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Immune dysregulation, specifically of inflammatory processes, has been linked to behavioral symptoms of depression in both human and rodent studies. Here, we evaluated the antidepressant effects of immunization with altered peptide ligands of myelin basic protein (MBP)—MBP87–99[A91, A96], MBP87–99[A91], and MBP87–99[R91, A96]—in different models of depression and examined the mechanism by which these peptides protect against stress-induced depression. We found that a single dose of subcutaneously administered MBP87–99[A91, A96] produced antidepressant-like effects by decreasing immobility in the forced swim test and by reducing the escape latency and escape failures in the learned helplessness paradigm. Moreover, immunization with MBP87–99[A91, A96] prevented and reversed depressive-like and anxiety-like behaviors that were induced by chronic unpredictable stress (CUS). However, MBP87–99[R91, A96] tended to aggravate CUS-induced anxiety-like behavior. Chronic stress increased the production of peripheral and central proinflammatory cytokines and induced the activation of microglia in the prelimbic cortex (PrL), which was blocked by MBP87–99[A91, A96]. Immunization with MBP-derived altered peptide ligands also rescued chronic stress-induced deficits in p11, phosphorylated cyclic adenosine monophosphate response element binding protein, and brain-derived neurotrophic factor expression. Moreover, microinjections of recombinant proinflammatory cytokines and the knockdown of p11 in the PrL blunted the antidepressant-like behavioral response to MBP87–99[A91, A96]. Altogether, these findings indicate that immunization with altered MBP peptide produces prolonged antidepressant-like effects in rats, and the behavioral response is mediated by inflammatory factors (particularly interleukin-6), and p11 signaling in the PrL. Immune–neural interactions may impact central nervous system function and alter an individual’s response to stress.

Memory reprocessing during sleep is a well-established phenomenon in numerous studies. However, it is unclear whether the intensity of memory reprocessing is consistently maintained throughout the night or exhibits dynamic changes. This study investigates the temporal dynamics of negative emotional memory reprocessing during sleep, with a specific focus on slow oscillation (SO)-spindle coupling and its role in memory reprocessing. In the first experiment ( N  = 40, mean age = 22.5 years), we detected the negative emotional memory reprocessing strength in each sleep cycle, we found that the 2nd sleep cycle after negative emotional memory learning constitute the most sensitive window for memory reprocessing, furthermore, SO-spindle coupling signals in this window plays a role in stabilizing negative emotional memory. To verify the role of SO-spindle coupling in negative emotional memory reprocessing, we utilized transcranial alternating current stimulation (tACS) to disrupt SO-spindle coupling during the 2 nd sleep cycle ( N  = 21, mean age = 19.3 years). Notably, the outcomes of the tACS intervention demonstrated a significant reduction in the recognition of negative emotional memories. These findings offer new insights into the mechanisms that regulate emotional memory consolidation during sleep and may have implications for addressing psychiatric disorders associated with pathological emotional memory.

Sleep spindles have been implicated in sleep protection, depression and anxiety. However, spindle-related brain imaging mechanism underpinning the deficient sleep protection and emotional regulation in insomnia disorder (ID) remains elusive. The aim of the current study is to investigate the relationship between spindle-related brain activations and sleep quality, symptoms of depression and anxiety in patients with ID. Participants (n = 46, 28 females, 18–60 years) were recruited through advertisements including 16 with ID, according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and 30 matched controls. Group differences in spindle-related brain activations were analyzed using multimodality data acquired with simultaneous electroencephalography and functional magnetic resonance imaging during sleep. Compared with controls, patients with ID showed significantly decreased bilateral spindle-related brain activations in the cingulate gyrus (familywise error corrected p ˂ 0.05, cluster size 4401 mm3). Activations in the cingulate gyrus were negatively correlated with Pittsburgh Sleep Quality Index scores (r = -0.404, p = 0.005) and Self-Rating Anxiety Scale scores (r = -0.364, p = 0.013), in the pooled sample. These findings underscore the key role of spindle-related brain activations in the cingulate gyrus in subjective sleep quality and emotional regulation in ID.

Objective sleep duration has been linked to insomnia severity. However, cognitive functions of people with insomnia with different sleep durations have been seldom addressed. Brain-derived neurotrophic factor (BDNF) has an important role in cognitive function and has been linked to clinical insomnia recently. The present study aimed to evaluate the comprehensive cognitive functions in people with primary insomnia with different objective sleep durations, and further examine the involvement of peripheral BDNF. Fifty-seven people with insomnia were subdivided into short sleep duration (SSD, sleep time < 6 hr) group and normal sleep duration (NSD, sleep time ≥ 6 hr) group based on polysomnography data. Twenty-nine healthy controls (HC) were matched on age, gender, and education. Cognitive function was assessed using a comprehensive and sensitive neuropsychological test battery. Both objective and subjective insomnia statuses were estimated. Serum BDNF level was measured using enzyme-linked immune sorbent assay. Compared with HC, the SSD group showed impaired neuropsychological performances in spatial span, brief visuospatial memory test, fluency, managing emotions, and continuous performance tests. In contrast, NSD had bad performance only in brief visuospatial memory test and continuous performance tests, and relatively better than SSD group in the latter test. People with SSD insomnia but not NSD had decreased BDNF levels compared with HC, and neuropsychological performance was positively correlated with BDNF levels only in SSD group. Primary insomnia was associated with impaired neuropsychological performance, and the impairment might be related to decreased objective sleep duration. In addition, decreased peripheral BDNF might mediate the impaired cognitive functions of people with insomnia with SSD.

Abstract To investigate effects of agomelatine and mirtazapine on sleep disturbances in patients with major depressive disorder. A total of 30 depressed patients with sleep disturbances, 27 of which completed the study, took agomelatine or mirtazapine for 8 weeks. Subjective scales were administered, and polysomnography was performed at baseline and at the end of week 1 and 8. Functional magnetic resonance imaging was performed at baseline and at the end of week 8. Compared with baseline, scores on the Hamilton Depression Scale, Hamilton Anxiety Scale, Pittsburgh Sleep Quality Index, Sleep Dysfunction Rating Scale, and Insomnia Severity Index after 8 weeks of treatment significantly decreased in both groups, with no significant differences between groups, accompanied by significant increases in total sleep time, sleep efficiency, and rapid eye movement (REM) sleep and significant decrease in wake after sleep onset. Mirtazapine treatment increased N3 sleep at week 1 compared with agomelatine treatment, but this difference disappeared at week 8. The increases in the percentage and duration of N3 sleep were positively correlated with increases in connectivity between right dorsal lateral prefrontal cortex (dlPFC) and right precuneus and between left posterior cingulate cortex and right precuneus in both groups, respectively. Functional connectivity (FC) between right dlPFC and left precuneus in mirtazapine group was higher compared with agomelatine group after 8 weeks of treatment. These findings indicated that both agomelatine and mirtazapine improved sleep in depressed patients, and the effect of mirtazapine was greater than agomelatine with regard to rapidly increasing N3 sleep and gradually improving FC in the brain.