The effects of venlafaxine on depressive-like behaviors and gut microbiome in cuprizone-treated mice.

Background: Cuprizone (CPZ)-treated mice show significant demyelination, altered gut microbiome, and depressive-like behaviors. However, the effects of venlafaxine (Ven) on the gut microbiome and depressive-like behavior of CPZ-treated mice are largely unclear. Methods: Male C57BL/6J mice were fed a chow containing 0.2% cuprizone (w/w) for 5 weeks to induce a model of demyelination. Meanwhile, the gut microbiota and depressive-like behaviors were assessed after the mice were fed with Ven (20 mg/kg/day) or equal volumes of distilled water for 2 weeks by oral gavage from the third week onward during CPZ treatment. Results: CPZ treatment decreased the sucrose preference rate in the sucrose preference test and increased the immobility time in the tail-suspension test, and it also induced an abnormality in ß-diversity and changes in microbial composition. Ven alleviated the depressive-like behavior and regulated the composition of the gut microbiota, such as the increase of Lactobacillus and Bifidobacterium in CPZ-treated mice. Conclusion: The anti-depressant effects of Ven might be related to the regulation of gut microbiota in the CPZ-treated mice.

Activation of pyramidal neurons in the infralimbic cortex alleviates LPS-induced depressive-like behavior in mice.

The infralimbic (IL) cortex dysfunction has been implicated in major depressive disorder (MDD), yet the precise cellular and molecular mechanisms remain poorly understood. In this study, we investigated the role of layer V pyramidal neurons in a mouse model of MDD induced by repeated lipopolysaccharide (LPS) administration. Our results demonstrate that three days of systemic LPS administration induced depressive-like behavior and upregulated mRNA levels of interleukin-1ß (IL-1ß), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-ß (TGF-ß) in the IL cortex. Electrophysiological recordings revealed a significant decrease in the intrinsic excitability of layer V pyramidal neurons in the IL following systemic LPS exposure. Importantly, chemogenetic activation of IL pyramidal neurons ameliorated LPS-induced depressive-like behavior. Additionally, LPS administration significantly increased microglial activity in the IL, as evidenced by a greater number of Ionized calcium binding adaptor molecule-1 (IBA-1)-positive cells. Morphometric analysis further unveiled enlarged soma, decreased branch numbers, and shorter branch lengths of microglial cells in the IL cortex following LPS exposure. Moreover, the activation of pyramidal neurons by clozapine-N-oxide increased the microglia branch length but did not change branch number or cytosolic area. These results collectively suggest that targeted activation of pyramidal neurons in the IL cortex mitigates microglial response and ameliorates depressive-like behaviors induced by systemic LPS administration. Therefore, our findings offer potential therapeutic targets for the development of interventions aimed at alleviating depressive symptoms by modulating IL cortical circuitry and microglial activity.

Prenatal exposure to fenvalerate causes depressive-like behavior in adulthood by inhibiting brain-derived 5-HT synthesis.

The developmental toxicity of fenvalerate, a representative pyrethroid insecticide, is well documented. The present study aimed to explore whether prenatal exposure to fenvalerate causes depression-like behavior in adulthood. Pregnant mice were orally administrated with either corn oil or fenvalerate (2 or 20 mg/kg) during pregnancy. Depressive-like behaviors were assessed by tail suspension test (TST), forced swim test (FST) and sucrose preference test (SPT). Immobility times in TST and FST were increased in offspring whose mothers were exposed to fenvalerate throughout pregnancy. By contrast, sugar preference index, as determined by SPT, was decreased in fenvalerate-exposed offspring. Prefrontal PSD95, a postsynaptic membrane marker, was downregulated in fenvalerate-exposed adulthood offspring. Fenvalerate-induced reduction of prefrontal PSD95 began at GD18 fetal period. Accordingly, prefrontal 5-HT, a neurotransmitter for synaptogenesis, was also reduced in fenvalerate-exposed GD18 fetuses. Tryptophan hydroxylase 2 (TPH2), a key enzyme for 5-HT synthesis, was downregulated in the midbrain of fenvalerate-exposed GD18 fetuses. Additional experiment showed that GRP78 and p-eIF2α, two endoplasmic reticulum stress-related proteins, were increased in the midbrain of fenvalerate-exposed fetal mice. The present results suggest that prenatal exposure to fenvalerate causes depressive-like behavior in adulthood, partially by inhibiting brain-derived 5-HT synthesis.

Repetitive transcranial magnetic stimulation (rTMS) for depressive-like symptoms in rodent animal models.

Repetitive transcranial magnetic stimulation (rTMS) emerged as a non-invasive brain stimulation technique in the treatment of psychiatric disorders. Both preclinical and clinical studies as well as systematic reviews provide a heterogeneous picture, particularly concerning the stimulation protocols used in rTMS. Here, we present a review of rTMS effects in rodent models of depressive-like symptoms with the aim to identify the most relevant factors that lead to an increased therapeutic success. The influence of different factors, such as the stimulation parameters (stimulus frequency and intensity, duration of stimulation, shape and positioning of the coil), symptom severity and individual characteristics (age, species and genetic background of the rodents), on the therapeutic success are discussed. Accumulating evidence indicates that rTMS ameliorates a multitude of depressive-like symptoms in rodent models, most effectively at high stimulation frequencies (≥5 Hz) especially in adult rodents with a pronounced pathological phenotype. The therapeutic success of rTMS might be increased in the future by considering these factors and using more standardized stimulation protocols.

BGP-15 alleviates LPS-induced depression-like behavior by promoting mitophagy.

The high prevalence of major depressive disorder (MDD) frequently imposes severe constraints on psychosocial functioning and detrimentally impacts overall well-being. Despite the growing interest in the hypothesis of mitochondrial dysfunction, the precise mechanistic underpinnings and therapeutic strategies remain unclear and require further investigation. In this study, an MDD model was established in mice using lipopolysaccharide (LPS). Our research findings demonstrated that LPS exposure induced depressive-like behaviors and disrupted mitophagy by diminishing the mitochondrial levels of PINK1/Parkin in the brains of mice. Furthermore, LPS exposure evoked the activation of the NLRP3 inflammasome, accompanied by a notable elevation in the concentrations of pro-inflammatory factors (TNF-α, IL-1ß, and IL-6). Additionally, neuronal apoptosis was stimulated through the JNK/p38 pathway. The administration of BGP-15 effectively nullified the impact of LPS, corresponding to the amelioration of depressive-like phenotypes and restoration of mitophagy, prevention of neuronal injury and inflammation, and suppression of reactive oxygen species (ROS)-mediated NLRP3 inflammasome activation. Furthermore, we elucidated the involvement of mitophagy in BGP-15-attenuated depressive-like behaviors using the inhibitors targeting autophagy (3-MA) and mitophagy (Mdivi-1). Notably, these inhibitors notably counteracted the antidepressant and anti-inflammatory effects exerted by BGP-15. Based on the research findings, it can be inferred that the antidepressant properties of BGP-15 in LPS-induced depressive-like behaviors could potentially be attributed to the involvement of the mitophagy pathway. These findings offer a potential novel therapeutic strategy for managing MDD.

Chronic defeat stress induces monoamine level dysregulation in the prefrontal cortex but not in the hippocampus of OF1 male mice.

Chronic social stress can increase susceptibility to chronic diseases such as depression. One of the most used models to study the physiological mechanisms and behavioral outcomes of this type of stress is chronic defeat stress (CDS) in male mice. OF1 male mice were subjected to a stress period lasting 18 days. During that time, non-stressed animals were housed in groups. The cluster analysis of the behavioral profile displayed during the first social interaction divided subjects into two groups: active/aggressive (AA) and passive/reactive (PR). The day after the end of the stress period, the following behavioral analyses were performed: the sucrose preference test (SPT) on day 19, the open field test (OFT) on day 20, and the forced swim test (FST) on day 21. Immediately after completing the last test, animals were weighed, and blood samples were obtained. Then, they were sacrificed, and their prefrontal cortices and hippocampi were removed and stored to analyze monoamine levels. Stressed animals displayed anhedonia, and solely the PR mice continued to show higher levels of immobility in the OFT and FST. All stressed animals, regardless of the coping strategy, presented higher plasma corticosterone levels. In addition, stressed mice showed lower levels of tyrosine, dopamine, DOPAC, MHPG, kynurenine, kynurenic acid, and 5-HIAA levels but higher serotonin levels in the prefrontal cortex, not in the hippocampus. In conclusion, our results show that CSD induces differences in monoamine levels between brain areas, and these differences did not respond to the coping strategy adopted.

Colon impairments and inflammation driven by an altered gut microbiota leads to social behavior deficits rescued by hyaluronic acid and celecoxib.

BACKGROUND: The exact mechanisms linking the gut microbiota and social behavior are still under investigation. We aimed to explore the role of the gut microbiota in shaping social behavior deficits using selectively bred mice possessing dominant (Dom) or submissive (Sub) behavior features. Sub mice exhibit asocial, depressive- and anxiety-like behaviors, as well as systemic inflammation, all of which are shaped by their impaired gut microbiota composition. METHODS: An age-dependent comparative analysis of the gut microbiota composition of Dom and Sub mice was performed using 16S rRNA sequencing, from early infancy to adulthood. Dom and Sub gastrointestinal (GI) tract anatomy, function, and immune profiling analyses were performed using histology, RT-PCR, flow cytometry, cytokine array, and dextran-FITC permeability assays. Short chain fatty acids (SCFA) levels in the colons of Dom and Sub mice were quantified using targeted metabolomics. To support our findings, adult Sub mice were orally treated with hyaluronic acid (HA) (30 mg/kg) or with the non-steroidal anti-inflammatory agent celecoxib (16 mg/kg). RESULTS: We demonstrate that from early infancy the Sub mouse gut microbiota lacks essential bacteria for immune maturation, including Lactobacillus and Bifidobacterium genera. Furthermore, from birth, Sub mice possess a thicker colon mucin layer, and from early adulthood, they exhibit shorter colonic length, altered colon integrity with increased gut permeability, reduced SCFA levels and decreased regulatory T-cells, compared to Dom mice. Therapeutic intervention in adult Sub mice treated with HA, celecoxib, or both agents, rescued Sub mice phenotypes. HA treatment reduced Sub mouse gut permeability, increased colon length, and improved mouse social behavior deficits. Treatment with celecoxib increased sociability, reduced depressive- and anxiety-like behaviors, and increased colon length, and a combined treatment resulted in similar effects as celecoxib administered as a single agent. CONCLUSIONS: Overall, our data suggest that treating colon inflammation and decreasing gut permeability can restore gut physiology and prevent social deficits later in life. These findings provide critical insights into the importance of early life gut microbiota in shaping gut immunity, functionality, and social behavior, and may be beneficial for the development of future therapeutic strategies.

Cannabinoid type-1 receptor signaling in dopaminergic Engrailed-1 expressing neurons modulates motivation and depressive-like behavior.

The endocannabinoid system comprises highly versatile signaling functions within the nervous system. It is reported to modulate the release of several neurotransmitters, consequently affecting the activity of neuronal circuits. Investigations have highlighted its roles in numerous processes, including appetite-stimulating characteristics, particularly for palatable food. Moreover, endocannabinoids are shown to fine-tune dopamine-signaled processes governing motivated behavior. Specifically, it has been demonstrated that excitatory and inhibitory inputs controlled by the cannabinoid type 1 receptor (CB1) regulate dopaminergic neurons in the mesocorticolimbic pathway. In the present study, we show that mesencephalic dopaminergic (mesDA) neurons in the ventral tegmental area (VTA) express CB1, and we investigated the consequences of specific deletion of CB1 in cells expressing the transcription factor Engrailed-1 (En1). To this end, we validated a new genetic mouse line EN1-CB1-KO, which displays a CB1 knockout in mesDA neurons beginning from their differentiation, as a tool to elucidate the functional contribution of CB1 in mesDA neurons. We revealed that EN1-CB1-KO mice display a significantly increased immobility time and shortened latency to the first immobility in the forced swim test of adult mice. Moreover, the maximal effort exerted to obtain access to chocolate-flavored pellets was significantly reduced under a progressive ratio schedule. In contrast, these mice do not differ in motor skills, anhedonia- or anxiety-like behavior compared to wild-type littermates. Taken together, these findings suggest a depressive-like or despair behavior in an inevitable situation and a lack of motivation to seek palatable food in EN1-CB1-KO mice, leading us to propose that CB1 plays an important role in the physiological functions of mesDA neurons. In particular, our data suggest that CB1 directly modifies the mesocorticolimbic pathway implicated in depressive-like/despair behavior and motivation. In contrast, the nigrostriatal pathway controlling voluntary movement seems to be unaffected.

Mixed probiotics reduce the severity of stress-induced depressive-like behaviors.

In recent years, the gut microbiome has gained significant attention in the spheres of research and public health. As a result, studies have increasingly explored the potential of probiotic dietary supplements as treatment interventions for conditions such as anxiety and depression. The present study examined the effect of mixed probiotics (Lacticaseibacillus rhamnosus and Enterococcus faecium) on inflammation, microbiome composition, and depressive-like behaviors in a macaque monkey model. The mixed probiotics effectively reduced the severity of depressive-like behaviors in macaque monkeys. Further, treatment with mixed probiotics gradually increased the abundance of beneficial bacteria in the gut, improving the balance of the gut microbiota. Additionally, macaques treated with the mixed probiotics showed decreased serum levels of inflammatory factors (P < 0.05), an increased rate of L-tryptophan metabolism (P < 0.05), and the restoration of 5-HT and 5-HTP levels (P < 0.05). Correlation analysis confirmed that Lacticaseibacillus and other beneficial bacteria exhibited a negative correlation with inflammation in the body (P < 0.05), and a positive correlation with tryptophan metabolism (P < 0.05). In conclusion, the mixed probiotics effectively restored intestinal homeostasis in macaques and enhanced tryptophan metabolism, ultimately alleviating inflammation and depressive-like behaviors.

TGR5-mediated lateral hypothalamus-dCA3-dorsolateral septum circuit regulates depressive-like behavior in male mice.

Although bile acids play a notable role in depression, the pathological significance of the bile acid TGR5 membrane-type receptor in this disorder remains elusive. Using depression models of chronic social defeat stress and chronic restraint stress in male mice, we found that TGR5 in the lateral hypothalamic area (LHA) predominantly decreased in GABAergic neurons, the excitability of which increased in depressive-like mice. Upregulation of TGR5 or inhibition of GABAergic excitability in LHA markedly alleviated depressive-like behavior, whereas down-regulation of TGR5 or enhancement of GABAergic excitability facilitated stress-induced depressive-like behavior. TGR5 also bidirectionally regulated excitability of LHA GABAergic neurons via extracellular regulated protein kinases-dependent Kv4.2 channels. Notably, LHA GABAergic neurons specifically innervated dorsal CA3 (dCA3) CaMKIIα neurons for mediation of depressive-like behavior. LHA GABAergic TGR5 exerted antidepressant-like effects by disinhibiting dCA3 CaMKIIα neurons projecting to the dorsolateral septum (DLS). These findings advance our understanding of TGR5 and the LHAGABA→dCA3CaMKIIα→DLSGABA circuit for the development of potential therapeutic strategies in depression.

Effect of Short Photoperiod on Behavior and Brain Plasticity in Mice Differing in Predisposition to Catalepsy: The Role of BDNF and Serotonin System.

Seasonal affective disorder is characterized by depression during fall/winter as a result of shorter daylight. Catalepsy is a syndrome of some grave mental diseases. Both the neurotransmitter serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) are involved in the pathophysiological mechanisms underlying catalepsy and depressive disorders. The aim was to compare the response of behavior and brain plasticity to photoperiod alterations in catalepsy-resistant C57BL/6J and catalepsy-prone CBA/Lac male mice. Mice of both strains were exposed for six weeks to standard-day (14 h light/10 h darkness) or short-day (4 h light/20 h darkness) conditions. Short photoperiod increased depressive-like behavior in both strains. Only treated CBA/Lac mice demonstrated increased cataleptic immobility, decreased brain 5-HT level, and the expression of Tph2 gene encoding the key enzyme for 5-HT biosynthesis. Mice of both strains maintained under short-day conditions, compared to those under standard-day conditions, showed a region-specific decrease in the brain transcription of the Htr1a, Htr4, and Htr7 genes. After a short photoperiod exposure, the mRNA levels of the BDNF-related genes were reduced in CBA/Lac mice and were increased in the C57BL/6J mice. Thus, the predisposition to catalepsy considerably influences the photoperiodic changes in neuroplasticity, wherein both C57BL/6J and CBA/Lac mice can serve as a powerful tool for investigating the link between seasons and mood.

Ketogenic diet and behavior: insights from experimental studies.

As a journal page for full details. The ketogenic diet (KD) has been established as a treatment for epilepsy, but more recently it has been explored as an alternative or add-on therapy for many other diseases ranging from weight loss to neurological disorders. Animal models are widely used in studies investigating the therapeutic effects of the KD as well as underlying mechanisms. Especially in the context of neurological, psychiatric, and neurodevelopmental disorders essential endpoints are assessed by behavioral and motor tests. Here we summarized research evaluating the influence of the KD on cognition, depressive and anxiety-related behaviors, and social and nutritional behaviors of laboratory rodents. Each section contains a brief description of commonly used behavioral tests highlighting their limitations. Ninety original research articles, written in English, performed on mice or rats, providing measurement of blood beta-hydroxybutyrate (BHB) levels and behavioral evaluation were selected for the review. The majority of research performed in various disease models shows that the KD positively impacts cognition. Almost an equal number of studies report a reduction or no effect of the KD on depressive-related behaviors. For anxiety-related behaviors, the majority of studies show no effect. Despite the increasing use of the KD in weight loss and its appetite-reducing properties the behavioral evaluation of appetite regulation has not been addressed in preclinical studies. This review provides an overview of the behavioral effects of nutritional ketosis addressed to a broad audience of scientists interested in the KD field but not necessarily specializing in behavioral tests.

Protective effect of Baoyuan Jieyu formula on long-term spaceflight composite stress-induced depressive-like behavior and memory deficits through regulation of Ca2+ channel currents.

Long-term spaceflight composite stress (LSCS) can cause adverse effects on human systems, especially the central nervous system. This study aimed to identify the underlying mechanisms of the protective effect of Baoyuan Jieyu Formula (BYJYF) on LSCS-induced depressive-like behavior and memory deficits. In this experiment, we simulated the real space station environment for a period of 42 days. Novel object recognition test and forced swimming test were used to assess the memory abilities and depression level of rats as well as test the therapeutic effects of BYJYF treatment. Results showed LSCS could induce depressive-like behavior and damage short-term memory in the behavioral level, and BYJYF could enhance the ability to resist LSCS. Meanwhile, LSCS increased the levels of CRH, ACTH, and CORT and induced HPA axis hyperactivity, which can be relieved by BYJYF. Further, we predicted and verified the potential signaling pathways of BYJYF. Results showed BYJYF may reverse the inhibition of LSCS on Ca2+ channel currents. And we also found that BYJYF may exert its medicinal effects via four main active components including saikosaponin A. Overall, BYJYF exhibited protective effects against LSCS-induced depressive-like behavior and memory deficits, which might be ascribed to the regulation of Ca2+ channel currents and four active components. And it might become a promising candidate medicine for diseases induced by LSCS.

Construction of antibiotic-induced depression mice model and the function of intestinal microbiota.

Many research studies focus on intestinal microbiota-related depression induced by the usage of antibiotics, but the use of antibiotics is fairly different. To construct an effective antibiotic-induced depression mice model and explore the effect of intestinal microbiota in antibiotic-induced depression, we used several kinds of antibiotic mixtures to induce mice depression and used depression-related behavioral tests and neurobiological factors to evaluate the construction of the antibiotic-induced depression mice model. SPSS statistical software was used to analyze the above data, and the optimal model was selected according to the stability of the results and the simplicity of the modeling methods. Metagenomic analysis and fecal microbiota transplantation (FMT) of intestinal microbiota from antibiotic-induced depression mice were performed to analyze the effect of intestinal microbiota. The results showed that antibiotic mixture A (1.25 µg/mL natamycin, 5 mg/mL neomycin sulfate, and 5 mg/mL bacitracin), antibiotic mixture B (24 mg/mL bacitracin, 24 mg/mL neomycin sulfate, 9.6 mg/mL ampicillin, 4.8 mg/mL meropenem, and 1.47 mg/mL vancomycin), and antibiotic solution D (only containing 5 mg/mL neomycin sulfate) could induce depression-like behavior in mice. By using these antibiotics, the concentrations of norepinephrine (NE), 5-hydroxytryptamine (5-HT), and brain-derived neurotrophic factor (BDNF) in mice hippocampus and prefrontal cortex tissues were significantly decreased. All the above results were consistent with those of chronic unpredictable mild stress (CUMS) depression mice. The FMT results showed that fecal microbiota from antibiotic-induced depressed mice transplanted into normal mice (8 weeks-old male C57BL/6J SPF mice) also could induce depression-like behavior and cause similar changes in neurobiological factors. Metagenomic analysis showed that the community structure of microbiota in the intestinal tract of antibiotic-induced depression mice was significantly different from that in control mice, the intestinal microbiota species diversity in antibiotic-induced depression mice was lower, the lipoic acid metabolism pathway was significantly activated, and the abundance of functional gene lipA was explicitly increased. Quantitative real-time PCR (qPCR) further verified the abundance of enriched bacteria in the intestinal microbiota of antibiotic-induced depression mice. In summary, the specific antibiotic mixtures can induce depression by causing changes in intestinal microbiota in mice. Antibiotic-induced depressed mice show differences in intestinal microbiota abundance, high enrichment of the unique metabolic pathway, and the functional gene.

Deciphering the interplay between LPS/TLR4 pathways, neurotransmitter, and deltamethrin-induced depressive-like behavior: Perspectives from the gut-brain axis.

The improper use of deltamethrin (DM) can result in its accumulation in soil, water, food, and even the human body, which is associated with an elevated risk of neurotoxicity and behavioral abnormalities; however, the underlying mechanisms remain insufficiently investigated. Emerging evidence underscores the significance of the gut-brain axis in central nervous system (CNS) dysfunctions. Accordingly, this study investigates the role of the gut-brain axis in DM-induced behavioral anomalies in mice. The results showed that DM exposure induced depressive-like behavior, and the hippocampus, the region that is responsible for the modulation of emotional behavior, showed structural integrity disrupted (neuronal nuclear shrinkage and decreased tight junction protein expression). In addition, DM exposure led to compromised gut barrier integrity (disruptions on crypt surfaces and decreased tight junction protein expression), which might contribute to the gut bacterial-derived lipopolysaccharide (LPS) leakage into the bloodstream and reaching the brain, triggering LPS/toll-like receptor (TLR) 4 -mediated increases in brain pro-inflammatory cytokines. Subsequently, we observed a disturbance in neurotransmitter metabolic pathways following DM exposure, which inhibited the production of 5-hydroxytryptamine (5-HT). Additionally, DM exposure resulted in gut microbiota dysbiosis. Characteristic bacteria, such as Alistipes, Bifidobacterium, Gram-negative bacterium cTPY-13, and Odoribacter exhibited significant correlations with behavior, tight junction proteins, inflammatory response, and neurotransmitters. Further fecal microbiota transplantation (FMT) experiments suggested that DM-induced gut microbiota dysbiosis might contribute to depressive-like behavior. These results provide a new perspective on the toxicity mechanism of DM, indicating that its neurotoxicity may be partially regulated by the microbiota-gut-brain axis.

Knocking out Selenium Binding Protein 1 Induces Depressive-Like Behavior in Mice.

Selenium binding protein 1 (SELENBP1) is involved in neurologic disorders, such as multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy, and schizophrenia. However, the role of SELENBP1 in the neurogenesis of depression, which is a neurologic disorder, and the underlying mechanisms of oxidative stress and inflammation in depression remain unknown. In this study, we evaluated the changes in the expression levels of SELENBP1 in the hippocampus of a mouse model of depression and in the serum of human patients with depression using the Gene Expression Omnibus database. These changes were validated using blood samples from human patients with depression and mouse models with chronic unpredictable mild stress (CUMS)-induced depressive-like behavior. We also investigated the effects of SELENBP1 knockout (KO) on inflammation, oxidative stress, and hippocampal neurogenesis in mice with CUMS-induced depression. Our results revealed that SELENBP1 levels was decreased in the blood of human patients with depression and in the hippocampus of mice with CUMS-induced depression. SELENBP1 KO increased CUMS-induced depressive behavior in mice and caused dysregulation of inflammatory cytokines and oxidative stress. This led to a decrease in the numbers of doublecortin- and Ki67-positive cells, which might aggravate CUMS-induced depressive symptoms. These findings suggest that SELENBP1 might be involved in the regulation of neurogenesis in mice with depression and could be served as a potential target for diagnosing and treating depression.

Evaluation of electroacupuncture as a non-pharmacological therapy for astrocytic structural aberrations and behavioral deficits in a post-ischemic depression model in mice.

Background: Ascending clinical evidence supports that electroacupuncture (EA) is effective in treating post-ischemic depression (PID), but little is known about how it works at the cellular level. Astrocytes are exquisitely sensitive to their extracellular environment, and under stressful conditions, they may experience aberrant structural remodeling that can potentially cause neuroplastic disturbances and contribute to subsequent changes in mood or behavior. Objectives: This study aimed to investigate the effect of EA on behavioral deficits associated with PID in mice and verify the hypothesis that astrocytic morphology may be involved in this impact. Methods: We established a PID animal model induced by transient bilateral common carotid artery occlusion (BCCAO, 20 min) and chronic restraint stress (CRS, 21 days). EA treatment (GV20 + ST36) was performed for 3 weeks, from Monday to Friday each week. Depressive- and anxiety-like behaviors and sociability were evaluated using SPT, FST, EPM, and SIT. Immunohistochemistry combined with Sholl and cell morphological analysis was utilized to assess the process morphology of GFAP+ astrocytes in mood-related regions. The potential relationship between morphological changes in astrocytes and behavioral output was detected by correlation analysis. Results: Behavioral assays demonstrated that EA treatment induced an overall reduction in behavioral deficits, as measured by the behavioral Z-score. Sholl and morphological analyses revealed that EA prevented the decline in cell complexity of astrocytes in the prefrontal cortex (PFC) and the CA1 region of the hippocampus, where astrocytes displayed evident deramification and atrophy of the branches. Eventually, the correlation analysis showed there was a relationship between behavioral emotionality and morphological changes. Conclusion: Our findings imply that EA prevents both behavioral deficits and structural abnormalities in astrocytes in the PID model. The strong correlation between behavioral Z-scores and the observed morphological changes confirms the notion that the weakening of astrocytic processes may play a crucial role in depressive symptoms, and astrocytes could be a potential target of EA in the treatment of PID.

Systemic Administration of Porphyromonas Gingivalis Lipopolysaccharide Induces Glial Activation and Depressive-Like Behavior in Rats.

BACKGROUND: Periodontitis is one of the most common chronic inflammatory disorders in adults. Although clinical studies have suggested a causal relationship between periodontitis and major depression (MD), the biological mechanisms by which periodontitis instigates MD are unknown. We investigated whether a systemic administration of lipopolysaccharide (LPS) from Porphyromonas gingivalis (Pg), a major Gram-negative pathogen of periodontitis, causes depressive-like behavior and glial activation in the hippocampus and the prefrontal cortex (PFC), which are MD-related brain regions. MATERIALS AND METHODS: Eight-week-old male Sprague Dawley rats were randomly divided into a behavioral test group and an immunohistochemistry group. The rats in each group were further assigned to the sham injection (saline) and Porphyromonas gingivalis-lipopolysaccharide (Pg-LPS) injection protocols. The rats received an intraperitoneal injection of saline or Pg-LPS with gradually increasing doses (day 1: 0.5, day 2: 0.5, day 3: 0.75, day 4: 0.75, day 5: 1.0, day 6: 1.0, and day 7: 1.0 mg/kg of body weight) for seven consecutive days. After the systemic administration, the behavior test group underwent the forced swimming test (FST) and Y-maze test. For the immunohistochemistry group, we quantified the immunoreactivity for microglial Iba-1 (ionized calcium-binding adapter molecule 1) and astrocytic glial fibrillary acidic protein (GFAP) in the hippocampus (dentate gyrus [DG], cornu ammonis [CA1 and CA3]) and PFC (prelimbic [PrL] and the infralimbic [IL]) areas. RESULTS: The FST immobility time in the Pg-LPS group was significantly longer than that in the sham group. In the Y-maze test, a significant decline in spontaneous alternation behavior was observed in the Pg-LPS group compared to the sham group. The peripheral administration of Pg-LPS significantly increased the immunoreactivity for Iba-1 in the CA3 and PrL. Pg-LPS injection significantly increased the immunoreactivity for GFAP in the DG, CA1, and CA3. CONCLUSIONS: The major result of this study is that a repeated systemic administration of Pg-LPS caused depressive-like behavior and both microglial and astrocytic activation in rats. This finding may comprise biological evidence of a causal relationship between periodontitis and MD.

Effect of Hippocampal Overexpression of Dopamine Neurotrophic Factor (CDNF) on Behavior of Mice with Genetic Predisposition to Depressive-Like Behavior.

Cerebral dopamine neurotrophic factor (CDNF) is a promising agent for Parkinson's disease treatment. However, its role in regulation of non-motor behavior including various psychopathologies remains unclear. In this regard, the aim of the present work was to study effect of CDNF overexpression in hippocampus on behavior of the ASC mice (Antidepressant Sensitive Cataleptics) with genetic predisposition to depressive-like behavior. CDNF overexpression in the mouse hippocampal neurons was induced using an adeno-associated viral vector. Four weeks after stereotaxic injection of the AAV-CDNF construct into the dorsal hippocampus home cage activity, exploratory, anxious and depressive-like types of behavior, as well as spatial and associative learning were assessed. We found significant improvements in the dynamics of spatial learning in the Morris water maze in the CDNF-overexpressing animals. At the same time, no effect of CDNF was found on other types of behavior under study. Behavior of the experimental animals under home cage conditions did not differ from that in the control group, except for the decrease in the total amount of food eaten and slight increase in the number of sleep episodes during the light phase of the day. In the present study we also attempted to determine molecular basis for the above-mentioned changes through assessment of the gene expression pattern. We did not find significant changes in the mRNA level of key kinases genes involved in neuroplasticity and neuronal survival, as well as genes encoding receptors for the main neurotransmitter systems. However, the CDNF-overexpressing animals showed increased level of the spliced Xbp indicating activation of the Ire1α/Xbp-1 pathway traditionally associated with ER stress. Immunohistochemical analysis showed that CDNF was co-localized with the ER marker calreticulin. Thus, the effects of endogenous CDNF on behavior that we have found could be mediated by a specific molecular cascade, which emphasizes its difference from the classical neurotrophic factors.

Impact of Elevated Brain IL-6 in Transgenic Mice on the Behavioral and Neurochemical Consequences of Chronic Alcohol Exposure.

Alcohol consumption activates the neuroimmune system of the brain, a system in which brain astrocytes and microglia play dominant roles. These glial cells normally produce low levels of neuroimmune factors, which are important signaling factors and regulators of brain function. Alcohol activation of the neuroimmune system is known to dysregulate the production of neuroimmune factors, such as the cytokine IL-6, thereby changing the neuroimmune status of the brain, which could impact the actions of alcohol. The consequences of neuroimmune-alcohol interactions are not fully known. In the current studies we investigated this issue in transgenic (TG) mice with altered neuroimmune status relative to IL-6. The TG mice express elevated levels of astrocyte-produced IL-6, a condition known to occur with alcohol exposure. Standard behavioral tests of alcohol drinking and negative affect/emotionality were carried out in homozygous and heterozygous TG mice and control mice to assess the impact of neuroimmune status on the actions of chronic intermittent alcohol (ethanol) (CIE) exposure on these behaviors. The expressions of signal transduction and synaptic proteins were also assessed by Western blot to identify the impact of alcohol-neuroimmune interactions on brain neurochemistry. The results from these studies show that neuroimmune status with respect to IL-6 significantly impacts the effects of alcohol on multiple levels.