Chronic exposure to fluoxetine of female mice before mating causes impaired stress resilience in female offspring.

Antidepressant agents have been proven their utilities in treating depression, but they also could serve as candidate drugs for misuse or abuse due to diverse pharmacologic properties. Potential detriments had also been multidimensionally investigated. However, there had been no study exploring whether treatment with antidepressants causes psychological and/or behavioral alterations in offspring. In this regard, we chronically treated normal female mice with different dosages (0, 10, and 20 mg/kg) of fluoxetine (FLU) for 2 weeks before mating them with drug-free male mice and then tested the offspring for anxiety/depression-like behaviors with the elevated plus maze and the tail-suspension test after exposing to acute or chronic stress in adult period. We found that there were significant increases for immobility time in the tail-suspension test as well as percentage of open arm entries and percentage of open arm time in the elevated plus maze test detected in the female offspring of the 20 mg group compared to both baseline and all other groups, with the exception that the female offspring of the 10 mg group showed an increased percentage of open arm entries after chronic stress exposure. Locomotor activity assessments showed that neither acute nor chronic stress protocol could significantly affect locomotor activities of mice. Conclusionally, we found that high-dosage FLU increased the risk of the female offspring developing into depression/anxiety-like behaviors after stress exposure, with chronic stress as the environmental-risk factor. Our study has important implications for the safe use of antidepressant agents and raises more concerns regarding long-term use of even second-generation antidepressants in clinical practice.

The sexually divergent cFos activation map of fear extinction.

Objective: Post-traumatic stress disorder (PTSD) is a neuropsychiatric disorder that can develop after experiencing or witnessing a traumatic event. Exposure therapy is a common treatment for PTSD, but it has varying levels of efficacy depending on sex. In this study, we aimed to compare the sexual dimorphism in brain activation during the extinction of fear conditioning in male and female rats by detecting the c-fos levels in the whole brain. Methods: Thirty-two rats (Male: n = 16; Female: n = 16) were randomly separated into the extinction group as well as the non-extinction group, and fear conditioning was followed by extinction and non-extinction, respectively. Subsequently, brain sections from the sacrificed animal were performed immunofluorescence and the collected data were analyzed by repeated two-way ANOVAs as well as Pearson Correlation Coefficient. Results: Our findings showed that most brain areas activated during extinction were similar in both male and female rats, except for the reuniens thalamic nucleus and ventral hippocampi. Furthermore, we found differences in the correlation between c-fos activation levels and freezing behavior during extinction between male and female rats. Specifically, in male rats, c-fos activation in the anterior cingulate cortex was negatively correlated with the freezing level, while c-fos activation in the retrosplenial granular cortex was positively correlated with the freezing level; but in female rats did not exhibit any correlation between c-fos activation and freezing level. Finally, the functional connectivity analysis revealed differences in the neural networks involved in extinction learning between male and female rats. In male rats, the infralimbic cortex and insular cortex, anterior cingulate cortex and retrosplenial granular cortex, and dorsal dentate gyrus and dCA3 were strongly correlated after extinction. In female rats, prelimbic cortex and basolateral amygdala, insular cortex and dCA3, and anterior cingulate cortex and dCA1 were significantly correlated. Conclusion: These results suggest divergent neural networks involved in extinction learning in male and female rats and provide a clue for improving the clinical treatment of exposure therapy based on the sexual difference.

TMS-EEG: An emerging tool to study the neurophysiologic biomarkers of psychiatric disorders.

The etiology of psychiatric disorders remains largely unknown. The exploration of the neurobiological mechanisms of mental illness helps improve diagnostic efficacy and develop new therapies. This review focuses on the application of concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) in various mental diseases, including major depressive disorder, bipolar disorder, schizophrenia, autism spectrum disorder, attention-deficit/hyperactivity disorder, substance use disorder, and insomnia. First, we summarize the commonly used protocols and output measures of TMS-EEG; then, we review the literature exploring the alterations in neural patterns, particularly cortical excitability, plasticity, and connectivity alterations, and studies that predict treatment responses and clinical states in mental disorders using TMS-EEG. Finally, we discuss the potential mechanisms underlying TMS-EEG in establishing biomarkers for psychiatric disorders and future research directions. This article is part of the special Issue on 'Stress, Addiction and Plasticity'.

Predictable chronic mild stress in adolescence increases resilience in adulthood.

Stress in adolescence has been widely demonstrated to have a lasting impact in humans and animal models. Developmental risk and protective factors play an important role in the responses to stress in adulthood. Mild-to-moderate stress in adolescence may resist the negative impacts of adverse events in adulthood. However, little research on resilience has been conducted. In this study, we used a predictable chronic mild stress (PCMS) procedure (5 min of daily restraint stress for 28 days) in adolescent rats (postnatal days (PNDs) 28-55) to test the resilience effect of PCMS on depressive-like behavior in the sucrose preference test and forced swim test and anxiety-like behavior in the novelty-suppressed feeding test and elevated plus maze in adulthood. We also investigated the role of mammalian target of rapamycin (mTOR) signaling in the brain during the PCMS procedure in adolescence. Moreover, we investigated the effect of PCMS in adolescence on subsequent responses to chronic unpredictable stress (CUS; PNDs 63-83) in adulthood. The results demonstrated that PCMS during adolescence produced antidepressant- and anxiolytic-like effects and increased mTOR signaling activity in the prefrontal cortex in early adulthood. Either systemic administration or intra-PFC infusion of the mTOR inhibitor rapamycin completely blocked the behavioral effects produced by PCMS in adolescence. PCMS during adolescence resisted depressive- and anxiety-like behavior caused by CUS in adulthood. These findings indicate that PCMS in adolescence can contribute to resilience against depression and anxiety caused by stress in adulthood.

Activation of NF-κB in basolateral amygdala is required for memory reconsolidation in auditory fear conditioning.

Posttraumatic stress disorder (PTSD) is characterized by acute and chronic changes in the stress response, manifested as conditioned fear memory. Previously formed memories that are susceptible to disruption immediately after retrieval undergo a protein synthesis-dependent process to become persistent, termed reconsolidation, a process that is regulated by many distinct molecular mechanisms that control gene expression. Increasing evidence supports the participation of the transcription factor NF-κB in the different phases of memory. Here, we demonstrate that inhibition of NF-κB in the basolateral amygdala (BLA), but not central nucleus of the amygdala, after memory reactivation impairs the retention of amygdala-dependent auditory fear conditioning (AFC). We used two independent pharmacological strategies to disrupt the reconsolidation of AFC. Bilateral intra-BLA infusion of sulfasalazine, an inhibitor of IκB kinase that activates NF-κB, and bilateral intra-BLA infusion of SN50, a direct inhibitor of the NF-κB DNA-binding complex, immediately after retrieval disrupted the reconsolidation of AFC. We also found that systemic pretreatment with sodium butyrate, a histone deacetylase inhibitor that enhances histone acetylation, in the amygdala rescued the disruption of reconsolidation induced by NF-κB inhibition in the BLA. These findings indicate that NF-κB activity in the BLA is required for memory reconsolidation in AFC, suggesting that NF-κB might be a potential pharmacotherapy target for posttraumatic stress disorder.

Venlafaxine facilitates between-session extinction and prevents reinstatement of auditory-cue conditioned fear.

Anxiety disorders, characterized by anxiety and fearfulness, are found to be able to cause abnormal emotional responses' associated with memories of negative events, which implicate pressure on society with an increasingly large burden. Better treatment has been of concern to the community. Venlafaxine (VEN), a nonclassical antidepressant agent, is applied in the treatment of social phobia, major depression (MD) and general anxiety disorder (GAD) and, to a certain extent, posttraumatic stress disorder (PTSD), which improves working memory and spatial memory as well as ameliorates emotion by affecting specified brain regions. In this study, we committed to seek a new way for using VEN on treatment of anxiety disorders. To investigate the effect of VEN on extinction of auditory-cue conditioned fear, conditioned rats received a treatment with VEN before extinction training and tests for freezing level of within-session and between-session extinction. To investigate the effect of VEN on reinstatement, all conditioned rats received a treatment with VEN over a period for 21 days. After a rest for 7 days, two tests for freezing level were conducted. We found that: (1) VEN (40mg/kg) treatment at 30min prior to extinction training significantly facilitated the between-session extinction, but not the within-session extinction; (2) chronic administration with VEN (40mg/kg) prevented the return of extinguished auditory-cue fear. These data elucidate the critical role of VEN in auditory-cue fear memory, suggesting that VEN may be an ideal choice for the exposure-based drug treatment and maintenance treatment in patients with GAD, SAD and PTSD.

PI3K/Akt signaling pathway in the basolateral amygdala mediates the rapid antidepressant-like effects of trefoil factor 3.

Depression is one of the most common and debilitating psychiatric illnesses around the world, but the current antidepressants used to treat depression have many limitations. Progressively more studies have shown that neuropeptide systems are potential novel therapeutic targets for depression. However, whether the neuropeptide trefoil factor 3 (TFF3) participates in the development of depression has not been examined. In the current experiments, we assessed the antidepressant effects of TFF3 using the forced swim test (FST), tail suspension test (TST), and chronic mild stress (CMS) paradigm. Furthermore, we determined the mechanism that underlies the antidepressant-like effects of TFF3 in the rat FST. TFF3 dose-dependently reduced immobility time in both FST and TST. CMS elevated plasma TFF3 and decreased basolateral amygdala (BLA) TFF3 levels in rats, and acute TFF3 (0.1 mg/kg, i.p.) treatment reversed the depressive-like behaviors induced by CMS. Furthermore, TFF3 (0.1 mg/kg, i.p.) significantly increased Fos expression in the BLA, medial prefrontal cortex, and hypothalamus in rats subjected to the FST. Intra-BLA infusions of TFF3 (1 ng/side) exerted rapid antidepressant-like effects in the rat FST. Additionally, acute systemic TFF3 administration increased the level of phosphorylated-Akt (p-Akt) in the BLA. Finally, intra-BLA infusions of LY294002 (5 mM/side), a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, significantly blocked the antidepressant-like effect of TFF3. Our results demonstrated that TFF3 exerts antidepressant-like effects that might be mediated by the PI3K/Akt signaling pathway in the BLA. These findings suggest a novel neuropeptide system target in the development of new antidepressants.

Role of IKK/NF-κB signaling in extinction of conditioned place aversion memory in rats.

The inhibitor κB protein kinase/nuclear factor κB (IKK/NF-κB) signaling pathway is critical for synaptic plasticity. However, the role of IKK/NF-κB in drug withdrawal-associated conditioned place aversion (CPA) memory is unknown. Here, we showed that inhibition of IKK/NF-κB by sulphasalazine (SSZ; 10 mM, i.c.v.) selectively blocked the extinction but not acquisition or expression of morphine-induced CPA in rats. The blockade of CPA extinction induced by SSZ was abolished by sodium butyrate, an inhibitor of histone deacetylase. Thus, the IKK/NF-κB signaling pathway might play a critical role in the extinction of morphine-induced CPA in rats and might be a potential pharmacotherapy target for opiate addiction.