Brain functional changes across mood states in bipolar disorder: from a large-scale network perspective.

BACKGROUND: Exploring the neural basis related to different mood states is a critical issue for understanding the pathophysiology underlying mood switching in bipolar disorder (BD), but research has been scarce and inconsistent. METHODS: Resting-state functional magnetic resonance imaging data were acquired from 162 patients with BD: 33 (hypo)manic, 64 euthymic, and 65 depressive, and 80 healthy controls (HCs). The differences of large-scale brain network functional connectivity (FC) between the four groups were compared and correlated with clinical characteristics. To validate the generalizability of our findings, we recruited a small longitudinal independent sample of BD patients (n = 11). In addition, we examined topological nodal properties across four groups as exploratory analysis. RESULTS: A specific strengthened pattern of network FC, predominantly involving the default mode network (DMN), was observed in (hypo)manic patients when compared with HCs and bipolar patients in other mood states. Longitudinal observation revealed an increase in several network FCs in patients during (hypo)manic episode. Both samples evidenced an increase in the FC between the DMN and ventral attention network, and between the DMN and limbic network (LN) related to (hypo)mania. The altered network connections were correlated with mania severity and positive affect. Bipolar depressive patients exhibited decreased FC within the LN compared with HCs. The exploratory analysis also revealed an increase in degree in (hypo)manic patients. CONCLUSIONS: Our findings identify a distributed pattern of large-scale network disturbances in the unique context of (hypo)mania and thus provide new evidence for our understanding of the neural mechanism of BD.

Profile of the gut microbiota of Pacific white shrimp under industrial indoor farming system.

The gut microbial communities interact with the host immunity and physiological functions. In this study, we investigated the bacterial composition in Litopenaeus vannamei shrimp's gut and rearing water under different host (developmental stage: juvenile and adult; health status: healthy and diseased) and environmental factors (temperature 25 °C and 28 °C; and light intensity: low and high). The PCoA analysis showed that all water samples were clustered together in a quarter, whereas the gut samples spread among three quarters. In terms of functional bacteria, gut samples of adult shrimp, healthy adult shrimp, adult shrimp raised at 28 °C, and juvenile shrimp under high light intensity exhibited a higher abundance of Vibrionaceae compared to each other opposite group. Gut samples of juvenile shrimp, infected adult shrimp, juvenile shrimp with low light intensity, and adult shrimp with a water temperature of 25 °C showed a higher abundance of Pseudoaltromonadaceae bacteria compared to each other opposite group. Gut samples of juvenile shrimp, healthy adult shrimp, adult shrimp raised at a water temperature of 28 °C, and juvenile shrimp with high light intensity showed the higher abundance of Firmicutes/Bacteroidota ratio compared to each other opposite group. Our results showed that L. vannamei juveniles are more sensitive to bacterial infections; besides, water temperature of 28 °C and high light intensity groups were both important conditions improving the shrimp gut bacterial composition under industrial indoor farming systems. KEY POINTS: • Bacteria diversity was higher among shrimp intestinal microbiota compared to the rearing water. • Shrimp juveniles are more sensitive to bacterial infection compared to adults. • Water temperature of 28 °C and high light intensity are recommended conditions for white shrimp aquaculture.

[Research progress of trace amine-associated receptor 1 signaling pathways].

Trace amine-associated receptor 1 (TAAR1) is a classical type of G-protein-coupled receptor, which is widely distributed in the brain of mammals, especially in the limbic system and the region rich in monoaminergic neurons, and it is a highly conserved TAAR subtype in all species. TAAR1 can specifically respond to endogenous trace amines in the central nervous system and peripheral tissues, and plays an important role in the pathophysiological mechanisms involving the dysregulation of monoamine system and glutamate system leading to mental disorders. In addition, TAAR1 modulator can act on inwardly rectifying potassium channels and regulate synaptic transmission and neuronal activity. According to the latest research findings, TAAR1 exerts a series of functions by regulating signal pathways and substrate phosphorylation, which is related to emotion, cognition, fear and addiction. Therefore, we conducted a detailed review of relevant studies on the TAAR1 signaling pathways, aiming at revealing the great potential of TAAR1 as a new target for drug treatment of neuropsychiatric disorders.

Aberrant modular segregation of brain networks in female patients with bulimia nervosa.

OBJECTIVE: Bulimia nervosa (BN) is an eating disorder associated with the dysfunction of intrinsic brain networks. However, whether the network disruptions in BN patients manifest as dysconnectivity or imbalances of network modular segregation remains unclear. METHOD: We collected data from 41 women with BN and 41 matched healthy control (HC) women. We performed graph theory analysis based on resting-state functional magnetic resonance imaging (RS-fMRI) data; then, we computed the participation coefficient (PC) among brain modules to characterize the modular segregation for the BN and HC groups. The number of intra- and inter-modular connections was calculated to explain the PC changes. Additionally, we examined the potential associations of the measures mentioned above with clinical variables within the BN group. RESULTS: Compared with the HC group, the BN group showed significantly decreased PC in the fronto-parietal network (FPN), cingulo-opercular network (CON), and cerebellum (Cere). Additionally, the number of intra-modular connections of the default mode network (DMN) and the number of the inter-modular connections between the DMN and CON, FPN and Cere, and CON and Cere in the BN group were lower than those in the HC group. The nodal level analysis showed that the BN group had a decreased PC of the anterior prefrontal cortex (aPFC), dorsal frontal cortex (dFC), inferior parietal lobule (IPL), thalamus, and angular gyrus. Further, these metrics were significantly correlated with clinical variables in the BN group. DISCUSSION: These findings may provide novel insights to capture atypical topologies associated with pathophysiology mechanisms and clinical symptoms underlying BN.

Intrinsic functional connectivity correlates of cognitive deficits involving sustained attention and executive function in bipolar disorder.

BACKGROUND: The neural correlate of cognitive deficits in bipolar disorder (BD) is an issue that warrants further investigation. However, relatively few studies have examined the intrinsic functional connectivity (FC) underlying cognitive deficits involving sustained attention and executive function at both the region and network levels, as well as the different relationships between connectivity patterns and cognitive performance, in BD patients and healthy controls (HCs). METHODS: Patients with BD (n = 59) and HCs (n = 52) underwent structural and resting-state functional magnetic resonance imaging and completed the Wisconsin Card Sorting Test (WCST), the continuous performance test and a clinical assessment. A seed-based approach was used to evaluate the intrinsic FC alterations in three core neurocognitive networks (the default mode network [DMN], the central executive network [CEN] and the salience network [SN]). Finally, we examined the relationship between FC and cognitive performance by using linear regression analyses. RESULTS: Decreased FC was observed within the DMN, in the DMN-SN and DMN-CEN and increased FC was observed in the SN-CEN in BD. The alteration direction of regional FC was consistent with that of FC at the brain network level. Decreased FC between the left posterior cingulate cortex and right anterior cingulate cortex was associated with longer WCST completion time in BD patients (but not in HCs). CONCLUSIONS: These findings emphasize the dominant role of the DMN in the psychopathology of BD and provide evidence that cognitive deficits in BD may be associated with aberrant FC between the anterior and posterior DMN.

[Research progress on the immunomodulatory effects and mechanisms of trace amine-associated receptor 1].

Trace amines are endogenous molecules distributed in the central nervous system and peripheral tissues that resemble common biogenic amines in terms of subcellular localization, chemical structure, and metabolism. Trace amine-associated receptor (TAAR) is a kind of evolutionarily conserved G-protein-coupled receptors in vertebrates, in which TAAR1 is a functional regulator of monoamine transmitters such as dopamine and serotonin. TAAR1 is widely considered as a potential therapeutic target for schizophrenia, depression and drug addiction. Moreover, TAAR1 is also expressed in peripheral tissues. The homeostasis imbalance of trace aminergic system can induce over-activation of peripheral immune system and central immune inflammatory response. TAAR1 modulators are becoming potential emerging drugs for the treatment of immune-related illnesses, because they may play a major role in the activation or modulation of immune response.

Anxiety symptom remission is associated with genetic variation of PTPRZ1 among patients with major depressive disorder treated with escitalopram.

OBJECTIVES: Genome-wide analyses of antidepressant response have suggested that genes initially associated with risk for schizophrenia may also serve as promising candidates for selective serotonin reuptake inhibitor (SSRI) efficacy. Protein tyrosine phosphatase, receptor-type, zeta-1 (PTPRZ1) has previously been shown to be associated with schizophrenia, but it has not been investigated as a predictor of antidepressant efficacy. The main objective of the study was to assess whether SSRI-mediated depressive and anxiety symptom remission in Chinese patients with major depressive disorder (MDD) are associated with specific PTPRZ1 variants. METHODS: Two independent cohorts were investigated, the first sample (N = 344) received an SSRI (i.e. fluoxetine, sertraline, citalopram, escitalopram, fluvoxamine, or paroxetine) for 8 weeks. The second sample (N = 160) only received escitalopram for 8 weeks. Hamilton Depression and Hamilton Anxiety Rating Scale scores at 8-weeks post-baseline in both cohorts were used to determine remission status. Five PTPRZ1 variants (rs12154537, rs6466810, rs6466808, rs6955395, and rs1918031) were genotyped in both cohorts. RESULTS: Anxiety symptom remission was robustly associated with PTPRZ1 rs12154537 (P = 0.004) and the G-G-G-G haplotype (rs12154537-rs6466810-rs6466808-rs6955395; P = 0.005) in cohort 2 but not cohort 1 (mixed SSRI use). Associations with depressive symptom remission did not survive correction for multiple testing. CONCLUSIONS: These findings suggest that PTPRZ1 variants may serve as a marker of escitalopram-mediated anxiety symptom remission in MDD.

Eight-week antidepressant treatment reduces functional connectivity in first-episode drug-naïve patients with major depressive disorder.

Previous neuroimaging studies have revealed abnormal functional connectivity of brain networks in patients with major depressive disorder (MDD), but findings have been inconsistent. A recent big-data study found abnormal intrinsic functional connectivity within the default mode network in patients with recurrent MDD but not in first-episode drug-naïve patients with MDD. This study also provided evidence for reduced default mode network functional connectivity in medicated MDD patients, raising the question of whether previously observed abnormalities may be attributable to antidepressant effects. The present study (ClinicalTrials.gov identifier: NCT03294525) aimed to disentangle the effects of antidepressant treatment from the pathophysiology of MDD and test the medication normalization hypothesis. Forty-one first-episode drug-naïve MDD patients were administrated antidepressant medication (escitalopram or duloxetine) for 8 weeks, with resting-state functional connectivity compared between posttreatment and baseline. To assess the replicability of the big-data finding, we also conducted a cross-sectional comparison of resting-state functional connectivity between the MDD patients and 92 matched healthy controls. Both Network-Based Statistic analyses and large-scale network analyses revealed intrinsic functional connectivity decreases in extensive brain networks after treatment, indicating considerable antidepressant effects. Neither Network-Based Statistic analyses nor large-scale network analyses detected significant functional connectivity differences between treatment-naïve patients and healthy controls. In short, antidepressant effects are widespread across most brain networks and need to be accounted for when considering functional connectivity abnormalities in MDD.

Role of trace amine­associated receptor 1 in the medial prefrontal cortex in chronic social stress-induced cognitive deficits in mice.

Emerging evidence supports an essential role of trace amine-associated receptor 1 (TAAR1) in neuropsychiatric disorders such as depression and schizophrenia. Stressful events are critical contributors to various neuropsychiatric disorders. This study examined the role of TAAR1 in mediating the negative outcomes of stressful events. In mice that experienced chronic social defeat stress but not acute stress, a significant reduction in the TAAR1 mRNA level was found in the medial prefrontal cortex (mPFC), a brain region that is known to be vulnerable to stress experience. Conditional TAAR1 knockout in the mPFC mimicked the cognitive deficits induced by chronic stress. In addition, chronic treatment with the selective TAAR1 partial agonist RO5263397 ameliorated chronic stress-induced changes in cognitive function, dendritic arborization, and the synapse number of pyramidal neurons in the mPFC but did not affect chronic stress-induced anxiety-like behaviors. Biochemically, chronic stress reduced the ratio of vesicular transporters of glutamate-1 (VGluT1) / vesicular GABA transporter (VGAT) in the mPFC，most prominently in the prelimbic cortex, and RO5263397 restored the excitatory-inhibitory (E/I) imbalance. Together, the results of this study reveal an essential role of TAAR1 in mediating chronic stress-induced cognitive impairments and suggest that TAAR1 agonists may be uniquely useful to treat MDD-related cognitive impairments.

Postnatal nectin-3 knockdown induces structural abnormalities of hippocampal principal neurons and memory deficits in adult mice.

The early postnatal stage is a critical period of hippocampal neurodevelopment and also a period of high vulnerability to adverse life experiences. Recent evidence suggests that nectin-3, a cell adhesion molecule, mediates memory dysfunction and dendritic alterations in the adult hippocampus induced by postnatal stress. But it is unknown whether postnatal nectin-3 reduction alone is sufficient to alter hippocampal structure and function in adulthood. Here, we down regulated hippocampal expression of nectin-3 and its heterophilic adhesion partner nectin-1, respectively, from early postnatal stage by injecting adeno-associated virus (AAV) into the cerebral lateral ventricles of neonatal mice (postnatal day 2). We found that suppression of nectin-3, but not nectin-1, expression from the early postnatal stage impaired hippocampus-dependent novel object recognition and spatial object recognition in adult mice. Moreover, AAV-mediated nectin-3 knockdown significantly reduced dendritic complexity and spine density of pyramidal neurons throughout the hippocampus, whereas nectin-1 knockdown only induced the loss of stubby spines in CA3. Our data provide direct evidence that nectins, especially nectin-3, are necessary for postnatal hippocampal development of memory functions and structural integrity.

Prenatal Exposure to Antipsychotics Disrupts the Plasticity of Dentate Neurons and Memory in Adult Male Mice.

Background: With the growing use of second-generation antipsychotics for the treatment of a spectrum of psychiatric illnesses in pregnancy, concerns have been raised about the long-term impact of these medications on offspring neurodevelopment. However, preclinical and clinical evidence on the lasting effects of prenatal antipsychotic exposure is still sparse. Methods: Risperidone, a widely used second-generation antipsychotic, and haloperidol, a representative first-generation antipsychotic, were administered to pregnant C57BL/6N mice from embryonic day 6 to 16. Behavioral tests, immunohistochemical staining, Golgi-Cox technique, and western blot were used to determine the effects of prenatal antipsychotic exposure on the plasticity of the dentate gyrus and related behavior in adult male mice. Results: Both prenatal haloperidol- and risperidone-exposed mice showed recognition memory deficits but had no anxiety-related behavior. In addition, both prenatal haloperidol and risperidone exposure impaired the proliferation and maturation of adult-born dentate granule cells. We found that haloperidol exposure decreased dendritic length of dentate granule cells, while risperidone had no effect. However, both drugs inhibited dendrite branching in granule cells. Haloperidol exposure also significantly reduced total spine density in the middle dendritic segment of dentate gyrus. Prenatally risperidone-exposed mice only displayed a loss in thin and mushroom spines of infrapyramidal blade of dentate gyrus. Collectively, prenatal haloperidol exposure exerted more robust negative effects than risperidone. Conclusion: These data provide evidence for the long-term programming effects of early-life exposure to antipsychotics on hippocampal plasticity and behavior.

Genetic variations in the ADCK1 gene predict paliperidone palmitate efficacy in Han Chinese patients with schizophrenia.

Genome-wide association study results have linked ADCK1 genetic variation with paliperidone efficacy in a European cohort. However, the generalizability of this locus to non-European populations is unknown. Han Chinese schizophrenia patients (n = 159) were treated with paliperidone palmitate and symptom severity was assessed over 3 months. Examination of 13 ADCK1 genetic variants revealed two single nucleotide polymorphisms (rs12590199, rs11159291) and one haplotype (rs2364747-rs12590199) associated with paliperidone palmitate response. Future work into ADCK1's function and its potential interaction with paliperidone is warranted.

Altered intrinsic functional brain architecture in female patients with bulimia nervosa.

BACKGROUND: Bulimia nervosa is a severe psychiatric syndrome with uncertain pathogenesis. Neural systems involved in sensorimotor and visual processing, reward and impulsive control may contribute to the binge eating and purging behaviours characterizing bulimia nervosa. However, little is known about the alterations of functional organization of whole brain networks in individuals with this disorder. METHODS: We used resting-state functional MRI and graph theory to characterize functional brain networks of unmedicated women with bulimia nervosa and healthy women. RESULTS: We included 44 unmedicated women with bulimia nervosa and 44 healthy women in our analyses. Women with bulimia nervosa showed increased clustering coefficient and path length compared with control women. The nodal strength in patients with the disorder was higher in the sensorimotor and visual regions as well as the precuneus, but lower in several subcortical regions, such as the hippocampus, parahippocampal gyrus and orbitofrontal cortex. Patients also showed hyperconnectivity primarily involving sensorimotor and unimodal visual association regions, but hypoconnectivity involving subcortical (striatum, thalamus), limbic (amygdala, hippocampus) and paralimbic (orbitofrontal cortex, parahippocampal gyrus) regions. The topological aberrations correlated significantly with scores of bulimia and drive for thinness and with body mass index. LIMITATIONS: We reruited patients with only acute bulimia nervosa, so it is unclear whether the topological abnormalities comprise vulnerability markers for the disorder developing or the changes associated with illness state. CONCLUSION: Our findings show altered intrinsic functional brain architecture, specifically abnormal global and local efficiency, as well as nodal- and network-level connectivity across sensorimotor, visual, subcortical and limbic systems in women with bulimia nervosa, suggesting that it is a disorder of dysfunctional integration among large-scale distributed brain regions. These abnormalities contribute to more comprehensive understanding of the neural mechanism underlying pathological eating and body perception in women with bulimia nervosa.

Blockade of corticotropin-releasing hormone receptor 1 attenuates early-life stress-induced synaptic abnormalities in the neonatal hippocampus.

Adult individuals with early stressful experience exhibit impaired hippocampal neuronal morphology, synaptic plasticity and cognitive performance. While our knowledge on the persistent effects of early-life stress on hippocampal structure and function and the underlying mechanisms has advanced over the recent years, the molecular basis of the immediate postnatal stress effects on hippocampal development remains to be investigated. Here, we reported that repeated blockade of corticotropin-releasing hormone receptor 1 (CRHR1) ameliorated postnatal stress-induced hippocampal synaptic abnormalities in neonatal mice. Following the stress exposure, pups with fragmented maternal care showed retarded dendritic outgrowth and spine formation in CA3 pyramidal neurons and reduced hippocampal levels of synapse-related proteins. During the stress exposure, repeated blockade of glucocorticoid receptors (GRs) by daily administration of RU486 (100 µg g(-1) ) failed to attenuate postnatal stress-evoked synaptic impairments. Conversely, daily administration of the CRHR1 antagonist antalarmin hydrochloride (20 µg g(-1) ) in stressed pups normalized hippocampal protein levels of synaptophysin, postsynaptic density-95, nectin-1, and nectin-3, but not the N-methyl-d-aspartate receptor subunits NR1 and NR2A. Additionally, GR or CRHR1 antagonism attenuated postnatal stress-induced endocrine alterations but not body growth retardation. Our data indicate that the CRH-CRHR1 system modulates the deleterious effects of early-life stress on dendritic development, spinogenesis, and synapse formation, and that early interventions of this system may prevent stress-induced hippocampal maldevelopment.

Dopamine D1 receptor in medial prefrontal cortex mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

Trace amine-associated receptor 1 (TAAR1) is an intracellular expressed G-protein-coupled receptor that is widely expressed in major dopaminergic areas and plays a crucial role in modulation of central dopaminergic neurotransmission and function. Pharmacological studies have clarified the roles of dopamine D1 receptor (D1R) in the medial prefrontal cortex (mPFC) in cognitive function and social behaviors, and chronic stress can inhibit D1R expression due to its susceptibility. Recently, we identified TAAR1 in the mPFC as a potential target for treating chronic stress-induced cognitive and social dysfunction, but whether D1R is involved in mediating the effects of TAAR1 agonist remains unclear. Combined genomics and transcriptomic studies revealed downregulation of D1R in the mPFC of TAAR1-/- mice. Molecular dynamics simulation showed that hydrogen bond, salt bridge, and Pi-Pi stacking interactions were formed between TAAR1 and D1R indicating a stable TAAR1-D1R complex structure. Using pharmacological interventions, we found that D1R antagonist disrupted therapeutic effect of TAAR1 partial agonist RO5263397 on stress-related cognitive and social dysfunction. Knockout TAAR1 in D1-type dopamine receptor-expressing neurons reproduced adverse effects of chronic stress, and TAAR1 conditional knockout in the mPFC led to similar deficits, along with downregulation of D1R expression, all of these effects were ameliorated by viral overexpression of D1R in the mPFC, suggesting the functional interaction between TAAR1 and D1R. Collectively, our data elucidate the possible molecular mechanism that D1R in the mPFC mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

TAAR1 in dentate gyrus is involved in chronic stress-induced impairments in hippocampal plasticity and cognitive function.

Multiple lines of evidence suggest that the trace amine-associated receptor 1 (TAAR1) holds promise as a potential target for stress-related disorders, such as treating major depressive disorder (MDD). The role of TAAR1 in the regulation of adult neurogenesis is recently supported by transcriptomic data. However, it remains unknown whether TAAR1 in dentate gyrus (DG) mediate chronic stress-induced negative effects on hippocampal plasticity and related behavior in mice. The present study consisted of a series of experiments using RNAscope, genetic approaches, behavioral tests, immunohistochemical staining, Golgi-Cox technique to unravel the effects of TAAR1 on alterations of dentate neuronal plasticity and cognitive function in the chronic social defeat stress model. The mice subjected to chronic defeat stress exhibited a noteworthy decrease in the mRNA level of TAAR1 in DG. Additionally, they exhibited compromised social memory and spatial object recognition memory, as well as impaired proliferation and maturation of adult-born dentate granule cells. Moreover, the selective knockout TAAR1 in DG mostly mimicked the cognitive function deficits and neurogenesis impairment induced by chronic stress. Importantly, the administration of the selective TAAR1 partial agonist RO5263397 during stress exposure attenuated the adverse effects of chronic stress on cognitive function, adult neurogenesis, dendritic arborization, and the synapse number of dentate neurons in DG. In summary, our findings suggest that TAAR1 plays a crucial role in mediating the detrimental effects of chronic stress on hippocampal plasticity and cognition. TAAR1 agonists exhibit therapeutic potential for individuals suffering from cognitive impairments associated with MDD.

A distinctive subcortical functional connectivity pattern linking negative affect and treatment outcome in major depressive disorder.

Major depressive disorder (MDD) is associated with functional disturbances in subcortical regions. In this naturalistic prospective study (NCT03294525), we aimed to investigate relationships among subcortical functional connectivity (FC), mood symptom profiles and treatment outcome in MDD using multivariate methods. Medication-free participants with MDD (n = 135) underwent a functional magnetic resonance imaging scan at baseline and completed posttreatment clinical assessment after 8 weeks of antidepressant monotherapy. We used partial least squares (PLS) correlation analysis to explore the association between subcortical FC and mood symptom profiles. FC score, reflecting the weighted representation of each individual in this association, was computed. Replication analysis was undertaken in an independent sample (n = 74). We also investigated the relationship between FC score and treatment outcome in the main sample. A distinctive subcortical connectivity pattern was found to be associated with negative affect. In general, higher FC between the caudate, putamen and thalamus was associated with greater negative affect. This association was partly replicated in the independent sample (similarity between the two samples: r = 0.66 for subcortical connectivity, r = 0.75 for mood symptom profile). Lower FC score predicted both remission and response to treatment after 8 weeks of antidepressant monotherapy. The emphasis here on the role of dorsal striatum and thalamus consolidates prior work of subcortical connectivity in MDD. The findings provide insight into the pathogenesis of MDD, linking subcortical FC with negative affect. However, while the FC score significantly predicted treatment outcome, the low odds ratio suggests that finding predictive biomarkers for depression remains an aspiration.

Fluoxetine reverses early-life stress-induced depressive-like behaviors and region-specific alterations of monoamine transporters in female mice.

The sex difference that females are more vulnerable to depression than males has been recently replicated in an animal model of early-life stress (ES) called the limited bedding and nesting material (LBN) paradigm. Adopting this animal model, we have previously examined the effects of ES on monoamine transporter (MATs) expression in stress-related regions in adult female mice, and the reversal effects of a novel multimodal antidepressant, vortioxetine. In this study, replacing vortioxetine with a classical antidepressant, fluoxetine, we aimed to replicate the ES effects in adult female mice and to elucidate the commonality and differences between fluoxetine and vortioxetine. We found that systemic 30-day treatment with fluoxetine successfully reversed ES-induced depression-like behaviors (especially sucrose preference) in adult female mice. At the molecular level, we largely replicated the ES effects, such as reduced serotonin transporter (SERT) expression in the amygdala and increased norepinephrine transporter (NET) expression in the medial prefrontal cortex (mPFC) and hippocampus. Similar reversal effects of fluoxetine and vortioxetine were observed, including SERT in the amygdala and NET in the mPFC, whereas different reversal effects were observed for NET in the hippocampus and vesicular monoamine transporters expression in the nucleus accumbens. Overall, these results demonstrate the validity of the LBN paradigm to induce depression-like behaviors in female mice, highlight the involvement of region-specific MATs in ES-induced depression-like behaviors, and provide insights for further investigation of neurobiological mechanisms, treatment, and prevention associated with depression in women.

Dorsal CA3 overactivation mediates witnessing stress-induced recognition memory deficits in adolescent male mice.

Witnessing violent or traumatic events is common during childhood and adolescence and could cause detrimental effects such as increased risks of psychiatric disorders. This stressor could be modeled in adolescent laboratory animals using the chronic witnessing social defeat (CWSD) paradigm, but the behavioral consequences of CWSD in adolescent animals remain to be validated for cognitive, anxiety-like, and depression-like behaviors and, more importantly, the underlying neural mechanisms remain to be uncovered. In this study, we first established the CWSD model in adolescent male mice and found that CWSD impaired cognitive function and increased anxiety levels and that these behavioral deficits persisted into adulthood. Based on the dorsal-ventral functional division in hippocampus, we employed immediate early gene c-fos immunostaining after behavioral tasks and found that CWSD-induced cognition deficits were associated with dorsal CA3 overactivation and anxiety-like behaviors were associated with ventral CA3 activity reduction. Indeed, chemogenetic activation and inhibition of dorsal CA3 neurons mimicked and reversed CWSD-induced recognition memory deficits (not anxiety-like behaviors), respectively, whereas both inhibition and activation of ventral CA3 neurons increased anxiety-like behaviors in adolescent mice. Finally, chronic administration of vortioxetine (a novel multimodal antidepressant) successfully restored the overactivation of dorsal CA3 neurons and the cognitive deficits in CWSD mice. Together, our findings suggest that dorsal CA3 overactivation mediates CWSD-induced recognition memory deficits in adolescent male mice, shedding light on the pathophysiology of adolescent CWSD-induced adverse effects and providing preclinical evidence for early treatment of stress-induced cognitive deficits.

The Nucleus Accumbens CRH-CRHR1 System Mediates Early-Life Stress-Induced Sleep Disturbance and Dendritic Atrophy in the Adult Mouse.

Adverse experiences in early life have long-lasting negative impacts on behavior and the brain in adulthood, one of which is sleep disturbance. As the corticotropin-releasing hormone (CRH)-corticotropin-releasing hormone receptor 1 (CRHR1) system and nucleus accumbens (NAc) play important roles in both stress responses and sleep-wake regulation, in this study we investigated whether the NAc CRH-CRHR1 system mediates early-life stress-induced abnormalities in sleep-wake behavior in adult mice. Using the limited nesting and bedding material paradigm from postnatal days 2 to 9, we found that early-life stress disrupted sleep-wake behaviors during adulthood, including increased wakefulness and decreased non-rapid eye movement (NREM) sleep time during the dark period and increased rapid eye movement (REM) sleep time during the light period. The stress-induced sleep disturbances were accompanied by dendritic atrophy in the NAc and both were largely reversed by daily systemic administration of the CRHR1 antagonist antalarmin during stress exposure. Importantly, Crh overexpression in the NAc reproduced the effects of early-life stress on sleep-wake behavior and NAc morphology, whereas NAc Crhr1 knockdown reversed these effects (including increased wakefulness and reduced NREM sleep in the dark period and NAc dendritic atrophy). Together, our findings demonstrate the negative influence of early-life stress on sleep architecture and the structural plasticity of the NAc, and highlight the critical role of the NAc CRH-CRHR1 system in modulating these negative outcomes evoked by early-life stress.