresses context fear memory retrieval and impairs the ability of PrL neurons to dynamically distinguish between distinct phases of fear learning. Using transgenic and circuit-specific molecular targeting approaches, we demonstrated that unique patterns of activity-dependent gene transcription associated with brain-derived neurotrophic factor signaling within vHC-PrL projectors causally regulated activity in excitatory and inhibitory PrL neurons during context fear memory retrieval. ConclusionsTogether, our data show that activity-dependent brain-derived neurotrophic factor release from molecularly distinct vHC-PrL projection neurons modulates postsynaptic signaling in both inhibitory and excitatory PrL neurons, modifying activity in discrete populations of PrL neurons to suppress freezing during context fear memory retrieval.