PurposeTo explore the Effects of Exercise Supplementary to Standard Therapy on Cognition and Sleep in Depression.MethodsWe randomized 273 inpatients with first-episode severe depression, 234 completed 6 weeks, conventional treatment, conventional treatment combined with aerobic exercises and conventional treatment combined with stretching or resistance training exercises group. Hamilton Depression Scale-24 (HAMD24), Pittsburgh Sleep Quality Index (PSQI), Montreal Cognitive Assessment (MOCA), Chinese Version of the Trail-Making Test (C-TMT), and Stroop Color and Word Test (SCWT) were used to evaluate the patients respectively before and after intervention. The primary analysis estimated was the between-group difference in post-treatment scores at 6 weeks under randomized allocation (post-status estimated); within-group changes were summarized descriptively.ResultsAfter intervention, HAMD24, PSQI, C-TMT-A, and C-TMT-B scores of patients in each group were all lower than those before intervention. HAMD24, PSQI, and C-TMT-A scores of patients in Groups B and C showed lower than those of Group A. C-TMT-B score of patients in Group B was lower than that of Group C, and the score of Group C was lower than that of Group A. MOCA, SCWT scores of patients in each group were higher than those before intervention. Stroop Word and Stroop Color scores were significantly higher in Groups B and C than in Group A. MOCA and Stroop Color-Word scores of patients in Group B were higher than those of Group C. However, scores of Group C were higher than those of Group A.ConclusionBoth aerobic exercises and stretching or resistance training exercises as adjuncts to conventional treatment improved depressive symptoms, sleep quality, and cognitive function in patients with first-episode severe depression. Patterns were consistent with greater improvement in select executive-function measures in the aerobic arm; confirmation with baseline-adjusted analyses is warranted.

The primary protein components of white matter include myelin basic protein (MBP) and 2’,3’-cyclic nucleotide 3’-phosphodiesterase (CNP). Alterations in their expression are significantly implicated in depression. This study investigated changes in MBP and CNP expression associated with depressive-like behaviors induced by chronic unpredictable stress (CUS) and evaluated therapeutic interventions using fluoxetine (FLU), an enriched environment (EE), or their combination. Male Sprague Dawley rats were randomly assigned to a control group and four CUS-exposed groups undergoing 6 weeks of stress. During the final 3 weeks of CUS, rats received daily fluoxetine (CUS + FLU group), were housed in EE (CUS + EE group), or received combined EE and fluoxetine (CUS + FLU + EE group). Depression-like behaviors were assessed through sucrose preference, forced swimming, and open field tests after CUS completion and at the end of weeks 4–6. Protein and mRNA expression levels of MBP and CNP in the prefrontal cortex were quantified via immunohistochemistry, western blot, and qRT-PCR. Three weeks following CUS exposure, rats demonstrated significant depression-like behavioral phenotypes. By the fifth week, these behavioral deficits were ameliorated in the CUS + FLU + EE, whereas the CUS + FLU and CUS + EE groups exhibited comparable behavioral recovery by week 6. Parallel molecular analyses revealed diminished protein and mRNA expression levels of MBP and CNP in the prefrontal cortex of CUS-exposed animals, accompanied by a pronounced elevation in IL-1β expression. Therapeutic interventions with FLU, EE, or their combination significantly attenuated these CUS-induced molecular alterations. The antidepressant effects correlated with restored MBP, CNP, and IL-1β expression levels, suggesting that MBP/CNP deficiencies in depression may involve IL-1β elevation. In particular, combined enriched environment and fluoxetine accelerated behavioral recovery.

BACKGROUND:Research into the shared and distinct brain dysfunctions in patients with schizophrenia (SCZ) and major depressive disorder (MDD) has been increasing. However, few studies have explored the application of functional near-infrared spectroscopy (fNIRS) in investigating brain dysfunction and enhancing diagnostic methodologies in these two conditions. METHODS:A general linear model was used for analysis of brain activation following task-state fNIRS from 131 patients with SCZ, 132 patients with MDD and 130 healthy controls (HCs). Subsequently, seventy-seven time-frequency analysis methods were used to construct new features of fNIRS, followed by the implementation of five machine learning algorithms to develop a differential diagnosis model for the three groups. This model was evaluated by comparing it to both a diagnostic model relying on traditional fNIRS features and assessments made by two psychiatrists. RESULTS:Brain activation analysis revealed significantly lower activation in Broca's area, the dorsolateral prefrontal cortex, and the middle temporal gyrus for both the SCZ and MDD groups compared to HCs. Additionally, the SCZ group exhibited notably lower activation in the superior temporal gyrus and the subcentral gyrus compared to the MDD group. When distinguishing among the three groups using independent validation datasets, the models utilizing new fNIRS features achieved an accuracy of 85.90 % (AUC = 0.95). In contrast, models based on traditional fNIRS features reached an accuracy of 52.56 % (AUC = 0.66). The accuracies of the two psychiatrists were 42.00 % (AUC = 0.60) and 38.00 % (AUC = 0.50), respectively. CONCLUSION:This investigation brings to light the shared and distinct neurobiological abnormalities present in SCZ and MDD, offering potential enhancements for extant diagnostic systems.

Schizophrenia (SCZ) is a complex psychiatric disorder presenting challenges for characterization. The current study aimed to identify and evaluate disease-responsive essential genes (DREGs) to enhance the molecular characterization of SCZ. RNA-sequencing data from PsychENCODE (536 SCZ patients, 832 controls) and peripheral blood transcriptome data from 144 recruited subjects (59 SCZ patients, 6 non-SCZ psychiatric patients, 79 controls) are analyzed. Shared differential expression genes are obtained using three algorithms. Support vector machine (SVM)-based recursive feature elimination is employed to identify DREGs. The biological relevance of these DREGs is examined through protein-protein interaction network, pathway enrichment, polygenic scoring, and brain tissue expression. Key DREGs are validated in SCZ animal models. A DREGs-based machine-learning model for SCZ characterization is developed and its performance is assessed using multiple datasets. The analysis identified 184 DREGs forming an interconnected network involved in synaptic plasticity, inflammation, neuronal development, and neurotransmission. DREGs exhibited distinct expression in SCZ-related brain regions and animal models. Their genetic contributions are comparable to genome-wide polygenic risk scores. The DREG-based SVM model demonstrated high performance (AUC 85% for SCZ characterization, 79% for specificity). These findings provide new insights into the molecular mechanisms underlying SCZ and emphasize the potential of DREGs in improving SCZ characterization.

Chronic stress is the primary environmental risk factor for major depressive disorder (MDD), and there is compelling evidence that neuroinflammation is the major pathomechanism linking chronic stress to MDD. Mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) is a negative regulator of MAPK signaling pathways involved in cellular stress responses, survival, and neuroinflammation. We examined the possible contributions of MKP-1 to stress-induced MDD by comparing depression-like behaviors (anhedonia, motor retardation, behavioral despair), neuroinflammatory marker expression, and MAPK signaling pathways among rats exposed to chronic unpredictable mild stress (CUMS), overexpressing MKP-1 in the hippocampus, and CUMS-exposed rats underexpressing MKP-1 in the hippocampus. Rats exposed to CUMS exhibited MKP-1 overexpression, greater numbers of activated microglia, and enhanced expressions of neuroinflammatory markers (interleukin [IL]-6, [IL]-1β, tumor necrosis factor [TNF]-ɑ, and decreased phosphorylation levels of ERK and p38 in the hippocampus as well as anhedonia in the sucrose preference test, motor retardation in the open field, and greater immobility (despair) in the forced swimming tests. These signs of neuroinflammation and depression-like behaviors and phosphorylation levels of ERK and p38 were also observed in rats overexpressing MKP-1 without CUMS exposure, while CUMS-induced neuroinflammation, microglial activation, phosphorylation levels of ERK and p38, and depression-like behaviors were significantly reversed by MKP-1 knockdown. Moreover, MKP-1 knockdown promoted the activation of the MAPK isoform ERK, implying that the antidepressant-like effects of MKP-1 knockdown may be mediated by the ERK pathway disinhibition. These findings suggested that hippocampal MKP-1 is an essential regulator of stress-induced neuroinflammation and a promising target for antidepressant development.

Neuroinflammation may inhibit oligodendrocyte and astrocyte differentiation, which causes demyelination and synaptic degeneration. The myelin component nervonic acid (NA) may improve demyelinating and neurodegenerative diseases. This study firstly explored relationships between glial cell dysfunction and demyelination or synaptic degeneration in schizophrenia patients, and secondly determined nervonic acid therapeutic effects in a preclinical schizophrenia model of mice. Plasma samples were collected from 18 male healthy controls and 18 male schizophrenic patients (diagnosed by DSM-V) at aged 18–55. Mouse brain samples were collected from a maternal immune activation (MIA) model of schizophrenia via injecting 5 mg/kg polyinosinic-polycytidylic acid. Male mouse offspring (age 2.5 months, n = 12) were treated by clozapine (15 mg/kg/day) or fed 0.5

BackgroundMitogen-activated protein kinase (MAPK) phosphatase-1 (MKP1) is upregulated in the hippocampus of patients with depression, while pharmacological inhibition of hippocampal MKP1 can mitigate depression-like behaviors in rodents. In addition, MAPK signaling regulates autophagy, and antidepressants were recently shown to target autophagic signaling pathways. We speculated that MKP1 contributes to depression by enhancing hippocampal autophagy through dephosphorylation of the MAPK isoform ERK1/2.MethodsWe established a rat depression model by exposure to chronic unpredictable mild stress (CUMS), and then examined depression-like behaviors in the sucrose preference test (SPT) and forced swimming test (FST) as well as expression changes in hippocampal MKP1, ERK1/2, phosphorylated ERK1/2, and autophagy-related proteins LC3II by Western blotting and immunostaining. These same measurements were repeated in rats exposed to CUMS following hippocampal infusion of a MKP1-targeted shRNA. Finally, the effects of MKP1 expression level on autophagy we examined in rat GMI-R1 microglia.ResultsCUMS-exposed rats demonstrated anhedonia in the SPT and helplessness in the FST, two core depression-like behaviors. Expression levels of MKP1 and LC3II were upregulated in the hippocampus of CUMS rats, suggesting enhanced autophagy, while pERK/ERK was downregulated. Knockdown of hippocampal MKP1 mitigated depression-like behaviors, downregulated hippocampal LC3II expression, and upregulated hippocampal pERK/ERK. Similarly, MKP1 knockdown in GMI-R1 cells upregulated pERK/ERK and reduced the number of LC3II autophagosomes, while MKP1 overexpression had the opposite effects.ConclusionEnhanced hippocampal autophagy via MKP1-mediated ERK dephosphorylation may contribute to the development of depression.

Autophagy can remove endogenous inflammasome and reduce pro-inflammatory cytokine releases. While, over-expression of proinflammatory cytokines may inhibit autophagy. The mTOR is a major regulator of the autophagic process, in which PI3K/Akt pathway underlies the upstream of mTOR and modulates its activity. Both inflammatory response and mTOR-PI3K/Akt expressions were up-regulated in schizophrenia. However, the inter-relationship between chronic inflammation and autophagy, whether inflammation suppresses autophagy via PI3K/Akt/mTOR signaling pathway, and how the imbalance between two immunities causes neuroinflammation and neuropathological changes remain unknown in schizophrenia. Thus, this study determined relationship between inflammation and PI3K/Akt/mTOR pathway in schizophrenia patients (SZ), and between autophagy and glia inflammatory/neuroprotective phenotypes in a mouse model of schizophrenia. 66 SZ and 44 healthy controls (CT) were enrolled. Clinical data as well as blood samples were collected. When compared to CT, peripheral autophagy factors MDC stain, and LC3 expression and autophagy activity were decreased, while the concentration of autophagy inhibitor P62, pro-inflammatory factors IL-1β, IL-6 and TNF-α concentrations were increased, and anti-inflammatory factors IL-10 and IL-4 were decreased in SZ. Blood microglia M1 marker IBA1 and astrocyte A1 S100B were up-regulated, while M2 CD206 and A2 P11 were downregulated. A negative correlation between inflammation and autophagy, and synaptic protein Beclin1 and MAP expression were found in SZ lymphocytes. In SZ lymphocytes, the PI3K/Akt/mTOR pathway was activated at both mRNA and protein levels. Then, IL-1 and IL-6 treatment significantly increased, while IL-10 decreased LC3 and Beclin 1 expression in SZ lymphocytes. Furthermore, 3-MA, an autophagy inhibitor, increased NLRP3, ASC, Caspase 1 and pro-inflammatory cytokines IL-1b and IL-6. Mouse model of schizophrenia induced by PolyI:C showed schizophrenia-like behaviors, such as increased spontaneous, impaired cognition and defected sensory-motor gating. In the brain, changes in proinflammatory cytokines, autophagy factors, glial phenotype patterns and synaptic protein were similar to peripheral changes in SZ. More important, clozapine or autophagy agonist RAPA reversed schizophrenia-like behavioral and neuropathological abnormalities, which were aborted by 3-MA. These data for the first time demonstrated imbalance between inflammation and autophagy may contribute to the neuropathology of schizophrenia.

Transforming growth factor (TGF)-β is a group of cytokines with anti-inflammatory effects in the TGF family, which participates in the development of stress and depression-related mechanisms, and plays roles in the regulation of inflammatory response in depression and the recovery of various cytokine imbalances. The core symptoms of depression is associated with TGF-β level, and the psychological symptoms of depression are related to TGF-β gene polymorphism. Various antidepressants may up-regulate TGF-β level through the complex interaction between neurotransmitters and inflammatory factors, inhibiting inflammatory response and regulating cytokine imbalance to improve depressive symptoms. Studies have shown that recombinant TGF-β1 protein has beneficial effects in mouse depression models, indicating TGF-β1 might be a potential therapeutic target for depression and nasal sprays having the advantage of being fast acting delivery method. This article reviews the research progress on dynamic changes of TGF-β level before and after depression treatment and the application of TGF-β level as an indicator for the improvement of depressive symptoms. We provide ideas for the development of new antidepressants and for the evaluation of the treatment efficacy in depression.

Background: Exploratory eye movements (EEMs) and P300 are often used to facilitate the clinical diagnosis of depression. However, There were few studies using the combination of EEMs and P300 to build a model for detecting depression and predicting a curative effect. Methods: Sixty patients were recruited for 2 groups: high frequency repetitive transcranial magnetic stimulation (rTMS) combined with paroxetine group and simple paroxetine group. Clinical efficacy was evaluated by the Hamilton Depression scale-24(HAMD-24), EEMs and P300. The classification model of the auxiliary diagnosis of depression and the prediction model of the two treatments were developed based on a machine learning algorithm. Results: The classification model with the greatest accuracy for patients with depression and healthy controls was 95.24% (AUC = 0.75, recall = 1.00, precision = 0.95, F1-score = 0.97). The root mean square error (RMSE) of the model for predicting the efficacy of high frequency rTMS combined with paroxetine was 3.54 (MAE [mean absolute error] = 2.56, R-2 = -0.53). The RMSE of the model for predicting the efficacy of paroxetine was 4.97 (MAE = 4.00, R-2 = -0.91). Conclusion: Based on the machine learning algorithm, P300 and EEMs data was suitable for modeling to distinguish depression patients and healthy individuals. However, it was not suitable for predicting the efficacy of high frequency rTMS combined with paroxetine or to predict the efficacy of paroxetine.

Objective:To investigate the role of mitogen-activated protein kinase phosphatase-1 (MKP-1) on depressive-like behaviors and hippocampal neuron apoptosis in chronic unpredictable mild stress (CUMS) rats.Methods:A total of 36 Sprague-Dawley male rats were randomly divided into 4 groups using a random number table, including the control group( n=8), CUMS group( n=8), virus control group( n=10), and MKP-1 down-regulated group( n=10), with 8 rats in each group. Except for the control group, rats in other groups were stressed by CUMS model of depression. Rats in the virus control group and MKP-1 down-regulated group received adeno-associated virus injections in the hippocampal CA1 and CA3 regions before CUMS modeling. Sucrose preference test, forced swimming test, and open field test were used to observe the behavioral changes of rats. Western blotting was used to detect the protein expression of MKP-1, B-cell lymphoma-2 gene (Bcl-2) and B-cell lymphoma-2 gene-related X protein (Bax), in the hippocampus. TUNEL staining was utilized to observe the morphology of apoptotic cells in the hippocampus CA1 area. Repeated measures variance was used to analyze body weight and behaviors, while an independent sample t-test was used to analyze protein levels. Results:Compared with the control group, the body weight of rats in the CUMS group decreased ( F=44.664); the sucrose preference rate decreased ( F=14.978); the forced swimming immobility time increased ( F=8.436); the number of defecation in the open field test increased ( F=9.572); the relative expression level of MKP-1 and Bax/Bcl-2 also significantly increased ( t=4.415,3.410), P<0.05 for all; Compared with the virus control group, rats in the MKP-1 down-regulation group showed a higher sucrose preference rate ( F=11.922) and a shorter forced swimming immobility time ( F=12.868), furthermore, the activity distance ratio in the central area increased ( F=6.291), the number of uprights in the open field test increased ( F=14.372), and the relative expression levels of MKP-1 and Bax/Bcl-2 ( t=3.775,6.193) decreased, P<0.05 for all. The number of DNA fragments in the nucleus of the hippocampal CA1 region of the CUMS group was significantly more than that of the control group. In comparison, the number of DNA fragments in the nucleus of the MKP-1 down-regulated group was substantially less than that of the virus control group. Conclusion:Down-regulation of MKP-1 gene alleviated depressive-like behavior and hippocampal neuron apoptosis in CUMS rats.

Background: Inflammation mediated by microglia has been shown to be involved in the pathogenesis of depression. The enriched environment (EE) can improve depression-like behaviors and reduce inflammatory reactions, but it is unclear whether this is by changing the inflammatory activation phenotype of microglia. Method: A depression rat model was established using chronic unpredictable stress (CUS) for four weeks. The rats were then treated with EE or fluoxetine administration during the following three weeks. Behavior tests including sucrose preference, forced swimming and open field were applied to evaluate the depression-like behaviors of rats at the baseline period prior to CUS, the end of fourth week and at the end of the seventh week. Microglial activation and hippocampal neuro-inflammation were detected on postmortem using immunofluorescence, western blotting, and real-time polymerase reaction (PCR). Result: The results showed that severe depressive-like behavior was induced by four weeks of CUS. Changes in peripheral blood inflammatory cytokines were detected by ELISA. Immunofluorescent staining showed the IBA-1 of microglia activation marker level significantly increased in affected rats. The hippocampal microglial activation state was determined by measuring the increased levels of iNOS an M1 marker and the decreased levels of CD206, an M2 marker. The activation of NF-kappa B upregulation of inflammatory cytokines in the hippocampus and factors such as IL-10 were decreased. This study showed that EE and chronic fluoxetine treatment alleviated the depressive-like behavior induced by chronic stress and significantly inhibited microglial activation, activated NF-kappa B inflammasome and increased pro-inflammatory cytokines. Conclusion: EE can alleviate depression-like behavior by modulating the phenotype of microglia, inhibiting pro inflammatory genes, and promoting anti-inflammatory genes. Furthermore, EE can effectively reduce the phosphorylation and expression levels of NF-kappa B.

本文综述了重度抑郁症的研究现状,并介绍了靶基因MKP-1与microRNAs同抑郁症的关系,同时分析了microRNAs与靶基因MKP-1的调控关系,通过生物信息学预测方法和生物学实验方法来建立二者的联系,主要谈及了let-7a与miR-101两种microRNAs在抑郁症中的研究.通过探索microRNAs调控MKP-1这一新的研究热点,为抑郁症发病机理的研究开拓出新的思路.

One hallmark of posttraumatic stress disorder (PTSD) involves impairments in the ability to extinguish conditioned fear memory. Accumulating evidence suggests that extinction training that occurs shortly after fear conditioning is less effective than delayed extinction training in yielding long-term extinction memory, a phenomenon that is referred to as immediate extinction deficit (IED). However, unknown is whether the IED is just an aberration or continues to affect re-extinction. In Experiment 1, 32 Sprague-Dawley rats were randomly divided into four groups (Immediate-Extinction, Immediate-No Extinction, Delayed-Extinction, Delayed-No Extinction) and underwent a standard fear conditioning procedure in which they received five tone-footshock trials in chamber A. After either 1 h (immediate) or 24 h (delayed), half of the animals underwent 30 extinction trials (1st extinction session) in chamber B where the tone was presented alone. The other half remained in chamber B without any tone or footshock (these animals served as a no-extinction control group). Twenty-four hours later, these rats underwent the 2nd extinction session (reextinction) in chamber B. Twenty-four hours after the 2nd extinction session, the rats were once again returned to chamber B and tested for their fear response to four continuous tones. The fear response was assessed by freezing behavior, and the effect of the 1st extinction session was assessed by the average freezing response across the first four trials of the 2nd extinction session. Compared with rats in the delayed extinction group, recently conditioned rats exhibited significantly higher levels of fear in the 2nd extinction session, although an equivalent decline in freezing was observed in both groups across the 1st extinction session, suggesting that immediate extinction failed to maintain fear suppression the next day. Furthermore, after undergoing two extinction training sessions, rats in the immediate extinction group exhibited no significant reduction of freezing compared with the non-extinguished control during the retention test, suggesting that the deficit reappeared during re-extinction. The aim of Experiment 2 was to investigate whether the deficit that was induced by immediate extinction could be rescued by the beta-adrenergic receptor antagonist propranolol. In Experiment 2, 20 Sprague-Dawley rats underwent the same procedures as the immediate extinction groups in Experiment 1, with the exception that they received saline or propranolol (10 mg/kg, i.p.) within minutes after fear conditioning. We found that one injection of propranolol immediately after fear acquisition rescued the deficit of re-extinction but not immediate extinction. This study revealed that the early extinction intervention after severe trauma may not only fail to inhibit the fear response but also act as a secondary trauma which can continually damage the ability to extinguish fear memory. Propranolol may be a good candidate to repair such damage. Our findings improve our understanding of the pathogenesis of PTSD and outcomes of an early intervention and may be helpful for selecting appropriate and effective interventions after trauma exposure and avoid secondary trauma that is caused by the intervention itself.

Background: As an atypical antipsychotic drug, quetiapine had been approved for bipolar disorder and for adjunctive therapy in major depressive disorder and schizophrenia. Recently quetiapine has been suggested to be a promising pharmacotherapy for alcohol dependence. This study was performed to determine the effects of quetiapine in rats chronically exposed to ethanol. Methods: Rats were exposed to ethanol solution (10 %; v/v) for 6 weeks. Saline or one of three doses of quetiapine (10, 20 or 40 mg/kg/day) was given by oral gavage while ethanol exposure for the next 14 weeks. Performance of learning and memory and withdrawal signs were evaluated. Then immunohistochemistry, western blot, quantitative real-time-PCR and transmission electron microscopy were performed to determine the effects of quetiapine on alterations of brain white matter markers (myelin basic protein, MBP; proteolipid protein, PLP) and morphology caused by chronic ethanol exposure. Results: Quetiapine treatment significantly alleviated withdrawal signs in the ethanol exposed rats. Chronic ethanol exposure reduced Y-type electric maze scores and the protein/mRNA expression levels of MBP and PLP in the prefrontal cortex and hippocampus, and these effects were reversed by quetiapine treatment. Similar ultrastructure morphological changes were observed. Conclusions: Chronic quetiapine treatment alleviated the damage induced by chronic ethanol exposure with regard to learning and memory ability and to brain white matter. Thus, quetiapine appears to be a potentially promising pharmacotherapy for the treatment of alcohol use disorder.

Orexin (hypocretin) neurons located in the posterior hypothalamus send projections to multiple areas of the brain involved in arousal and experimental evidence indicates that these neurons play a role in the physiological and behavioral responses to stress. This study was done to determine if the orexin system was involved in mediating the fear associated with shock context (5 × 2 s of 1.5 mA). First, real-time RT-PCR was used to examine changes in the mRNA levels for prepro-orexin (ppOX), the orexin-1 receptor (OX1R) and the orexin-2 receptor (OX2R) at two weeks post-shock. We found that the mRNA levels for ppOX and OX1R were increased in the posterior hypothalamus of shocked rats. In contrast, no significant difference was found in the midline thalamus or the locus coeruleus/parabrachial region. Second, the study examined if systemic injections of antagonists for orexin receptors attenuated the freezing related to contextual fear. The OX1R antagonist SB334867 (20 or 30 mg/kg; i.p.) decreased freezing while the same doses of the OX2R antagonist TCSOX229 had no effect. The dual orexin antagonist TCS1102 (20 mg/kg; i.p.) also decreased the freezing to the shock context. The results of the present study show upregulation of orexin activity and of the OX1R in the hypothalamus following exposure of rats to footshocks and highlight a specific role of OX1R in contextual fear.

Post-traumatic stress disorder (PTSD) is a chronic syndrome triggered by exposure to trauma and a failure to recover from a normal negative emotional reaction to traumatic stress. The neurobiology of PTSD and the participation of neuropeptides in the neural systems and circuits that control fear and anxiety are not fully understood. The long-term dysregulation of neuropeptide systems contributes to the development of anxiety disorders, including PTSD. The neuropeptide galanin (Gal) and its receptors participate in anxiety-like and depression-related behaviors via the modulation of neuroendocrine and monoaminergic systems. The objective of this research was to investigate how Gal expression changes in the brain of rats 2 weeks after exposure to footshock. Rats exposed to footshocks were subdivided into high responders (HR; immobility>60%) and low responders (LR; immobility<40%) based on immobility elicited by a novel tone one day after exposure. On day 14, rats were anesthetized, and the amygdala, hypothalamus, pituitary and adrenal glands were removed for analysis using real-time polymerase chain reaction (RT-PCR). Gal mRNA levels were increased in the amygdala and hypothalamus of HR compared with the control and LR. In contrast, Gal mRNA levels were decreased in the adrenal and pituitary glands of HR compared with the control and LR. Thus, the differential regulation (dysregulation) of the neuropeptide Gal in these tissues may contribute to anxiety and PTSD development.

Corticotropin releasing factor (CRF) and dynorphin are neuropeptides that are associated with the negative emotional states. Experimental evidence indicates that dynorphin neurons located in the nucleus accumbens and CRF neurons in the bed nucleus of the stria terminalis (BST) and the central nucleus of the amygdala (CeA) mediate anxiety-like behaviors immediately after the stressful experience (24–48h). The present study was done to evaluate if changes in the levels of the mRNA for these peptides in the striatum, BST, and CeA were associated with the long-lasting avoidance of novelty, a measure of an anxiety-like state, in a subset of rats exposed to unpredictable and moderately intense footshocks (5×2s of 1.5mA). Shocked rats with enhanced fear to a novel tone 24h after the footshocks (high responders; HR) displayed long-lasting avoidance in the elevated T-maze whereas shocked rats with low levels of acute fear (low responders; LR) had low levels of avoidance similar to nonshocked rats. An increase in the level of proCRF mRNA was detected in the CeA of the HR compared to LR and nonshocked rats but not in other areas of the brain sampled. In contrast, prodynorphin and proenkephalin mRNA levels in the striatum, BST and CeA were not different between HR, LR and nonshocked rats. This study provides evidence that CRF neurons in the CeA may play a role in the anxiety-like state produced in a subset of rats exposed to footshocks.

Orexins (hypocretins) are peptides that have been shown to regulate behavioral arousal and wakefulness. Recent evidence indicates that orexin neurons are activated by stress and that orexins play a role in anxiety. The present paper describes a series of experiments that examined whether orexins are involved in the anxiety that resulted from exposing rats to an acute episode of footshocks (5 × 2 s of 1.5 mA shocks). We found that prepro-orexin (ppOX) mRNA was elevated in rats at 6 and 14 days after exposure to footshock and that ppOX mRNA levels were correlated with fear at 14 days post-shock. Systemic injections of the non-selective dual orexin receptor antagonist TCS-1102 (10 and 20 mg/kg, i.p.) were found to decrease fear and anxiety in rats 14 days after exposure to footshock. We also found that rats that exhibited a high level of immobility to a novel tone the day after the footshock episode (high responders, HR) showed significantly elevated levels of ppOX mRNA at 14 days post-shock compared to control rats. Furthermore, TCS-1102 (10 mg/kg, i.p.) was found to have anxiolytic effects that were specific for HR when tested in the elevated T-maze. This study provides evidence linking the orexin system to the anxiety produced by exposure of rats to a single episode of footshocks. It also provides preclinical evidence in support of the use of orexin antagonists for the treatment of anxiety in response to an acute episode of stress.