[Show abstract][Hide abstract] ABSTRACT: Psychiatric disorders are caused not only by genetic factors but also by complicated factors such as environmental ones. Moreover, environmental factors are rarely quantitated as biological and biochemical indicators, making it extremely difficult to understand the pathological conditions of psychiatric disorders as well as their underlying pathogenic mechanisms. Additionally, we have actually no other option but to perform biological studies on postmortem human brains that display features of psychiatric disorders, thereby resulting in a lack of experimental materials to characterize the basic biology of these disorders. From these backgrounds, animal, tissue, or cell models that can be used in basic research are indispensable to understand biologically the pathogenic mechanisms of psychiatric disorders. In this review, we discuss the importance of microendophenotypes of psychiatric disorders, i.e., phenotypes at the level of molecular dynamics, neurons, synapses, and neural circuits, as targets of basic research on these disorders.
Current Molecular Medicine 03/2015; 15(2). DOI:10.2174/1566524015666150303002128 · 3.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: eLife digest
Video cameras allow us to record events as they happen. When we look back at a video clip, what we see is an exact replica of what was originally recorded. We tend to assume that our memories work in a similar manner. However, recent research suggests that our memories may be more malleable than we realize. Once a memory has been reactivated, it goes through a process known as reconsolidation that can make it stronger or weaker, or that can change its content.
Now, Fukushima et al. have carried out a series of experiments which shed light on the process of memory reconsolidation. Mice were trained to remember a negative event, and later tested on their memory of this event. Some of the mice were also given a ‘reactivation’ session, during which they were reminded of the original memory. These mice were more fearful of the event during the memory test than those who had not been reminded of it. This suggests that the process of reconsolidating the memory after it had been retrieved had the effect of making the memory stronger.
Fukushima et al. then demonstrated that this enhancement depended on the synthesis of proteins in particular regions of the brain. When the mice were given an injection to block protein synthesis immediately after reactivation of the memory, their memory of the negative event was weakened. Crucially, this effect only happened when the injection was given immediately after reactivation of the memory; if the memory had not been reactivated, the injection did not change its strength.
Fukushima et al. went on to show that three regions of the brain—the amygdala, the hippocampus, and the medial prefrontal cortex—are involved in memory enhancement. However, only one of them, the amygdala, is involved in the other aspects of reconsolidation. This research could support clinical work by elucidating the potential role of reconsolidation in conditions such as post-traumatic stress disorder.
[Show abstract][Hide abstract] ABSTRACT: cAMP response element-binding (CREB) has been known to be an essential transcription factor that activates the gene expression required for the formation of long-term memory (LTM) in a wide range of animal models, from nematodes to higher animals such as Aplysia, Drosophila, and rodents. In mammals, various CREB mutant mice have been developed and analyzed. These studies have shown that gain or loss of CREB function improves and impairs, respectively, the formation of LTMs, enabling us to understand the roles of CREB in the formation and enhancement of memory. In this article, the analyses conducted on CREB mutant mice are reviewed with a particular focus on learning and memory formation.
Brain research bulletin 05/2014; 105. DOI:10.1016/j.brainresbull.2014.04.011 · 2.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
αCaMKII plays central and essential roles in long-term potentiation (LTP), learning and memory. αCaMKII is activated via binding with Ca2+/CaM in response to elevated Ca2+ concentration. Furthermore, prolonged increase in Ca2+ concentration leads to the auto-phosphorylation of αCaMKII at T286, maintaining the activation of αCaMKII even after Ca2+/CaM dissociation. Importantly, the active form of αCaMKII is thought to exhibit conformational change. In order to elucidate the relationships between the interaction of αCaMKII with CaM and the conformational change of αCaMKII, we generated molecular probes (YFP-αCaMKII with CFP-CaM and YFP-αCaMKII-CFP) and performed time-lapse imaging of the interaction with CaM and the conformational change, respectively, in living cells using FRET.
The interaction of YFP-αCaMKII with CFP-CaM and the conformational change of YFP-αCaMKII-CFP were induced simultaneously in response to increased concentrations of Ca2+. Consistent with previous predictions, high levels of Ca2+ signaling maintained the conformational change of YFP-αCaMKII-CFP at the time when CFP-CaM was released from YFP-αCaMKII. These observations indicated the transfer of αCaMKII conformational change from CaM-dependence to CaM-independence. Furthermore, analyses using αCaMKII mutants showed that phosphorylation at T286 and T305/306 played positive and negative roles, respectively, during in vivo interaction with CaM and further suggested that CaM-dependent and CaM-independent conformational changed forms displays similar but distinct structures.
Importantly, these structual differences between CaM-dependent and -independent forms of αCaMKII may exhibit differential functions for αCaMKII, such as interactions with other molecules required for LTP and memory. Our molecular probes could thus be used to identify therapeutic targets for cognitive disorders that are associated with the misregulation of αCaMKII.
[Show abstract][Hide abstract] ABSTRACT: CREB has been reported to be activated by injury and is commonly used as marker for pain-related plasticity changes in somatosensory pathways, including spinal dorsal horn neurons and the anterior cingulate cortex (ACC). However no evidence has been reported to support the direct role of activated CREB in injury-related behavioral sensitization (or allodynia). Here we report that genetic enhancement of CREB-mediated transcription selectively in forebrain areas enhanced behavioral responses to non-noxious stimuli after chronic inflammation (CFA model) or nerve injury. In contrast, behavioral acute responses to peripheral subcutaneous injection of formalin did not show any significant difference. Furthermore, acute pain responses to noxious thermal stimuli were also not affected. Our results thus provide direct evidence that cortical CREB-mediated transcription contributes to behavioral allodynia in animal models of chronic inflammatory or neuropathic pain.
[Show abstract][Hide abstract] ABSTRACT: cAMP response element-binding protein (CREB), a transcription factor, has been shown to play a central role in memory formation, and its involvement in this process has been investigated using a wide range of animal models, from nematodes to higher animals. Various CREB mutant mice have been developed and investigated. Several types of mutant mice with loss of CREB function have impaired memory formation and long-term potentiation (LTP), suggesting that CREB plays essential roles in these processes. To characterize the roles of CREB in memory formation and LTP further, mutant mice displaying gain of CREB function have been generated and analyzed. Importantly, CREB-DIEDML mice and CREB-Y134F mice showed enhanced memory formation, whereas CREB-VP16 mice displayed a lowered threshold of long-lasting LTP (L-LTP) induction, strongly suggesting that CREB functions as a positive regulator of memory formation and LTP. In this review, I focus on the effects of the genetic activation of CREB in LTP and memory formation and summarize previous findings.
[Show abstract][Hide abstract] ABSTRACT: Fragile X syndrome is caused by lack of fragile X mental retardation protein (FMRP) due to silencing of the FMR1 gene. The metabotropic glutamate receptors (mGluRs) in the central nervous system contribute to higher brain functions including learning/memory, mental disorders and persistent pain. The transcription factor cyclic AMP-responsive element binding protein (CREB) is involved in important neuronal functions, such as synaptic plasticity and neuronal survival. Our recent study has shown that stimulation of Group I mGluRs upregulated FMRP and activated CREB in anterior cingulate cortex (ACC), a key region for brain cognitive and executive functions, suggesting that activation of Group I mGluRs may upregulate FMRP through CREB signaling pathway.
In this study, we demonstrate that CREB contributes to the regulation of FMRP by Group I mGluRs. In ACC neurons of adult mice overexpressing dominant active CREB mutant, the upregulation of FMRP by stimulating Group I mGluR is enhanced compared to wild-type mice. However, the regulation of FMRP by Group I mGluRs is not altered by overexpression of Ca2+-insensitive mutant form of downstream regulatory element antagonist modulator (DREAM), a transcriptional repressor involved in synaptic transmission and plasticity.
Our study has provided further evidence for CREB involvement in regulation of FMRP by Group I mGluRs in ACC neurons, and may help to elucidate the pathogenesis of fragile X syndrome.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
These results indicate that the quality of place memories is not determined by brain regions on which the memory depends.