Central Entries Research Articles

Macaiba palm pulp (Acrocomia intumescens Drude) improves memory and induces anxiolytic-like behavior in dyslipidemic rats.

Macaiba pulp is a source of bioactive compounds. This study aimed to evaluate the effects of macaiba pulp on anxiety behavior, memory and brain oxidative stress in dyslipidemic rats. The animals were divided into four groups (n = 10): Control (CG), Macaíba (MG), Dyslipidemic (DG) and Dyslipidemic Macaiba (DMG). Animals from the DG and DMG were induced to dyslipidemia consuming a high fatty emulsion for 14days before treatment with macaiba pulp. During treatment the MG and DMG received the macaiba pulp (1g/kg body weight) for 28days. The rats were evaluated with the open field (OFT) and elevated plus maze (EPM) tests to measure anxiety-like behavior; memory was evaluated using the object recognition test (ORT). After euthanasia, the fatty acid profile of the animals' brain tissue was measured and the levels of malondialdehyde (MDA) and total glutathione (GSH) were quantified. The data were evaluated using one-way ANOVA followed by the Tukey (p < 0.05) test. Both groups (MG and DMG) that consumed the macaiba pulp showed anxiolytic-like behavior for parameters of grooming, rearing and ambulation in the OFT test and time in the center and time and entries in the open arms in the EMP test; The MG and DMG groups increased exploration rate in the ORT. The DMG showed a reduction in MDA levels (p < 0.05); however, MG and DMG had decreased in GSH (p < 0.05). The results showed that macaiba pulp consumption induces anxiolytic-like behavior and reduces brain oxidative damage in dyslipidemic animals, and improves memory in healthy and dyslipidemic rats.

Effect of high-intensity interval training on self-care and anxiety-like behaviors in naive rats.

Self-care behavior covers individual's health, life and well-being to maintain the necessary activities. The aim of this study is to examine the self-care and possible anxiolytic effects of high-intensity interval exercise (HIIT). Eight-week-old Wistar Albino male rats were divided into Control (n = 8), and Exercise (n = 8). Rat exercised for 38min a day, 5days a week, for 8weeks The animals were then subjected to open field test and splash test, and the behaviors were video recorded. Student t test and Shapiro-Wilk test were used as statistical tests. In the exercise group, spray-induced grooming behavior increased significantly in terms of duration and frequency (p < 0.05), but no significant difference was observed in the latency of grooming (p > 0.05). In the open-field test, the total distance traveled, which is a locomotor activity parameter, did not change between the groups. Anxiolytic-like behaviors such as total rearing behavior, unsupported rearing, central time, and central region entries increased remarkably in the exercise group vs. control (p < 0.0001). Freezing as an anxiogenic behavior decreased in the exercise group positively (p < 0.0001). Intermittent high-intensity exercise improved and increased self-care behaviors. Further, the present study shows that HIIT has beneficial effects on different aspects of behaviors such as exploratory behaviors, increasing anxiolytic behaviors, and reducing anxiogenic behavior. The present study is a preclinical study that will pave the way for new studies.

Subgroups of Persistent Juvenile Offenders: Latent Class Analysis of Repeated Juvenile Assessment Center Entries

ABSTRACT Many juvenile justice agencies rely on risk assessments to inform administrative decisions about youth placement. While many studies within recent years have explored patterns in criminal offending over time, little research has explored the heterogeneity in youth placement decisions by the juvenile justice system. There is a need to document the patterns, levels, and trends in offense risk among youth entering and reentering the justice system. This study used latent class analysis to identify subgroups of n = 388 male juveniles repeatedly entering a U.S. juvenile justice system based on youth placement decisions. The persistent juvenile offenders were best classified into either a moderately increasing risk placement group or a severely increasing risk placement group. The moderately increasing group experienced more bullying involvement, while the severely increasing group was older and experienced more sexual assault, sexual partners, treatment for drug use problems, and elevated depression. Policy recommendations are made.

Anxiolytic-like effect of Suanzaoren–Wuweizi herb-pair and evidence for the involvement of the monoaminergic system in mice based on network pharmacology

BackgroundSuanzaoren-Wuweizi herb-pair (SWHP), composed of Zizyphi Spinosi Semen (Suanzaoren in Chinese) and Schisandrae Chinensis Fructus (Wuweizi in Chinese), is a traditional herbal formula that has been extensively used for the treatment of insomnia. The study aimed to explore the targets and signal pathways of Suanzaoren-Wuweizi (S-W) in the treatment of anxiety by network pharmacology, and to verify the pharmacodynamics and key targets of SWHP in mice.MethodsThe Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) as well as literature mining were used to obtain the main chemical ingredients of Suanzaoren and Wuweizi. The SwissTargetPrediction platform was used to predict drug-related targets. The GeneCards, TTD, DisGeNET and OMIM databases were used to obtain potential targets for the treatment of anxiety with the chemical components of S-W. Drug-disease intersection genes were selected, and a protein-protein interaction (PPI) network was constructed using STRING. The core targets of S-W in the treatment of anxiety were selected according to the topological parameters, and GO functional enrichment as well as KEGG pathways enrichment analyses were performed for potential targets. The relationship network of the “drug-active ingredient-disease-target-pathway” was constructed through Cytoscape 3.8.0. The pharmacodynamics of SWHP in the treatment of anxiety was evaluated by the elevated plus maze (EPM), the light/dark box test (LDB) and the open field test (OFT). The mechanisms were examined by measuring monoamine neurotransmitters in brain of mice.ResultsThe results showed that there were 13 active ingredients for the treatment of anxiety in the network. This includes sanjoinenine, swertisin, daucosterol, schizandrer B, wuweizisu C and gomisin-A. Additionally, there were 148 targets, such as AKT1, TNF, SLC6A4, SLC6A3, EGFR, ESR1, HSP90AA1, CCND1, and DRD2, mainly involved in neuroactive ligand-receptor interactions, the Serotonergic synapse pathway and the cAMP signaling pathway. After 1 week of treatment, SWHP (2 and 3 g/kg) induced a significant increase on the percentage of entries into and time spent on the open arms of the EPM. In the LDB test, SWHP exerted anxiolytic-like effect at 2 g/kg. In the open-field test, SWHP (2 g/kg) increased the number of central entries and time spent in central areas. The levels of brain monoamines (5-HT and DA) and their metabolites (5-HIAA, DOPAC) were decreased after SWHP treatment.ConclusionsThe anti-anxiety effect of SWHP may be mediated by regulating 5-HT, DA and other signaling pathways. These findings demonstrated that SWHP produced an anxiolytic-like effect and the mechanism of action involves the serotonergic and dopaminergic systems, although underlying mechanism remains to be further elucidated.

Neuroprotective Effects of Selegiline Agent Methamphetamine-Prompted Mood-Related Behavior Disorder Mediated Via 5-HT2 and D2 Receptors.

Many previous studies demonstrated that methamphetamine (METH) abuses can cause mood-related behavioral changes. Previous studies indicated neuroprotective effects of Selegiline. Seventy male Wistar rats were randomly divided into eight groups (10 rats in each group). Group 1 and Group 2 received normal saline and methamphetamine (10 mg/kg) for 21 days, respectively. Groups 3, 4, and 5 were treated simultaneously with methamphetamine and Selegiline with doses of 10, 15, and 20 mg/kg for 21 days. Groups 6 and 7 are methamphetamine-dependent groups which received 15 mg/kg of Selegiline with haloperidol (as D2 receptor antagonist) and trazodone (as 5-HT2 receptor antagonist) for 21 days, respectively. In days 23 and 24, elevated plus maze (EPM) and open-field test (OFT) were conducted to assess motor activity and mood (anxiety and depression) levels. METH as 10 mg/kg causes reduction of rearing number, ambulation distances, time spent in central square and also number of central square entries in OFT. Also METH administration causes decreases of time spent in open arm and number of open arm entries and increases of time spent in closed arm and number of closed arm entries in EPM. In contrast, Selegiline (of 10, 15, and 20 mg/kg) inhibited behavioral effects of methamphetamine in both OFT and EPM. Also administration of haloperidol and trazodone inhibited these behavioral protective effects of Selegiline and caused decrease of OFT behaviors (rearing number, ambulation distances, time spent in central square, and also number of central square entries) and also caused decreases of spend times in open arm, number of open arm entries, and also increased closed arm time spending and number of entries in closed arm in EPM. Current research showed that Selegiline via mediation of D2 and 5-HT2 receptors inhibits METH-induced neurobehavioral changes, mood-related behavior, and motor activity disturbances.

On the matrices in B‐spline collocation methods for Riesz fractional equations and their spectral properties

AbstractIn this work, we focus on a fractional differential equation in Riesz form discretized by a polynomial B‐spline collocation method. For an arbitrary polynomial degree , we show that the resulting coefficient matrices possess a Toeplitz‐like structure. We investigate their spectral properties via their symbol and we prove that, like for second order differential problems, the given matrices are ill‐conditioned both in the low and high frequencies for large . More precisely, in the fractional scenario the symbol vanishes at 0 with order , the fractional derivative order that ranges from 1 to 2, and it decays exponentially to zero at for increasing at a rate that becomes faster as approaches 1. This translates into a mitigated conditioning in the low frequencies and into a deterioration in the high frequencies when compared to second order problems. Furthermore, the derivation of the symbol reveals another similarity of our problem with a classical diffusion problem. Since the entries of the coefficient matrices are defined as evaluations of fractional derivatives of the B‐spline basis at the collocation points, we are able to express the central entries of the coefficient matrix as inner products of two fractional derivatives of cardinal B‐splines. Finally, we perform a numerical study of the approximation behavior of polynomial B‐spline collocation. This study suggests that, in line with nonfractional diffusion problems, the approximation order for smooth solutions in the fractional case is for even , and for odd .

Identification of a Novel Functional Non-synonymous Single Nucleotide Polymorphism in Frizzled Class Receptor 6 Gene for Involvement in Depressive Symptoms.

Although numerous susceptibility loci for depression have been identified in recent years, their biological function and molecular mechanism remain largely unknown. By using an exome-wide association study for depressive symptoms assessed by the Center for Epidemiological Studies Depression (CES-D) score, we discovered a novel missense single nucleotide polymorphism (SNP), rs61753730 (Q152E), located in the fourth exon of the frizzled class receptor 6 gene (FZD6), which is a potential causal variant and is significantly associated with the CES-D score. Computer-based in silico analysis revealed that the protein configuration and stability, as well as the secondary structure of FZD6 differed greatly between the wild-type (WT) and Q152E mutant. We further found that rs61753730 significantly affected the luciferase activity and expression of FZD6 in an allele-specific way. Finally, we generated Fzd6-knockin (Fzd6-KI) mice with rs61753730 mutation using the CRISPR/Cas9 genome editing system and found that these mice presented greater immobility in the forced swimming test, less preference for sucrose in the sucrose preference test, as well as decreased center entries, center time, and distance traveled in the open filed test compared with WT mice after exposed to chronic social defeat stress. These results indicate the involvement of rs61753730 in depression. Taken together, our findings demonstrate that SNP rs61753730 is a novel functional variant and plays an important role in depressive symptoms.

The Effect of Atrazine on Fear Behaviors in Rats

Atrazine (ATR) is a widely used herbicide in agriculture. Unfortunately, excessive use of ATR has led to the contamination of food and drinking sources (Mosquin et al., 2012; Whitmore and Chen, 2013). Subsequently, this has led to humans becoming exposed to ATR in their daily life. Animal studies have shown that ATR can influence emotionally relevant behaviors such as anxiety in rodents (Ma et al., 2018; Chavez‐Pichardo et al., 2020). However, other emotional behaviors such as fear remain unexplored. To address this gap, rats were exposed to ATR in their drinking water at a dose considered safe for ingestion (0.035mg/kg; Environmental Protection Agency), whereas control animals received filtered water. Both groups had ad libitum access to water for four months. Following exposure, fear was assessed using Pavlovian fear conditioning where rats learn that a tone predicts a shock by exhibiting freezing behavior to the tone. We hypothesized that rats exposed to ATR would show increased fear expression compared to control rats. Anxiety‐like behavior was also examined using the open field test. During fear conditioning no differences were observed in freezing behavior between groups (ATR: 58%, Controls: 59%; n=10; p=0.3714). In the open field test, ATR rats trended towards having more center entries (ATR: 23.8, Controls: 14.8; n=10, p=0.0570) and decreased time spent in corners (ATR: 70.5 s, Controls: 114.2 s; n=10, p=0.0248) compared to controls. These results suggest that ATR does not affect fear behaviors, but it can decrease anxiety‐like behaviors. Future directions aim at examining brain regions key to emotional behaviors, such as the amygdala, using immunohistochemistry. Our findings may help elucidate how prolonged ingestion of atrazine at a dose considered safe for humans may influence emotionally relevant behaviors.

Role of locus coeruleus expressing angiotensin type 1 receptors (AT1R) neurons in fear learning and stress‐induced anxiety

BackgroundThe renin‐angiotensin system (RAS) has been implicated in stress‐related disorders, however the central mechanisms responsible for this remains unknown. The locus coeruleus (LC), a major noradrenergic nucleus of the brain, plays a critical role in modulating anxiety‐like behaviors. The LC has also been previously shown to express angiotensinogen (AGT), the pre‐cursor for angiotensin, as well as strong expression of angiotensin II receptors, but its role in stress‐related disorders has not been examined. Using angiotensin II type 1 receptor (AT1R)‐eGFP and Cre mice combined with neuroanatomical and behavioral approaches, we examined the role of LC expressing AT1R in fear‐ and anxiety‐related behavior.MethodsRNAscope® in situ hybridization assay was used to analyze cellular mRNA expression of AGT in the LC while in vivo chemogenetics combined with behavioral testing in AT1R‐Cre mice mouse was used to examine the role of LC‐AT1R cells in fear memory and stress‐induced anxiety. Further, dual immunohistochemistry plus retrograde tract tracing was used to characterize LC AT1R‐eGFP+ cells and limbic circuit connections.ResultsAGT mRNA and AT1R‐eGFP+ immunoactivity was found localized to the LC. The majority of AT1R‐eGFP+neurons (94%) in LC were co‐localized with tyrosine hydroxylase, a marker for norepinephrine‐containing neurons. Retrograde labeling revealed that some of these AT1R‐eGFP+ neurons send projections to the basolateral amygdala (BLA), an important brain structure for modulating stress induced fear related anxiety responses. Next, the AT1R+ neurons in LC were silenced using Cre‐dependent inhibitory designer receptor exclusively activated by designer drug (hM4Di DREADD) expression followed by Clozapine‐n‐oxide (CNO) administration. Silencing the LC AT1R‐expressing neurons prior to fear extinction training impaired the extinction of learned fear as shown by increased percent freezing during the training (time × drug interaction, F (7, 70) = 3.219, p&lt;0.01, n=6) (Fig 1). Furthermore, restraint stress‐induced anxiety behavior was attenuated by LC AT1R+ neuron inhibition, as shown by increased center entries (22.7 ± 7.3 Saline v.s. 50.5 ± 8.8 CNO, p&lt;0.05, n=6) and % time in center (2.97 ± 1.14 Saline v.s. 8.6 ± 1.4 CNO, p&lt;0.05, n=6) in the open field test, and increased open arm entries (5 ± 1.3 Saline v.s. 12 ± 1.1 CNO, p&lt;0.05, n=6) in the elevated plus maze test (Fig. 2).ConclusionThese findings provide evidence for a novel angiotensinergic LC cell type and position the LC AT1R as a potential mediator of noradrenergic regulation in learned fear and stress‐induced anxiety. Future studies are needed to fully characterize the underlying neurocircuits and neuropeptide modulators that likely interact with the LC AT1R expressing neurons during stress‐related behaviors.

Glutamate released by Cajal-Retzius cells impacts specific hippocampal circuits and behaviors.

SUMMARYThe impact of Cajal-Retzius cells on the regulation of hippocampal circuits and related behaviors is unresolved. Here, we directly address this issue by impairing the glutamatergic output of Cajal-Retzius cells with the conditional ablation of vGluT2, which is their main vesicular glutamate transporter. Although two distinct conditional knockout lines do not reveal major alterations in hippocampal-layer organization and dendritic length of principal neurons or GABAergic cells, we find parallel deficits in specific hippocampal-dependent behaviors and in their putative underlying microcircuits. First, conditional knockout animals show increased innate anxiety and decreased feedforward GABAergic inhibition on dentate gyrus granule cells. Second, we observe impaired spatial memory processing, which is associated with decreased spine density and reduced AMPA/NMDA ratio of postsynaptic responses at the perforant- and entorhino-hippocampal pathways. We conclude that glutamate synaptically released by Cajal-Retzius cells is critical for the regulation of hippocampal microcircuits and specific types of behaviors.

The role of amygdala neuropsin/serpinb6 pathway in the regulation of gastric hypersensitivity and anxiety by electroacupuncture.

To investigate whether the neuropsin pathway in the amygdala and stomach may participate in the development of anxiety-related gastric hypersensitivity, and whether electroacupuncture (EA) at the Zusanli acupoint could improve this condition by regulating such pathway in the rat model of functional dyspepsia (FD). A total of 48 SD rats were randomly divided into the control group, FD model group and FD + EA group (stimulation at Zusanli acupoint for 30 min daily for 7 consecutive days). Abdominal withdrawal reflex (AWR) score and open field test were used to evaluate visceral hypersensitivity and anxiety-like disorder, respectively. Electrical activity in the amygdala nucleus in each group was recorded by extracellular electrophysiology. Neuropsin and serpinb6 protein expressions in the amygdala and stomach were detected by Western blot. AWR score in the FD group increased but did not differ after EA therapy than that in the contro group. Both the center square entries and center entries ratio in the FD group were lower than those in the control and FD + EA groups. The total number and frequency of amygdala nucleus discharges induced by gastric distension in the FD group were significantly higher than those in the control and FD + EA groups. Expression of neuropsin increased and that of serpinb6 decreased in the gastric mucosa and amygdale in the FD group, while no change was observed in gastric mucosa after EA therapy. EA stimulation at the Zusanli acupoint may improve visceral hypersensitivity and anxiety in FD rats through the neuropsin/serpinb6 pathway.

Anti-depressant Activity of Hydroalcoholic Extract of Asperula odorata L. in Mice

Background: The relationship between the treatment of depression and plant-derived substances (e.g., flavonoids, coumarin, and scopoletin) has been demonstrated through interference with the monoamine system. The present study was planned to evaluate the anti-depressant effects of Asperula odorata L. plant through behavioral tests in mice. Material and Methods: In this experimental study, 35 male Syrian mice weighing 30-40 g were examined in five groups (n=7) as follow: received oral distilled water gavage (control), 10 mg/kg of fluoxetine solution gavage (reference standard), 10, 5, and 2.5 mg/kg of A. odorata L. extract gavage (treatment groups). After one week, all behavioral tests, including tail suspension test (TST), forced swimming test (FST), open field test (OFT), elevated plus maze test (EPMT), and fractionation tests were performed each morning for 4-6 h within five days. Results: The hydroalcoholic extract of A. odorata contained phenolic and flavonoid substances (Shinoda test confirmed flavonoid family). Administration of extract (10 and 5 mg/kg doses) versus fluoxetine (10 mg/kg dose) reduced the immobility of animals in both FST and TST (P&lt;0.05). At the OFT, the administered extract increased the number of central square entries of animals with higher mobility (P&lt;0.05). At a 10 mg/kg dose, the active flavonoid ingredients increased the mice's incline to entre and spent more time within no wall parts of EPMT (P&lt;0.05). Conclusion: Our study suggests that the hydroalcoholic extract of A. odorata L. could have significant anti-depressant activity. [GMJ.2021;10:e2206]

Beta‐adrenergic‐related cardiac interoception in Pavlovian fear conditioning

Background Memory formation is enhanced by stress and b-Adrenergic signaling is largely involved in consolidation and reconsolidation processes. Current FDA-approved drugs for the treatment of post-traumatic stress disorder (PTSD) are limited in number and in efficacy. Pharmacological agents that modulate b-Adrenergic activity, such as propranolol, have shown some potential clinical utility in treating PTSD. However, the specific mechanisms of b-Adrenergic activity on fear memory and cardiac interoception are unknown. In the current study we investigated the effects of the beta-agonist isoproterenol (ISO) on short- and long-term memory in mice. We hypothesized that acute ISO would enhance short- and long-term memory and increase behavioral displays of anxiety. Methods Male C57Bl/6J mice completed a Pavlovian auditory fear conditioning protocol assessing fear expression. We evaluated the effect of two doses of acute peripherally administered (i.p) isoproterenol (0.1 mg/kg, 0.01 mg/kg) versus saline (i.p) on freezing behavior during fear conditioning. In fear expression studies, mice were conditioned with 5 auditory tones (CS's) each paired with a foot shock (UCS). Twenty-four hours later, mice received injections 20 minutes prior to a fear expression test involving presentation of 4 CS's. Long-term memory was assessed 24 hours later with another 4-CS presentation. Open field testing and elevated plus maze (EPM) were also used to assess the effects of .1 mg/kg ISO on generalized measures of anxiety. Results In fear expression studies, 0.1 mg/kg ISO mice showed significantly greater freezing (M=71.9%, SD=30.5) to 4-CS presentation compared to saline mice (M=58.1%, SD=32.5), F(1,6)=11.81, p=.01. We found no significant effects of .01 mg/kg on fear expression. In open field studies, ISO mice displayed significantly less locomotion compared to saline, as shown across multiple parameters including total center entries and distance travelled in center. An unpaired t-test showed that ISO mice made significantly less center entries in a 30-minute test (M=27.2, SD=10.94) than saline mice (M=48.3, SD=11.47), t(6)=3.90, p=.001. For EPM testing, ISO injected mice displayed increased percentage of time in closed arms versus open arms (M=85.9% time, SD= 10.03) compared to saline mice (M=67.1 % time, SD=16.32), t(10)=2.41, p=.04. Conclusion: Overall, these results suggest that acute peripheral administration of isoproterenol enhances short-term expression of fear responses independent of long-term responses in mice. Together, these studies help elucidate physiological mechanisms underlying fear learning, namely, receptor-mediated b-adrenergic responses, cardioceptive influences on fear expression, and afferent feedback as part of an internal context cue in fear memory.

Sex differences in the elevated plus-maze test and large open field test in adult Wistar rats

There is a growing need for a better understanding of sex differences in animal models of psychiatric disorders. The elevated plus-maze (EPM) test and large open field (LOF) test are widely used to study anxiety-like behavior in rodents. Our studies explored sex differences in anxiety and activity parameters in the LOF and EPM and determined whether these parameters correlate within and between tests. Drug naïve adult male and female Wistar rats (n = 47/sex) were used for the studies, and the rats were tested for 5 min in the EPM and 10 min in the LOF. The females spent more time on the open arms of the EPM and made more open arms entries than the males. The females also spent more time in the center zone of the LOF and made more center zone entries. The females traveled a greater distance in the LOF and EPM. There was a moderate positive correlation between time on the open arms of the EPM and time in the center zone of the LOF. There was also a moderate positive correlation between open arms entries in the EPM and center zone entries in the LOF. A hierarchical cluster analysis revealed one cluster with LOF parameters, one cluster with EPM parameters, and one cluster with parameters related to the avoidance of open spaces. In conclusion, these findings indicate that female rats display less anxiety-like behavior in the EPM and LOF. Furthermore, there are sex differences for almost all behavioral parameters in these anxiety tests.

The Volatile Oil of Zanthoxylum bungeanum Pericarp Improved the Hypothalamic-Pituitary-Adrenal Axis and Gut Microbiota to Attenuate Chronic Unpredictable Stress-Induced Anxiety Behavior in Rats.

BackgroundAnxiety disorders (ADs) are the most prevalent mental disorders worldwide. Stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis and dysbiosis of gut microbiota seem to contribute to the onset of ADs. This study was designed to investigate the ameliorative effect of volatile oil of Zanthoxylum bungeanum (VOZB) on chronic unpredictable stress (CUS) induced anxiety behavior, as well as the altered HPA axis and gut microbiota.MethodsExperimental rats were exposed to the CUS for 14 consecutive days. Meanwhile, VOZB was administered at doses of 50, 100 and 200 mg/kg/day for 14 days. The anxiety behavior was evaluated by elevated plus-maze (EPM) and open field (OF). The protein expressions and mRNA levels of corticotropin-releasing hormone (CRH) and glucocorticoid receptor (GR) in hypothalamus was determined, as well the hormone levels of HPA axis in serum. Furthermore, gut microbiota was detected by16S rRNA gene sequencing. The chemical constituents of VOZB were identified by GC-MS analysis.ResultsVOZB treatment (100 and 200 mg/kg/day) increased the ratio of open-arm entries and time in EPM test, as well as the central zone entries and time in OF test. Moreover, VOZB treatment reduced the protein expressions and mRNA levels of CRH, but elevated those of GR in hypothalamus. Similarly, the hormone levels of the HPA axis in serum were decreased by VOZB treatment. Besides, VOZB treatment restored the CUS-induced dysbiosis of gut microbiota, raising the Sobs and Chao indexes, inhibiting Lachnospiraceae, but facilitating Bacteroidales_S24-7_group, Lactobacillaceae, and Prevotellaceae. Additionally, Sobs and Chao indexes were negatively correlated to the serum corticosterone and CRH levels.ConclusionVOZB showed an ameliorative effect on CUS-induced anxiety behavior, potentially via inhibiting activation of the HPA axis and restoring the dysbiosis of gut microbiota, thus improving the stress-induced abnormality of the microbiota-gut-brain axis.

High-caloric or isocaloric maternal high-fat diets differently affect young-adult offspring behavior in anxiety-related tests and offspring sensitivity to acute fluoxetine

Objectiveto evaluate the influence of two maternal high-fat diets with different caloric contents on anxiety-like behavior in young-adult offspring and their sensitivity to acute fluoxetine. Methodsfemales Wistar rats were used and divided according to diet received during gestation and lactation: Control (CTR), high-fat/isocaloric (HI) and high-fat/high-caloric (HH). Offspring were subsequently divided into three subgroups according to acute administration of vehicle or fluoxetine (1 or 10 mg/kg). To assess animals’ anxiety-like behaviors, three tests were used: open field (OF), elevated plus-maze (EPM) and free-exploratory paradigm (FEP). ResultsIn OF, HI and HH showed increased hyperactivity- and anxiety-related behaviors, HI being more hyperactive than HH. In response to fluoxetine, HI offspring decreased number of quadrants entered, decreased number of central entries and spent less time in rearing in peripheral areas, while HH offspring showed less time spent in rearing in the OF peripheral area. In EPM test, HI pups spent more time in closed arms than the HH pups. Fluoxetine decreased number of open arms entries for HI offspring and increased percentage of time spent in central area for HH animals. Maternal diet did not influence FEP test, neither HI nor HH presented a response after fluoxetine acute administration. ConclusionMaternal high-fat diets influence offspring anxiety-like behavior in state-anxiety tests but not in trait-anxiety test. Responsiveness to acute fluoxetine depended on maternal diet, dose and which behavioral tests were being evaluated.

Neuromodulatory effect of cinnamon oil on behavioural disturbance, CYP1A1, iNOStranscripts and neurochemical alterations induced by deltamethrin in rat brain

The objective of this study was to investigate the influence of deltamethrin (DLM)on brain function and to find whether DLM-induced neurotoxicity is prevented by the treatment with cinnamon oil. Four groups of ten Wistar albino male rats each were used. Group I (control) received saline only. Group II received cinnamon oil alone at 0.5 mg/kg B.W. intraperitonally, whereas Group III received orally DLM alone at 6 mg/kg B.W. Groups IV was treated with cinnamon oil plus DLM for 21 days to induce neurotoxicity. Rat behaviour, brain acetylcholine esterase (AChE), serotonin, oxidative stress profile were assessed. Serum sampling for the assessment of corticosterone concentration was also carried out. Finally, we demonstrate the gene expression of CYP1A1 and iNOS and the histological picture of the brain. Considering the behaviour assessment, DLM administration alone caused neurobehavioral deficits manifested by anxiety-like behavior which represented ina marked decrease in the sleeping frequency and duration, and marked increase the digging frequency and a wake non-active behavior duration. Moreover, the open field result showed a significant decrease in central square entries and duration. The neurochemical analysis revealed that DLM significantly suppressed AChE activity and elevated serotonin and corticosterone concentrations. Furthermore, results revealed thatthe brain reduced glutathione (GSH) content, superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentration were significantly altered in DLM treated rats. Neurochemical disturbances were confirmed by histopathological changes in the brain. Furthermore, DLM up-regulates the mRNA expression of brain CYP1A1 and iNOS. Co-treatment with cinnamon oil exhibited significant improvement in behavioural performance and the brain antioxidant capacities with an increase in AChE activity and diminished the concentration of serotonin, serum corticosterone and MDA. Cinnamon oil treatment resulted in down-regulation of CYP1A1 and iNOS and improve the histologically picture. In conclusion, cinnamon oil ameliorated DLM-induced neurotoxicity through preventing oxidative stress-induced genotoxicity and apoptosis of brain in rats.

Behavioral and Neurochemical Effects of Extra Virgin Olive Oil Total Phenolic Content and Sideritis Extract in Female Mice

The aim of this study was to determine the cognitive and behavioral effects of extra virgin olive oil total phenolic content (TPC) and Sideritis (SID) extracts in female mice, and identify the associated neurochemical changes in the hippocampus and the prefrontal cortex. All animals received intraperitoneal low or high doses of TPC, SID or vehicle treatment for 7 days and were subjected to the Open Field (OF), Novel Object Recognition (NOR) and Tail Suspension Test (TST). The prefrontal cortex and hippocampus were dissected for analysis of neurotransmitters and aminoacids with high performance liquid chromatography with electrochemical detection (HPLC-ED). Both TPC doses enhanced vertical activity and center entries in the OF, which could indicate an anxiolytic-like effect. In addition, TPC enhanced non-spatial working memory and, in high doses, exerted antidepressant effects. On the other hand, high SID doses remarkably decreased the animals’ overall activity. Locomotor and exploratory activities were closely associated with cortical increases in serotonin turnover induced by both treatments. Cognitive performance was linked to glutamate level changes. Furthermore, TPC reduced cortical taurine levels, while SID reduced cortical aspartate levels. TPC seems to have promising cognitive, anxiolytic and antidepressant effects, whereas SID has sedative effects in high doses. Both extracts act in the brain, but their specific actions and properties merit further exploration.

Does chronic systemic injection of the DREADD agonists clozapine-N-oxide or Compound 21 change behavior relevant to locomotion, exploration, anxiety, and depression in male non-DREADD-expressing mice?

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are chemogenetic tools commonly-used to manipulate brain activity. The most widely-used synthetic DREADD ligand, clozapine-N-oxide (CNO), is back-metabolized to clozapine which can itself activate endogenous receptors. Studies in non-DREADD-expressing rodents suggest CNO or a DREADD agonist that lacks active metabolites, such as Compound 21 (C21), change rodent behavior (e.g. decrease locomotion), but chronic injection of CNO does not change locomotion. However, it is unknown if chronic CNO changes behaviors relevant to locomotion, exploration, anxiety, and depression, or if chronic C21 changes any aspect of mouse behavior. Here non-DREADD-expressing mice received i.p. Vehicle (Veh), CNO, or C21 (1 mg/kg) 5 days/week for 16 weeks and behaviors were assessed over time. Veh, CNO, and C21 mice had similar weight gain over the 16-week-experiment. During the 3rd injection week, CNO and C21 mice explored more than Veh mice in a novel context and had more open field center entries; however, groups were similar in other measures of locomotion and anxiety. During the 14th-16th injection weeks, Veh, CNO, and C21 mice had similar locomotion and anxiety-like behaviors. We interpret these data as showing chronic Veh, CNO, and C21 injections given to male non-DREADD-expressing mice largely lack behavioral effects. These data may be helpful for behavioral neuroscientists when study design requires repeated injection of these DREADD agonists.

Long-term Exercise Training Prevents Anxious-depressive-like Behavior In Transgenic Alzheimer Rats

PURPOSE: This study examined the effects of long-term treadmill exercise training on the anxious-depressive-like behavioral phenotype of transgenic Alzheimer rats in the early stage of Alzheimer's disease (AD) development and provided evidence that exercise alleviated fear-avoidance behavior deficits. METHODS: 2-month-old Male TgF344-AD and wild-type (WT) rats were separated into WT (n = 9), AD (n = 8), and AD + treadmill exercise (Exe) groups (n = 12). Following 8 months of exercise, the passive avoidance test, Barnes maze task, novel object recognition test, and object location test were used to measure learning and memory function. The open field test, elevated plus maze, sucrose preference test, and forced swim test were conducted to measure anxious-depressive-like behavior of AD rats. Immunofluorescence staining, Western blot analysis, enzyme-linked immunosorbent assay (ELISA) analysis, and related assay kits were used to measure levels of inflammatory cytokines, oxidative stress, amyloid-beta production, and tau hyperphosphorylation. RESULTS: Behavioral tests indicated that AD rats aged 12-months did not exhibit spatial learning and memory deficits, but did display anxious-depressive-like behaviors (open field, Center time: P = 0.008; Center entries: P = 0.009; Line crossings: P = 0.001). Long-term exercise significantly prevented anxious-depressive-like behaviors in AD rats (Center time: P = 0.016; Center entries: P = 0.004; Line crossings: P = 0.033). In addition, AD animals displayed enhanced Aβ deposition (P < 0.001), Tau hyperphosphorylation (P < 0.001), microglial activation (P <0.001), inflammatory cytokine release (P < 0.05), and oxidative damage (P < 0.05) that was attenuated significantly after long-term exercise training ( P < 0.05). CONCLUSIONS: Long-term exercise training ameliorated anxious-depressive-like behaviors and improved fear-avoidance behavior in transgenic AD rats, supporting exercise training as an effective strategy to prevent or reduce anxiety, depression and fear-avoidance behavior deficits in the early stages of AD pathogenesis.