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1.
Mol Psychiatry ; 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38409596

RESUMO

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.

2.
Learn Mem ; 29(3): 77-82, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35169046

RESUMO

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.


Assuntos
Medo , Giro do Cíngulo , Animais , Medo/fisiologia , Generalização Psicológica/fisiologia , Giro do Cíngulo/fisiologia , Hipocampo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL
3.
J Neurosci ; 41(6): 1288-1300, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33293359

RESUMO

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.


Assuntos
Tonsila do Cerebelo/enzimologia , Extinção Psicológica/fisiologia , Hipocampo/enzimologia , Sistema de Sinalização das MAP Quinases/fisiologia , Consolidação da Memória/fisiologia , Córtex Pré-Frontal/enzimologia , Animais , Medo , Masculino , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL
4.
Neurochem Res ; 47(9): 2715-2727, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35469366

RESUMO

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.


Assuntos
Córtex Auditivo , Esquizofrenia , Animais , Córtex Auditivo/metabolismo , Modelos Animais de Doenças , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Fator de Crescimento Epidérmico , Proteínas do Tecido Nervoso/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos
5.
Brain Behav Immun ; 94: 79-88, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33677026

RESUMO

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.


Assuntos
Medo , Hipocampo , Memória Espacial , Fator de Necrose Tumoral alfa , Animais , Hipocampo/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo
6.
Artigo em Inglês | MEDLINE | ID: mdl-32161213

RESUMO

Memory retrieval is not a passive process. When a memory is retrieved, the retrieved memory is destabilized, similar to short-term memory just after learning, and requires memory reconsolidation to re-stabilize the memory. Recent studies characterizing destabilization and reconsolidation showed that a retrieved memory is not always destabilized and that there are boundary conditions that determine the induction of destabilization and reconsolidation according to certain parameters, such as the duration of retrieval and the memory strength and age. Moreover, the reconsolidation of contextual fear memory is not independent of memory extinction; rather, these memory processes interact with each other. There is an increasing number of findings suggesting that destabilization following retrieval facilitates the modification, weakening, or strengthening of the original memory, and the resultant updated memory is stabilized through reconsolidation. Reconsolidation could be targeted therapeutically to improve emotional disorders such as post-traumatic stress disorder and phobia. Thus, this review summarizes recent findings to understand the mechanisms and function of reconsolidation.


Assuntos
Extinção Psicológica/fisiologia , Consolidação da Memória/fisiologia , Animais , Encéfalo , Medo , Humanos , Transtornos da Memória/metabolismo , Transtornos Mentais/metabolismo , Transtornos Fóbicos/metabolismo , Transdução de Sinais , Transtornos de Estresse Traumático/metabolismo
7.
Nihon Hoshasen Gijutsu Gakkai Zasshi ; 76(11): 1173-1184, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33229847

RESUMO

PURPOSE: Volumetric modulated arc therapy (VMAT) can acquire projection images during rotational irradiation, and cone-beam computed tomography (CBCT) images during VMAT delivery can be reconstructed. The poor quality of CBCT images prevents accurate recognition of organ position during the treatment. The purpose of this study was to improve the image quality of CBCT during the treatment by cycle generative adversarial network (CycleGAN). METHOD: Twenty patients with clinically localized prostate cancer were treated with VMAT, and projection images for intra-treatment CBCT (iCBCT) were acquired. Synthesis of PCT (SynPCT) with improved image quality by CycleGAN requires only unpaired and unaligned iCBCT and planning CT (PCT) images for training. We performed visual and quantitative evaluation to compare iCBCT, SynPCT and PCT deformable image registration (DIR) to confirm the clinical usefulness. RESULT: We demonstrated suitable CycleGAN networks and hyperparameters for SynPCT. The image quality of SynPCT improved visually and quantitatively while preserving anatomical structures of the original iCBCT. The undesirable deformation of PCT was reduced when SynPCT was used as its reference instead of iCBCT. CONCLUSION: We have performed image synthesis with preservation of organ position by CycleGAN for iCBCT and confirmed the clinical usefulness.


Assuntos
Radioterapia de Intensidade Modulada , Tomografia Computadorizada de Feixe Cônico Espiral , Algoritmos , Tomografia Computadorizada de Feixe Cônico , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador
8.
J Neurosci ; 37(15): 4103-4116, 2017 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-28292834

RESUMO

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.


Assuntos
Tonsila do Cerebelo/fisiologia , Hipocampo/fisiologia , Rede Nervosa/fisiologia , Córtex Pré-Frontal/fisiologia , Reconhecimento Psicológico/fisiologia , Comportamento Social , Animais , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Masculino , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
9.
Brain Behav Immun ; 59: 313-321, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27562421

RESUMO

The proinflammatory cytokine productions in the brain are altered in a process of fear memory formation, indicating a possibility that altered microglial function may contribute to fear memory formation. We aimed to investigate whether and how microglial function contributes to fear memory formation. Expression levels of M1- and M2-type microglial marker molecules in microglia isolated from each conditioned mice group were assessed by real-time PCR and immunohistochemistry. Levels of tumor necrosis factor (TNF)-α, but not of other proinflammatory cytokines produced by M1-type microglia, increased in microglia from mice representing retention of fear memory, and returned to basal levels in microglia from mice representing extinction of fear memory. Administration of inhibitors of TNF-α production facilitated extinction of fear memory. On the other hand, expression levels of M2-type microglia-specific cell adhesion molecules, CD206 and CD209, were decreased in microglia from mice representing retention of fear memory, and returned to basal levels in microglia from mice representing extinction of fear memory. Our findings indicate that microglial TNF-α is a key element of sustained fear memory and suggest that TNF-α inhibitors can be candidate molecules for mitigating posttraumatic reactions caused by persistent fear memory.


Assuntos
Medo , Memória , Microglia/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Animais , Moléculas de Adesão Celular/metabolismo , Citocinas/metabolismo , Extinção Psicológica , Hipocampo/metabolismo , Lectinas Tipo C/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Receptor de Manose , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Minociclina/farmacologia , Receptores de Superfície Celular/metabolismo , Fator de Necrose Tumoral alfa/sangue
11.
Neurobiol Learn Mem ; 135: 57-65, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27343988

RESUMO

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.


Assuntos
Comportamento Animal/fisiologia , Inibidores Enzimáticos/farmacologia , Medo/fisiologia , Expressão Gênica/fisiologia , Hipocampo/metabolismo , Consolidação da Memória/fisiologia , Memória de Longo Prazo/fisiologia , Memória de Curto Prazo/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Medo/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Glucosiltransferases/metabolismo , Glicosilação , Hipocampo/efeitos dos fármacos , Masculino , Consolidação da Memória/efeitos dos fármacos , Memória de Longo Prazo/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-fos/metabolismo
12.
Biosci Biotechnol Biochem ; 80(6): 1131-40, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27022680

RESUMO

The circadian rhythm generated by circadian clock underlies a molecular mechanism of rhythmic transcriptional regulation by transcription factor BMAL1/CLOCK. Importantly, the circadian clock is coordinated by exogenous cues to accommodate to changes in the external environment. However, the molecular mechanisms by which intracellular-signaling pathways mediate the adjustments of the circadian transcriptional rhythms remain unclear. In this study, we found that pharmacological inhibition or shRNA-mediated knockdown of phosphatidylinositol 3-kinase (PI3K) blocked upregulation of Dbp mRNA induced by serum shock in NIH 3T3 cells. Moreover, the inhibition of PI3K significantly reduced the promoter activity of the Dbp gene, as well as decreased the recruitment of BMAL1/CLOCK to the E-box in the Dbp promoter. Interestingly, the inhibition of PI3K blocked heterodimerization of BMAL1 and CLOCK. Our findings suggest that PI3K signaling plays a modulatory role in the regulation of the transcriptional rhythm of the Dbp gene by targeting BMAL1 and CLOCK.


Assuntos
Fatores de Transcrição ARNTL/genética , Proteínas CLOCK/genética , Relógios Circadianos/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Proteínas CLOCK/metabolismo , Cromonas/farmacologia , Ritmo Circadiano/genética , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Camundongos , Morfolinas/farmacologia , Células NIH 3T3 , Regiões Promotoras Genéticas , Multimerização Proteica , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Transcrição Gênica
13.
Biosci Biotechnol Biochem ; 80(12): 2425-2436, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27576603

RESUMO

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.


Assuntos
Espinhas Dendríticas/patologia , Hipocampo/fisiopatologia , Síndrome de Korsakoff , Memória , Fenótipo , Deficiência de Tiamina/patologia , Deficiência de Tiamina/fisiopatologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiopatologia , Animais , Ataxia/complicações , Peso Corporal , Hipocampo/patologia , Camundongos , Piritiamina/farmacologia , Deficiência de Tiamina/induzido quimicamente , Deficiência de Tiamina/complicações
15.
Hippocampus ; 24(7): 784-93, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24599753

RESUMO

Adult hippocampal neurogenesis has been suggested to play modulatory roles in learning and memory. Importantly, previous studies have shown that newborn neurons in the adult hippocampus are integrated into the dentate gyrus circuit and are recruited more efficiently into the hippocampal memory trace of mice when they become 3 weeks old. Interestingly, a single high-dose treatment with the N-methyl-d-aspartate receptor antagonist memantine (MEM) has been shown to increase hippocampal neurogenesis dramatically by promoting cell proliferation. In the present study, to understand the impact of increased adult neurogenesis on memory performance, we examined the effects of a single treatment of MEM on hippocampus-dependent memory in mice. Interestingly, mice treated with MEM showed an improvement of hippocampus-dependent spatial and social recognition memories when they were trained and tested at 3-6 weeks, but not at 3 days or 4 months, after treatment with MEM. Importantly, we observed a significant positive correlation between the scores for spatial memory (probe trial in the Morris water maze task) and the number of young mature neurons (3 weeks old) in MEM-treated mice, but not saline-treated mice. We also observed that the young mature neurons generated by treatment with MEM were recruited into the trace of spatial memory similarly to those generated through endogenous neurogenesis. Taken together, our observations suggest that treatment with MEM temporally improves hippocampus-dependent memory formation and that the newborn neurons increased by treatment with MEM contribute to this improvement when they become 3 weeks old.


Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Memantina/farmacologia , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Células-Tronco Adultas/citologia , Animais , Divisão Celular/efeitos dos fármacos , Senescência Celular , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/fisiologia , Neurônios/fisiologia , Reconhecimento Psicológico/fisiologia , Comportamento Social , Memória Espacial/fisiologia
16.
Proc Natl Acad Sci U S A ; 108(4): 1681-6, 2011 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-21205885

RESUMO

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.


Assuntos
Comportamento Animal/fisiologia , Proteínas de Ligação a DNA/metabolismo , Hipocampo/metabolismo , Fatores de Transcrição/metabolismo , Animais , Animais Recém-Nascidos , Ansiedade/fisiopatologia , Sequência de Bases , Western Blotting , Proteínas de Ligação a DNA/genética , Espinhas Dendríticas/fisiologia , Comportamento Alimentar/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Fatores de Transcrição de Choque Térmico , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Knockout , Dados de Sequência Molecular , Atividade Motora/fisiologia , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Neurogênese/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ácidos Siálicos/genética , Ácidos Siálicos/metabolismo , Sialiltransferases/genética , Sialiltransferases/metabolismo , Fatores de Transcrição/genética
17.
Nihon Shinkei Seishin Yakurigaku Zasshi ; 34(5-6): 117-25, 2014 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-25536762

RESUMO

Pavlovian fear conditioning is a model of fear learning and memory. The mechanisms regulating fear conditioning and memory have been investigated in humans and rodents. In this paradigm, animals learn and memorize an association between a conditioned stimulus (CS), such as context, and an unconditioned stimulus (US), such as an electrical footshock that induces fear. Fear memory generated though fear conditioning is stabilized via a memory consolidation process. Moreover, recent studies have shown the existence of memory processes that control fear memory following the retrieval of consolidated memory. Indeed, when fear memory is retrieved by re-exposure to the CS, the retrieved memory is re-stabilized via the reconsolidation process. On the other hand, the retrieval of fear memory by prolonged re-exposure to the CS also leads to fear memory extinction, new inhibitory learning against the fear memory, in which animals learn that they do not need to respond to the CS. Importantly, the reinforcement of fear memory after retrieval (i.e., re-experience such as flashbacks or nightmares) has been thought to be associated with the development of emotional disorders such as post-traumatic stress disorder (PTSD). In this review, I summarize recent progress in studies on the mechanism of fear conditioning and memory consolidation, reconsolidation and extinction, and furthermore, introduce our recent establishment of a mouse PTSD model that shows enhancement of fear memory after retrieval.


Assuntos
Encéfalo/fisiologia , Condicionamento Psicológico/fisiologia , Medo/psicologia , Memória/fisiologia , Animais , Modelos Animais de Doenças , Humanos , Aprendizagem/fisiologia
18.
Nihon Hoshasen Gijutsu Gakkai Zasshi ; 70(11): 1225-34, 2014 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-25410328

RESUMO

PURPOSE: Volumetric modulated arc therapy (VMAT) is a rotational intensity-modulated radiotherapy (IMRT) technique capable of acquiring projection images during treatment. The purpose of this study was to reconstruct the dose distribution from respiratory signals and machine parameters acquired during stereotactic body radiotherapy (SBRT). METHODS: The treatment plans created for VMAT-SBRT included the constraint of 1 mm/degree in multileaf collimator (MLC) for a moving phantom and three patients with lung tumors. The respiratory signals were derived from projection images acquired during VMAT delivery, while the machine parameters were derived from machine logs. The respiratory signals and machine parameters were then linked along with the gantry angle. With this data, the dose distribution of each respiratory phase was calculated on the planned four-dimensional CT (4D CT). The doses at the isocenter, the point of max dose and the centroid of the target were compared with those of the corresponding plans. RESULTS AND DISCUSSION: In the phantom study, the maximum dose difference between the plan and "in-treatment" results was -0.4% at the centroid of the target. In the patient study, the difference was -1.8 ± 0.4% at the centroid of the target. Dose differences of the evaluated points between 4 and 10 phases were not significant. CONCLUSION: The present method successfully reconstructed the dose distribution using the respiratory signals and machine parameters acquired during treatment. This is a feasible method for verifying the actual dose for a moving target.


Assuntos
Neoplasias Pulmonares/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/radioterapia , Masculino , Imagens de Fantasmas , Dosagem Radioterapêutica , Tomografia Computadorizada por Raios X/instrumentação
19.
Brain Res Bull ; 195: 141-144, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36801360

RESUMO

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.


Assuntos
Extinção Psicológica , Medo , Memória , Aprendizagem
20.
Brain Res Bull ; 202: 110746, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37604301

RESUMO

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.


Assuntos
Locus Cerúleo , Consolidação da Memória , Extinção Psicológica/fisiologia , Medo/fisiologia , Memória de Longo Prazo , Memória de Curto Prazo , Consolidação da Memória/fisiologia
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