The nucleus accumbens (NAc), ventromedial prefrontal cortex (vmPFC), and cingulate gyrus (Cg) are key regions in the control of mood-related behaviors. Electrical stimulation of these areas induces antidepressant-like effects in both patients and animal models. Another structure whose limbic connections are receiving more interest in the context of mood-related behaviors is the medial part of the subthalamic nucleus (STN). Here, we tested the hypothesis that the mood-related effects of NAc, vmPFC, and Cg are accompanied by changes in the neural activity of the STN. We performed high-frequency stimulation (HFS) of the NAc, vmPFC, and Cg. Animals were behaviorally tested for hedonia and forced swim immobility; and the cellular activities in the different parts of the STN were assessed by means of c-Fos immunoreactivity (c-Fos-ir). Our results showed that HFS of the NAc and vmPFC, but not Cg reduced anhedonic-like and forced swim immobility behaviors. Interestingly, there was a significant increase of c-Fos-ir in the medial STN with HFS of the vmPFC, but not the NAc and Cg as compared to the sham. Correlation analysis showed that the medial STN is associated with the antidepressant-like behaviors in vmPFC HFS animals. No behavioral correlation was found with respect to behavioral outcome and activity in the lateral STN. In conclusion, HFS of the vmPFC induced profound antidepressant-like effects with enhanced neural activity in the medial part of the STN.
Cerebral ischemia is one of the leading causes of death and long-term disability in aging populations, due to the frequent occurrence of irreversible brain damage and subsequent loss of neuronal function which lead to cognitive impairment and some motor dysfunction. In the present study, the real time course of motor and cognitive functions were evaluated following the chronic cerebral ischemia induced by permanent, bilateral occlusion of the common carotid arteries (PBOCCA). Male Sprague Dawley rats (200-300g) were subjected to PBOCCA or sham-operated surgery and tested 1, 2, 3 and 4 weeks following the ischemic insult. The results showed that PBOCCA significantly reduced step-through latency in a passive avoidance task at all time points when compared to the sham-operated group. PBOCCA rats also showed significant increase in escape latencies during training in the Morris water maze, as well as a reduction of the percentage of times spend in target quadrant of the maze at all time points following the occlusion. Importantly, there were no significant changes in locomotor activity between PBOCCA and sham-operated groups. The BDNF expression in the hippocampus was 29.3±3.1% and 40.1±2.6% on day 14 and 28 post PBOCCA, respectively compared to sham-operated group. Present data suggest that the PBOCCA procedure effectively induces behavioral, cognitive symptoms associated with cerebral ischemia and, consequently, provides a valuable model to study ischemia and related neurodegenerative disorder such as Alzheimer's disease and vascular dementia.
Serotonergic (5-HT) drugs are widely used in the clinical management of mood and anxiety disorders. However, it is reported that acute 5-HT treatment elicits anxiogenic-like behavior. Interestingly, the periaqueductal gray (PAG), a midbrain structure which regulates anxiety behavior - has robust 5-HT fibers and reciprocal connections with the hypothalamic-pituitary-adrenal (HPA) axis. Although the HPA axis and the 5-HT system are well investigated, the relationship between the stress hormones induced by 5-HT drug treatment and the PAG neural correlates of the behavior remain largely unknown. In this study, the effects of acute and chronic treatments with buspirone (BUSP) and escitalopram (ESCIT) on anxiety-related behaviors were tested in an open-field (OF). The treatment effects on PAG c-Fos immunoreactivity (c-Fos-ir) and corticosterone (CORT) concentration were measured in order to determine the neural-endocrine correlates of anxiety-related behaviors and drug treatments. Our results demonstrate that acute BUSP and ESCIT treatments induced anxiogenic behaviors with elevation of CORT compared to the baseline. A decrease of c-Fos-ir was found in the dorsomedial PAG region of both the treatment groups. Correlation analysis showed that the CORT were not associated with the OF anxiogenic behavior and PAG c-Fos-ir. No significant differences were found in behaviors and CORT after chronic treatment. In conclusion, acute BUSP and ESCIT treatments elicited anxiogenic response with activation of the HPA axis and reduction of c-Fos-ir in the dorsomedial PAG. Although no correlation was found between the stress hormone and the PAG c-Fos-ir, this does not imply the lack of cause-and-effect relationship between neuroendocrine effects and PAG function in anxiety responses. These correlation studies suggest that the regulation of 5-HT system was probably disrupted by acute 5-HT treatment.
Postpartum depression (PPD) is a psychiatric disorder that occurs in 10-15% of childbearing women. It is hypothesized that omega-3 fatty acids, which are components of fish oil, may attenuate depression symptoms. In order to examine this hypothesis, the animal model of postpartum depression was established in the present study. Ovariectomized female rats underwent hormone-simulated pregnancy (HSP) regimen and received progesterone and estradiol benzoate or vehicle for 23 days, mimicking the actual rat's pregnancy. The days after hormone termination were considered as the postpartum period. Forced feeding of menhaden fish oil, as a source of omega-3, with three doses of 1, 3, and 9g/kg/d, fluoxetine 15mg/kg/d, and distilled water 2ml/d per rat started in five postpartum-induced and one vehicle group on postpartum day 1 and continued for 15 consecutive days. On postpartum day 15, all groups were tested in the forced swimming test (FST) and open field test (OFT), followed by a biochemical assay. Results showed that the postpartum-induced rats not treated with menhaden fish oil, exhibited an increase in immobility time seen in FST, hippocampal concentration of corticosterone and plasmatic level of corticosterone, and pro-inflammatory cytokines. These depression-related effects were attenuated by supplementation of menhaden fish oil with doses of 3 and 9g/kg. Moreover, results of rats supplemented with menhaden fish oil were comparable to rats treated with the clinically effective antidepressant, fluoxetine. Taken together, these results suggest that menhaden fish oil, rich in omega-3, exerts beneficial effect on postpartum depression and decreases the biomarkers related to depression such as corticosterone and pro-inflammatory cytokines.
Alzheimer's disease (AD) as a neurodegenerative brain disorder is the most common cause of dementia. To date, there is no causative treatment for AD and there are few preventive treatments either. The sphingosine-1-phosphate receptor modulator FTY720 (fingolimod) prevents lymphocytes from contributing to an autoimmune reaction and has been approved for multiple sclerosis treatment. In concert with other studies showing the anti-inflammatory and protective effect of FTY720 in some neurodegenerative disorders like ischemia, we have recently shown that FTY720 chronic administration prevents from impairment of spatial learning and memory in AD rats. Here FTY720 was examined on AD rats in comparison to the only clinically approved NMDA receptor antagonist, Memantine. Passive avoidance task showed significant memory restoration in AD animals received FTY720 comparable to Memantine. Upon gene profiling by QuantiGene Plex, this behavioral outcomes was concurrent with considerable alterations in some genes transcripts like that of mitogen activated protein kinases (MAPKs) and some inflammatory markers that may particularly account for the detected decline in hippocampal neural damage or memory impairment associated with AD. From a therapeutic standpoint, our findings conclude that FTY720 may suggest new opportunities for AD management probably based on several modulatory effects on genes involved in cell death or survival.
Successful emotional communication is crucial for social interactions and social relationships. Parkinson's Disease (PD) patients have shown deficits in emotional recognition abilities although the research findings are inconclusive. This paper presents an investigation of six emotions (happiness, sadness, fear, anger, surprise, and disgust) of twenty non-demented (Mini-Mental State Examination score >24) PD patients and twenty Healthy Controls (HCs) using Electroencephalogram (EEG)-based Brain Functional Connectivity (BFC) patterns. The functional connectivity index feature in EEG signals is computed using three different methods: Correlation (COR), Coherence (COH), and Phase Synchronization Index (PSI). Further, a new functional connectivity index feature is proposed using bispectral analysis. The experimental results indicate that the BFC change is significantly different among emotional states of PD patients compared with HC. Also, the emotional connectivity pattern classified using Support Vector Machine (SVM) classifier yielded the highest accuracy for the new bispectral functional connectivity index. The PD patients showed emotional impairments as demonstrated by a poor classification performance. This finding suggests that decrease in the functional connectivity indices during emotional stimulation in PD, indicating functional disconnections between cortical areas.
The present study aimed to investigate the behavior and neuronal morphological changes in the perihaemorrhagic tissue of the mouse intracerebellar haemorrhage experimental model. Adult male Swiss albino mice were stereotactically infused with collagenase type VII (0.4U/μl of saline) unilaterally in to the cerebellum, following anaesthesia. Motor deficits were assessed using open field and composite score for evaluating the mouse model of cerebellar ataxia at 1, 3, 7, 14 and 21 days after collagenase infusion. The animals were sacrificed at the same time interval for evaluation of perihaematomal neuronal degeneration using haematoxylin and eosin staining and Annexin V-FITC/Propidium iodide assay. At the end of the study, it was found that infusion of 0.4U collagenase produces significant locomotor and ataxic deficit in the mice especially within the first week post surgery, and that this gradually improved within three weeks. Neuronal degeneration evident by cytoplasmic shrinkage and nuclear pyknosis was observed at the perihaematomal area after one day; especially at 3 and 7 days post haemorrhage. By 21 days, both the haematoma and degenerating neurons in the perihaematomal area were phagocytosed and the remaining neuronal cells around the scar tissue appeared normal. Moreover, Annexin-V/propidium iodide-positive cells were observed at the perihaematomal area at 3 and 7 days implying that the neurons likely die via apoptosis. It was concluded that a population of potentially salvageable neurons exist in the perihaematomal area after cerebellar haemorrhage throughout a wide time window that could be amenable to treatment.
A unique feature of the space radiation environment is the presence of high-energy charged particles, including (56)Fe ions, which can present a significant hazard to space flight crews during and following a mission. (56)Fe irradiation-induced cognitive changes often involve alterations in hippocampal function. These alterations might involve changes in spine morphology and density. In addition to irradiation, performing a cognitive task can also affect spine morphology. Therefore, it is often hard to determine whether changes in spine morphology and density are due to an environmental challenge or group differences in performance on cognitive tests. In this study, we tested the hypothesis that the ability of exploratory behavior to increase specific measures of hippocampal spine morphology and density is affected by (56)Fe irradiation. In sham-irradiated mice, exploratory behavior increased basal spine density in the CA1 region of the hippocampus and the enclosed blade of the dentate gyrus. These effects were not seen in irradiated mice. In addition, following exploratory behavior, there was a trend toward a decrease in the percent stubby spines on apical dendrites in the CA3 region of the hippocampus in (56)Fe-irradiated, but not sham-irradiated, mice. Other hippocampal regions and spine measures affected by (56)Fe irradiation showed comparable radiation effects in behaviorally naïve and cognitively tested mice. Thus, the ability of exploratory behavior to alter spine density and morphology in specific hippocampal regions is affected by (56)Fe irradiation.
Deep brain stimulation (DBS) has gained interest as a potential therapy for advanced treatment-resistant dementia. However, possible targets for DBS and the optimal stimulation parameters are not yet clear. Here, we compared the effects of DBS of the CA1 sub-region of the hippocampus, mammillothalamic tract, anterior thalamic nucleus, and entorhinal cortex in an experimental rat model of dementia. Rats with scopolamine-induced amnesia were assessed in the object location task with different DBS parameters. Moreover, anxiety-related side effects were evaluated in the elevated zero maze and open field. After sacrifice, we applied c-Fos immunohistochemistry to assess which memory-related regions were affected by DBS. When comparing all structures, DBS of the entorhinal cortex and CA1 sub-region was able to restore memory loss when a specific set of stimulation parameters was used. No anxiety-related side effects were found following DBS. The beneficial behavioral performance of CA1 DBS rats was accompanied with an activation of cells in the anterior cingulate gyrus. Therefore, we conclude that acute CA1 DBS restores memory loss possibly through improved attentional and cognitive processes in the limbic cortex.
Boosting accuracy in automatically discriminating patients with Alzheimer's disease (AD) and normal controls (NC), based on multidimensional classification of longitudinal whole brain atrophy rates and their intermediate counterparts in analyzing magnetic resonance images (MRI).
Measures of anxiety in behavioural tests remain largely unclear even decades after their establishment. Differences in the severity of anxiety measured by anxiety tests is an important issue that must be addressed. To test the hypothesis that the addition of light as an aversive stimulus will elicit a difference in behaviour between aged and young animals, we compared the responses of aged and young animals in the home cage emergence test (HCET) and elevated plus maze (EPM), in high aversive bright light and low aversive dim light conditions. In the HCET, our results demonstrated that young animals escaped with shorter latency and greater frequency than aged animals in both bright and dim light conditions, indicating that young animals display greater exploratory tendencies than aged animals. In the EPM, bright light conditions induced anxiogenic effects in both age groups. Interestingly, two-way ANOVA showed a significant interaction effect of age and light on the number of entries into the open arms of the EPM as well as frequency of escape in the HCET. These results show that the addition of light as an aversive stimulus in the EPM and HCET produced different responses in aged versus young animals in each test. In conclusion, significant interactions between age and light affected aged and young animals differently in the HCET and EPM, indicating that the two tests measure different aspects of anxiety.
Chronic cerebral hypoperfusion (CCH) been well characterized as a common pathological status contributing to neurodegenerative diseases such as Alzheimer's disease and vascular dementia. CCH is an important factor that leads to cognitive impairment, but the underlying neurobiological mechanism is poorly understood and no effective treatment is available. Recently, transient receptor potential melastatin 4 (TRPM4) cation channel has been identified as an important molecular element in focal cerebral ischemia. Over activation of the channel is a major molecular mechanism of oncotic cell death. However, the role of TRPM4 in CCH that propagates global brain hypoxia have not been explored. Therefore, the present study is designed to investigate the effect of TRPM4 inhibition on the cognitive functions of the rats following CCH via permanent bilateral occlusion of common carotid arteries (PBOCCA) model. In this model, treatment with siRNA suppressed TRPM4 expression at both the mRNA and protein levels and improved cognitive deficits of the CCH rats without affecting their motor function. Furthermore, treatment with siRNA rescued the LTP impairment in CCH-induced rats. Consistent with the restored of LTP, western blot analysis revealed that siRNA treatment prevented the reduction of synaptic proteins, including calcium/calmodulin-dependent kinase II alpha (CaMKIIα) and brain-derived neurotrophic factor (BDNF) in brain regions of CCH rats. The present findings provide a novel role of TRPM4 in restricting cognitive functions in CCH and suggest inhibiting TRPM4 may represent a promising therapeutic strategy in targeting ion channels to prevent the progression of cognitive deficits induced by ischemia.
Kratom is a medicinal plant that exhibits promising results as an opiate substitute. However, there is little information regarding the abuse profile of its main psychoactive constituent, mitragynine (MG), particularly in relapse to drug abuse. Using the place conditioning procedure as a model of relapse, this study aims to evaluate the ability of MG to induce conditioned place preference (CPP) reinstatement in rats. To evaluate the cross-reinstatement effects, MG and morphine were injected to rats that previously extinguished a morphine- or MG-induced CPP. Following a CPP acquisition induced by either MG (10 and 30 mg/kg, i.p.) or morphine (10 mg/kg, i.p.), rats were subjected to repeated CPP extinction sessions. A low dose priming injection of MG or morphine produced a reinstatement of the previously extinguished CPP. In the second experiment of this study, a priming injection of morphine (1, 3 and 10 mg/kg, i.p.) dose-dependently reinstated an MG-induced CPP. Likewise, a priming injection of MG (3, 10 and 30 mg/kg, i.p.) was able to dose-dependently reinstate a morphine-induced CPP. The present study demonstrates a cross-reinstatement effect between MG and morphine, thereby suggesting a similar interaction in their rewarding motivational properties. The findings from this study also suggesting that a priming exposure to kratom and an opioid may cause relapse for a previously abused drug.
This review aims to establish the cognitive processing of patients with attention-deficit hyperactive disorder (ADHD) across age. Functional magnetic resonance imaging (fMRI) studies on children and adult populations were conducted, thus delineating deficits that could have been maintained and ameliorated across age. This allowed for the examination of the correlation between patterns of brain activation and the corresponding development of functional heterogeneity in ADHD. A systematic literature search of fMRI studies on ADHD was conducted using the PubMed and Scopus electronic databases based on PRISMA guidelines. References and citations were verified in Scopus database. The present study has identified 14 studies on children, 16 studies on adults, and one study on both populations of ADHD consisting of 1371 participants. Functional heterogeneity is present in ADHD across age, which can manifest either as different brain activation patterns, intra-subject variability, or both. This is shown in the increased role of the frontal regions and the specialized network in adults with ADHD from inefficient non-specific activation in childhood. Functional heterogeneity may manifest when delayed maturation is insufficient to normalize frontal lobe functions.
Mitragynine is the major alkaloid found in the leaves of M. speciosa Korth (Rubiaceae), a plant that is native to Southeast Asia. This compound has been used, either traditionally or recreationally, due to its psychostimulant and opioid-like effects. Recently, mitragynine has been shown to exert conditioned place preference (CPP), indicating the rewarding and motivational properties of M. speciosa. Here, the involvement of GABAB receptors in mediating mitragynine reward is studied using a CPP paradigm in rats. First, we examined the effects of GABAB receptor agonist baclofen (1.25, 2.5 and 5 mg/kg) on the acquisition of mitragynine (10 mg/kg)-induced CPP. Second, the involvement of GABAB receptors in the expression of mitragynine-induced CPP was tested. We found that the acquisition of mitragynine-induced CPP could be blocked by higher doses (2.5 and 5 mg/kg) of baclofen. Baclofen at a high dose inhibited locomotor activity and caused a CPP. Furthermore, we found that baclofen (2.5 and 5 mg/kg) also blocked the expression of mitragynine-induced CPP. These findings suggest that both, the acquisition and expression of mitragynine's reinforcing properties is controlled by the GABAB receptor.
Exposure to ethanol during critical period of development can cause severe impairments in the central nervous system (CNS). This study was conducted to assess the neurotoxic effects of chronic embryonic exposure to ethanol in the zebrafish, taking into consideration the time dependent effect. Two types of exposure regimen were applied in this study. Withdrawal exposure group received daily exposure starting from gastrulation until hatching, while continuous exposure group received daily exposure from gastrulation until behavioural assessment at 6dpf (days post fertilization). Chronic embryonic exposure to ethanol decreased spontaneous tail coiling at 24hpf (hour post fertilization), heart rate at 48hpf and increased mortality rate at 72hpf. The number of apoptotic cells in the embryos treated with ethanol was significantly increased as compared to the control. We also measured the morphological abnormalities and the most prominent effects can be observed in the treated embryos exposed to 1.50% and 2.00%. The treated embryos showed shorter body length, larger egg yolk, smaller eye diameter and heart edema as compared to the control. Larvae received 0.75% continuous ethanol exposure exhibited decreased swimming activity and increased anxiety related behavior, while withdrawal ethanol exposure showed increased swimming activity and decreased anxiety related behavior as compared to the respective control. Biochemical analysis exhibited that ethanol exposure for both exposure regimens altered proteins, lipids, carbohydrates and nucleic acids of the zebrafish larvae. Our results indicated that time dependent effect of ethanol exposure during development could target the biochemical processes thus leading to induction of apoptosis and neurobehavioral deficits in the zebrafish larvae. Thus it raised our concern about the safe limit of alcohol consumption for pregnant mother especially during critical periods of vulnerability for developing nervous system.
Mitragynine is the main psychoactive ingredient of the herbal drug preparation Kratom (Ketum), derived from the plant Mitragyna speciosa. Kratom is a widely abused drug in Southeast Asian and has a psychostimulant profile at low-medium doses, while high doses have opioidergic effects. Mitragynine was shown to possess opiate receptor affinity. However, its role in the behavioural effects of mitragynine is unclear. Here we asked whether the reinforcing effects of mitragynine are mediated by opiate receptors using a conditioned place preference (CPP) paradigm in rats. In the first experiment we tested the effects of the opiate receptor antagonist naloxone (0.1, 0.3 and 1.0mg/kg) on the acquisition of mitragynine (10mg/kg)-induced CPP. In the second experiment, we tested the involvement of opiate receptors in the expression of mitragynine-induced CPP in rats. We found that naloxone suppresses the acquisition of mitragynine-induced CPP. This effect was already evident at a dose of naloxone (0.1mg/kg) which, by itself, had no conditioned place aversion (CPA) effect. Higher doses of naloxone induced a CPA and blocked mitragynine-induced CPP. In contrast, naloxone had no effect on the expression of mitragynine-induced CPP. These findings suggest that the acquisition, but not the expression of the reinforcing effects of mitragynine is mediated by opiate receptors.
Prenatal stress is a critical life event often resulting in mental illnesses in the offspring. The critical developmental processes, which might trigger a cascade of molecular events resulting in mental disorders in adulthood, are still to be elucidated. Here we proposed that sex hormones, particularly testosterone, might determine the "developmental programming" of long-term consequences of prenatal stress in foetuses of both sexes. We observed that severe prenatal stress in the model of repeated corticosterone injections enhanced brain levels of corticosterone and testosterone in male foetuses. The expression of GluN1 and GluN2A, but not GluN2B NMDA receptor subunits were significantly reduced in the brain of stressed male foetuses. However, female foetuses were protected against stress effects on the brain corticosterone and testosterone levels. More moderate types of stress, such as repeated restraint stress and chronic unpredictable stress, did not induce an increase in brain corticosterone in dams and testosterone concentrations in foetuses of both sexes. Moreover, chronic unpredictable stress reduced brain testosterone concentration in male foetuses. Altogether, changes in brain testosterone level might be one of the crucial mechanisms determining the development of long-term consequences of severe prenatal stress in male, but not in female foetuses. Targeting this mechanism might allow to develop principally new prediction and therapeutic approaches for prenatal stress-associated psychiatric disorders.
Mitragynine exerts its analgesic effect mainly via opioid receptors activation. Additionally, the effect may be mediated via mitragynine's anti-inflammatory property and non-opioid receptor pain pathways, namely through the TRPV1 receptor. No studies identify hitherto, hence, the current study aimed to investigate the mitragynine's analgesic effect via the anti-inflammatory property, non-opioid receptor (TRPV1) and the effective dose (ED) to alleviate pain. Male and female Sprague Dawley rats were pre-treated intraperitoneally with either mitragynine (1, 5, 10, 13, 15 or 30 mg/kg), vehicle, or indomethacin (1 mg/kg) 30 min before inducing inflammatory pain using acetic acid. The writhes and pain-related withdrawal behaviour occurrence were counted within a 1-h duration. Percentage of writhes inhibition, pain-related withdrawal behaviour aggregate, ED50 and ED95 were determined. The body temperature was recorded and TRPV1 expression in the rats' brains was measured. Mitragynine (except 1 mg/kg) significantly reduced the number of writhes compared with the vehicle administered group. Mitragynine (30 mg/kg) demonstrated 99.5% inhibition of writhing behaviour and low withdrawal behaviour score compared with vehicle and indomethacin and successfully blocked the hypothermia induced by acetic acid. The overall ED50 and ED95 values of mitragynine were 3.62 and 20.84 mg/kg, respectively. The percentage of writhing inhibition and withdrawal behaviour were similar in both genders. Mitragynine (15 and 30 mg/kg) significantly reduced the TRPV1 expression in the brain of the rats. Mitragynine alleviated pain-like behaviour and showed analgesic effects via anti-inflammatory and non-opioid receptor pathways. The findings also suggest that mitragynine might regulate some physiological functions of the rat.