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Essential nutrient factors, including water- and fat-soluble vitamins, minerals, and essential amino acids, play an important role in brain function. We have investigated the roles of these nutrients in learning and memory in mice. Interestingly, we found that dietary deficiency of vitamin B1 or magnesium, inhibition of the vitamin A signaling pathway, and restricted intake of tryptophan impair hippocampus-dependent memory. Furthermore, magnesium deficiency causes neuroinflammation in the hippocampus. Conversely, dietary heat-killed Lactobacillus species enhance hippocampus-dependent memory. These results suggest that the nutrient factors investigated in our studies have strong influences on hippocampus-dependent memory performance.

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Memory reconsolidation is thought to maintain or enhance an original memory or add new information to the memory. Retrieved inhibitory avoidance (IA) memory is enhanced through memory reconsolidation by activating gene expression in the amygdala, medial prefrontal cortex (mPFC), and hippocampus. However, it remains unclear how these regions interact to reconsolidate/enhance IA memory. Here, we found the interactions between the amygdala and mPFC as upstream regulators of the hippocampus for IA memory reconsolidation. Pharmacological inactivation of the amygdala, mPFC, or hippocampus immediately after IA memory retrieval blocked IA memory enhancement. More importantly, inactivation of the amygdala or mPFC blocked the induction of c-Fos in the amygdala, mPFC, and hippocampus, whereas hippocampal blockade inhibited it only in the hippocampus. These observations suggest interactions between the amygdala and mPFC and they both function as upstream regulators of the hippocampus to reconsolidate IA memory. Our findings suggest circuitry mechanisms underlying IA memory enhancement through reconsolidation between the amygdala, mPFC, and hippocampus.

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., (Copyright © 2021 the authors.)

Cognitive performance in people varies according to time-of-day, with memory retrieval declining in the late afternoon-early evening. However, functional roles of local brain circadian clocks in memory performance remains unclear. Here, we show that hippocampal clock controlled by the circadian-dependent transcription factor BMAL1 regulates time-of-day retrieval profile. Inducible transgenic dominant negative BMAL1 (dnBMAL1) expression in mouse forebrain or hippocampus disrupted retrieval of hippocampal memories at Zeitgeber Time 8-12, independently of retention delay, encoding time and Zeitgeber entrainment cue. This altered retrieval profile was associated with downregulation of hippocampal Dopamine-cAMP signaling in dnBMAL1 mice. These changes included decreases in Dopamine Receptors (D1-R and D5-R) and GluA1-S845 phosphorylation by PKA. Consistently, pharmacological activation of cAMP-signals or D1/5Rs rescued impaired retrieval in dnBMAL1 mice. Importantly, GluA1 S845A knock-in mice showed similar retrieval deficits with dnBMAL1 mice. Our findings suggest mechanisms underlying regulation of retrieval by hippocampal clock through D1/5R-cAMP-PKA-mediated GluA1 phosphorylation.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder associated with memories of traumatic experiences. Recent studies have shown that the forgetting of contextual fear memory is promoted via increased adult hippocampal neurogenesis induced by neurogenesis enhancers, such as memantine (MEM) and exercise, raising the possibility that neurogenesis enhancers improve PTSD by facilitating the forgetting of traumatic memory. On the other hand, repeated exposure to social defeat (SD) stress by aggressor mice induces social avoidance behavior to the aggressor and chronic anxiety-like behavior. In this study, we assumed this SD stress paradigm as a PTSD-like model and examined the effects of treatment with neurogenesis enhancer MEM on SD stress-induced PTSD-like behavior. Male C57BL/6 mice received SD stress for 10 consecutive days and were assessed for social avoidance memory to the aggressor (memory of aggressor mice) and anxiety-like behavior using social interaction and elevated zero maze tasks. Consistent with previous studies, SD mice formed social avoidance memory and exhibited increased anxiety-like behavior. Importantly, subsequent MEM treatment (once a week for 4 weeks) significantly reduced social avoidance behavior, suggesting that MEM-treated SD mice showed forgetting of social avoidance memory. Interestingly, MEM-treated SD mice showed comparable anxiety-like behavior with control mice that were not exposed to SD stress. Moreover, MEM-treated SD mice showed no reinstatement of social avoidance memory following single re-exposure to the aggressor. Our findings suggest that neurogenesis enhancer not only enhanced the forgetting of traumatic memory but also improved PTSD (anxiety)-like behavior.

Aims: Lactobacillus species are used widely as various food and supplements to improve health. Previous studies have shown that heat-killed Lactobacillus brevis SBC8803 induces serotonin release from intestinal cells and affects sleep rhythm and the autonomic nervous system. However, the effect of SBC8803 on cognitive function remains unknown. Here, we examined the effects of dietary heat-killed SBC8803 on hippocampus-dependent memory and adult hippocampal neurogenesis., Methods: Hippocampus-dependent memory performance was assessed in mice fed heat-killed SBC8803 using social recognition and contextual fear conditioning tasks. Adult hippocampal neurogenesis was evaluated before, during, and after feeding heat-killed SBC8803 by measuring the number of 5-bromo-2-deoxyuridine (BrdU)-positive cells following systemic injections of BrdU using immunohistochemistry., Results: Mice fed a heat-killed SBC8803 diet showed an improvement of hippocampus-dependent social recognition and contextual fear memories and enhanced adult hippocampal neurogenesis by increasing the survival, but not proliferation, of newborn neurons., Conclusion: Dietary heat-killed SBC8803 functions as memory and neurogenesis enhancers., (© 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Memory consolidation, reconsolidation, and extinction have been shown to share similar molecular signatures, including new gene expression. Calpain is a Ca 2+ -dependent protease that exerts its effects through the proteolytic cleavage of target proteins. Neuron-specific conditional deletions of calpain 1 and 2 impair long-term potentiation in the hippocampus and spatial learning. Moreover, recent studies have suggested distinct roles of calpain 1 and 2 in synaptic plasticity. However, the role of hippocampal calpain in memory processes, especially memory consolidation, reconsolidation, and extinction, is still unclear. In the current study, we demonstrated the critical roles of hippocampal calpain in the consolidation, reconsolidation, and extinction of contextual fear memory in mice. We examined the effects of pharmacological inhibition of calpain in the hippocampus on these memory processes, using the N-Acetyl-Leu-Leu-norleucinal (ALLN; calpain 1 and 2 inhibitor). Microinfusion of ALLN into the dorsal hippocampus impaired long-term memory (24 h memory) without affecting short-term memory (2 h memory). Similarly, this pharmacological blockade of calpain in the dorsal hippocampus also disrupted reactivated memory but did not affect memory extinction. Importantly, the systemic administration of ALLN inhibited the induction of c-fos in the hippocampus, which is observed when memory is consolidated. Our observations showed that hippocampal calpain is required for the consolidation and reconsolidation of contextual fear memory. Further, the results suggested that calpain contributes to the regulation of new gene expression that is necessary for these memory processes as a regulator of Ca 2+ -signal transduction pathway.

Social recognition memory is an essential and basic component of social behavior that is used to discriminate familiar and novel animals/humans. Previous studies have shown the importance of several brain regions for social recognition memories; however, the mechanisms underlying the consolidation of social recognition memory at the molecular and anatomic levels remain unknown. Here, we show a brain network necessary for the generation of social recognition memory in mice. A mouse genetic study showed that cAMP-responsive element-binding protein (CREB)-mediated transcription is required for the formation of social recognition memory. Importantly, significant inductions of the CREB target immediate-early genes c-fos and Arc were observed in the hippocampus (CA1 and CA3 regions), medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), and amygdala (basolateral region) when social recognition memory was generated. Pharmacological experiments using a microinfusion of the protein synthesis inhibitor anisomycin showed that protein synthesis in these brain regions is required for the consolidation of social recognition memory. These findings suggested that social recognition memory is consolidated through the activation of CREB-mediated gene expression in the hippocampus/mPFC/ACC/amygdala. Network analyses suggested that these four brain regions show functional connectivity with other brain regions and, more importantly, that the hippocampus functions as a hub to integrate brain networks and generate social recognition memory, whereas the ACC and amygdala are important for coordinating brain activity when social interaction is initiated by connecting with other brain regions. We have found that a brain network composed of the hippocampus/mPFC/ACC/amygdala is required for the consolidation of social recognition memory. SIGNIFICANCE STATEMENT Here, we identify brain networks composed of multiple brain regions for the consolidation of social recognition memory. We found that social recognition memory is consolidated through CREB-meditated gene expression in the hippocampus, medial prefrontal cortex, anterior cingulate cortex (ACC), and amygdala. Importantly, network analyses based on c-fos expression suggest that functional connectivity of these four brain regions with other brain regions is increased with time spent in social investigation toward the generation of brain networks to consolidate social recognition memory. Furthermore, our findings suggest that hippocampus functions as a hub to integrate brain networks and generate social recognition memory, whereas ACC and amygdala are important for coordinating brain activity when social interaction is initiated by connecting with other brain regions., (Copyright © 2017 the authors 0270-6474/17/374103-14$15.00/0.)

Patients with severe Wernicke-Korsakoff syndrome (WKS) associated with vitamin B1 (thiamine) deficiency (TD) show enduring impairment of memory formation. The mechanisms of memory impairment induced by TD remain unknown. Here, we show that hippocampal degeneration is a potential microendophenotype (an endophenotype of brain disease at the cellular and synaptic levels) of WKS in pyrithiamine-induced thiamine deficiency (PTD) mice, a rodent model of WKS. PTD mice show deficits in the hippocampus-dependent memory formation, although they show normal hippocampus-independent memory. Similarly with WKS, impairments in memory formation did not recover even at 6 months after treatment with PTD. Importantly, PTD mice exhibit a decrease in neurons in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus and reduced density of wide dendritic spines in the DG. Our findings suggest that TD induces hippocampal degeneration, including the loss of neurons and spines, thereby leading to enduring impairment of hippocampus-dependent memory formation.

Memory consolidation and reconsolidation have been shown to require new gene expression. N-glycosylation, one of the major post-translational modifications, is known to play essential or regulatory roles in protein function. A previous study suggested that N-glycosylation is required for the maintenance of long-term potentiation in hippocampal CA1 neurons. However, the role of de novo N-glycosylation in learning and memory, such as memory consolidation and reconsolidation, still remains unclear. Here, we show critical roles for N-glycosylation in the consolidation and reconsolidation of contextual fear memory in mice. We examined the effects of pharmacological inhibition of N-glycosylation in the hippocampus on these memory processes using three different inhibitors (tunicamycin, 1-deoxynojirimycin, and swainsonine) that block the enzymatic activity required for N-glycosylation at different steps. Microinfusions of the N-glycosylation inhibitors into the dorsal hippocampus impaired long-term memory (LTM) formation without affecting short-term memory (STM). Similarly, this pharmacological blockade of N-glycosylation in the dorsal hippocampus also disrupted post-reactivation LTM after retrieval without affecting post-reactivation STM. Additionally, a microinfusion of swainsonine blocked c-fos induction in the hippocampus, which is observed when memory is consolidated. Our observations showed that N-glycosylation is required for the consolidation and reconsolidation of contextual fear memory and suggested that N-glycosylation contributes to the new gene expression necessary for these memory processes., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

CREB is a pivotal mediator of activity-regulated gene transcription that underlies memory formation and allocation. The contribution of a key CREB cofactor, CREB-regulated transcription coactivator 1 (CRTC1), has, however, remained elusive. Here we show that several constitutive kinase pathways and an activity-regulated phosphatase, calcineurin, converge to determine the nucleocytoplasmic shuttling of CRTC1. This, in turn, triggered an activity-dependent association of CRTC1 with CREB-dependent regulatory elements found on IEG promoters. Forced expression of nuclear CRTC1 in hippocampal neurons activated CREB-dependent transcription, and was sufficient to enhance contextual fear memory. Surprisingly, during contextual fear conditioning, we found evidence of nuclear recruitment of endogenous CRTC1 only in the basolateral amygdala, and not in the hippocampus. Consistently, CRTC1 knockdown in the amygdala, but not in the hippocampus, significantly attenuated fear memory. Thus, CRTC1 has a wide impact on CREB-dependent memory processes, but fine-tunes CREB output in a region-specific manner., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Retinoid signaling pathways mediated by retinoic acid receptor (RAR)/retinoid × receptor (RXR)-mediated transcription play critical roles in hippocampal synaptic plasticity. Furthermore, recent studies have shown that treatment with retinoic acid alleviates age-related deficits in hippocampal long-term potentiation (LTP) and memory performance and, furthermore, memory deficits in a transgenic mouse model of Alzheimer's disease. However, the roles of the RAR/RXR signaling pathway in learning and memory at the behavioral level have still not been well characterized in the adult brain. We here show essential roles for RAR/RXR in hippocampus-dependent learning and memory. In the current study, we generated transgenic mice in which the expression of dominant-negative RAR (dnRAR) could be induced in the mature brain using a tetracycline-dependent transcription factor and examined the effects of RAR/RXR loss., Results: The expression of dnRAR in the forebrain down-regulated the expression of RARβ, a target gene of RAR/RXR, indicating that dnRAR mice exhibit dysfunction of the RAR/RXR signaling pathway. Similar with previous findings, dnRAR mice displayed impaired LTP and AMPA-mediated synaptic transmission in the hippocampus. More importantly, these mutant mice displayed impaired hippocampus-dependent social recognition and spatial memory. However, these deficits of LTP and memory performance were rescued by stronger conditioning stimulation and spaced training, respectively. Finally, we found that pharmacological blockade of RARα in the hippocampus impairs social recognition memory., Conclusions: From these observations, we concluded that the RAR/RXR signaling pathway greatly contributes to learning and memory, and LTP in the hippocampus in the adult brain.

Background: During permanent memory formation, recall of acquired place memories initially depends on the hippocampus and eventually become hippocampus-independent with time. It has been suggested that the quality of original place memories also transforms from a precise form to a less precise form with similar time course. The question arises of whether the quality of original place memories is determined by brain regions on which the memory depends., Results: To directly test this idea, we introduced a new procedure: a non-associative place recognition memory test in mice. Combined with genetic and pharmacological approaches, our analyses revealed that place memory is precisely maintained for 28 days, although the recall of place memory shifts from hippocampus-dependent to hippocampus-independent with time. Moreover, the inactivation of the hippocampal function does not inhibit the precision of remote place memory., Conclusion: These results indicate that the quality of place memories is not determined by brain regions on which the memory depends.

Aberrant transcriptional regulation in the brain is thought to be one of the key components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Heat shock factors (HSFs) modulate cellular homeostasis through the control of gene expression. However, the roles of HSFs in brain function have yet to be elucidated fully. In the present study, we attempted to clarify the role of HSF1-mediated gene regulation in neuronal and behavioral development using HSF1-deficient (HSF1(-/-)) mice. We found granule neurons of aberrant morphology and impaired neurogenesis in the dentate gyrus of HSF1(-/-) mice. In addition, HSF1(-/-) mice showed aberrant affective behavior, including reduced anxiety and sociability but increased depression-like behavior and aggression. Furthermore, HSF1 deficiency enhanced behavioral vulnerability to repeated exposure to restraint stress. Importantly, rescuing the HSF1 deficiency in the neonatal but not the adult hippocampus reversed the aberrant anxiety and depression-like behaviors. These results indicate a crucial role for hippocampal HSF1 in neuronal and behavioral development. Analysis of the molecular mechanisms revealed that HSF1 directly modulates the expression of polysialyltransferase genes, which then modulate polysialic acid-neural cell adhesion molecule (PSA-NCAM) levels in the hippocampus. Enzymatic removal of PSA from the neonatal hippocampus resulted in aberrant behavior during adulthood, similar to that observed in HSF1(-/-) mice. Thus, these results suggest that one role of HSF1 is to control hippocampal PSA-NCAM levels through the transcriptional regulation of polysialyltransferases, a process that might be involved in neuronal and behavioral development in mice.

Contextual fear memory is attenuated by reexposure of animals to a context alone without pairing it with an unconditioned stimulus, a phenomenon referred to as fear extinction. Here, we report that Fyn tyrosine kinase in the hippocampus is involved in the extinction of contextual fear. We inhibited Src-family tyrosine kinases in the dorsal hippocampus by stereotaxic injection of an inhibitor, PP2, and observed facilitation of extinction. We then biochemically analyzed dorsal hippocampal tissue during extinction training, and found that activated Fyn was significantly downregulated among the Src-family tyrosine kinases examined. These findings suggest that downregulation of Fyn activity facilitates the extinction of contextual fear.

Fyn-tyrosine-kinase-deficient mice exhibit defects in the Morris water maze test and long-term potentiation (LTP) induction in the hippocampus, and given that LTP has been postulated as the neural basis for memory formation, Fyn may be required for hippocampus-dependent memory formation. However, how Fyn is involved in the process of memory formation is unclear. To investigate the role of Fyn in hippocampal memory formation, we first tested the behavior of Fyn-deficient mice by contextual fear conditioning. A mouse was placed in a context and a foot shock was delivered, so that the mouse associated the context with the shock. We found that the freezing response of Fyn-deficient mice to the context was impaired at 24 h after conditioning. We then measured freezing at 1 h after conditioning, and found that their short-term contextual fear memory was also impaired. We used Western blotting to examine the mode of Fyn activation in dorsal hippocampal tissue following contextual fear conditioning. Fyn activation peaked as early as 5-10 min after contextual fear conditioning and persisted for at least 40 min. Concomitant increases in tyrosine phosphorylation of several proteins, including NR2B, were also observed, but no increases in tyrosine phosphorylation were observed in Fyn-deficient mice. Thus, both short-term and long-term (24-h) contextual fear memory were impaired in Fyn-deficient mice, and Fyn activation in the dorsal hippocampus transiently increased after contextual fear conditioning. These findings strongly suggest that activation of the Fyn signaling pathway is involved in hippocampus-dependent formation of contextual fear memory.

Previous studies have shown that inhibiting protein synthesis shortly after reactivation impairs the subsequent expression of a previously consolidated fear memory. This has suggested that reactivation returns a memory to a labile state and that protein synthesis is required for the subsequent restabilization of memory. While the molecular mechanisms underlying the restabilization of reactivated memories are being uncovered, those underlying the initial destabilization are not known at all. Using a contextual fear conditioning paradigm in mice, here we show that LVGCCs or CB1 receptors in hippocampus are required for the initial destabilization of reactivated memory. Either pharmacological blockade of hippocampal protein synthesis or genetic disruption of CREB-dependent transcription disrupts memory restabilization following reactivation. However, these effects were completely blocked when mice were treated with inhibitors of either LVGCCs or CB1 receptors, indicating that LVGCCs or CB1 receptors are required for the initial destabilization of reactivated memory. In control experiments, we show that blockade of LVGCCs or CB1 receptors does not interfere with the ability of ANI to block protein synthesis, or with the ability of ANI to impair initial consolidation. These experiments begin to reveal mechanisms underlying the destabilization of previously consolidated memories following reactivation and indicate the importance of activation of LVGCCs and CB1 in this process.

During fear conditioning, animals learn an association between a previously neutral or conditioned stimulus (CS) and an aversive or unconditioned stimulus (US). Subsequent reexposure to the CS alone triggers two competing processes. Brief reexposure to the CS initiates reconsolidation processes that serve to stabilize or maintain the original CS-US memory. In contrast, more prolonged reexposure to the CS leads to the formation of an inhibitory extinction (CS-no US) memory. Previous studies have established that both reconsolidation and extinction require gene expression. Consistent with this, here we first show that genetic disruption of cAM-Presponsive element-binding protein (CREB)-mediated transcription blocks both reconsolidation and long-term extinction of contextual fear memory. We next asked whether reconsolidation and extinction engage CREB-mediated transcription in distinct brain regions. Accordingly, we used immunohistochemical approaches to characterize the activation of the transcription factor CREB [as well as the expression of the CREB-dependent gene Arc (activity-regulated cytoskeleton-associated protein)] after brief versus prolonged reexposure to a previously conditioned context. After brief reexposure, we observed significant activation of CREB-mediated gene expression in the hippocampus and amygdala. In contrast, after the prolonged reexposure, we observed significant activation of CREB-mediated gene expression in the amygdala and prefrontal cortex. Finally, we showed that blocking protein synthesis in either the hippocampus or the amygdala blocked reconsolidation of contextual fear memory, whereas similar blockade in the amygdala and prefrontal cortex prevented the formation of extinction memory. These experiments establish that reactivated contextual fear memories undergo CREB-dependent reconsolidation or extinction in distinct brain regions. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that calcium/calmodulin-dependent protein kinase IV (CaMKIV) functions as a positive regulator for memory formation and that age-related memory deficits are the result of dysfunctional signaling pathways mediated by cAMP response element-binding protein (CREB), the downstream transcription factor of CaMKIV. Little is known, however, about the effects of increasedCaMKIVlevels on the ability to formmemoryin adult and aged stages.Wegenerated a transgenic mouse overexpressingCaMKIV in the forebrain and showed that the upregulation of CaMKIV led to an increase in learning-induced CREB activity, increased learningrelated hippocampal potentiation, and enhanced consolidation of contextual fear and social memories. Importantly, we also observed reduced hippocampal CaMKIV expression with aging and a correlation between CaMKIV expression level and memory performance in aged mice. Genetic overexpression of CaMKIV was able to rescue associated memory deficits in aged mice. Our findings suggest that the level of CaMKIV expression correlates positively with the ability to form long-term memory and implicate the decline of CaMKIV signaling mechanisms in age-related memory deficits. [ABSTRACT FROM AUTHOR]

Highlights • Effects of Mg2+ deficiency (MgD) on memory and neuron morphology were examined. • Mice fed MgD diet show deficits in hippocampus-dependent memories. • MgD did not affect amygdala-dependent memory, locomotion, or emotional behaviors. • Mice fed MgD diet show normal spine density and morphology of hippocampal neurons. • Dietary Mg2+ is important for memory function of the hippocampus. Abstract Magnesium (Mg2+) is an essential mineral for maintaining biological functions. One major action of Mg2+ in the brain is modulating the voltage-dependent blockade of N -methyl- d -aspartate type glutamate receptors, thereby controlling their opening, which is crucial for synaptic plasticity. Therefore, Mg2+ has been shown to play critical roles in learning and memory, and synaptic plasticity. However, the effects of dietary Mg2+ deficiency (MgD) on learning and memory and the morphology of neurons contributing to memory performance have not been examined in depth. Here, we show that MgD impairs hippocampus-dependent memories in mice. Mice fed an MgD diet showed deficits in hippocampus-dependent contextual fear, spatial and social recognition memories, although they showed normal amygdala- and insular cortex-dependent conditioned taste aversion memory, locomotor activity, and emotional behaviors such as anxiety-related and social behaviors. However, MgD mice showed normal spine density and morphology of hippocampal neurons. These findings suggest that MgD impairs hippocampus-dependent memory without affecting the morphology of hippocampal neurons. [ABSTRACT FROM AUTHOR]