Search

Post-traumatic stress disorder (PTSD) is a trauma- and stressor-related disorder, characterized by bi-directional symptomatic manifestations of increase in both hyperarousal/hypervigilance and numbing/avoidance. In our previous reports, we have proposed an animal model of PTSD using avoidance/escape task sessions in the shuttle box after delivering an inescapable foot-shock traumatization in the same box (Wakizono et al., 2007), and demonstrated the efficacy of 2-week administration of antidepressant on the hyperarousal/hypervigilant behavioral parameters (Sawamura et al., 2004) in the model. In this study, we observed a partial but significant efficacy of oral supplementation of eicosapentaenoic acid (EPA) for five weeks on the numbing/avoidance behavior in the experimental model. Additionally, western blot analyses using brain-derived neurotrophic factor (BDNF) monoclonal antibody revealed a decreased expression of BDNF protein, in the hippocampal region of the rats, due to foot-shock traumatization and a significantly increased expression of BDNF protein after oral EPA supplementation. The results indicate a possibility that alteration of the numbing/avoidance behavior parallels the expression of hippocampal BDNF in the rat brain. The present study suggests a possibility that EPA supplementation in the treatment of PTSD ameliorates persistent numbing/avoidance symptoms. (185 words)., (Copyright © 2019. Published by Elsevier B.V.)

The monoamine hypothesis has been accepted as the most common hypothesis of major depressive disorder (MDD) for a long period because of its simplicity and understandability. Actually, most currently used antidepressants have been considered to act based on the monoamine hypothesis. However, an important problem of the monoamine hypothesis has been pointed out as follows: it fails to explain the latency of response to antidepressants. In addition, many patients with MDD have remained refractory to currently used antidepressants. Therefore, monoamine-alternate hypotheses are required to explain the latency of response to antidepressants. Such hypotheses have been expected to contribute to identifying hopeful new therapeutic targets for MDD. Past studies have revealed that the volume of the hippocampus is decreased in patients with MDD, which is likely caused by the failure of the hypothalamic-pituitary-adrenal axis and following elevation of glucocorticoids. Two hypotheses have been proposed to explain the volume of the hippocampus: (i) the neuroplasticity hypothesis; and (ii) the neurogenesis hypothesis. The neuroplasticity hypothesis explains how the hippocampal volume is decreased by the morphological changes of hippocampal neurons, such as the shortening length of dendrites and the decreased number and density of spines. The neurogenesis hypothesis explains how the hippocampal volume is decreased by the decrease of neurogenesis in the hippocampal dentate gyrus. These hypotheses are able to explain the latency of response to antidepressants. In this review, we first overview how the neuroplasticity and neurogenesis hypotheses have been developed. We then describe the details of these hypotheses., (© 2017 The Authors. Psychiatry and Clinical Neurosciences © 2017 Japanese Society of Psychiatry and Neurology.)

Although electroconvulsive therapy (ECT) is clinically used for severe depression and drug-resistant Parkinson's disease, its exact biological background and mechanism have not yet been fully elucidated. Two potential explanations have been presented so far to explain the increased neuroplastic and resilient profiles of multiple ECT administrations. One is the alteration of central neurotransmitter receptor densities and the other is the expressional upregulation of brain derived neurotrophic factor in various brain regions with enhanced hippocampal neurogenesis and mossy fiber sprouting. In the present report, western blot analyses revealed significantly upregulated expression of various endocytosis-related proteins following 10-day electroconvulsive seizure (ECS) treatment in rat hippocampal homogenates and hippocampal lipid raft fractions extracted using an ultracentrifugation procedure. Upregulated proteins included endocytosis-related scaffolding proteins (caveolin-1, flotillin-1, and heavy and light chains of clathrin) and small GTPases (Rab5, Rab7, Rab11, and Rab4) specifically expressed on various types of endosomes. Two scaffolding proteins, caveolin-1 and flotillin-1, were also increased in the lipid raft fraction. Together with our previous finding of increased autophagy-related proteins in the hippocampal region, the present results suggest membrane trafficking machinery is enhanced following 10-day ECS treatment. We consider that the membrane trafficking machinery that transports functional proteins in the neuronal cells and from or into the synaptic membranes is one of the new candidates supporting the cellular and behavioral neuroplastic profiles of ECS treatments in animal experiments and ECT administrations in clinical settings., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

The findings that antidepressive treatments increase hippocampal neurotrophins have led researchers to emphasize the importance of neurogenesis, formation of new dendrites, and survival of neurons in the brain. However, it is difficult to maintain neural plasticity just by enriching the environment to facilitate formation of new networks. Neural plasticity also requires a degradation process that clears off unnecessary and undesirable components. We have recently reported an increase in autophagy signaling (wherein the cell digests components of itself) that has the potential of enhancing neuronal and synaptic plasticity after multiple sessions of electroconvulsive seizure treatment. The present study revealed an increase in autophagy signaling in the rat hippocampus following 2 weeks of environmental enrichment (EE), a procedure known to elicit antidepressive and anxiolytic behavioral changes in various animal paradigms. Western blot analysis showed an increase in hippocampal expression of microtubule-associated protein light chain 3-II (LC3-II), which is lipidated from LC3-I, in rats in the EE group. The effectiveness of the 2-week EE housing condition was validated by anxiolytic effects observed in the elevated plus maze test, enhanced habituation in the open field test, and elevation of hippocampal brain-derived neurotrophic factor expression. In addition, we showed that the EE housing condition ameliorated numbing/avoidance behaviors, but not hypervigilant behaviors, in an animal model of post-traumatic stress disorder (PTSD). This is the first report to show that EE can increase autophagy signaling and improve numbing/avoidance behaviors in an animal model of PTSD.

The putative antidepressive mechanisms of a series of electroconvulsive seizures (ECS) are the following: 1) downregulation of monoaminergic receptor expression in several brain regions, 2) upregulation of the expression of brain-derived neurotrophic factor (BDNF), and 3) increased neurogenesis in the hippocampus. In this study, we used Western blot techniques to present another mechanism in which ECS enhances the autophagy signaling that is involved in the machinery related to synaptic and neural plasticity. Antibodies for conjugated Atg5-Atg12 (58kD) and cleaved light chain protein 3-II (LC3-II; 14 kD) were used to detect autophagy signals. An antibody for cleaved caspase-3 (17 kD) was used to detect alterations in apoptotic signals. Mature BDNF (14kD) expression in the hippocampus was evaluated in order to qualify the effectiveness of the ECS or stress-loading treatment. While significantly increased autophagy signals and no increases in apoptotic signals were detected in the ECS-treated rat hippocampus, the reverse (increased apoptotic signals and no altered autophagy signals) was observed in stressed rat hippocampus. No neuronal cell loss but new mossy fiber sprouting has been reported to accompany multiple ECS treatments, and recent studies have revealed that autophagy processes regulate the number of specific neurotransmitter receptors and the plasticity of synaptic components. The present study illustrated the neuroplastic and neurotrophic profiles of ECS and the neurotoxic impact of severe stress loading on hippocampal regions. This is the first report to demonstrate increased autophagy signals in ECS-treated rat hippocampus and no alterations in autophagy signals in stress-loaded rat hippocampus., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Calcium-calmodulin dependent protein kinase IV (CaMKIV) is a protein kinase that has been suggested to participate in fluoxetine (FLX)-induced phosphorylation of cyclic AMP-response element binding protein (CREB). CREB is a key transcription factor in adult neurogenesis. The present study aimed at evaluating whether CaMKIV is involved in adult hippocampal neurogenesis with FLX treatment. Effects of chronic FLX on hippocampal cell proliferation, survival and phenotypes were assessed using bromodeoxyuridine (BrdU) immunohistochemistry or BrdU/neuronal nuclei (NeuN)/S100β immunofluorescence staining in wild-type (WT) and CaMKIV knockout (KO) mice. Expression and phosphorylation of CaMKIV and CREB were assessed using RT-PCR and Western blotting. The behavioural action with FLX was assessed in the novelty suppressed feeding test (NSF), which is considered neurogenesis-dependent. CaMKIV KO mice have reduced cell proliferation, but not survival in the dentate gyrus of hippocampus with chronic treatment of FLX when compared to wild littermates. Phenotype analysis showed that most newborn cells matured into neurons. Phosphorylation of CaMKIV was up-regulated in WT mice and phosphorylation of CREB was impaired in CaMKIV KO mice after FLX treatment. The behavioural effects of FLX in NSF were similar in both types. These data suggest that CaMKIV is involved in some aspects of FLX-promoting hippocampal neurogenesis.

The splicing of 26 nucleotides in the coding region of the X-box binding protein-1 (XBP-1) transcript to generate a mature active transcription factor is a part of the unfolded protein response to intracellular endoplasmic reticulum stress. In this study, we demonstrated that XBP-1 splicing is promptly induced in the rat brain including the hippocampus by both inescapable electric foot shock (IS) and pharmacologically manipulated activation of 5-hydroxytryptamine release in a dose-dependent manner. By administering ketanserin, a 5-hydroxytryptamine 2A antagonist, however, we could only partially block the increased splicing by IS and observed that the splicing was not influenced by lithium carbonate pretreatment. Although it is still unclear whether the enhanced unfolded protein response functions neuroprotectively by modulating the rate of general translation and increasing chaperone proteins or whether it eventually induces cellular damage by triggering apoptosis, the present results indicate the possible existence of a new adaptive intracellular signaling pathway in the brain that responds to environmentally challenged behavioral stress loading.

Abstract: Adult neurogenesis in dentate gyrus (DG) is involved in the action mechanism of mood stabilizers. However, it is poorly understood how mood stabilizers affect adult neurogenesis in DG. Neurogenesis consists of proliferation, survival (anti-apoptosis) and differentiation of neural precursor cells in adult DG. Using in vitro culture of adult rat DG-derived neural precursor cells (ADP), we have already shown that four mood stabilizers, such as lithium (Li), valproate (VPA), carbamazepine (CBZ) and lamotrigine (LTG), commonly decrease staurosporine (STS)-induced apoptosis of ADP. These suggest that the common anti-apoptotic effect of mood stabilizers could be involved in mood-stabilizing effects. Past studies have shown that Li and VPA increase the expression of Bcl-2, an anti-apoptotic gene. In addition, it has been shown that Li decreases the expression of p53, which plays a prominent role in apoptosis and regulates the expression of Bcl-2. Therefore, p53 and Bcl-2 can be considered to mediate the common anti-apoptotic effects of Li, VPA, CBZ and LTG. To elucidate the molecular mechanism underlying the common anti-apoptotic effects of mood stabilizers, we investigated the effects of Li, VPA, CBZ and LTG on STS-induced expression changes of p53, Bcl-2 and other p53-related molecules using SH-SY5Y cells as a model of neural precursor-like cells. STS increased the expression of p53 and decreased that of Bcl-2. These effects of STS on p53 and Bcl-2 are restored by all of Li, VPA, CBZ and LTG. In addition, p53 overexpression decreased the expression of Bcl-2. Taken together, these results suggest that p53 and Bcl-2 may be involved in a part of mood-stabilizing effects. [Copyright &y& Elsevier]