Contextual Fear Conditioning Memory Research Articles

Activity of hippocampal CA1 field neurons during aversive memory formation and reactivation in mice <i>in vivo</i>

Activity of hippocampal CA1 field neurons during aversive memory formation and reactivation in mice <i>in vivo</i>

Neuronal IGF-1 overexpression restores hippocampal newborn cell survival and recent CFC memory consolidation in Cav1.3 knock-out mice

Insulin-like growth factor-1 (IGF-1) exogenously supplied in the brain was shown to enhance the survival of hippocampal dentate gyrus (DG) newborn cells and some cognitive functions of mice. This study aims to test whether IGF-1 requires Cav1.3 activity critically while enhancing newborn cell survival and cognitive functions. We used Cav1.3 KO mice, where both DG newborn cell survival and the recent (1 day) single-trial contextual fear conditioning (CFC) memory consolidation were impaired. To supply IGF-1, we overexpressed (OX) IGF-1 in DG mature neurons by injecting an adeno-associated virus (AAV-IGF-1-mCherry) into the hippocampal areas of Cav1.3 KO mice. Our results, first, confirmed the enhanced expression of IGF-1 in the DG granule cell layer by immunohistochemistry. Next, we found this IGF-1 OX resulted in fully restoring both the survival rate of DCX (+) newborn cells and the recent single-trial CFC memory formation in Cav1.3 KO mice. Our results show that IGF-1 can enhance the survival of DG immature newborn cells and the recent CFC memory formation in a Cav1.3 channel-independent manner in vivo, suggesting activation of complementary pathways including the Cav1.2 channel. The result will help the application of adult newborn cell-based therapy improve the cognitive functions of neurological disorders.

Cellular mechanisms of contextual fear memory reconsolidation: Role of hippocampal SFKs, TrkB receptors and GluN2B-containing NMDA receptors.

Memories are stored into long-term representations through a process that depends on protein synthesis. However, a consolidated memory is not static and inflexible and can be reactivated under certain circumstances, the retrieval is able to reactivate memories and destabilize them engaging a process of restabilization known as reconsolidation. Although the molecular mechanisms that mediate fear memory reconsolidation are not entirely known, so here we investigated the molecular mechanisms in the hippocampus involved in contextual fear conditioning memory (CFC) reconsolidation in male Wistar rats. We demonstrated that the blockade of Src family kinases (SFKs), GluN2B-containing NMDA receptors and TrkB receptors (TrkBR) in the CA1 region of the hippocampus immediately after the reactivation session impaired contextual fear memory reconsolidation. These impairments were blocked by the neurotrophin BDNF and the NMDAR agonist, D-Serine. Considering that the study of the link between synaptic proteins is crucial for understanding memory processes, targeting the reconsolidation process may provide new ways of disrupting maladaptive memories, such as those seen in post-traumatic stress disorder. Here we provide new insights into the cellular mechanisms involved in contextual fear memory reconsolidation, demonstrating that SFKs, GluN2B-containing NMDAR, and TrkBR are necessary for the reconsolidation process. Our findings suggest a link between BDNF and SFKs and GluN2B-containing NMDAR as well as a link between NMDAR and SFKs and TrkBR in fear memory reconsolidation. These preliminary pharmacological findings provide new evidence of the mechanisms involved in the reconsolidation of fear memory and have the potential to contribute to the development of treatments for psychiatric disorders involving maladaptive memories.

Systems consolidation induces multiple memory engrams for a flexible recall strategy in observational fear memory in male mice

Observers learn to fear the context in which they witnessed a demonstrator’s aversive experience, called observational contextual fear conditioning (CFC). The neural mechanisms governing whether recall of the observational CFC memory occurs from the observer’s own or from the demonstrator’s point of view remain unclear. Here, we show in male mice that recent observational CFC memory is recalled in the observer’s context only, but remote memory is recalled in both observer and demonstrator contexts. Recall of recent memory in the observer’s context requires dorsal hippocampus activity, while recall of remote memory in both contexts requires the medial prefrontal cortex (mPFC)-basolateral amygdala pathway. Although mPFC neurons activated by observational CFC are involved in remote recall in both contexts, distinct mPFC subpopulations regulate remote recall in each context. Our data provide insights into a flexible recall strategy and the functional reorganization of circuits and memory engram cells underlying observational CFC memory.

Role of Hippocampal Wnt Signaling Pathways on Contextual Fear Memory Reconsolidation

Memories already consolidated when reactivated return to a labile state and can be modified, this process is known as reconsolidation. It is known the Wnt signaling pathways can modulate hippocampal synaptic plasticity as well as learning and memory. Yet, Wnt signaling pathways interact with NMDA (N-methyl-D-aspartate) receptors. However, whether canonical Wnt/β-catenin and non-canonical Wnt/Ca2 + signaling pathways are required in the CA1 region of hippocampus for contextual fear memory reconsolidation remains unclear. So, here we verified that the inhibition of canonical Wnt/β-catenin pathway with DKK1 (Dickkopf-1) into CA1 impaired the reconsolidation of contextual fear conditioning (CFC) memory when administered immediately and 2 h after reactivation session but not 6 h later, while the inhibition of non-canonical Wnt/Ca2+ signaling pathway with SFRP1 (Secreted frizzled-related protein-1) into CA1 immediately after reactivation session had no effect. Moreover, the impairment induced by DKK1 was blocked by the administration of the agonist of the NMDA receptors glycine site, D-Serine, immediately and 2 h after reactivation session. We found that hippocampal canonical Wnt/β-catenin is necessary to the reconsolidation of CFC memory at least two hours after reactivation, while non-canonical Wnt/Ca2+ signaling pathway is not involved in this process and, that there is a link between Wnt/β-catenin signaling pathway and NMDA receptors. In view of this, this study provides new evidence regarding the neural mechanisms underlying contextual fear memory reconsolidation and contributes to provide a new possible target for the treatment of fear related disorders.

GADD34 suppresses eIF2α phosphorylation and improves cognitive function in Alzheimer's disease-model mice

Alzheimer's disease (AD) causes neurodegeneration, leading to cognitive impairment and memory loss. Our previous studies have demonstrated that the induction of growth arrest and DNA damage-inducible gene 34 (GADD34) by quercetin can affect eukaryotic translation initiation factor 2α (eIF2α) phosphorylation-activated transcription factor 4 (ATF4) signaling. However, the relationship between GADD34 expression and cognitive function has not been clarified. In this study, we determined the direct effect of GADD34 on memory. To achieve this, truncated GADD34 (GADD34.5) was injected into the mouse brain to suppress eIF2α phosphorylation and evaluate memory. The injection of GADD34.5 into the hippocampus in AD-model mice did not improve novel object recognition but improved novel object location. The injection of GADD34.5 into the amygdala also resulted in the maintenance of contextual fear memory based on the fear condition test. These results suggest that GADD34 is effective in improving memory for spatial cognition and contextual fear conditioning in AD by inhibiting eIF2α phosphorylation. In summary, GADD34 suppresses eIF2α phosphorylation in the brain and prevents memory loss. As quercetin feeding increases GADD34 expression, it might be used in preventative applications for AD.

Chromatin Remodeling Factor SMARCA5 is Essential for Hippocampal Memory Maintenance via Metabolic Pathways in Mice.

Gene transcription and new protein synthesis regulated by epigenetics play integral roles in the formation of new memories. However, as an important part of epigenetics, the function of chromatin remodeling in learning and memory has been less studied. Here, we showed that SMARCA5 (SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 5), a critical chromatin remodeler, was responsible for hippocampus-dependent memory maintenance and neurogenesis. Using proteomics analysis, we found protein expression changes in the hippocampal dentate gyrus (DG) after the knockdown of SMARCA5 during contextual fear conditioning (CFC) memory maintenance in mice. Moreover, SMARCA5 was revealed to participate in CFC memory maintenance via modulating the proteins of metabolic pathways such as nucleoside diphosphate kinase-3 (NME3) and aminoacylase 1 (ACY1). This work is the first to describe the role of SMARCA5 in memory maintenance and to demonstrate the involvement of metabolic pathways regulated by SMARCA5 in learning and memory.

The Effect of Zonisamide and Ethanol on Various Types of Memory in Rats.

Background: Antiepileptic drugs might be useful in the treatment of alcohol use disorder. One of these drugs is zonisamide, which has been found to decrease alcohol intake and cravings. An important structure in the pathophysiology of addiction is the hippocampus. Memory deficits, which frequently occur in alcoholics, are associated with ethanol-induced changes in hippocampal plasticity and neurogenesis. The aim of this study was to assess the potential protective effect of zonisamide on memory in rats receiving alcohol and after the discontinuation of its administration. Methods: Wistar rats (n = 43) were tested in four behavioral models, namely: Morris water maze (MWM), passive avoidance (PA), contextual fear conditioning (CFC), and cued fear conditioning (CuFC). Results: Zonisamide co-administered with ethanol impaired spatial memory in MWM, but the drug did not affect memory in PA. However, the beneficial effect of zonisamide was observed after the discontinuation of ethanol administration, which was associated with the improvement of associative memory in CFC and the alleviation of alcohol-induced locomotor disturbances in CuFC. Conclusion: Zonisamide has a differential influence on memory, which depends inter alia on type of the memory, length of ethanol administration, or its absence.

Cell-type-specific translational control of spatial working memory by the cap-binding protein 4EHP

The consolidation of learned information into long-lasting memories requires the strengthening of synaptic connections through de novo protein synthesis. Translation initiation factors play a cardinal role in gating the production of new proteins thereby regulating memory formation. Both positive and negative regulators of translation play a critical role in learning and memory consolidation. The eukaryotic initiation factor 4E (eIF4E) homologous protein (4EHP, encoded by the gene Eif4e2) is a pivotal negative regulator of translation but its role in learning and memory is unknown. To address this gap in knowledge, we generated excitatory (glutamatergic: CaMKIIα-positive) and inhibitory (GABAergic: GAD65-positive) conditional knockout mice for 4EHP, which were analyzed in various behavioral memory tasks. Knockout of 4EHP in Camk2a-expressing neurons (4EHP-cKOexc) did not impact long-term memory in either contextual fear conditioning or Morris water maze tasks. Similarly, long-term contextual fear memory was not altered in Gad2-directed 4EHP knockout mice (4EHP-cKOinh). However, when subjected to a short-term T-maze working memory task, both mouse models exhibited impaired cognition. We therefore tested the hypothesis that de novo protein synthesis plays a direct role in working memory. We discovered that phosphorylation of ribosomal protein S6, a measure of mTORC1 activity, is dramatically reduced in the CA1 hippocampus of 4EHP-cKOexc mice. Consistently, genetic reduction of mTORC1 activity in either excitatory or inhibitory neurons was sufficient to impair working memory. Taken together, these findings indicate that translational control by 4EHP and mTORC1 in both excitatory and inhibitory neurons are necessary for working memory.

A search pattern for the engram.

Roy and colleagues (Nature Communications, 13.1, 1-16, 2022) examined neuronal ensembles associated with contextual fear conditioning memory across multiple brain regions, referred to as a unified engram complex. Their four-step approach incorporating brain-wide mapping of activated neurons, engram indexing, and optogenetic and chemogenetic manipulations could offer a novel, holistic approach to implement in our continued search for the engram.

Noradrenergic signaling mediates cortical early tagging and storage of remote memory.

The neocortical prefrontal memory engram generated during initial learning is critical for remote episodic memory storage, however, the nature of early cortical tagging remains unknown. Here we found that in mice, increased norepinephrine (NE) release from the locus coeruleus (LC) to the medial prefrontal cortex (mPFC) during contextual fear conditioning (CFC) was critical for engram tagging and remote memory storage, which was regulated by the ventrolateral periaqueductal grey. β-Blocker infusion, or knockout of β1-adrenergic receptor (β1-AR) in the mPFC, impaired the storage of remote CFC memory, which could not be rescued by activation of LC-mPFC NE projection. Remote memory retrieval induced the activation of mPFC engram cells that were tagged during CFC. Inhibition of LC-mPFC NE projection or β1-AR knockout impaired mPFC engram tagging. Juvenile mice had fewer LC NE neurons than adults and showed deficiency in mPFC engram tagging and remote memory of CFC. Activation of β1-AR signaling promoted mPFC early tagging and remote memory storage in juvenile mice. Our data demonstrate that activation of LC NEergic signaling during CFC memory encoding mediates engram early tagging in the mPFC and systems consolidation of remote memory.

Calcineurin activation and scaffolding in Aß‐induced synaptic dysfunction

AbstractBackgroundCalcineurin (CaN) is a protein phosphatase that is essential for synaptic long‐term depression (LTD) through its regulation of AMPA‐type glutamate receptors (AMPAR). AMPAR regulation by CaN is critically mediated by the postsynaptic scaffold protein A‐kinase anchoring protein 150 (AKAP150), which localizes a pool of CaN to the postsynaptic membrane. Our lab has generated knockin mice carrying a mutant version of AKAP150 lacking its CaN‐binding site, the PxIxIT motif; AKAP150ΔPIX (PIX). LTD does not occur in these mice, underscoring the importance of the synaptic pool of CaN for normal synaptic function and plasticity. Pharmacological inhibition of calcineurin prevents diverse manifestations of Aβ‐mediated synaptotoxicity, including long‐term potentiation (LTP) blockade, synapse loss, and impaired learning and memory in AD mouse models. However, the importance of synaptically‐localized calcineurin in Aβ synaptotoxicity is unknown.MethodTo test our novel hypothesis that Aβ synaptotoxicity requires spatial positioning of CaN at the synapse via AKAP150 anchoring, we used our innovative AKAP150ΔPIX (PIX) knock‐in mouse model. Primary hippocampal neuronal cultures and acute hippocampal slices from WT and PIX mice were treated with various doses of Aβ oligomers and assayed for Aβ’s effect on dendritic spine density, quantal calcium transients through NMDA receptors (both in culture), and LTP through extracellular field recordings (in slices). Additionally, utilizing the 5xFAD AD mouse model, we generated PIX/5xFAD mice to test long‐term behavioral (via radial arm water maze and contextual fear conditioning tasks) and electrophysiological effects (through field recordings) of the PIX mutation on the 5xFAD phenotype in 6‐month‐old animals.ResultThe PIX mutation protects against acute Aβ‐mediated synaptic loss, decreased Ca2+ entry through NMDA receptors, and LTP deficits. Long‐term, the PIX mutation rescues contextual fear conditioning memory, but not radial arm water maze performance or chronic LTP deficits of 5xFAD mice.ConclusionSynaptically‐localized calcineurin is necessary for early Aβ‐mediated synaptic deficits. Long‐term Aβ exposure engages mechanisms beyond its AKAP‐anchored calcineurin pathway.

Post cardiac arrest physical exercise mitigates cell death in the septal and thalamic nuclei and ameliorates contextual fear conditioning deficits in rats

A major concern for cardiac arrest (CA) survivors is the manifestation of long-term cognitive impairments. Physical exercise (PE) is a well-established approach to improve cognitive functions under certain pathological conditions. We previously showed that PE post-CA mitigates cognitive deficits, but the underlying mechanisms remain unknown. To define neuroprotective mechanisms, we analyzed whether PE post-CA protects neurons involved in memory. We first performed a contextual fear conditioning (CFC) test to confirm that PE post-CA preserves memory in rats. We then conducted a cell-count analysis and determined the number of live cells in the hippocampus, and septal and thalamic nuclei, all areas involved in cognitive functions. Lastly, we performed RNA-seq to determine PE post-CA effect on gene expression. Following CA, exercised rats had preserved CFC memory than sham PE animals. Despite this outcome, PE post-CA did not protect hippocampal cells from dying. However, PE ameliorated cell death in septal and thalamic nuclei compared to sham PE animals, suggesting that these nuclei are crucial in mitigating cognitive decline post-CA. Interestingly, PE affected regulation of genes related to neuroinflammation, plasticity, and cell death. These findings reveal potential mechanisms whereby PE post-CA preserves cognitive functions by protecting septal and thalamic cells via gene regulation.

Brain-wide mapping reveals that engrams for a single memory are distributed across multiple brain regions

Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, or cortex. However, it has been hypothesized that engrams of a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Here, we report a partial map of the engram complex for contextual fear conditioning memory by characterizing encoding activated neuronal ensembles in 247 regions using tissue phenotyping in mice. The mapping was aided by an engram index, which identified 117 cFos+ brain regions holding engrams with high probability, and brain-wide reactivation of these neuronal ensembles by recall. Optogenetic manipulation experiments revealed engram ensembles, many of which were functionally connected to hippocampal or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engram ensembles conferred a greater level of memory recall than reactivation of a single engram ensemble, reflecting the natural memory recall process. Overall, our study supports the unified engram complex hypothesis for memory storage.

D1 Receptor Mediated Dopaminergic Neurotransmission Facilitates Remote Memory of Contextual Fear Conditioning.

Dopaminergic neurotransmission via dopamine D1 receptors (D1Rs) is considered to play an important role not only in reward-based learning but also in aversive learning. The contextual and auditory cued fear conditioning tests involve the processing of classical fear conditioning and evaluates aversive learning memory. It is possible to evaluate aversive learning memory in two different types of neural transmission circuits. In addition, when evaluating the role of dopaminergic neurotransmission via D1R, to avoid the effects in D1R-mediated neural circuitry alterations during development, it is important to examine using mice who D1R expression in the mature stage is suppressed. Herein, we investigated the role of dopaminergic neurotransmission via D1Rs in aversive memory formation in contextual and auditory cued fear conditioning tests using D1R knockdown (KD) mice, in which the expression of D1Rs could be conditionally and reversibly controlled with doxycycline (Dox) treatment. For aversive memory, we examined memory formation using recent memory 1 day after conditioning, and remote memory 4 weeks after conditioning. Furthermore, immunostaining of the brain tissues of D1RKD mice was performed after aversive footshock stimulation to investigate the distribution of activated c-Fos, an immediate-early gene, in the hippocampus (CA1, CA3, dentate gyrus), striatum, amygdala, and prefrontal cortex during aversive memory formation. After aversive footshock stimulation, immunoblotting was performed using hippocampal, striatal, and amygdalar samples from D1RKD mice to investigate the increase in the amount of c-Fos and phosphorylated SNAP-25 at Ser187 residue. When D1R expression was suppressed using Dox, behavioral experiments revealed impaired contextual fear learning in remote aversion memory following footshock stimulation. Furthermore, expression analysis showed a slight increase in the post-stimulation amount of c-Fos in the hippocampus and striatum, and a significant increase in the amount of phosphorylated SNAP-25 in the hippocampus, striatum, and prefrontal cortex before and after stimulation. These findings indicate that deficiency in D1R-mediated dopaminergic neurotransmission is an important factor in impairing contextual fear memory formation for remote 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.

Differential Recruitment of the Infralimbic Cortex in Recent and Remote Retrieval and Extinction of Aversive Memory in Post-Weanling Rats.

BackgroundWe previously showed that the infralimbic medial prefrontal cortex (IL-mPFC) plays an important role in recent and remote memory retrieval and extinction of conditioned odor aversion (COA) and contextual fear conditioning (CFC) in adult rats. Because the mPFC undergoes maturation during post-weaning, here, we aimed to explore (1) whether post-weanling rats can form recent and remote COA and CFC memory, and (2) the role of the IL-mPFC in mediating these processes.MethodsTo investigate the retrieval process, we transiently inactivated the IL-mPFC with lidocaine prior to the retrieval test at either recent or remote time points. To target the consolidation process, we applied the protein synthesis inhibitor after the retrieval at recent or remote time points.ResultsOur results show that the post-weanling animals were able to develop both recent and remote memory of both COA and CFC. IL-mPFC manipulations had no effect on retrieval or extinction of recent and remote COA memory, suggesting that the IL has no effect in COA at this developmental stage. In contrast, the IL-mPFC played a role in (1) the extinction of recent, but not remote, CFC memory, and (2) the retrieval of remote, but not recent, CFC memory. Moreover, remote, but not recent, CFC retrieval enhanced c-Fos protein expression in the IL-mPFC.ConclusionsAltogether, these results point to a differential role of the IL-mPFC in recent and remote CFC memory retrieval and extinction and further confirm the differences in the role of IL-mPFC in these processes in post-weanling and adult animals.

Reduced Expression of Hippocampal GluN2A-NMDAR Increases Seizure Susceptibility and Causes Deficits in Contextual Memory.

N-methyl-D-aspartate receptors are heterotetramers composed of two GluN1 obligatory subunits and two regulatory subunits. In cognitive-related brain structures, GluN2A and GluN2B are the most abundant regulatory subunits, and their expression is subjected to tight regulation. During development, GluN2B expression is characteristic of immature synapses, whereas GluN2A is present in mature ones. This change in expression induces a shift in GluN2A/GluN2B ratio known as developmental switch. Moreover, modifications in this relationship have been associated with learning and memory, as well as different pathologies. In this work, we used a specific shRNA to induce a reduction in GluN2A expression after the developmental switch, both in vitro in primary cultured hippocampal neurons and in vivo in adult male Wistar rats. After in vitro characterization, we performed a cognitive profile and evaluated seizure susceptibility in vivo. Our in vitro results showed that the decrease in the expression of GluN2A changes GluN2A/GluN2B ratio without altering the expression of other regulatory subunits. Moreover, rats expressing the anti-GluN2A shRNA in vivo displayed an impaired contextual fear-conditioning memory. In addition, these animals showed increased seizure susceptibility, in terms of both time and intensity, which led us to conclude that deregulation in GluN2A expression at the hippocampus is associated with seizure susceptibility and learning–memory mechanisms.

Role of densin‐180 in mouse ventral hippocampal neurons in 24‐hr retention of contextual fear conditioning

IntroductionDensin‐180 interacts with postsynaptic molecules including calcium/calmodulin‐dependent protein kinase IIα (CaMKIIα) but its function in learning and memory process has been unclear.MethodsTo investigate a role of hippocampal densin‐180 in contextual fear conditioning (CFC) learning and memory processes, knockdown (KD) of densin‐180 in hippocampal subareas was applied.ResultsFirst, ventral hippocampal (vHC) densin‐180 KD impaired single‐trial CFC (stCFC) memory one day later. stCFC caused freezing behaviors to reach the peak about one hour later in both control and KD mice, but then freezing was disappeared at 2 hr postshock in KD mice. Second, stCFC caused an immediate and transient reduction of vHC densin‐180 in control mice, which was not observed in KD mice. Third, stCFC caused phosphorylated‐T286 (p‐T286) CaMKIIα to change similarly to densin‐180, but p‐T305 CaMKIIα was increased 1 hr later in control mice. In KD mice, these effects were gone. Moreover, both basal levels of p‐T286 and p‐T305 CaMKIIα were reduced without change in total CaMKIIα in KD mice. Fourth, we found double‐trial CFC (dtCFC) memory acquisition and retrieval kinetics were different from those of stCFC in vHC KD mice. In addition, densin‐180 in dorsal hippocampal area appeared to play its unique role during the very early retrieval period of both CFC memories.ConclusionThis study shows that vHC densin‐180 is necessary for stCFC memory formation and retrieval and suggests that both densin‐180 and p‐T305 CaMKIIα at 1 ~ 2 hr postshock are important for stCFC memory formation. We conclude that roles of hippocampal neuronal densin‐180 in CFC are temporally dynamic and differential depending on the pattern of conditioning stimuli and its location along the dorsoventral axis of hippocampal formation.

Impaired memory and marble burying activity in deformed epidermal autoregulatory factor 1 (Deaf1) conditional knockout mice

Deleterious mutations within the DNA binding domain of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of neurodevelopmental disorders including intellectual disabilities and autism spectrum disorders. While whole animal deletion of Deaf1 in mice is lethal, mice with conditional disruption of the gene in neuronal precursor cells can display memory deficits and increased anxiety-like behavior. This study aimed to further characterize learning and memory alterations and assess changes in marble burying activity and hippocampal size in mice with conditional deletion of Deaf1. Mice lacking DEAF1 in the CNS (NKO) displayed reduced memory in both contextual fear conditioning and a 3-day massed trials Morris water maze paradigm. NKO mice had reduced marble burying activity in full cage marble burying tests. Using a half-cage marble test, NKO mice again buried fewer marbles and spent significantly more time on the side of the cage away from the marbles compared to control animals. The area of the dorsal hippocampus of NKO mice was decreased compared to control and animals with a single Deaf1 allele. These results continue to establish the importance of DEAF1 in cognitive behavior and provide new evidence that DEAF1 regulates hippocampal morphology.