Behavioral stress and antidepressant treatments altered hippocampal expression of Nogo signal-related proteins in rats.

Some immune molecules including neurite outgrowth inhibitor (Nogo) ligands and their receptor（Nogo receptor-1: NgR1）are expressed at the neuronal synaptic sites. Paired immunoglobulin-like receptor B (PirB) is another Nogo receptor that also binds to major histocompatibility complex I and ß-amyloid and suppresses dendritic immune cell functions and neuronal plasticity in the central nervous system. Augmenting structural and functional neural plasticity by manipulating the Nogo signaling pathway is a novel promising strategy for treating brain ischemia and degenerative processes such as Alzheimer's disease. In recent decades psychiatric research using experimental animals has focused on the attenuation of neural plasticity by stress loadings and on the enhanced resilience by psychopharmacological treatments. In the present study, we examined possible expressional alterations in Nogo signal-related proteins in the rat hippocampus after behavioral stress loadings and antidepressant treatments. To validate the effectiveness of the procedures, previously reported increase in brain-derived neurotrophic factor (BDNF) by ECS or ketamine administration and decrease of BDNF by stress loadings are also shown in the present study. Significant increases in hippocampal NgR1 and PirB expression were observed following chronic variable stress, and a significant increase in NgR1 expression was observed under a single prolonged stress paradigm. These results indicate a possible contribution of enhanced Nogo signaling to the attenuation of neural plasticity in response to stressful experiences. Additionally, the suppression of hippocampal NgR1 expression using electroconvulsive seizure treatment and administration of subanesthetic dose of ketamine supported the increased neural plasticity induced by the antidepressant treatments.

The analysis of telephone consultation contents of patients with bipolar disorder received by a self-help group.

Aim: Previous research shows that telephone consultation is useful in suicide prevention, substance use disorder, and other mental illnesses. However, no study has been conducted with a specific focus on telephone consultation for patients with bipolar disorder (BPD). Therefore, this study investigates the utilization of telephone consultation by patients with BPD and their families and analyzes the consultation contents to identify specific issues that they face. Methods: We investigated a record book of telephone consultation conducted between 2013 and 2019 provided by the Japanese Alliance of Bipolar Disorder, which is a self-help group in Japan specializing in BPD. The main themes regarding consultation were extracted and labelled as diagnosis, symptoms, treatment, laws and social support, interpersonal relations, social life, other people with BPD, and others, with up to three items being labeled per consultation. Results: A total of 3540 consultations were sought, and consulters who were patients accounted for 74% of the calls. The largest number of consultations were those related to symptoms (1522), followed by interpersonal relations (1003), social life (896), and treatment (797). There was a significant difference in the distribution of consultation contents between patients and their families (χ 2 = 44.595, p < 0.0001). Conclusion: Most consultations by patients with BPD were about their psychiatric symptoms. Consultation contents differed between patients and families, with patients focusing more on their own social life and families focusing more on the treatment of BPD. These findings could help health-care professionals in formulating effective psychoeducation and psychotherapy programs.

Kleptomania Induced by Venlafaxine.

Introduction. Kleptomania is an impulse-control disorder that results in an irresistible urge to steal. It is often observed as a comorbidity in patients undergoing pharmacological treatment for Parkinson's disease. Recurrent shopliftings are also observed in the clinical course of frontotemporal dementia. Case Presentation. After successful treatment of severe depression with venlafaxine at a dose of 225 mg/day, a 54-year-old euthymic female patient exhibited recurrent stealing behavior. After the diagnostic exclusion of frontotemporal dementia, kleptomania induced by venlafaxine administration was suspected. The symptoms of kleptomania disappeared with the gradual decrease in the venlafaxine dosage to 37.5 mg/day. Discussion. Venlafaxine is a dual serotonin-norepinephrine reuptake inhibitor. We considered two possible mechanisms to explain the pathophysiology of kleptomania in the present case: (1) increased dopaminergic neural transmission due to the inhibited dopamine reuptake by the norepinephrine transporter with a high dose of venlafaxine or (2) enhanced serotonergic neural transmission by the inhibition of serotonin reuptake by venlafaxine. In past studies, five cases of impulse-control disorder induced by selective serotonin reuptake inhibitors have been reported. This is the fourth report of venlafaxine-induced kleptomania and highlights the importance of considering the possibility of a rare side effect of kleptomania induced by antidepressant.

The effects of eicosapentaenoic acid dietary supplementation on behavioral parameters and expression of hippocampal brain-derived neurotrophic factor in an animal model of post-traumatic stress disorder.

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).

Allergy to chlorpromazine and valproic acid following carbamazepine hypersensitivity in a patient with an HLA-B*4601 allele.

A 73-year-old man, exhibiting psychomotor excitement after traumatic brain injury, developed allergic cutaneous eruptions and hepatic inflammation that did not resolve after the cessation of carbamazepine (CBZ). Fusing maculopapular erythema was observed in the face, neck, presternal region, and bilaterally in the forearms and feet. A drug-induced lymphocyte stimulation test revealed hypersensitivity to chlorpromazine (CPZ) and valproic acid (VPA), as well as to CBZ. The allergic reaction with eosinophilia to CPZ and VPA was suspected to have emerged following CBZ hypersensitivity, since previous treatment with CPZ and VPA prior to the introduction of CBZ had not been associated with adverse reactions earlier in the course of treatment. Recent studies have indicated linkages between severe CBZ hypersensitivity - but not mild CBZ hypersensitivity - and specific leukocyte antigens, HLA-B*1502 and HLA-A*3101, in Asian and European populations. The present case exhibited the HLA-B*4601 allele, which is associated with a high relative risk for the development of CBZ-induced maculopapular eruptions in Japanese and Han Chinese populations. Although cross-hypersensitivity among aromatic compounds, including CBZ and CPZ, is well-established, data regarding CBZ allergy-associated hypersensitivity to VPA are limited. In the present case, a cutaneous allergy to mianserin (a tetracyclic antidepressant) was also observed later in the course of treatment, suggesting additional cross-reactivity exists among aromatic psychotropic drugs. Thus, the association between the HLA-B*4601 allele and allergic reactions to VPA, aromatic psychotropic drugs, and CBZ should be further examined in future studies.

Activated brain-derived neurotrophic factor/TrkB signaling in rat dorsal and ventral hippocampi following 10-day electroconvulsive seizure treatment.

Electroconvulsive therapy (ECT) is still the most effective strategy to treat severe and drug-resistant depressive disorders. Electroconvulsive seizure (ECS), which induces neuroplastic structural alterations and resilient behavioral changes in experimental animals, is the model of the ECT for human depression. ECT is typically administered three times per week for up to 4 weeks, while ECS treatments are administered daily for 10days. The increased expression of hippocampal brain-derived neurotrophic factor (BDNF) induced by antidepressive ECS treatment in experimental animals has been well documented. BDNF executes various neuroplastic functions by phosphorylating its high-affinity receptor, full-length TrkB, which has an intrinsic tyrosine kinase domain. However, the exact activation of BDNF/TrkB signaling following multiple ECS treatments has not been well elucidated. In epileptogenesis, conflicting effects of BDNF have been reported; while acute BDNF administration enhanced neuronal hyperexcitability and induced epileptiform activities, continuous BDNF infusion inhibited epileptogenesis. These conflicting results have been attributed to agonist-induced adaptive response of expressional down-regulation of the BDNF receptor. In the present study, using western blotting, we demonstrated increased phosphorylation as well as decreased expression of the full-length TrkB receptor (145kD) in both dorsal and ventral hippocampal regions of rats after a 10-day ECS treatment. The expression of mature BDNF (14kD) was up-regulated while that of proBDNF (32kD) remained unaltered in both hippocampal regions after the ECS treatment. Our results indicate that the hippocampal BDNF/TrkB signaling pathway is activated by multiple ECS treatments despite the ligand-induced down-regulation of the full-length TrkB receptor.

Human herpesvirus 6 and 7 are biomarkers for fatigue, which distinguish between physiological fatigue and pathological fatigue.

Fatigue reduces productivity and is a risk factor for lifestyle diseases and mental disorders. Everyone experiences physiological fatigue and recovers with rest. Pathological fatigue, however, greatly reduces quality of life and requires therapeutic interventions. It is therefore necessary to distinguish between the two but there has been no biomarker for this. We report on the measurement of salivary human herpesvirus (HHV-) 6 and HHV-7 as biomarkers for quantifying physiological fatigue. They increased with military training and work and rapidly decreased with rest. Our results suggested that macrophage activation and differentiation were necessary for virus reactivation. However, HHV-6 and HHV-7 did not increase in obstructive sleep apnea syndrome (OSAS), chronic fatigue syndrome (CFS) and major depressive disorder (MDD), which are thought to cause pathological fatigue. Thus, HHV-6 and HHV-7 would be useful biomarkers for distinguishing between physiological and pathological fatigue. Our findings suggest a fundamentally new approach to evaluating fatigue and preventing fatigue-related diseases.

Increased expression of endocytosis-Related proteins in rat hippocampus following 10-day electroconvulsive seizure treatment.

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.

Neuroprotective effects of adenosine deaminase in the striatum.

Adenosine deaminase (ADA) is a ubiquitous enzyme that catabolizes adenosine and deoxyadenosine. During cerebral ischemia, extracellular adenosine levels increase acutely and adenosine deaminase catabolizes the increased levels of adenosine. Since adenosine is a known neuroprotective agent, adenosine deaminase was thought to have a negative effect during ischemia. In this study, however, we demonstrate that adenosine deaminase has substantial neuroprotective effects in the striatum, which is especially vulnerable during cerebral ischemia. We used temporary oxygen/glucose deprivation (OGD) to simulate ischemia in rat corticostriatal brain slices. We used field potentials as the primary measure of neuronal damage. For stable and efficient electrophysiological assessment, we used transgenic rats expressing channelrhodopsin-2, which depolarizes neurons in response to blue light. Time courses of electrically evoked striatal field potential (eFP) and optogenetically evoked striatal field potential (optFP) were recorded during and after oxygen/glucose deprivation. The levels of both eFP and optFP decreased after 10 min of oxygen/glucose deprivation. Bath-application of 10 µg/ml adenosine deaminase during oxygen/glucose deprivation significantly attenuated the oxygen/glucose deprivation-induced reduction in levels of eFP and optFP. The number of injured cells decreased significantly, and western blot analysis indicated a significant decrease of autophagic signaling in the adenosine deaminase-treated oxygen/glucose deprivation slices. These results indicate that adenosine deaminase has protective effects in the striatum.

Affective temperaments play an important role in the relationship between childhood abuse and depressive symptoms in major depressive disorder.

Previous studies have shown that various factors, such as genetic and environmental factors, contribute to the development of major depressive disorder (MDD). The aim of this study is to clarify how multiple factors, including affective temperaments, childhood abuse and adult life events, are involved in the severity of depressive symptoms in MDD. A total of 98 participants with MDD were studied using the following self-administered questionnaire surveys: Patient Health Questionnaire-9 measuring the severity of depressive symptoms; Life Experiences Survey (LES) measuring negative and positive adult life events; Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego auto-questionnaire (TEMPS-A) measuring affective temperaments; and the Child Abuse and Trauma Scale (CATS) measuring childhood abuse. The data were analyzed using single and multiple regression analyses and structural equation modeling (SEM). The neglect score reported by CATS indirectly predicted the severity of depressive symptoms through affective temperaments measured by TEMPS-A in SEM. Four temperaments (depressive, cyclothymic, irritable, and anxious) directly predicted the severity of depressive symptoms. The negative change in the LES score also directly predicted severity. This study suggests that childhood abuse, especially neglect, indirectly increases the severity of depressive symptoms through increased scores of affective temperaments in MDD.

The structural equation analysis of childhood abuse, adult stressful life events, and temperaments in major depressive disorders and their influence on refractoriness.

BACKGROUND: Previous studies have shown the interaction between heredity and childhood stress or life events on the pathogenesis of a major depressive disorder (MDD). In this study, we tested our hypothesis that childhood abuse, affective temperaments, and adult stressful life events interact and influence the diagnosis of MDD. PATIENTS AND METHODS: A total of 170 healthy controls and 98 MDD patients were studied using the following self-administered questionnaire surveys: the Patient Health Questionnaire-9 (PHQ-9), the Life Experiences Survey, the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire, and the Child Abuse and Trauma Scale (CATS). The data were analyzed with univariate analysis, multivariable analysis, and structural equation modeling. RESULTS: The neglect scores of the CATS indirectly predicted the diagnosis of MDD through cyclothymic and anxious temperament scores of the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire in the structural equation modeling. Two temperaments - cyclothymic and anxious - directly predicted the diagnosis of MDD. The validity of this result was supported by the results of the stepwise multivariate logistic regression analysis as follows: three factors - neglect, cyclothymic, and anxious temperaments - were significant predictors of MDD. Neglect and the total CATS scores were also predictors of remission vs treatment-resistance in MDD patients independently of depressive symptoms. LIMITATIONS: The sample size was small for the comparison between the remission and treatment-resistant groups in MDD patients in multivariable analysis. CONCLUSION: This study suggests that childhood abuse, especially neglect, indirectly predicted the diagnosis of MDD through increased affective temperaments. The important role as a mediator of affective temperaments in the effect of childhood abuse on MDD was suggested.

Low-level laser therapy for prevention of noise-induced hearing loss in rats.

Noninvasive low-level laser therapy (LLLT) is neuroprotective, but the mechanism of this effect is not fully understood. In this study, the use of LLLT as a novel treatment for noise-induced hearing loss (NIHL) is investigated. Sprague-Dawley rats were exposed to intense noise and their right ears were irradiated with an 808nm diode laser at an output power density of 110 or 165mW/cm(2) for a 30min period for 5 consecutive days. Measurement of the auditory brainstem response revealed an accelerated recovery of auditory function in the groups treated with LLLT compared with the non-treatment group at days 2, 4, 7 and 14 after noise exposure. Morphological observations also revealed a significantly higher outer hair cell survival rate in the LLLT groups. Immunohistochemical analyses for inducible nitric oxide synthase (iNOS) and cleaved caspase-3 were used to examine oxidative stress and apoptosis. Strong immunoreactivities were observed in the inner ear tissues of the non-treatment group, whereas these signals were decreased in the LLLT group at 165mW/cm(2) power density. Our findings suggest that LLLT has cytoprotective effects against NIHL via the inhibition of iNOS expression and apoptosis.

Environmental enrichment enhances autophagy signaling in the rat hippocampus.

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.

Maternal separation enhances conditioned fear and decreases the mRNA levels of the neurotensin receptor 1 gene with hypermethylation of this gene in the rat amygdala.

Stress during postnatal development is associated with an increased risk for depression, anxiety disorders, and substance abuse later in life, almost as if mental illness is able to be programed by early life stressors. Recent studies suggest that such "programmed" effects can be caused by epigenetic regulation. With respect to conditioned fear, previous studies have indicated that early life stress influences its development in adulthood, whereas no potential role of epigenetic regulation has been reported. Neurotensin (NTS) is an endogenous neuropeptide that has receptors densely located in the amygdala and hippocampus. Recently, NTS systems have constituted an emerging target for the treatment of anxiety. The aim of the present work is to clarify whether the NTS system is involved in the disturbance of conditioned fear in rats stressed by maternal separation (MS). The results showed that MS enhanced freezing behaviors in fear-conditioned stress and reduced the gene expression of NTS receptor (NTSR) 1 but not of NTS or NTSR2 in the amygdalas of adult rats. The microinjection of a NTSR1 antagonist into the amygdala increased the percentage of freezing in conditioned fear, whereas the microinjection of NTSR1 agonist decreased freezing. These results suggest that NTSR1 in the amygdala may play a role in the effects of MS on conditioned fear stress in adult rats. Moreover, MS increased DNA methylation in the promoter region of NTSR1 in the amygdala. Taken together, MS may leave epigenetic marks in the NTSR1 gene in the amygdala, which may enhance conditioned fear in adulthood. The MS-induced alternations of DNA methylation in the promoter region of NTSR1 in the amygdala may be associated with vulnerability to the development of anxiety disorders and depression in adulthood.

Decreased plasma brain-derived neurotrophic factor and vascular endothelial growth factor concentrations during military training.

Decreased concentrations of plasma brain-derived neurotrophic factor (BDNF) and serum BDNF have been proposed to be a state marker of depression and a biological indicator of loaded psychosocial stress. Stress evaluations of participants in military mission are critically important and appropriate objective biological parameters that evaluate stress are needed. In military circumstances, there are several problems to adopt plasma BDNF concentration as a stress biomarker. First, in addition to psychosocial stress, military missions inevitably involve physical exercise that increases plasma BDNF concentrations. Second, most participants in the mission do not have adequate quality or quantity of sleep, and sleep deprivation has also been reported to increase plasma BDNF concentration. We evaluated plasma BDNF concentrations in 52 participants on a 9-week military mission. The present study revealed that plasma BDNF concentration significantly decreased despite elevated serum enzymes that escaped from muscle and decreased quantity and quality of sleep, as detected by a wearable watch-type sensor. In addition, we observed a significant decrease in plasma vascular endothelial growth factor (VEGF) during the mission. VEGF is also neurotrophic and its expression in the brain has been reported to be up-regulated by antidepressive treatments and down-regulated by stress. This is the first report of decreased plasma VEGF concentrations by stress. We conclude that decreased plasma concentrations of neurotrophins can be candidates for mental stress indicators in actual stressful environments that include physical exercise and limited sleep.

Two cases of mild serotonin toxicity via 5-hydroxytryptamine 1A receptor stimulation.

We propose the possibility of 5-hydroxytryptamine (5-HT)1A receptor involvement in mild serotonin toxicity. A 64-year-old woman who experienced hallucinations was treated with perospirone (8 mg/day). She also complained of depressed mood and was prescribed paroxetine (10 mg/day). She exhibited finger tremors, sweating, coarse shivering, hyperactive knee jerks, vomiting, diarrhea, tachycardia, and psychomotor agitation. After the discontinuation of paroxetine and perospirone, the symptoms disappeared. Another 81-year-old woman, who experienced delusions, was treated with perospirone (8 mg/day). Depressive symptoms appeared and paroxetine (10 mg/day) was added. She exhibited tachycardia, finger tremors, anxiety, agitation, and hyperactive knee jerks. The symptoms disappeared after the cessation of paroxetine and perospirone. Recently, the effectiveness of coadministrating 5-HT1A agonistic psychotropics with selective serotonin reuptake inhibitors (SSRIs) has been reported, and SSRIs with 5-HT1A agonistic activity have been newly approved in the treatment of depression. Perospirone is a serotonin-dopamine antagonist and agonistic on the 5-HT1A receptors. Animal studies have indicated that mild serotonin excess induces low body temperature through 5-HT1A, whereas severe serotonin excess induces high body temperature through 5-HT2A activation. Therefore, it could be hypothesized that mild serotonin excess induces side effects through 5-HT1A, and severe serotonin excess induces lethal side effects with hyperthermia through 5-HT2A. Serotonin toxicity via a low dose of paroxetine that is coadministered with perospirone, which acts agonistically on the 5-HT1A receptor and antagonistically on the 5-HT2A receptor, clearly indicated 5-HT1A receptor involvement in mild serotonin toxicity. Careful measures should be adopted to avoid serotonin toxicity following the combined use of SSRIs and 5-HT1A agonists.

Electroconvulsive seizures enhance autophagy signaling in rat hippocampus.

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.