Ratio In Hippocampus Research Articles

Duration of fetoscopic spina bifida repair does not affect the central nervous system in fetal lambs

Prenatal spina bifida aperta (SBA) repair improves neurologic outcomes, yet comes with a significant risk of prematurity and uterine scar-related complications. To reduce those, different fetoscopic techniques, e.g. with varying number of ports, are being explored. This has an impact on the duration of the procedure, potentially affecting central nervous system (CNS) development. Both the condition and anesthesia can impact the CNS, particularly the hippocampus, a region vital for prospective and episodic memory. Previous animal studies have shown the potential influence of anesthesia, premature delivery, and maternal surgery during pregnancy on this area. To compare the effects of 2- versus 3-port fetoscopic SBA repair in the fetal lamb model using neuron count of the hippocampus as primary outcome. Based on the hippocampal neuron count from previous lamb experiments, we calculated that we required five animals per group to achieve a statistical power of ≥ 80%. A SBA defect was created in fetal lambs at 75 days of gestation (term: 145 days). At 100 days, fetuses underwent either a 2-port or 3-port fetoscopic repair. At 143 days, all surviving fetuses were delivered by cesarean section, anesthetized and transcardially perfused with a mixture of formaldehyde and gadolinium. Next, they underwent neonatal brain and spine MRI following which these organs were harvested for histology. Hippocampus, frontal cortex, caudate nucleus, and cerebellum samples were immunostained to identify neurons, astrocytes, microglia, and markers associated with cell proliferation, myelination, and synapses. The degree of hindbrain herniation and the ventricular diameter were measured on MRI images and volumes of relevant brain and medulla areas were segmented. Both treatment groups included five fetuses and nine unoperated littermates served as normal controls. The durations for both skin-to-skin (341 ± 31 vs 287 ± 40 min; P=0.04) and fetal surgery (183 ± 30 vs 128 ± 22; P=0.01) were longer for the 2-port than for the 3-port approach. There were no significant differences in neuron density in the hippocampus, frontal cortex and cerebellum. In the caudate nucleus, the neuron count was higher in the 2-port group (965 ± 156 vs. 767 ± 92 neurons/mm2, P=0.04). There were neither differences in proliferation, astrogliosis, synaptophysin, or myelin. The tip of the cerebellar vermis was closer to the foramen magnum in 2-port animals compared to 3-port animals (-0.72 ± 0.67 mm vs. -2.47 ± 0.91 mm, P=0.009). There were no significant differences in the ratio of hippocampus, caudate nucleus, or cerebellar volume to body weight. For the spine, no differences were noted in spine volume/body weight ratio for the lower (L1/L2), mid (L3/L4), and higher (L5/6) levels. Compared to controls, in repaired animals the cerebellar vermis tip lays closer to the foramen magnum, parietal ventricles were enlarged and medulla volumes were reduced. In the experimental spina bifida fetal lamb model, a 2-port repair took 40% longer than a 3-port repair. There was however no indication of any relevant morphologic differences in the fetal brain.

Effects of Moxa Cone Moxibustion Therapy on Cognitive Function and Brain Metabolic Changes in MCI Patients: A Pilot 1H-MRS Study.

ObjectiveTo explore the effect of moxa cone moxibustion on N-acetyl aspartate/total creatinine (NAA/tCr) and choline/total creatinine (Cho/tCr) in the bilateral hippocampus (HIP) and bilateral posterior cingulate gyrus (PCG) in patients with mild cognitive impairment (MCI) using hydrogen proton magnetic resonance spectroscopy (1H-MRS) and to provide imaging basis for moxa cone moxibustion treatment for MCI.MethodsOne hundred eight patients with MCI were served as the MCI group, and 67 age-matched subjects were enrolled as the normal control group. The MCI group was randomized and allocated into acupoint group, drug group, and sham acupoint group, with 36 cases in each group. Some patients in each group withdrew. Finally, 25 cases were included in the acupoint group, 24 cases in the drug group, and 20 cases in the sham acupoint group. The drug group was treated with oral donepezil hydrochloride. The acupoint group and sham acupoint group received moxa cone moxibustion treatment. Mini-mental state exam (MMSE) and Montreal cognitive assessment (MoCA) scores were recorded before intervention, at the end of the first and the second months of intervention, and in the 5th month of follow-up. The NAA/tCr and Cho/tCr ratios in the HIP and PCG were bilaterally measured by 1H-MRS before and after intervention.ResultsBefore intervention, compared with the normal control group, the MMSE and MoCA scores, the Cho/tCr ratio in the right HIP, the NAA/tCr ratio in the bilateral HIP, and the NAA/tCr ratio in the left PCG in the three treatment groups decreased significantly (both p < 0.01), and the NAA/tCr ratio in the right PCG significantly reduced in the acupoint and drug groups (p < 0.05). After two months of treatment, compared with the normal control group, there were no differences in the MoCA scores, the NAA/tCr, and Cho/tCr ratios in the bilateral PCG and bilateral HIP in the three treatment groups (p > 0.05). However, the MMSE scores in the drug group decreased when compared with the acupoint group and normal control group (p < 0.05, p < 0.01). The scores of MMSE and MoCA in the acupoint group and sham acupoint group at all time points were better than those in the drug group, which were similar to those in the normal control group.ConclusionOur findings suggest that moxibustion could improve the cognitive function of patients with MCI. The mechanism may be related to the improvement of abnormal brain metabolism in HIP and PCG.

Cannabidiol antidepressant-like effect in the lipopolysaccharide model in mice: Modulation of inflammatory pathways

Major Depression is a severe psychiatric condition with a still poorly understood etiology. In the last years, evidence supporting the neuroinflammatory hypothesis of depression has increased. In the current clinical scenario, in which the available treatments for depression is far from optimal, there is an urgent need to develop fast-acting drugs with fewer side effects. In this regard, recent pieces of evidence suggest that cannabidiol (CBD), the major non-psychotropic component of Cannabis sativa with anti-inflammatory properties, appears as a drug with antidepressant properties. In this work, CBD 30 mg/kg was administered systemically to mice 30 min before lipopolysaccharide (LPS; 0.83 mg/kg) administration as a neuroinflammatory model, and behavioral tests for depressive-, anhedonic- and anxious-like behavior were performed. NF-ĸB, IκBα and PPARγ levels were analyzed by western blot in nuclear and cytosolic fractions of cortical samples. IL-6 and TNFα levels were determined in plasma and prefrontal cortex using ELISA and qPCR techniques, respectively. The precursor tryptophan (TRP), and its metabolites kynurenine (KYN) and serotonin (5-HT) were measured in hippocampus and cortex by HPLC. The ratios KYN/TRP and KYN/5-HT were used to estimate indoleamine 2,3-dioxygenase (IDO) activity and the balance of both metabolic pathways, respectively. CBD reduced the immobility time in the tail suspension test and increased sucrose preference in the LPS model, without affecting locomotion and central activity in the open-field test. CBD diminished cortical NF-ĸB activation, IL-6 levels in plasma and brain, and the increased KYN/TRP and KYN/5-HT ratios in hippocampus and cortex in the LPS model. Our results demonstrate that CBD produced antidepressant-like effects in the LPS neuroinflammatory model, associated to a reduction in the kynurenine pathway activation, IL-6 levels and NF-ĸB activation. As CBD stands out as a promising antidepressant drug, more research is needed to completely understand its mechanisms of action in depression linked to inflammation.

Enriched Environment Reverts Somatostatin Interneuron Loss in MK-801 Model of Schizophrenia.

Dysregulation of the inhibitory drive has been proposed to be a central mechanism to explain symptoms and pathophysiological hallmarks in schizophrenia. A number of recent neuroanatomical studies suggest that certain types of inhibitory cells are deficient in schizophrenia, including somatostatin-immunoreactive interneurons (SST+). The present study sought to use stereological methods to investigate whether the number of SST+ interneurons decreased after repeated injections of NMDA receptor antagonist MK-801 (0.5mg/kg) and to determine the effect of limited exposure to an enriched environment (EE) in adult life on this sub-population of inhibitory cells. Considering that somatostatin expression is highly dependent on neurotrophic support, we explored the changes in the relative expression of proteins related to brain-derived neurotrophic factor-tyrosine kinase B (BDNF-TrkB) signaling between the experimental groups. We observed that early-life MK-801 treatment significantly decreased the number of SST+ interneurons in the medial prefrontal cortex (mPFC) and the hippocampus (HPC) of adult Long Evans rats. Contrarily, short-term exposure to EE increased the number of SST+ interneurons in MK-801-injected animals, except in the CA1 region of the hippocampus, whereas this increase was not observed in vehicle-injected rats. We also found upregulated BDNF-TrkB signaling after EE that triggered an increase in the pERK/ERK ratio in mPFC and HPC, and the pAkt/Akt ratio in HPC. Thus, the present results support the notion that SST+ interneurons are markedly affected after early-life NMDAR blockade and that EE promotes SST+ interneuron expression, which is partly mediated through the BDNF-TrkB signaling pathway. These results may have important implicationsfor schizophrenia, as SST+ interneuron loss is also observed in the MK-801 pre-clinical model, and its expression can be rescued by non-pharmacological approaches.

Exercise Attenuates Anabolic Steroids-Induced Anxiety via Hippocampal NPY and MC4 Receptor in Rats.

The aim of our study was to evaluate the effects of chronic administration of nandrolone-decanoate (ND) or testosterone-enanthate (TE) in supraphysiological doses and a prolonged swimming protocol, alone and in combination with ND or TE, on anxiety-like behavior in rats. We investigated the immunohistochemical alterations of the hippocampal neuropeptide Y (NPY) and melanocortin 4 receptor (MC4R) neurons, as a possible underlying mechanism in a modulation of anxiety-like behavior in rats. Both applied anabolic androgenic steroids (AASs) induced anxiogenic effect accompanied with decreased serum and hippocampal NPY. The exercise-induced anxiolytic effect was associated with increased hippocampal NPY expression. ND and TE increased the number of MC4R, while the swimming protocol was followed by the reduction of MC4R in the CA1 region of the hippocampus. However, NPY/MC4R ratio in hippocampus was lowered by AASs and elevated by exercise in all hippocampal regions. An augmentation of this ratio strongly and positively correlated to increased time in open arms of elevated plus maze, in the context that indicates anxiolytic effect. Our findings support the conclusion that alterations in both hippocampal NPY and MC4R expression are involved in anxiety level changes in rats, while their quantitative relationship (NPY/MC4R ratio) is even more valuable in the estimation of anxiety regulation than individual alterations for both NPY and MC4R expression in the hippocampus.

Effect of photoperiodic alterations on depression-like behavior and the brain serotonin system in mice genetically different in tryptophan hydroxylase 2 activity

Reduction of natural illumination in fall/winter months causes seasonal affective disorders (SAD) in vulnerable individuals. Neurotransmitter serotonin (5-HT) is involved in the mechanism of SAD. Tryptophan hydroxylase-2 (TPH2) is the key enzyme of 5-HT synthesis in the brain. C1473 G polymorphism in the Tph2 gene is a key factor defining the enzyme activity in the mouse brain. The main aims of the study were to investigate the effects of C1473 G polymorphism on behavior and brain 5-HT system responses to photoperiod alterations. The experiment was carried out on adult mouse males of B6-1473C and B6-1473 G congenic lines with normal and low TPH2 activities, respectively. B6-1473C and B6-1473 G mice were divided into four groups of 8 each and exposed for 28 days to standard-day (14 h light and 10 h darkness) or short-day (4 h light and 20 h darkness) conditions. No effect of photoperiod on locomotor, exploratory activities and anxiety in the open field test was observed. At the same time, photoperiod alterations affected depressive-like immobility in the forced swim test, the 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) levels, 5-HIAA/5-HT ratio and the Htr2a mRNA level in hippocampus and midbrain. The effect of the interaction between C1473 G polymorphism and photoperiod on 5-HT level and 5-HIAA/5-HT ratio in hippocampus was revealed. Short-day conditions reduced the level and increased 5-HIAA/5-HT ratio in this structure only in B6-1473 G mice. At the same time, C1473 G polymorphism does not alter effects of short-day conditions on immobility time in the forced swim test and the Htr2a mRNA level in the brain.

Stress does not increase blood–brain barrier permeability in mice

Several studies have reported that exposure to acute psychophysiological stressors can lead to an increase in blood–brain barrier permeability, but these findings remain controversial and disputed. We thoroughly examined this issue by assessing the effect of several well-established paradigms of acute stress and chronic stress on blood–brain barrier permeability in several brain areas of adult mice. Using cerebral extraction ratio for the small molecule tracer sodium fluorescein (NaF, 376 Da) as a sensitive measure of blood–brain barrier permeability, we find that neither acute swim nor restraint stress lead to increased cerebral extraction ratio. Daily 6-h restraint stress for 21 days, a model for the severe detrimental impact of chronic stress on brain function, also does not alter cerebral extraction ratio. In contrast, we find that cold forced swim and cold restraint stress both lead to a transient, pronounced decrease of cerebral extraction ratio in hippocampus and cortex, suggesting that body temperature can be an important confounding factor in studies of blood–brain barrier permeability. To additionally assess if stress could change blood–brain barrier permeability for macromolecules, we measured cerebral extraction ratio for fluorescein isothiocyanate-dextran (70 kDa). We find that neither acute restraint nor cold swim stress affected blood–brain barrier permeability for macromolecules, thus corroborating our findings that various stressors do not increase blood–brain barrier permeability.

Effects of Sevoflurane on Young Male Adult C57BL/6 Mice Spatial Cognition.

Inhalation anesthetics are reported to affect cognition in both animals and humans. The influence of inhalation anesthetics in learning and memory are contradictory. We therefore investigated the effects of sevoflurane anesthesia with different durations on cognitive performance and the levels of NMDA receptor subunit NR2B, phosphorylated ERK1/2 (p-ERK1/2) and activated caspase3 in mouse hippocampus. We anaesthetized eight-week old male C57BL/6 mice with 2.5% sevoflurane for durations ranging from one to four hours. Non-anaesthetized mice served as controls. Mice exposed to sevoflurane for one to three hours showed improved performance, whereas mice with exposure up to four hours displayed similar behavioral performance as control group. NR2B was increased both at 24h and at two weeks post sevoflurane exposure in all groups. The p-ERK1/2: total ERK1/2 ratio increased at 24h in all anesthesia groups. The ratio remained elevated at two weeks in groups with two- to four-hour exposure. Activated caspase3 was detected elevated at 24h in groups with two- to four-hour exposure. The elevated trend of activated caspase3 was still detectable at two weeks in groups with three- to four-hour exposure. At two weeks post anesthesia, the typical morphology associated with apoptotic cells was observed in the hippocampus of mice exposed to four hours of sevoflurane. Our results indicate that 2.5% sevoflurane exposure for one to three hours improved spatial cognitive performance in young adult mice. The cognitive improvement might be related to the increase of NR2B, the p-ERK1/2: total ERK1/2 ratio in hippocampus. However, exposure to sevoflurane for four hours caused neurotoxicity due to caspase3 activation and apoptosis.

Serum UCH-L1 as a Novel Biomarker to Predict Neuronal Apoptosis Following Deep Hypothermic Circulatory Arrest.

Background: Deep hypothermic circulatory arrest (DHCA) has been used in cardiac surgery involving infant complex congenital heart disease and aortic dissection. DHCA carries a risk of neuronal apoptotic death in brain. Serum ubiquitin C-terminal hydrolase L1 (UCH-L1) level is elevated in a number of neurological diseases involving neuron injury and death. We studied the hypothesis that UCH-L1 may be a potential biomarker for DHCA-induced ischemic neuronal apoptosis.Methods: Anesthetized piglets were used to perform cardiopulmonary bypass (CPB). DHCA was induced for 1 hour followed by CPB rewarming. Blood samples were collected and serum UCH-L1 levels were measured. Neuron apoptosis and Bax and Bcl-2 proteins in hippocampus were examined. The relationship between neuron apoptosis and UCH-L1 level was determined by receiver operating characteristics (ROC) curves and correlation analysis.Results: DHCA resulted in marked neuronal apoptosis, significant increase in Bax:Bcl-2 ratio in hippocampus and UCH-L1 level elevations in serum (all P<0.05). Positive correlation was obtained between serum UCH-L1 level and the severity of neuron apoptosis (r= 0.78, P<0.01). By ROC, the area under the curve were 0.88 (95% CI: 0.74-0.99; P<0.01), 0.81 (95% CI: 0.81-0.96; P<0.05), 0.71 (95% CI: 0.47-0.92; P=0.11) for UCH-L1, Bax/Bcl-2 ratio and Bax, respectively. Using a cut-off point of 0.25, the UCH-L1 predicted neuronal apoptosis with a sensitivity of 85% and specificity of 57%.Conclusion: Serum UCH-L1, as an easy and quick measurable biomarker, can predict neural apoptosis induced by DHCA. The elevation in UCH-L1 concentration is consistent with the severity of neural apoptosis following DHCA.

Regional Analysis of the Magnetization Transfer Ratio of the Brain in Mild Alzheimer Disease and Amnestic Mild Cognitive Impairment

Manually drawn VOI-based analysis shows a decrease in magnetization transfer ratio in the hippocampus of patients with Alzheimer disease. We investigated with whole-brain voxelwise analysis the regional changes of the magnetization transfer ratio in patients with mild Alzheimer disease and patients with amnestic mild cognitive impairment. Twenty patients with mild Alzheimer disease, 27 patients with amnestic mild cognitive impairment, and 30 healthy elderly control subjects were examined with high-resolution T1WI and 3-mm-thick magnetization transfer images. Whole-brain voxelwise analysis of magnetization transfer ratio maps was performed by use of Statistical Parametric Mapping 8 software and was supplemented by the analysis of the magnetization transfer ratio in FreeSurfer parcellation-derived VOIs. Voxelwise analysis showed 2 clusters of significantly decreased magnetization transfer ratio in the left hippocampus and amygdala and in the left posterior mesial temporal cortex (fusiform gyrus) of patients with Alzheimer disease as compared with control subjects but no difference between patients with amnestic mild cognitive impairment and either patients with Alzheimer disease or control subjects. VOI analysis showed that the magnetization transfer ratio in the hippocampus and amygdala was significantly lower (bilaterally) in patients with Alzheimer disease when compared with control subjects (ANOVA with Bonferroni correction, at P < .05). Mean magnetization transfer ratio values in the hippocampus and amygdala in patients with amnestic mild cognitive impairment were between those of healthy control subjects and those of patients with mild Alzheimer disease. Support vector machine-based classification demonstrated improved classification performance after inclusion of magnetization transfer ratio-related features, especially between patients with Alzheimer disease versus healthy subjects. Bilateral but asymmetric decrease of magnetization transfer ratio reflecting microstructural changes of the residual GM is present not only in the hippocampus but also in the amygdala in patients with mild Alzheimer disease.

Effects of perinatal exposure to low dose of bisphenol A on anxiety like behavior and dopamine metabolites in brain

Bisphenol A (BPA), an endocrine-disrupting chemical, is widely present in the environment. It has been reported that perinatal exposure to low doses of BPA that are less than the tolerable daily intake level (50μg/kg/day) affects anxiety-like behavior and dopamine levels in the brain. Although the dopaminergic system in the brain is considered to be related to anxiety, no study has reported the effects of low-dose BPA exposure on the dopaminergic system in the brain and on anxiety-like behavior using the same methods of BPA exposure. To investigate the relationship between alterations in anxiety-like behavior and changes in the dopaminergic system in the brain induced by BPA, we examined the effects of BPA on anxiety-like behavior using an open field test in juvenile and adult mice and measured DA and DOPAC levels and the DOPAC/DA ratio in the dorsal hippocampus (HIP), amygdala (AMY), and medulla oblongata (MED) using high-performance liquid chromatography (HPLC) in adult mice. In males, BPA decreased the time spent in the center area of the open field in both juveniles and adults. In addition, BPA increased DA levels in the dorsal HIP and MED and decreased the DOPAC/DA ratio in the dorsal HIP, AMY, and MED in adults. The activity of monoamine oxidase (MAO)-B, the enzyme that metabolizes DA into DOPAC, was reduced in the MED. In females, those changes were not observed. These results suggest that an increase in anxiety-like behavior induced by perinatal exposure to BPA may be related to decreases in DA metabolites in the brain, and there are sex differences in those BPA effects.

Study of the hippocampus and the anterior cingulate gyrus by proton MR spectroscopy in patients with post–traumatic stress disorder

Objective To explore the characteristics of metabolic changes in patients with post-traumatic stress disorder through 1H-MRS in neuroanatomical circuit comparing with age-matches controls. Methods Fifty patients with post-traumatic stress disorder and 50 gender-and age-matched normal controls were involved. The neurochemical abnormalities including the levels of choline (Cho)/creatine(Cr) and N-acetylaspartate (NAA)/Cr were measured respectively in hippocampus and the anterior cingulate gyrus with three-dimension 1H-proton spectroscopy(3D 1H-MRS). Results The values of NAA/Cr ratios in hippocampus and the anterior cingulate gyrus were significant lower in patients with post-traumatic stress disorder(1.71±0.32, left 1.58±0.29, right 1.55±0.31) than that in controls(2.24±0.41, left 1.98±0.27, right 2.02±0.36)( P<0.05), but the values of Cho/Cr in hippocampus(left 1.64±0.23, right 1.66±0.34) were no significant with that of controls (left 1.48±0.29, right 1.54±0.38). Values of Cho/Cr in cingulate gyrus were significant higher in post-traumatic stress disorder patients (1.88±0.44) than that in controls (1.37.±0.32) ( P<0.05). Conclusions The results indicate some special neurochemical and histological structure changes in post-traumatic stress disorder patients, which might occurre earlier in anterior cingulate gyrusthe than in hippocampus.

Osthole improves chronic cerebral hypoperfusion induced cognitive deficits and neuronal damage in hippocampus

This study is to investigate the effects of osthole on cognitive impairment and neuronal degeneration in hippocampus induced by chronic cerebral hypoperfusion in rats, as well as the potential mechanism. Permanent occlusion of bilateral common carotid arteries (2VO) induced severe cognitive deficits tested by the water maze task, along with oxidative stress and neuronal loss in hippocampus. Oral administration of osthole for 3 weeks markedly attenuated cognitive deficits and neuronal damage. Biochemical experiments revealed that osthole decreased the production of malondialdehyde (MDA) and significantly increased the activities of Glutathione Peroxidase (GPx) and Catalase. Western blot analyses indicated that osthole prevented the downregulation of bcl-2 expression and upregulation of bax expression, which resulted in decreasing bax/bcl-2 ratio in hippocampus of 2VO rats. Additionally, osthole effectively alleviated the activation of caspase-3 induced by permanent occlusion of bilateral common carotid arteries. The observed results in present study suggest that osthole exhibits therapeutic potential for vascular dementia, which is most likely related, at least in part, to its antioxidation and anti-apoptotic actions.

The Early Decrease in N-Acetyl Aspartate / Glutathione, a Brain Health Marker, Induced by Vitamin A Deprivation in Rat is Reversed by Retinoic Acid†

Retinoids are involved in adult brain function and in neurodegenerative diseases. Decreased expression of syn- aptic plasticity markers and metabolic changes induced by 14 weeks of vitamin A deprivation (VAD 14 ) were previously evidenced in rat brain. We evaluate early metabolic changes (by HRMAS proton NMR spectroscopy) on biopsies of cor- tex, hippocampus and striatum (i) during VAD and (ii) after all trans Retinoic Acid administration. In 10 wk VAD (VAD 10 ), metabolic changes appeared in the cortex: (i) N-acetyl aspartate (NAA, +15%, P=0.05 vs C 10 ), a neuronal density indicator, (ii) glutathione (GSH, +30%, P=0.05 vs C 10 ), an antioxidant status marker. Concerning the im- pact of VAD duration, the NAA/GSH ratio in cortex, hippocampus and striatum was unchanged in all controls, whereas it decreased in striatum and hippocampus of VAD 10 and in striatum and cortex of VAD 14 . ATRA had an apparent regulatory action by increasing NAA/GSH ratio in hippocampus (VAD 10+ATRA vs VAD 10 : +34%, P=0.03), the striatal ratio being res- cued to control level. Gene expression of BACE and APP, which are amyloidogenesis markers, were unchanged in VAD 10 whereas VAD 14 seemed to activate cortical amyloidogenesis. Hypoexpression of retinoid signaling during a short 10 wk period has consequences on brain metabolic profile and pre- cedes the impaired expression of both amyloidogenesis and synaptic plasticity markers. Rat nutritional VAD represents a model of accelerated aging which mimics the course of aging. The NAA/GSH ratio reflects the balance between neuronal health and protection against reactive oxygen species, and could thus serve as a marker of brain health.

Effects of propofol pretreatment on the levels of glutamate and gamma-aminobutyric acid in hippocampus of mentally depressed rats after electro-convulsive therapy

Objective To investigate the effects of propofol pretreatment on the levels of glutamate (Glu) and gamma-aminobytyric acid (GABA) in hippocampus of mentally depressed rats after electro-convulsive therapy.Methods Thirty male 2-3 month old SD rats weighing 200-250 g were randomly divided into 5 groups ( n = 6each) : group Ⅰ control (C) ; group Ⅱ mental depression (D) ; group Ⅲ propofol (P) ; group Ⅳ electric shock (E) and groupV propofol + electric shock (PE). Mental depression was induced by subjecting the animals to different kinds of stresses every day for 21 consecutive days in group Ⅱ - Ⅴ. After mental depression had been induced, the animals received intraperitoneal (IP) propofol 100 mg/kg in group P, electric shock in group E and propefol 100 mg/kg + electric shock in group PE respectively once every 2 days × 6 times. The anxiety-related behavior was assessed by open-field test and scored (the higher the score the better) on the day before induction of mental depression was started (To ,baseline), on the 1st day after mental depression had been induced (T1) and on the 2nd day after treatment (T2). The learning ability and memory were evaluated by Morris water maze at T1 and T2. The animals were killed after the last test and their brains were removed and bilateral hippocampi were isolated for determination of glutamate and GABA contents by high performance liquid chromatography (HPLC).Results The behavior scores and learning ability and memory were significandy decreased in group Ⅱ-Ⅴ as compared with the control group (P<0.05). The behavior scores were significandy higher in group E (Ⅳ) and PE (Ⅴ) than ingroup D (Ⅱ) and P (Ⅲ)(P<0.05). The learning ability and memory were significantly better after treatment (T2) in group PE than in group E (P<0.05). The Glu/GABA ratio in hippocampus was significantly higher but GABA content was significantly lower and Glu content was signficantly higher in group D and P than in group C, E and PE (P<0.05). The Glu/GABA ratio was significantly lower but GABA content was significantly higher and Glu content was significantly lower in group E than in group C and PE (P<0.05).Conclusion Propofol pretreatment can improve the learning ability and memory of the mentally depressed rats under electro-convulsive therapy by regulating the balance between Glu and GABA in the brain. Key words: Propofol ; Electric stimulation therapy; Depressive disorder; Cognition disorders; Glutamie acid ; GABA

Chronic intermittent but not constant hypoxia decreases NAA/Cr ratios in neonatal mouse hippocampus and thalamus

Chronic constant hypoxia (CCH) and chronic intermittent hypoxia (CIH) are known to have deleterious effects on the central nervous system. Because of the difference in the pattern of hypoxic exposure, it is possible that the pathological outcome would vary. The N-acetyl aspartate/creatine (NAA/Cr) ratio is a reliable marker of neuronal integrity, and this can be noninvasively measured by proton nuclear magnetic resonance spectroscopy. P2 CD1 mouse pups with their dams were exposed to either CCH, where the Fi(O(2)) was maintained at 11% continuously or to CIH, where the Fi(O(2)) was varied between 21 and 11% every 4 min. P30 mice exposed to intermittent hypoxia for 4 wk demonstrated a significant decrease in the NAA/Cr ratio in the hippocampus and thalamus, which was reversed by a subsequent exposure to 4 wk of normoxia. Meanwhile, mice exposed to 4 wk of constant hypoxia did not demonstrate any differences in their NAA/Cr ratios from controls in these brain regions. These results indicate that an intermittent pattern of hypoxic exposure may have a more adverse effect on neuronal function and integrity than a continuous one. The reversal of NAA/Cr levels to baseline during the return to normoxia indicates that therapeutic strategies targeted at alleviating the intermittent hypoxic stress in diseases, such as obstructive sleep apnea, have the potential for inducing significant neurocognitive recovery in these patients.

Hippocampal neurochemical pathology in patients at first episode of affective psychosis: a proton magnetic resonance spectroscopic imaging study

While several studies have suggested a relationship between the hippocampus and psychosis in schizophrenia, fewer studies have specifically investigated the presence of psychosis in mood disorders from a neurobiological perspective. Moreover, a limitation of these earlier studies is that the majority of them were performed in chronic patients. The present proton magnetic resonance spectroscopic imaging ( 1H-MRSI) study assessed neuronal integrity (as assessed with N-acetylaspartate, NAA) in the hippocampus of patients with a first episode of mood disorders with psychotic symptoms. We studied 17 patients and 17 healthy subjects matched for age and sex. Subjects underwent 1H-MRSI, and measures of NAA, choline-containing compounds (CHO), and creatine+phosphocreatine (CRE) in 11 brain regions were obtained, i.e. hippocampus (HIPPO), dorsolateral prefrontal cortex, superior temporal gyrus, inferior frontal gyrus, occipital cortex, anterior and posterior cingulate, centrum semiovale, prefrontal white matter, thalamus and putamen. NAA/CRE ratios in HIPPO of patients were significantly lower than in controls. Sporadic and non-hypothesis-driven results were found in occipital cortex and prefrontal white matter as a main effect of diagnosis, and in superior temporal gyrus as a hemisphere by diagnosis interaction. These results would not survive a Bonferroni correction for the number of ROIs. No correlations were found with the available demographic and clinical data. Therefore, hippocampal neuronal abnormalities are present at the onset of mood disorders with psychotic symptoms. These data suggest that neuronal abnormalities in HIPPO may be associated with psychosis in mood disorders. Since these data were obtained in patients at first episode, they cannot be explained by chronicity of illness or pharmacological treatment.

A non-radioactive assay for the cAMP-dependent protein kinase activity in rat brain homogenates and age-related changes in hippocampus and cortex

Cyclic AMP-dependent protein kinase (PKA) activity was involved in a number of brain functions such as cognitive process or aging. The measurement of PKA activity is traditionally based on the use of [ 32P]ATP in phosphorylation of specific protein. Recently non-isotopic PKA assays have been developed, but none has been tested on brain homogenates. This work aimed to adapt a fluorimetric method of PKA activity into a novel assay never applied before in brain homogenate, and to characterize the enzyme activity and ratio in hippocampus and cortex from rats of different ages. Optimal conditions of homogenization and enzyme protection were determined. The method was sensitive and reproducible (intra-assay and interassay variation was 5.0% and 9.0%, respectively). In hippocampal cytosol, PKA activity was 27±8 and 80±9 nmol/min per mg protein in basal and cAMP-stimulated activity, repectively, and accounted for 80% of total cell PKA activity. The non-PKA activity, assessed by the use of the PKA specific inhibitor (PKI) accounted for 49.0% and 65.0% of endogenous levels in cytosol and membrane, respectively. cAMP-augmenting drugs effects were measured and increase of 53%, 273% and 118% over basal by 10 μM isoproterenol, 100 μM forskolin, 1 μM Sp-AMP, respectively, was observed. With respect to the changes in animal age, PKA activity increased from newborn to the mature rats but decreased in older rats. The PKA ratio was higher in cytosol than in particulate fraction, and was decreased in hippocampal sample from old rats ( P<0.05). This last result was interpreted as related to the loss of cognitive capacities in old animals.