Depression-related Behaviors Research Articles

Phytochemical Profile and Antidepressant Effect of Ormosia henryi Prain Leaf Ethanol Extract

The Ormosia henryi Prain leaf (OHPL) is a new bioactive resource with potential antidepressant activity, but few reports have confirmed its chemical composition or antidepressant effect. To investigate the phytochemical profile of OHPL ethanol extract (OHPLE), six flavone C-glycosides and two flavone O-glycosides were purified by high-speed counter-current chromatography combined with preparative high-performance liquid chromatography (HSCCC-prep-HPLC). The eight isolated compounds were identified by NMR and MS. Forty-six flavonoids, including flavones, flavone C-glycosides, flavone O-glycosides, isoflavones, isoflavone O-glycosides, prenylflavones and polymethoxyflavones were definitively or tentatively identified from OHPLE using ultra-performance liquid chromatography/ electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS/MS) on the basis of fragment ions that are characteristic of these isolated compounds. The results of the antidepressant assay suggest that OHPLE significantly improved depression-related behaviors of chronic unpredictable mild stress (CUMS) mice. The observed changes in these mice after OHPLE treatment were an increased sucrose preference index, reduced feeding latency, prolonged tail suspension time, and upregulated expression of brain-derived neurotrophic factor (BDNF). The details of the phytochemicals and the antidepressant effect of OHPLE are reported here for the first time. This study indicates that the OHPL, enriched in flavone C-glycosides, is a new resource that might be potentially applied in the field of nutraceuticals (or functional additives) with depression-regulating functions.

Connexin43 in neonatal excitatory neurons is important for short-term motor learning

In the neocortex, gap junctions are expressed at very early developmental stages, and they are involved in many processes such as neurogenesis, neuronal migration and synapse formation. Connexin43 (Cx43), a gap junction protein, has been found to be abundantly expressed in radial glial cells, excitatory neurons and astrocytes. Although accumulating evidence suggests that Cx43-mediated gap-junctional coupling between astrocytes plays an important role in the central nervous system, the function of Cx43 in early excitatory neurons remains elusive. To investigate the impact of Cx43 deficiency in excitatory neurons at early postnatal stages, we conditionally knocked out Cx43 in excitatory neurons under the Emx1 promoter by tamoxifen induction. We found that deletion of Cx43 around birth did not impair the laminar distribution of excitatory neurons in the neocortex. Moreover, mice with Cx43 deletion during the early postnatal stages had normal anxiety-like behaviors, depression-related behaviors, learning and memory-associated behaviors at adolescent stages. However, Cx43 conditional knockout mice exhibited impaired motor-learning behavior. These results suggested that Cx43 expression in excitatory neurons at early postnatal stages contributes to short-term motor learning capacity.

Attenuating Effects of Lactobacillus Acidophilus YT1 on Menopausal Symptoms in Ovariectomized Rats (P20-014-19)

ObjectivesMenopause is a natural process, where ovaries produce less reproductive hormones, which degrades the quality of life. Hormone replacement therapy was used primarily to reduce menopausal symptoms but new therapies are needed because they have a risk in long-term use. Probiotics are well known for their beneficial effects on bowel health, obesity, and immunity, and they have been reported to have useful effects on menopause in recent years. This study examined the effects of Lactobacillus acidophilus YT1 on menopausal symptoms in ovariectomized (OVX) rats. MethodsTwelve weeks-old female SD rats were divided into five groups: (1) sham + DW, (2) OVX + DW, (3) OVX + estradiol, (4) OVX + L. acidophilus YT1, and (5) OVX + Lactobacillus reuteri that were treated once daily for 12 weeks after OVX. ResultsPain sensitivity, depression-related behavior, and fat mass were significantly increased at 12 weeks after OVX and the bone mineral density was decreased. These menopause symptoms were significantly recovered by a daily oral treatment of L. acidophilus YT1 for 12 weeks. In addition, L. acidophilus YT1 enhanced intestinal barrier function by up-regulation tight junction expression in Caco-2 cell monolayers. ConclusionsThe treatment of L. acidophilus YT1 could alleviate menopausal symptoms, such as increased pain sensitivity, depression, body fat, and bone loss in menopausal women, which suggests it could be developed as a functional food and probiotics for elderly women health. Funding SourcesThis research was supported by the main research Program (E0164502-03) of the Korea Food Research Institute funded by the Minstry of Science and ICT.

Neuroimmune Responses Mediate Depression-Related Behaviors following Acute Colitis

SummaryMany patients with visceral inflammation develop pain and psychiatric comorbidities such as major depressive disorder, worsening the quality of life and increasing the risk of suicide. Here we show that neuroimmune activation in mice with dextran sodium sulfate-induced colitis is accompanied by the development of pain and depressive behaviors. Importantly, treatment with the flavonoid luteolin prevented both neuroimmune responses and behavioral abnormalities, suggesting a new potential therapeutic approach for patients with inflammatory bowel diseases.

Functional and Optogenetic Approaches to Discovering Stable Subtype-Specific Circuit Mechanisms in Depression

BackgroundPreviously, we identified four depression subtypes defined by distinct functional connectivity alterations in depression-related brain networks, which in turn predicted clinical symptoms and treatment response. Optogenetic functional magnetic resonance imaging offers a promising approach for testing how dysfunction in specific circuits gives rise to subtype-specific, depression-related behaviors. However, this approach assumes that there are robust, reproducible correlations between functional connectivity and depressive symptoms—an assumption that was not extensively tested in previous work. MethodsFirst, we comprehensively reevaluated the stability of canonical correlations between functional connectivity and symptoms (N = 220 subjects) using optimized approaches for large-scale statistical hypothesis testing, and we validated methods for improving estimation of latent variables driving brain-behavior correlations. Having confirmed this necessary condition, we reviewed recent advances in optogenetic functional magnetic resonance imaging and illustrated one approach to formulating hypotheses regarding latent subtype-specific circuit mechanisms and testing them in animal models. ResultsCorrelations between connectivity features and clinical symptoms were robustly significant, and canonical correlation analysis solutions tested repeatedly on held-out data generalized. However, they were sensitive to data quality, preprocessing, and clinical heterogeneity, which can reduce effect sizes. Generalization could be markedly improved by adding L2 regularization, which decreased estimator variance, increased canonical correlations in left-out data, and stabilized feature selection. These improvements were useful for identifying candidate circuits for optogenetic interrogation in animal models. ConclusionsMultiview, latent-variable approaches such as canonical correlation analysis offer a conceptually useful framework for discovering stable patient subtypes by synthesizing multiple clinical and functional measures. Optogenetic functional magnetic resonance imaging holds promise for testing hypotheses regarding latent, subtype-specific mechanisms driving depressive symptoms and behaviors.

A Role for Matrix Metalloproteases in Antidepressant Efficacy.

Major depressive disorder is a debilitating condition that affects approximately 15% of the United States population. Though the neurophysiological mechanisms that underlie this disorder are not completely understood, both human and rodent studies suggest that excitatory/inhibitory (E/I) balance is reduced with the depressive phenotype. In contrast, antidepressant efficacy in responsive individuals correlates with increased excitatory neurotransmission in select brain regions, suggesting that the restoration of E/I balance may improve mood. Enhanced excitatory transmission can occur through mechanisms including increased dendritic arborization and synapse formation in pyramidal neurons. Reduced activity of inhibitory neurons may also contribute to antidepressant efficacy. Consistent with this possibility, the fast-acting antidepressant ketamine may act by selective inhibition of glutamatergic input to GABA releasing parvalbumin (PV)-expressing interneurons. Recent work has also shown that a negative allosteric modulator of the GABA-A receptor α subunit can improve depression-related behavior. PV-expressing interneurons are thought to represent critical pacemakers for synchronous network events. These neurons also represent the predominant GABAergic neuronal population that is enveloped by the perineuronal net (PNN), a lattice-like structure that is thought to stabilize glutamatergic input to this cell type. Disruption of the PNN reduces PV excitability and increases pyramidal cell excitability. Various antidepressant medications increase the expression of matrix metalloproteinases (MMPs), enzymes that can increase pyramidal cell dendritic arborization and spine formation. MMPs can also cleave PNN proteins to reduce PV neuron-mediated inhibition. The present review will focus on mechanisms that may underlie antidepressant efficacy, with a focus on monoamines as facilitators of increased matrix metalloprotease (MMP) expression and activation. Discussion will include MMP-dependent effects on pyramidal cell structure and function, as well as MMP-dependent effects on PV expressing interneurons. We conclude with discussion of antidepressant use for those at risk for Alzheimer’s disease, and we also highlight areas for further study.

Suppressing the Na+/H+ exchanger 1: a new sight to treat depression

Na+/H+ exchanger 1 (NHE1), an important regulator of intracellular pH (pHi) and extracellular pH (pHe), plays a crucial role in various physiological and pathological processes. However, the role of NHE1 in depression has not yet been reported. This study was designed to investigate the role of NHE1 in the animal model of depression and explore the underlying mechanisms. Our results showed that inhibition of rho-associated kinase 2 (ROCK2) by fasudil (Fas) or baicalin (BA) significantly alleviated chronic unpredictable mild stress (CUMS) paradigm-induced depression-related behaviours in mice, as shown by decreased sucrose consumption in sucrose preference test (SPT), reduced locomotor activity in the open field test (OFT), and increased immobility time in the tail suspension test (TST) and forced swimming test (FST). Furthermore, ROCK2 inhibition inhibited the activation of NHE1, calpain1, and reduced neuronal apoptosis in the CUMS animal model of depression. Next, we used the lipopolysaccharide (LPS)-challenged animal model of depression to induce NHE1 activation. Our results revealed that mice subjected to 1 μl LPS (10 mg/ml) injection intracerebroventricularly (i.c.v.) showed depressive-like behaviours and NHE1 activation. Amiloride (Ami), an NHE1 inhibitor, significantly reversed the decrease in sucrose consumption and reduction in immobility time in the TST and FST induced by LPS challenge. Furthermore, Ami decreased the expression of ROCK2, NHE1, calpain1, and caspase-3 and increased the Bcl-1/Bax ratio in the hippocampus of LPS-challenged mice. Ami treatment also led to antidepressive effects in the CUMS-induced animal model of depression. Thus ROCK2 inhibition could be proposed as a neuroprotective strategy against neuronal apoptosis, and NHE1 might be a potential therapeutic target in depression.

GHS-R1a Deficiency Alleviates Depression-Related Behaviors After Chronic Social Defeat Stress

Ghrelin is an important orexigenic hormone that regulates feeding, metabolism and glucose homeostasis in human and rodents. Ghrelin functions by binding to its receptor, the growth hormone secretagogue receptor 1a (GHS-R1a), which is widely expressed inside and outside of the brain. Recent studies suggested that acyl-ghrelin, the active form of ghrelin, is a persistent biomarker for chronic stress exposure. However, how ghrelin/GHS-R1a signaling contributes to stress responses and mood regulation remains uncertain. In this study, we applied the chronic social defeat stress (CSDS) paradigm to both GHS-R1a knock-out (Ghsr-/-) mice and littermate control (Ghsr+/+) mice, and then measured their depression- and anxiety-related behaviors. We found that Ghsr+/+ mice, but not Ghsr-/- mice, displayed apparent anxiety and depression after CSDS, while two groups mice showed identical behaviors at baseline, non-stress state. By screening the central and peripheral responses of Ghsr-/- mice and Ghsr+/+ mice to chronic stress, we found similar elevations of total ghrelin and adrenocorticotropic hormone (ACTH) in the serum of Ghsr-/- mice and Ghsr+/+ mice after CSDS, but decreased interleukin-6 (IL-6) in the serum of defeated Ghsr-/- mice compared to defeated Ghsr+/+ mice. We also found increased concentration of brain derived neurotropic factor (BDNF) in the hippocampus of Ghsr-/- mice compared to Ghsr+/+ mice after CSDS. The basal levels of ghrelin, ACTH, IL-6, and BDNF were not different between Ghsr-/- mice and Ghsr+/+ mice. Our findings thus suggested that the differential expressions of BDNF and IL-6 after CSDS may contribute to less anxiety and less despair observed in GHS-R1a-deficient mice than in WT control mice. Therefore, ghrelin/GHS-R1a signaling may play a pro-anxiety and pro-depression effect in response to chronic stress, while GHS-R1a deficiency may provide resistance to depressive symptoms of CSDS.

Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions.

Major depressive disorder (MDD) is a debilitating illness characterized by neuroanatomical and functional alterations in limbic structures, notably the prefrontal cortex (PFC), that can be precipitated by exposure to chronic stress. For decades, the monoaminergic deficit hypothesis of depression provided the conceptual framework to understand the pathophysiology of MDD. However, accumulating evidence suggests that MDD and chronic stress are associated with an imbalance of excitation–inhibition (E:I) within the PFC, generated by a deficit of inhibitory synaptic transmission onto principal glutamatergic neurons. MDD patients and chronically stressed animals show a reduction in GABA and GAD67 levels in the brain, decreased expression of GABAergic interneuron markers, and alterations in GABAA and GABAB receptor levels. Moreover, genetically modified animals with deletion of specific GABA receptors subunits or interneuron function show depressive-like behaviors. Here, we provide further evidence supporting the role of cortical GABAergic interneurons, mainly somatostatin- and parvalbumin-expressing cells, required for the optimal E:I balance in the PFC and discuss how the malfunction of these cells can result in depression-related behaviors. Finally, considering the relatively low efficacy of current available medications, we review new fast-acting pharmacological approaches that target the GABAergic system to treat MDD. We conclude that deficits in cortical inhibitory neurotransmission and interneuron function resulting from chronic stress exposure can compromise the integrity of neurocircuits and result in the development of MDD and other stress-related disorders. Drugs that can establish a new E:I balance in the PFC by targeting the glutamatergic and GABAergic systems show promising as fast-acting antidepressants and represent breakthrough strategies for the treatment of depression.

Alpha-7 nicotinic receptor allosteric modulator PNU120596 prevents lipopolysaccharide-induced anxiety, cognitive deficit and depression-like behaviors in mice

Neuroinflammation is often associated with the development of major depressive disorder (MDD)-related symptoms. Previous studies have indicated that activation of glial cells, upregulation of proinflammatory cytokines and dysregulation of adrenergic system in the central nervous system (CNS) could be the key mediators to modulate depression-related behaviors after peripheral immune activation. Central α7 nicotinic acetylcholine receptor (α7 nAChR) has a role in the regulation of the cholinergic anti-inflammatory pathway. The present study determined the effects of PNU120596, α7 nAChR positive allosteric modulator (PAM), on lipopolysaccharide (LPS)-induced anxiety, cognitive deficit, and depression-like behaviors in mice. These behaviors were evaluated 24 h after LPS (1 mg/kg) administration using elevated plus-maze, Y-maze, and forced swim test, respectively. The effects of PNU120596 on mRNA of neuroinflammatory markers and norepinephrine (NE) level in behaviorally-relevant brain regions such as the hippocampus and prefrontal cortex were examined. PNU120596 administration (1 or 4 mg/kg) showed anxiolytic, pro-cognitive, and antidepressant-like effects by preventing LPS-induced behavioral abnormalities. Following LPS treatment, PNU120596 hindered activation markers of the microglia and astrocytes (cluster of differentiation molecule 11b and glial fibrillary acidic protein) and upregulation of proinflammatory cytokines such as interleukin 1 beta and tumor necrosis factor-alpha in the hippocampus and prefrontal cortex. NE level that was reduced by peripheral LPS challenge was normalized by PNU120596 effects in both brain regions. Overall, the results in this study indicate that activation of α7 nAChR by PAM effectively prevents LPS-induced anxiety, cognitive deficit, and depression-like behaviors and regulates relevant neuroinflammatory markers in the hippocampus and prefrontal cortex.

GIRK Channel Activity in Dopamine Neurons of the Ventral Tegmental Area Bidirectionally Regulates Behavioral Sensitivity to Cocaine.

Dopamine (DA) neurons of the VTA have been widely implicated in the cellular and behavioral responses to drugs of abuse. Inhibitory G protein signaling mediated by GABAB receptors (GABABRs) and D2 DA receptors (D2Rs) regulates the excitability of VTA DA neurons, DA neurotransmission, and behaviors modulated by DA. Most of the somatodendritic inhibitory effect of GABABR and D2R activation on DA neurons reflects the activation of G protein-gated inwardly rectifying K+ (GIRK) channels. Furthermore, GIRK-dependent signaling in VTA DA neurons can be weakened by exposure to psychostimulants and strengthened by phasic DA neuron firing. The objective of this study was to determine how the strength of GIRK channel activity in VTA DA neurons influences sensitivity to cocaine. We used a Cre-dependent viral strategy to overexpress the individual GIRK channel subunits in VTA DA neurons of male and female adult mice, leading to enhancement (GIRK2) or suppression (GIRK3) of GIRK channel activity. Overexpression of GIRK3 decreased somatodendritic GABABR- and D2R-dependent signaling and increased cocaine-induced locomotor activity, whereas overexpression of GIRK2 increased GABABR-dependent signaling and decreased cocaine-induced locomotion. Neither manipulation impacted anxiety- or depression-related behavior, despite the link between such behaviors and DA signaling. Together, these data show that behavioral sensitivity to cocaine in mice is inversely proportional to the strength of GIRK channel activity in VTA DA neurons and suggest that direct activators of the unique VTA DA neuron GIRK channel subtype (GIRK2/GIRK3 heteromer) could represent a promising therapeutic target for treatment of addiction.SIGNIFICANCE STATEMENT Inhibitory G protein signaling in dopamine (DA) neurons, including that mediated by G protein-gated inwardly rectifying K+ (GIRK) channels, has been implicated in behavioral sensitivity to cocaine. Here, we used a viral approach to bidirectionally manipulate GIRK channel activity in DA neurons of the VTA. We found that decreasing GIRK channel activity in VTA DA neurons increased behavioral sensitivity to cocaine, whereas increasing GIRK channel activity decreased behavioral sensitivity to cocaine. These manipulations did not alter anxiety- or depression-related behaviors. These data highlight the unique GIRK channel subtype in VTA DA neurons as a possible therapeutic target for addiction.

Ketamine-induced antidepressant like effects in mice: A possible involvement of cannabinoid system

The purpose of this study was to explore the possible interaction between ketamine and cannabinoid system in the modulation of depression-related responses using the forced swimming test (FST), tail suspension test (TST) and open-field test (OFT) in mice. Our results revealed that intra-peritoneal (i.p.) injection of ketamine (5 and 10 mg/kg), a non-competitive NMDA antagonist, dose-dependently produced antidepressant-like effect in the FST. Moreover, i.p. administration of both CB1 and CB2 receptor drugs: ACPA (1 mg/kg; CB1 receptor agonist), AM251 (1 mg/kg; CB1 receptor antagonist), GP1a (2 mg/kg; CB2 receptor agonist) and AM630 (0.5 mg/kg; CB2 receptor antagonist) exhibited antidepressant action. Interestingly, the concomitant administration of ineffective doses of ketamine and cannabinoid receptor antagonists provoked the antidepressant-like effects as compared to control group. It should be considered, all above mentioned doses of drugs could not change locomotor activity in the OFT. It seems that possible interaction between ketamine and cannabinoid system may modulate depression-related behavior.

Age-related behavioral changes from young to old age in male mice of a C57BL/6J strain maintained under a genetic stability program.

AimAging is thought to coincide with gradual and progressive changes in brain function and behavior over the lifetime. Our previous meta‐analytic study reported age‐related behavioral changes from young to middle age in male C57BL/6J mice. However, the previous study had some limitations that could affect the generalizability of the findings because of the potential influence of genetic and environmental factors on behavior, in addition to a lack of information regarding the behaviors of old‐aged mice. Here, to investigate age‐related behavioral changes from young to old age in mice, we analyzed the behaviors of male C57BL/6J mice from four different age groups (8, 47, 73, and 99 weeks of age at the beginning of the experiment) from a colony that had been maintained in a genetically controlled condition based on The Jackson Laboratory's Genetic Stability Program in an environmentally controlled animal facility.MethodsWe used a battery of behavioral tests, including the light/dark transition, open field, elevated plus maze, hot plate, social interaction, rotarod, three‐chamber social approach, prepulse inhibition, Porsolt forced swim, T‐maze, Barnes maze, tail suspension, and fear‐conditioning tests.ResultsSome behavioral changes occurred between young and middle age, and further changes in various behaviors were observed in old age. Decreased locomotor activity and increased anxiety‐like behavior were found in old‐aged mice compared to those in young and middle‐aged mice in the light/dark transition test. Similarly, an age‐dependent decrease in locomotor activity was observed in the open field test and the elevated plus maze test, while there was an age‐dependent increase in the time spent in the center area in the open field test and there were no significant differences among age groups in behavioral measures of anxiety in the elevated plus maze test. Decreases in motor performance and the auditory startle response were found in middle‐aged mice compared to those in young mice. Similar behavioral changes and increased pain sensitivity, decreased social novelty preference, reduced working and spatial memory, and impaired cued fear memory were observed in old‐aged mice compared to those in young mice. Prepulse inhibition was higher in middle‐aged mice than in young and old‐aged mice. Age‐related changes in depression‐related behavior were dependent on the type of test and the test time period.ConclusionsThis study generally confirmed our previous report regarding age‐related behavioral changes from young to middle age and expanded the previous observations by examining the behaviors of old‐aged mice. Our results show age‐related changes in a wide range of behaviors in mice from young to old age. Most behaviors showed gradual changes with advancing age, but some types of behaviors, such as vertical activity, prepulse inhibition, and depression‐related behavior, did not show unidirectional changes with age. These findings provide basic information about the behavioral characteristics of young, middle‐aged, and aged male C57BL/6J mice.

Anxiolytic and antidepressant effects of ACPA and harmaline co-treatment.

Depression and anxiety disorders are among the most common illnesses and a close relationship between them has been found. Because the psychotropic effects and abuse liability of cannabis prevent its therapeutic application in depression and anxiety states, we decided to investigate the effects of the combination of ineffective doses of cannabinoid CB1 receptor agonist arachidonylcyclopropylamide (ACPA) and β-carbolines on anxiety- and depression-related behaviors in male NMRI mice. Anxiety- and depression-related behaviors were assesses using elevated plus maze (EPM) and forced swim test (FST), respectively. Intraperitoneal administration of ACPA (1 mg/kg) decreased the percentage of time spent in the open-arms (%OAT) and the number of entries to the open-arms (OAE) in the EPM, indicating an anxiogenic-like effect. ACPA also decreased immobility time in the FST compared to the control group, suggesting an antidepressant-like effect. β-carbolines including harmane (5 and 10 mg/kg), norharmane (5 mg/kg) and harmaline (2.5 and 5 mg/kg) produced an anxiogenic-like response, while the highest dose of harmane or harmaline and the middle dose of norharmane induced an antidepressant-like behavior. Furthermore, co-administration of a subthreshold dose of ACPA (0.5 mg/kg) and harmaline (1.25 mg/kg), but not harmane or norharmane (both at the dose of 2.5 mg/kg), caused anxiolytic- and antidepressant-like behaviors and decreased locomotor activity. Our findings suggest a therapeutic potential for combined ineffective doses of ACPA and harmaline on anxiety- and depression-related processes.

Disabling the Gβγ-SNARE interaction disrupts GPCR-mediated presynaptic inhibition, leading to physiological and behavioral phenotypes.

G protein-coupled receptors (GPCRs) that couple to Gi/o proteins modulate neurotransmission presynaptically by inhibiting exocytosis. Release of Gβγ subunits from activated G proteins decreases the activity of voltage-gated Ca2+ channels (VGCCs), decreasing excitability. A less understood Gβγ-mediated mechanism downstream of Ca2+ entry is the binding of Gβγ to SNARE complexes, which facilitate the fusion of vesicles with the cell plasma membrane in exocytosis. Here, we generated mice expressing a form of the SNARE protein SNAP25 with premature truncation of the C terminus and that were therefore partially deficient in this interaction. SNAP25Δ3 homozygote mice exhibited normal presynaptic inhibition by GABAB receptors, which inhibit VGCCs, but defective presynaptic inhibition by receptors that work directly on the SNARE complex, such as 5-hydroxytryptamine (serotonin) 5-HT1b receptors and adrenergic α2a receptors. Simultaneously stimulating receptors that act through both mechanisms showed synergistic inhibitory effects. SNAP25Δ3 homozygote mice had various behavioral phenotypes, including increased stress-induced hyperthermia, defective spatial learning, impaired gait, and supraspinal nociception. These data suggest that the inhibition of exocytosis by Gi/o-coupled GPCRs through the Gβγ-SNARE interaction is a crucial component of numerous physiological and behavioral processes.

Anxiogenic-like behavior and deficient attention/working memory in rats expressing the human DISC1 gene

In humans, mutations in the Disrupted-in-schizophrenia 1 (DISC1) gene have been related to psychiatric disorders, including symptoms of abnormal cognitive and emotional behaviors. In our previous studies, overexpression of the human DISC1 gene in rats resulted in schizophrenia-like phenotypes showing deficits in motor learning, impaired cognitive function and dysfunctions of the dopamine system. Here we asked, whether the DISC1 overexpression affects locomotor activity in the open field (OF), anxiety in the elevated plus-maze (EPM), depression-related behavior in the forced swim test (FST), and attention-like/short-term working-memory in the spontaneous alternation behavior (SAB) in the T-maze in transgenic DISC1 (tgDISC1) rats and littermate controls (WT). TgDISC1 rats showed enhanced anxiety behavior in the EPM and an impairment in attention-like/short-term working-memory in the SAB. However, tgDISC1 animals showed no locomotor impairments or depression-like behavior in the OF and FST. These results suggest that DISC1 overexpression leads to higher anxiety level and an attention-like/working-memory deficit. These findings may expand the causal role of DISC1 in its contribution to multiple symptom dimensions of psychiatric disorders.

Glucocorticoid receptor dysfunction orchestrates inflammasome effects on chronic obstructive pulmonary disease-induced depression: A potential mechanism underlying the cross talk between lung and brain

Depression is highly prevalent among patients with chronic obstructive pulmonary disease (COPD). However, depression with COPD comorbidity is often underdiagnosed and undertreated, and pathogenic research is also insufficient. In the present study, we characterised pulmonary and hippocampal dysfunction by researching the interaction between inflammasome-regulated cytokines and glucocorticoid receptor (GR) signalling by investigating the role of fluoxetine (FLU), one of the most widely used antidepressants in clinical practice. Mice were exposed to cigarette smoke (CS) to induce the model of COPD with comorbid depression, and pathological alterations in serum, hippocampus, lung, and bronchoalveolar lavage fluid were determined. Our results showed that the CS procedure induced the accumulation of inflammatory cells (macrophages, neutrophils, and lymphocytes), the production of cytokines, the activation of inflammasome components (NLRP3, ASC, caspase-1), depression-related behaviours, and the stimulation of GR signalling. Intriguingly, glucocorticoid resistance occurred in CS-exposed mice, with elevated serum corticosterone and suppressed hippocampal GR levels, which suggested a novel potential regulatory mechanism underlying COPD-induced depression comorbidity. Furthermore, chronic CS exposure decreased the pGR-S211/pGR-S226 ratio, increased the active nuclear GR, and impaired cytosolic GR binding capacity and GR transcriptional activity, which might be responsible for the activation of the inflammasome-induced inflammatory cascade. These alterations were reversed by chronic FLU treatment, indicating that FLU-mediated GR signalling was involved in the COPD induced inflammasome activation. Our research explored the underlying molecular mechanism of comorbid COPD/depression and provided in vivo evidence that glucocorticoid resistance occurred during CS-induced central nervous system inflammation, a potential mechanism underlying the cross talk between the lung and brain.

Neuroligin-2 Determines Inhibitory Synaptic Transmission in the Lateral Septum to Optimize Stress-Induced Neuronal Activation and Avoidance Behavior

BackgroundInvestigations in the neocortex have revealed that the balance of excitatory and inhibitory synaptic transmission (E/I ratio) is important for proper information processing. The disturbance of this balance underlies many neuropsychiatric illnesses, including autism spectrum disorder and schizophrenia. However, little is known about the contribution of E/I balance to the functioning of subcortical brain regions, such as the lateral septum (LS), a structure that plays important roles in regulating anxiety-related behavior. MethodsWe manipulated E/I balance in the mouse LS by localized conditional deletion of neuroligin-2, a postsynaptic cell adhesion protein located at gamma-aminobutyric acidergic synapses and important for inhibitory synaptic transmission. We then performed analyses of synaptic transmission in the LS, stress-induced expression of immediate early gene c-fos, and anxiety-related and depression-related behavior. ResultsThe absence of neuroligin-2 in the LS in the mature mouse brain resulted in postsynaptic impairment of inhibitory synaptic transmission. Importantly, the reduced inhibition and resulting E/I imbalance decreased the responsiveness of LS neurons to stress. Furthermore, this E/I imbalance in the LS was associated with impaired stress-induced activation of downstream hypothalamic nuclei and reduced avoidance behavior of the animals in the elevated plus maze. ConclusionsOur results described the synaptic function of neuroligin-2 in the LS, uncovered a positive association between c-Fos–expressing neurons in the LS and downstream hypothalamic areas and avoidance behavior, and demonstrated that intact inhibitory synaptic transmission and proper E/I balance are required for the optimal functioning of this subcortical circuit.

SIRT1 in forebrain excitatory neurons produces sexually dimorphic effects on depression-related behaviors and modulates neuronal excitability and synaptic transmission in the medial prefrontal cortex

Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, is a key regulator of cellular metabolism. Recent genome-wide association studies identified genetic variants of SIRT1 linked to major depressive disorders. SIRT1 is widely expressed in the brain; however, neuronal substrates that mediate SIRT1 action on depressive behaviors remain largely unknown. Here we show that selective deletion of SIRT1 in forebrain excitatory neurons causes depression-like phenotypes in male but not female mice. AAV-Cre-mediated SIRT1 knockdown in the medial prefrontal cortex (mPFC) of adult male mice induces depressive-like behaviors. Whole-cell patch-clamp recordings demonstrate that loss of SIRT1 decreases intrinsic excitability and spontaneous excitatory synaptic transmission in layer V pyramidal neurons in the prelimbic mPFC. Consistent with neuronal hypoexcitability, SIRT1 knockout reduces mitochondrial density and expression levels of genes involved in mitochondrial biogenesis and dynamics in the prelimbic mPFC. When a SIRT1 activator (SRT2104) is injected into the mPFC or lateral ventricle of wild-type mice, it reverses chronic unpredictable stress-induced anhedonia and behavioral despair, indicating an antidepressant-like effect. These results suggest that SIRT1 in mPFC excitatory neurons is required for normal neuronal excitability and synaptic transmission and regulates depression-related behaviors in a sex-specific manner.

The susceptibility to chronic social defeat stress is related to low hippocampal extrasynaptic NMDA receptor function.

N-methyl-D-aspartate receptors (NMDARs) have been highly implicated in the pathogenesis and treatment of depression. While NMDARs can be found inside and outside glutamate synapses, it remains unclear if NMDARs at synaptic (sNMDAR) and extrasynaptic locations (exNMDAR) play different roles in the formation of depression-related behaviors. Using chronic social defeat stress (CSDS), an animal model for anxiety- and depression-related behaviors, we found that mice susceptible to CSDS exhibited low hippocampal exNMDAR function. Raising exNMDAR function by enhancing the release of glutamate from astrocytic cystine-glutamate antiporters or targeting extrasynaptic receptors with agonist-coated gold nanoparticles that cannot enter the synaptic cleft prevented social avoidance behavior in stressed mice. Interestingly, ketamine, which is a fast-acting antidepressant, exhibited stronger blockade to sNMDARs than to exNMDARs. These findings suggest that the susceptibility and resilience of mice toward CSDS is related to low and high exNMDAR function in the hippocampus, respectively. Enhancing exNMDAR function could be a novel treatment approach for mood and anxiety disorders.