Human and non-human infants can form memories for events, but these memories are not successfully consolidated into remote memory. While the neurobiological basis of this phenomenon-known as infantile amnesia-remains unclear, it is hypothesized that the neural circuits required for successful consolidation are insufficiently mature. Here we find that heightened activity in the prelimbic cortex of developing mice triggers a sequalae of maturational steps that culminates in adult-like memory persistence: Activity-dependent increases in brain-derived neurotrophic factor (BDNF) promote myelination of prelimbic circuits via activation of tyrosine kinase receptor B (TrkB) receptors on oligodendrocyte precursor cells (OPCs). Inhibiting any of these steps within a critical developmental window delays the offset of infantile amnesia, whereas promoting this sequalae results in the precocial emergence of memory persistence. Similar to critical periods in sensory cortices, our results indicate that developmental myelination is required for proper circuit maturation and emergence of adult-like memory function.

Circadian rhythms are generated by the periodic transcriptional regulation of a group of clock genes by the transcription factors clock circadian regulator (CLOCK) and basic helix-loop-helix ARNT-like 1 (BMAL1). Intracellular circadian rhythms are regulated by multiple signaling pathways. The calcium signaling pathway especially plays an important role in the rhythmic regulation of clock genes; however, the precise molecular mechanisms underlying calcium signaling-mediated rhythmic transcriptional regulation remain largely unclear. Here, we found that calcium-responsive transactivator (CREST) plays an important role in activating period circadian regulator 1 (Per1) and D-box binding PAR bZIP transcription factor (Dbp) gene expression by increasing intracellular calcium ion concentrations and rhythmic transcriptional regulation of these genes. Importantly, CREST increases the promoter activity of Per1 and Dbp by forming a complex with CLOCK and BMAL1. Finally, we found that CREST binds to the E-box-containing promoters of Per1 and Dbp. Taken together, we conclude that the formation of CREST and CLOCK/BMAL1 complexes at the E-boxes of the Per1 and Dbp promoters increases their mRNA expression in response to increased intracellular calcium ion concentrations.

Retinoic acid (RA), a biologically active metabolite of vitamin A, regulates gene expression through retinoic acid receptor/retinoid X receptor (RAR/RXR)-dependent transcription and is important for various biological phenomena. To understand the role of forebrain RA signaling in synaptic plasticity and memory, we generated transgenic mice expressing a dominant-negative form of retinoic acid receptor α (dnRARα) in adult forebrain. We previously showed that dnRARα expression in the adult forebrain impairs α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated synaptic transmission and long-term potentiation (LTP) in hippocampal CA1 neurons and hippocampus-dependent memory. To investigate the molecular basis of these impairments, we here examined expressions of synaptic plasticity-related molecules in the hippocampus of dnRARα mice. We found that protein levels of GluA1 and postsynaptic density protein 95 (PSD-95) were significantly reduced in the hippocampus of dnRARα mice in a dnRARα expression-dependent manner. To further examine protein expression changes in dnRARα mice, we performed proteome analysis and found that expression of actin-related protein 3 (ARP3), a molecule implicated in activity-dependent spine enlargement and maturation, was also reduced. Combined with our previous findings, these results suggest that forebrain RAR/RXR signaling is crucial for maintaining synaptic transmission, plasticity, and memory formation by upregulating GluA1, PSD-95, and ARP3.

The dysregulation of sleep-wake patterns that occurs during aging is well documented and coincides with changes in intracellular signaling pathways that regulate sleep, such as the calcium/calmodulin-dependent protein kinase (CaMKII)/cyclic-AMP response element-binding protein (CREB) pathway. However, much less is known about the relationship between other CREB-activating members of the CaMK family, such as calcium/calmodulin-dependent protein kinase IV (CaMKIV), and the regulation of sleep. Using 2- to 4-month-old (young adult) and 22- to 24-month-old (aged) male and female CaMKIV-overexpressing (CaMKIV-OE) mice, we observed that overexpression of CaMKIV in the forebrain decreased wakefulness and increased the amount of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep in aged male mice, but not young adult male mice, in comparison to age- and sex-matched controls. Conversely, female mice overexpressing CaMKIV displayed no significant differences in the percentage of time spent in each vigilance state compared to their wild-type counterparts, regardless of age. While CaMKIV overexpression also led to more sleep-wake fragmentation in young adult and aged male mice, aged female mice displayed more consolidated NREM sleep. Overall, our results suggest that CaMKIV overexpression enhances sleep in aged male mice, and differentially affects sleep-wake architecture based on sex and age, providing insights into the potential mechanism by which CaMKIV overexpression enhances memory.

AbstractAimsEating disorders represent an aspect of mental illness involving failure to control eating behaviors. Food valence plays a regulatory role in eating behaviors and changes with eating experiences. Failure to control food valence may be associated with eating disorders. This study presents a newly developed behavior task—food reservation task, which assesses changes in food valence.MethodsOver three consecutive days, mice were fed a regular diet for 30 min and subsequently were offered either palatable or low‐palatable foods for 30 min.ResultsMice decreased regular diet consumption on the days that it was followed by a palatable food—sweet chocolate (SC) or cheese (CH) and increased it when it was followed by a low‐palatable food—bitter (dark) chocolate (BC). Our findings indicate that mice can change regular diet consumption by learning whether it will be followed by a palatable or low‐palatable food. This suggests that palatable food devaluated the food valence of regular diet, whereas low‐palatable food evaluated it.ConclusionWe developed a new food reservation task, which allows to assess experience‐dependent change in the food valence of a regular diet. This task will contribute to a better understanding of the neural mechanisms underlying those changes.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder associated with traumatic memory, yet its etiology remains unclear. Reexperiencing symptoms are specific to PTSD compared to other anxiety-related disorders. Importantly, reexperiencing can be mimicked by retrieval-related events of fear memory in animal models of traumatic memory. Recent studies revealed candidate PTSD-associated genes that were related to the cyclic adenosine monophosphate (cAMP) signaling pathway. Here, we demonstrate the tight linkage between facilitated cAMP signaling and PTSD by analyzing loss- and gain-of-cAMP signaling effects on fear memory in mice and the transcriptomes of fear memory-activated mice and female PTSD patients with reexperiencing symptoms. Pharmacological and optogenetic upregulation or downregulation of cAMP signaling transduction enhanced or impaired, respectively, the retrieval and subsequent maintenance of fear memory in mice. In line with these observations, integrative mouse and human transcriptome analysis revealed the reduced mRNA expression of phosphodiesterase 4B (PDE4B), an enzyme that degrades cAMP, in the peripheral blood of PTSD patients showing more severe reexperiencing symptoms and the mouse hippocampus after fear memory retrieval. Importantly, more severe reexperiencing symptoms and lower PDE4B mRNA levels were correlated with decreased DNA methylation of a locus within PDE4B, suggesting the involvement of methylation in the mechanism of PTSD. These findings raise the possibility that the facilitation of cAMP signaling mediating the downregulation of PDE4B expression enhances traumatic memory, thereby playing a key role in the reexperiencing symptoms of PTSD patients as a functional index of these symptoms.

現在, 脳に良い栄養素や食品に注目が集まっているが, 脳機能に対する栄養素と食品の役割とその作用メカニズムが神経科学的に解明された例は少ない。一方, イメージング, 電気生理学, 分子生物学, 行動学などの脳機能制御のメカニズムを解析する技術の確立が進んでいる。我々はこれら技術を用いて, 記憶能力を中心に脳機能に対する必須栄養素の役割の解明を進めてきた。本総説では, 我々が明らかにしてきた記憶能力に対するマグネシウムとビタミンB1欠乏の影響を紹介する。マグネシウムやビタミンB1の欠乏により, 行動レベルでは海馬依存性記憶に障害が観察されること, また, 分子レベルでは脳内炎症が誘導されることが明らかとなった。特にビタミンB1欠乏では強い脳内炎症のみならず, 海馬の神経変性が誘導されることも示された。以上の結果や他の知見と考え合わせると, 栄養摂取異常により脳内炎症が誘導され, 脳の最も高次な機能である記憶機能がダメージを受ける共通メカニズムの存在が示唆された。

Memory consolidation is the process underlying the stabilization of labile short-term memory and the generation of long-term memory for persistent memory storage. The retrieval of contextual fear memory induces two distinct and opposite memory processes: reconsolidation and extinction. Reconsolidation re-stabilizes retrieved memory for re-storage, whereas memory extinction weakens fear memory and generates a new inhibitory memory. Importantly, the requirement for new gene expression is a critical biochemical feature of the consolidation, reconsolidation, and long-term extinction of memory. The locus coeruleus (LC) is a small nucleus in the brain stem that is composed predominantly of noradrenergic neurons that project to many brain regions. Recent studies have shown that the LC plays modulatory roles in the consolidation and extinction of auditory fear memory through its projections to brain regions contributing to memory storage. Here, we show that the LC is required for the consolidation, reconsolidation, and long-term extinction of contextual fear memory. We first observed that c-fos expression was induced in the LC following contextual fear conditioning to induce consolidation and following short and long re-exposure to the conditioning context to induce reconsolidation and long-term extinction, respectively. More importantly, inhibition of protein synthesis in the LC by a micro-infusion of anisomycin blocked the consolidation, reconsolidation, and long-term extinction of contextual fear memory. Our findings suggest that consolidation, reconsolidation, and long-term extinction occur in the LC and that the LC plays an essential role in memory storage and maintenance.

Memory retrieval is not a passive process. When a memory is retrieved, it returns to a labile state and undergoes reconsolidation to be re-stored. The discovery of this memory reconsolidation has had a major impact on memory consolidation theory. In other words, it suggested that memory is more dynamic than expected and can be modified through reconsolidation. Conversely, a conditioned fear memory undergoes memory extinction after retrieval, and it is thought that extinction does not reflect its erasure, but rather new inhibitory learning of the original conditioned memory. We have investigated the relationship between memory reconsolidation and extinction by comparing their behavioral, cellular, and molecular mechanisms. Memory reconsolidation and extinction have opposite functions on contextual fear and inhibitory avoidance memories; reconsolidation maintains or strengthens fear memory, whereas extinction weakens it. Importantly, reconsolidation and extinction are contrasting memory processes not only at the behavioral level but also at cellular and molecular levels. Furthermore, our analysis revealed that reconsolidation and extinction are not independent processes, but interact with each other. Interestingly, we also found a "memory transition process" that switches the fear memory process from reconsolidation to extinction after retrieval. Investigating the mechanisms of reconsolidation and extinction will contribute to our understanding of the dynamic nature of memory.

The family of epidermal growth factor (EGF) including neuregulin-1 are implicated in the neuropathology of schizophrenia. We established a rat model of schizophrenia by exposing perinatal rats to EGF and reported that the auditory pathophysiological traits of this model such as prepulse inhibition, auditory steady-state response, and mismatch negativity are relevant to those of schizophrenia. We assessed the activation status of the auditory cortex in this model, as well as that in patients with schizophrenia, by monitoring the three neural activity-induced proteins: EGR1 (zif268), c-fos, and Arc. Among the activity markers, protein levels of EGR1 were significantly higher at the adult stage in EGF model rats than those in control rats. The group difference was observed despite an EGF model rat and a control rat being housed together, ruling out the contribution of rat vocalization effects. These changes in EGR1 levels were seen to be specific to the auditory cortex of this model. The increase in EGR1 levels were detectable at the juvenile stage and continued until old ages but displayed a peak immediately after puberty, whereas c-fos and Arc levels were nearly indistinguishable between groups at all ages with an exception of Arc decrease at the juvenile stage. A similar increase in EGR1 levels was observed in the postmortem superior temporal cortex of patients with schizophrenia. The commonality of the EGR1 increase indicates that the EGR1 elevation in the auditory cortex might be one of the molecular signatures of this animal model and schizophrenia associating with hallucination.

Microglia have been suggested to be involved in the underlying mechanism of conditional fear memory formation by regulating inflammatory cytokines. However, the mechanism linking microglia and neuronal activity related to fear conditioning remains unclear. This study characterized the transcription profile of microglia in a fear memory conditional mouse model. Compared with those in control mice microglia, the most significantly induced genes were synapse-related, whereas immune-related genes were reduced due to fear memory consolidation. Whilst the increased expression of synapse-related genes was reversed after fear memory extinction, that of immunological genes was not, strongly suggesting a connection between microglia, neurons, and a dysregulated immune response following contextual fear conditioning. Furthermore, in the hippocampal microglia, we found that the expression of neurotransmitter release regulators, γ-aminobutyric acid (GABA) receptor GABRB3 and synapsin 1/2, increased under fear memory consolidation and restored (decreased) after extinction. In addition, compared with the transcription profile in peripheral monocytes, few overlapping genes were not enriched in biological processes. Taken together, the identified conditional fear stress-induced changes in mouse microglial transcription profiles suggest that microglia-neuron communication mediates contextual fear conditioning.

Pediatrics InternationalVolume 64, Issue 1 e15198 Clinical Notes MIS-C with clinically mild encephalitis with a reversible splenial lesion in a Japanese boy Satoshi Kida, Corresponding Author Satoshi Kida satoshikida1492@gmail.com orcid.org/0000-0003-4836-9141 Department of Pediatrics, Iwaki City Medical Center, Iwaki-shi, Japan Correspondence: Satoshi Kida MD PhD, Iwaki City Medical Center, 16 Kusehara, Mimaya-cho, Uchigo, Iwaki-shi, Fukushima, 973-8555, Japan. Email: satoshikida1492@gmail.comSearch for more papers by this authorKenji Mima, Kenji Mima Department of Pediatrics, Iwaki City Medical Center, Iwaki-shi, JapanSearch for more papers by this authorAtsumi Hanawa, Atsumi Hanawa Department of Pediatrics, Iwaki City Medical Center, Iwaki-shi, JapanSearch for more papers by this authorMaki Nodera, Maki Nodera Department of Pediatrics, Iwaki City Medical Center, Iwaki-shi, JapanSearch for more papers by this authorKisei Endo, Kisei Endo Department of Pediatrics, Iwaki City Medical Center, Iwaki-shi, JapanSearch for more papers by this author Satoshi Kida, Corresponding Author Satoshi Kida satoshikida1492@gmail.com orcid.org/0000-0003-4836-9141 Department of Pediatrics, Iwaki City Medical Center, Iwaki-shi, Japan Correspondence: Satoshi Kida MD PhD, Iwaki City Medical Center, 16 Kusehara, Mimaya-cho, Uchigo, Iwaki-shi, Fukushima, 973-8555, Japan. Email: satoshikida1492@gmail.comSearch for more papers by this authorKenji Mima, Kenji Mima Department of Pediatrics, Iwaki City Medical Center, Iwaki-shi, JapanSearch for more papers by this authorAtsumi Hanawa, Atsumi Hanawa Department of Pediatrics, Iwaki City Medical Center, Iwaki-shi, JapanSearch for more papers by this authorMaki Nodera, Maki Nodera Department of Pediatrics, Iwaki City Medical Center, Iwaki-shi, JapanSearch for more papers by this authorKisei Endo, Kisei Endo Department of Pediatrics, Iwaki City Medical Center, Iwaki-shi, JapanSearch for more papers by this author First published: 21 June 2022 https://doi.org/10.1111/ped.15198Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume64, Issue1January/December 2022e15198 RelatedInformation

The transcription profile of microglia related to fear conditioning remains unclear. Here, we used Illumina MouseWG-6v2 microarrays to investigate the gene transcription changes in microglia and peripheral monocytes after contextual fear conditioning of C57BL/6 J mice. Mice were trained with or without a single minimized footshock stimulation (0-s or 2-s, 0.4 mA) and re-exposed to the training context without footshock for three different durations 24 h later: 0 min (FS0), 3 min (FS3), or 30 min (FS30). Whole brain microglia and peripheral monocytes were prepared 24 h after re-exposure using a neural tissue dissociation kit, including non-footshock controls for two re-exposure durations (Con3 and Con30). The data can be valuable for researchers interested in glial cells and neurotransmission studies and are related to the research article “Contextual fear conditioning regulates synapse-related gene transcription in mouse microglia”.

Fear generalization is one of the main symptoms of posttraumatic stress disorder. In rodents, the anterior cingulate cortex (ACC) and the hippocampus (HPC) control the expression of contextual fear memory generalization. Consistently, ACC projections to the ventral HPC contribute to contextual fear generalization. However, the roles of ACC projections to the dorsal HPC (dHPC) in fear generalization are unclear, although the dHPC is required for the retrieval of recent contextual fear memory. To investigate these roles, we examined the effects of optogenetic silencing and stimulation of these projections in contextual fear generalization at the recent and remote time points. Mice underwent contextual fear conditioning and, at 1 or 28 d later, were tested in the conditioned chamber, a novel context, or a similar context. Optogenetic activation of these projections induced higher freezing in mice in the novel context compared with the control group at a recent (1-d), but not remote (28-d), time point following conditioning, suggesting that activation of this pathway enhances contextual fear generalization. In contrast, optogenetic inactivation of these projections induced lower freezing in the similar context compared with the control group at a recent, but not remote, time point, suggesting that inactivation of this pathway impaired contextual fear generalization. These observations suggest that the ACC to the dHPC projections positively regulate the expression of contextual fear generalization when contextual fear memory is recent.

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.

Vitamin B1 (thiamine) deficiency (TD) has been known to induce cognitive dysfunction including deficits in memory formation known as Wernicke-Korsakoff's syndrome in humans. However, mechanisms by which TD leads to deficits in learning and memory still remain unclear. In this study, to understand them, we examined the effects of pyrithiamine-induced thiamine deficiency (PTD) on learning and memory in mice. PTD-treated mice showed chronic impairments in the formation of hippocampus-dependent memories. Importantly, anatomical analyses indicated that PTD-treated mice displayed significant decreases in sizes of hippocampus and spine density of hippocampal neurons, suggesting the degeneration of hippocampal neurons by PTD-treatment. We next performed RNA-seq analyses of the hippocampus using next-generation sequencing and found that PTD mice showed increases in expressions of inflammation-related genes in the hippocampus and significant decreases in mRNA expressions of transcription factor CREB in the hippocampus, suggesting that PTD showed impaired CREB signaling pathways in the hippocampus. We finally examined the effects of PTD on transgenic mice increasing the CREB activity by expressing a constitutively active CREB mutant in the forebrain (DIEDML mice, Suzuki et al 2011) and found that activation of CREB rescued impairments in hippocampal degeneration and hippocampus-dependent memory by PTD. Taken together, our findings suggest that PTD causes strong inflammation, thereby leading to hippocampal degeneration and subsequent impairments in CREB signaling pathways that play essential roles in memory formation.