Chronic Treatment of Ascorbic Acid Leads to Age-Dependent Neuroprotection against Oxidative Injury in Hippocampal Slice Cultures.

Increased oxidative damage in the brain, which increases with age, is the cause of abnormal brain function and various diseases. Ascorbic acid (AA) is known as an endogenous antioxidant that provides neuronal protection against oxidative damage. However, with aging, its extracellular concentrations and uptake decrease in the brain. Few studies have dealt with age-related functional changes in the brain to sustained ascorbate supplementation. This study aimed to investigate the susceptibility of hippocampal neurons to oxidative injury following acute and chronic AA administration. Oxidative stress was induced by kainic acid (KA, 5 µM) for 18 h in hippocampal slice cultures. After KA exposure, less neuronal cell death was observed in the 3 w cultured slice compared to the 9 w cultured slice. In the chronic AA treatment (6 w), the 9 w-daily group showed reduced neuronal cell death and increased superoxide dismutase (SOD) and Nrf2 expressions compared to the 9 w. In addition, the 9 w group showed delayed latencies and reduced signal activity compared to the 3 w, while the 9 w-daily group showed shorter latencies and increased signal activity than the 9 w. These results suggest that the maintenance of the antioxidant system by chronic AA treatment during aging could preserve redox capacity to protect hippocampal neurons from age-related oxidative stress.

Wuzang Wenyang Huayu decoction regulates differentially expressed transcripts in the rats' hippocampus after cerebral hypoperfusion.

The modified Wenyang Huayu decoction has been widely used to treat vascular dementia in China for thousands of years. We have previously proved that a modified version, Wuzang Wenyang Huayu decoction has the potential to be a more effective clinical treatment that can attenuate cerebral ischaemic injury. However, the global transcript profile and signalling conduction pathways regulated by this recipe remains unclear. This study established a two-vessel occlusion rat model by bilateral common carotid artery occlusion. Two groups of rats were intragastrically treated Wuzang Wenyang Huayu 2.5 g/kg vs or Piracetam 0.15 g/kg for 2 weeks. Learning and memory abilities were measured with Morris water maze. Neuronal plasticity was observed by HE staining. Differentially expressed transcripts of rat hippocampus were analysed by transcriptomics with Illumina HiSeq2500 platform. Results showed that Wuzang Wenyang Huayu decoction significantly alleviated learning, memory deficits, coordination dysfunction and prevented hippocampus cellular injury; Results further revealed the increased gene expression in KEGG metabolic pathways (MT-ND2. MT-ND3, MT-ND4, MT-ND4L, MT-ND5 and MT-ATP8) and genes involved in signal transduction, carcinogenesis, immune system, endocrine system, nervous system etc (Results further revealed differential expression of genes involved in various systems, including MT-ND2) Our discovery is likely to provide new insights to molecular mechanisms of Wuzang Wenyang Huayu regarding hippocampal transcripts in a murine vascular dementia model.

Mind-Wandering in People with Hippocampal Damage.

Subjective inner experiences, such as mind-wandering, represent the fundaments of human cognition. Although the precise function of mind-wandering is still debated, it is increasingly acknowledged to have influence across cognition on processes such as future planning, creative thinking, and problem-solving and even on depressive rumination and other mental health disorders. Recently, there has been important progress in characterizing mind-wandering and identifying the associated neural networks. Two prominent features of mind-wandering are mental time travel and visuospatial imagery, which are often linked with the hippocampus. People with selective bilateral hippocampal damage cannot vividly recall events from their past, envision their future, or imagine fictitious scenes. This raises the question of whether the hippocampus plays a causal role in mind-wandering and, if so, in what way. Leveraging a unique opportunity to shadow people (all males) with bilateral hippocampal damage for several days, we examined, for the first time, what they thought about spontaneously, without direct task demands. We found that they engaged in as much mind-wandering as control participants. However, whereas controls thought about the past, present, and future, imagining vivid visual scenes, hippocampal damage resulted in thoughts primarily about the present comprising verbally mediated semantic knowledge. These findings expose the hippocampus as a key pillar in the neural architecture of mind-wandering and also reveal its impact beyond episodic memory, placing it at the heart of our mental life.SIGNIFICANCE STATEMENT Humans tend to mind-wander ∼30-50% of their waking time. Two prominent features of this pervasive form of thought are mental time travel and visuospatial imagery, which are often associated with the hippocampus. To examine whether the hippocampus plays a causal role in mind-wandering, we examined the frequency and phenomenology of mind-wandering in patients with selective bilateral hippocampal damage. We found that they engaged in as much mind-wandering as controls. However, hippocampal damage changed the form and content of mind-wandering from flexible, episodic, and scene based to abstract, semanticized, and verbal. These findings expose the hippocampus as a key pillar in the neural architecture of mind-wandering and reveal its impact beyond episodic memory, placing it at the heart of our mental life.

Effects of Extremely Low-Frequency Electromagnetic Fields on Neurogenesis and Cognitive Behavior in an Experimental Model of Hippocampal Injury.

Exposure to extremely low-frequency electromagnetic fields may induce constant modulation in neuronal plasticity. In recent years, tremendous efforts have been made to design a suitable strategy for enhancing adult neurogenesis, which seems to be deterred due to brain senescence and several neurodegenerative diseases. In this study, we evaluated the effects of ELF-EMF on neurogenesis and memory, following treatment with trimethyltin chloride (TMT) as a neurotoxicant. The mice in all groups (n = 56) were injected with BrdU during the experiment for seven consecutive days to label newborn cells. Spatial memory was assessed by the Morris water maze (MWM) test. By the end of the experiment, neurogenesis and neuronal differentiation were assessed in the hippocampus, using immunohistochemistry and Western blot analysis. Based on the findings, exposure to ELF-EMF enhanced spatial learning and memory in the MWM test. ELF-EMF exposure significantly enhanced the number of BrdU+ and NeuN+ cells in the dentate gyrus of adult mice (P < 0.001 and P < 0.05, resp.). Western blot analysis revealed significant upregulation of NeuroD2 in ELF-EMF-exposed mice compared to the TMT-treated group (P < 0.05). These findings suggest that ELF-EMF might have clinical implications for the improvement of neurodegenerative processes and could help develop a novel therapeutic approach in regenerative medicine.

Trans-resveratrol enriched maternal diet protects the immature hippocampus from perinatal asphyxia in rats.

Trans-resveratrol (tRESV), a polyphenol with antioxidant properties, is common in many food sources, hence easily accessible for study as a maternal dietary supplement in perinatal asphyxia (PA). Hypoxic-ischemic encephalopathy secondary to PA affects especially vulnerable brain areas such as hippocampus and is a leading cause of neonatal morbidity. The purpose of this study is to identify new epigenetic mechanisms of brain inflammation and injury related to PA and to explore the benefit of tRESV enriched maternal diet. The hippocampal interleukin 1 beta (IL-1b), tumour necrosis factor alpha (TNFα) and S-100B protein, at 24-48h after 90min of asphyxia were assessed in postnatal day 6 rats whose mothers received either standard or tRESV enriched diet. The expression of non-coding microRNAs miR124, miR132, miR134, miR146 and miR15a as epigenetic markers of hippocampus response to PA was determined 24h post-asphyxia. Our results indicate that neural response to PA could be epigenetically controlled and that tRESV reduces asphyxia-related neuroinflammation and neural injury. Moreover, tRESV could increase, through epigenetic mechanisms, the tolerance to asphyxia, with possible impact on the neuronal maturation. Our data support the neuroprotective quality of tRESV when used as a supplement in the maternal diet on the offspring's outcome in PA.

Vitamin D supplement ameliorates hippocampal metabolism in diabetic rats.

Vitamin D deficiency induced by diabetes mellitus is tightly associated with neurodegenerative diseases, but the mechanism is still unknown. Endoplasmic reticulum stress (ER stress) is involved in hippocampal lesion and promote diabetic neuropathy, so we focus on the effects of 1, 25-dihydroxy vitamin D3 on ER stress in hippocampus of diabetic rats. Streptozotocin (STZ)-induced diabetic rats were administrated with different doses of vitamin D and divided into 3 groups: high, low, and blank, compared to wild-type rats which were received the same treatment. At the end of 12 weeks of treatment, the brains of the rats were analyzed by proton magnetic resonance spectroscopy (1H-MRS). Rats were then weighed, tested for blood glucose, serum Ca, P, and vitamin D3, and sacrificed for histopathological analysis of the hippocampus. Neuronal nitric oxide synthase (nNOS) and vitamin D receptor (VDR) expression were measured, as well as ER stress markers, including glucose-regulated protein78 (GRP78), protein kinase-like endoplasmic reticulum kinase (PERK) phosphorylation, eukaryotic initiation factor 2α(eIF-2α) phosphorylation, and CCAAT enhancer-binding protein homologous protein (CHOP). Our study showed that treated with appropriate concentration of active vitamin D could decrease the number of pathological pyramidal neurons, improve hippocampal nerve metabolism, and reduce the over-expression of nNOS, along with the relieved activation of ER stress in hippocampus of diabetic rats. These results suggest that 1,25-dihydroxy vitamin D3 treatment can ameliorate hyperglycemia-induced damage on hippocampal metabolism, possibly through alleviating the aberrant activation of ER stress.

Brain injury results in lower levels of melatonin receptors subtypes MT1 and MT2.

BACKGROUND: Traumatic brain injury (TBI) is a devastating and costly acquired condition that affects individuals of all ages, races, and geographies via a number of mechanisms. The effects of TBI on melatonin receptors remain unknown. PURPOSE: The purpose of this study is to explore whether endogenous changes in two melatonin receptor subtypes (MT1 and MT2) occur after experimental TBI. SAMPLE: A total of 25 adult male Sprague Dawley rats were used with 6 or 7 rats per group. METHODS: Rats were randomly assigned to receive either TBI modeled using controlled cortical impact or sham surgery and to be sacrificed at either 6- or 24-h post-operatively. Brains were harvested, dissected, and flash frozen until whole cell lysates were prepared, and the supernatant fluid aliquoted and used for western blotting. Primary antibodies were used to probe for melatonin receptors (MT1 and MT2), and beta actin, used for a loading control. ImageJ and Image Lab software were used to quantify the data which was analyzed using t-tests to compare means. RESULTS: Melatonin receptor levels were reduced in a brain region- and time point- dependent manner. Both MT1 and MT2 were reduced in the frontal cortex at 24h and in the hippocampus at both 6h and 24h. DISCUSSION: MT1 and MT2 are less abundant after injury, which may alter response to MEL therapy. Studies characterizing MT1 and MT2 after TBI are needed, including exploration of the time course and regional patterns, replication in diverse samples, and use of additional variables, especially sleep-related outcomes. CONCLUSION: TBI in rats resulted in lower levels of MT1 and MT2; replication of these findings is necessary as is evaluation of the consequences of lower receptor levels.

Salvia miltiorrhiza extract protects white matter and the hippocampus from damage induced by chronic cerebral hypoperfusion in rats.

BACKGROUND: Salvia miltiorrhiza (SM), an herbal plant, is traditionally used in the treatment of cardiovascular and cerebrovascular diseases in Asian countries. SM has multiple biological effects including anti-inflammatory activity. The present study is aimed at investigating the effects of SM extract in rats with chronic cerebral hypoperfusion. METHODS: Chronic cerebral hypoperfusion was induced in male Wistar rats by permanent bilateral common carotid artery occlusion (BCCAo). The rats were divided into 3 groups: sham-control, BCCAo treated with vehicle, and BCCAo treated with SM extract. Vehicle or SM extract (200 mg/kg) were administered daily by oral gavage beginning on day 21 after BCCAo and continuing to day 42. Immunohistochemical analyses were used to measure Iba-1-positive microglia and myelin basic protein (MBP) in white matter and hippocampal tissue. In addition, the expression levels of proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6, and the toll-like receptor (TLR) pathway in the hippocampus, were analyzed by western blot. RESULTS: Administration of SM extract attenuated the activation of microglial cells in the white matter and hippocampus after BCCAo. SM extract also prevented neuroinflammation after BCCAo by reducing hippocampal levels of TNF-α, IL-1ß, and IL-6, and increasing the reduced levels of MBP in the white matter and hippocampus. Further, the administration of SM extract alleviated the up-regulation of hippocampal TLR4 and myeloid differentiation primary response gene 88 (MyD88) in rats with chronic BCCAo. CONCLUSIONS: Our findings suggest that SM may be a promising therapeutic candidate in vascular dementia because of its protective effects against damage to the white matter and hippocampus after BCCAo.

Use of Anisotropy, 3D Segmented Atlas, and Computational Analysis to Identify Gray Matter Subcortical Lesions Common to Concussive Injury from Different Sites on the Cortex.

Traumatic brain injury (TBI) can occur anywhere along the cortical mantel. While the cortical contusions may be random and disparate in their locations, the clinical outcomes are often similar and difficult to explain. Thus a question that arises is, do concussions at different sites on the cortex affect similar subcortical brain regions? To address this question we used a fluid percussion model to concuss the right caudal or rostral cortices in rats. Five days later, diffusion tensor MRI data were acquired for indices of anisotropy (IA) for use in a novel method of analysis to detect changes in gray matter microarchitecture. IA values from over 20,000 voxels were registered into a 3D segmented, annotated rat atlas covering 150 brain areas. Comparisons between left and right hemispheres revealed a small population of subcortical sites with altered IA values. Rostral and caudal concussions were of striking similarity in the impacted subcortical locations, particularly the central nucleus of the amygdala, laterodorsal thalamus, and hippocampal complex. Subsequent immunohistochemical analysis of these sites showed significant neuroinflammation. This study presents three significant findings that advance our understanding and evaluation of TBI: 1) the introduction of a new method to identify highly localized disturbances in discrete gray matter, subcortical brain nuclei without postmortem histology, 2) the use of this method to demonstrate that separate injuries to the rostral and caudal cortex produce the same subcortical, disturbances, and 3) the central nucleus of the amygdala, critical in the regulation of emotion, is vulnerable to concussion.

The neuroprotective effect of salubrinal in a mouse model of traumatic brain injury.

We have previously reported that mild traumatic brain injury (mTBI) induced cognitive deficits as well as apoptotic changes in the brains of mice. Apoptosis may be caused by severe, prolonged accumulation of misfolded proteins, and protein aggregation in the endoplasmic reticulum (ER stress). In an additional study, we have reported that mTBI activated the pro-apoptotic arm of the integrated stress response (ISR). The main goal of the present study was to test the involvement of the adaptive eIF2α/ATF4 pathway in mTBI-affected brains. Head injury was induced with a noninvasive, closed-head weight drop (30 g) to ICR mice. Salubrinal, the selective phosphatase inhibitor of p-eIF2α, was injected immediately and 24 h after mTBI (1 mg/kg, ip). Y-maze and novel object recognition tests to assess spatial and visual memories, respectively, were conducted either 7 or 30 days post-trauma. Salubrinal administration significantly improved memory deficits following mTBI. Slaubrinal also prevented the elevation of degenerating neurons and the reduction of mature neurons in the cortex (as seen by immunofluorescent staining with Fluoro-Jade-B and NeuN antibodies, 72 h and 1 week post-mTBI, respectively). Western blot analysis revealed that salubrinal prevented the significant reduction in eIF2α and ATF4 phosphorylation in mTBI brains 72 h post-injury. Immunofluorescence staining revealed that although the reduction in p-eIF2α did not reach significance, salubrinal administration elevated it dramatically. Our results show that targeting the translational/adaptive arm of the ISR with salubrinal may serve as a therapeutic strategy for brain damage.

[PI 3 K/Akt signaling pathway contributed to the protective effect of acupuncture intervention on epileptic seizure-induced injury of hippocampal pyramidal cells in epilepsy rats].

OBJECTIVE: To observe the protective effect of acupuncture stimulation on pyramidal cells in hippocampal CA 1 and CA 3 regions and to analyze the involvement of phosphatidy linositol-3-kinase (PI 3 K)/protein kinase B(PKB or Akt) signaling pathway in the acupuncture effect in epilepsy rats. METHODS: A total of 120 SD rats were randomly divided into normal control group, model group, LY 294002 (a specific antagonist for PI 3 K/Akt signaling) group, acupuncture+ LY 294002 group and acupuncture group (n = 24 in each group, 12 for H. E. staining, and 12 for electron microscope observation). Epilepsy model was established by intraperitoneal injection of pentylenetetrazol (PTZ, 5 microL). Manual acupuncture stimulation was applied to "Baihui" (GV 20) and "Dazhui" (GV 14) once daily for 5 days. Dimethyl Sulfoxide (DMSO, 5 microL, a control solvent) was given to rats of the normal, model and acupuncture groups, and LY294002 (5 microL, dissolved in DMSO) given to rats of the LY 294002 and acupuncture+ LY 294002 groups by lateral ventricular injection. Four hours and 24 h after modeling, the hippocampus tissues were sampled for observing pathological changes of CA 1 and CA 3 regions after H. E. staining under light microscope and for checkin ultrastructural changes of the pyramidal cells under transmission electron microscope. RESULTS: In comparison with the normal control group, the numbers of pyramidal cells of hippocampal CA 3 region in the model group were decreased significantly 4 h and 24 h after epileptic seizure (P < 0.01). While compared to the model group, the pyramidal cells of hippocampal CA 3 region in the acupuncture group were increased considerably in the number at both 4 h and 24 h after seizure (P < 0.01). No significant differences were found between the LY 294002 and model groups, and between the acupuncture+ LY 294002 and model groups in the numbers of pyramidal cells at 4 h and 24 h after seizure (P > 0.05). Findings of the light microscope and electron microscope showed that the injury severity of pyramidal cells of hippocampal CA 1 and CA 3 regions was moderate 4 h after epileptic seizure and even worse 24 h after seizure in the model group, LY 294002 group and acupuncture+ LY 294002 group, but relatively lighter in the acupuncture group. These results suggested an elimination of the acupuncture effect after blocking the PI 3 K/Akt signaling pathway by lateral ventricular injection of LY 294002 in epilepsy rats. CONCLUSION: Acupuncture intervention has a protective effect on pyramidal cells of hippocampal CA 1 and CA 3 regions in epilepsy rats, which is associated with the normal function of intracellular PI 3 K/Akt signaling pathway.

Neonatal ventral hippocampal lesions modify pain perception and evoked potentials in rats.

This work concerns the debate surrounding the modified pain reactivity of patients with schizophrenia and other possible perceptive distortions. Rats with a neonatal ventral hippocampal lesion (NVHL) were used to model the neuro-developmental aspect of schizophrenia, and their reactivity to various stimuli was evaluated. The results could also help understand sensory deficits in other neuro-developmental disorders. Behavioural reactions to graduated painful thermal and mechanical stimuli were observed, and evoked potential responsiveness to tactile, visual and acoustic non-painful stimuli was recorded and compared to non-operated and sham lesioned controls. A higher threshold was observed with painful mechanical stimuli and shorter paw withdrawal latency with thermal stimuli. This was particularly relevant as there was no change in the evoked potentials triggered by non-nociceptive tactile stimulation of the same part of the body. There was a 10 dB(A) increase in the auditory threshold and a suppression of auditory sensory motor gating. Visually evoked potentials did not appear to be affected. Taken together, the results showed that NVHL-evoked alteration of brain development induces mechanical hypoalgesia, thermal hyperalgesia and auditory sensory changes. The data also contribute towards elucidating mechanisms underlying sensory deficits in neurodevelopmental diseases, including schizophrenia.

Sensory and sensorimotor gating deficits after neonatal ventral hippocampal lesions in rats.

Neonatal ventral hippocampal lesions (NVHLs) in rats lead to reduced prepulse inhibition (PPI) of startle and other behavioral deficits in adulthood that model abnormalities in schizophrenia patients. A neurophysiological deficit in schizophrenia patients and their first-degree relatives is reduced gating of the P50 event-related potential (ERP). N40 ERP gating in rats may be a cross-species analog of P50 gating, and is disrupted in experimental manipulations related to schizophrenia. Here, we tested whether N40 gating as well as PPI is disrupted after NVHLs, using contemporaneous measures of these two conceptually related phenomena. Male rat pups received sham or ibotenic acid NVHLs on postnatal day 7. PPI was tested on days 35 and 56, after which rats were equipped with cortical surface electrodes for ERP measurements. One week later, PPI and N40 gating were measured in a single test, using paired S1-S2 clicks spaced 500 ms apart to elicit N40 gating. Compared to sham-lesioned rats, those with NVHLs exhibited PPI deficits on days 35 and 56. NVHL rats also exhibited reduced N40 gating and reduced PPI, when measured contemporaneously at day 65. Deficits in PPI and N40 gating appeared most pronounced in rats with larger lesions, focused within the ventral hippocampus. In this first report of contemporaneous measures of two important schizophrenia-related phenotypes in NVHL rats, NVHLs reproduce both sensory (N40) and sensorimotor (PPI) gating deficits exhibited in schizophrenia. In this study, lesion effects were detected prior to pubertal onset, and were sustained well into adulthood.

Neuroprotective effects of INM-176 against lipopolysaccharide-induced neuronal injury.

Neuroinflammation plays a critical role in the etiology of chronic neurodegenerative diseases such as Alzheimer's disease. INM-176 is a standardized ethanolic extract of Angelica gigas, which has been traditionally used as a tonic to treat anemia. In the present study, we investigated whether INM-176 exhibits neuroprotective activities against lipopolysaccharide (LPS)-induced neuronal damage in vitro and in vivo. In primary microglial cells, INM-176 significantly inhibited LPS-induced nitric oxide release and expression of tumor necrosis factor-α and interleukin-1ß. The expression levels of inducible nitric oxide synthase and cylcooxygenase-2 in BV2 microglial cells were markedly upregulated by LPS, but this increased expression was counteracted by INM-176. LPS-mediated neuronal damage in an organotypic hippocampal slice culture was also attenuated by the administration of INM-176. In addition, LPS (1 µg/2 µl, i.c.v.)-induced cognitive dysfunction in mice, as determined by passive avoidance and Y-maze tasks, was significantly attenuated by the administration of INM-176. Furthermore, the activation of microglia or astrocytes by LPS in the hippocampal regions of mice was suppressed by INM-176. These results suggest that the neuroprotective and cognition ameliorating effects of INM-176 against LPS-induced damage are mediated, in part, by its anti-inflammatory activities.

Protective effects of a Rhodiola crenulata extract and salidroside on hippocampal neurogenesis against streptozotocin-induced neural injury in the rat.

Previously we have demonstrated that a Rhodiola crenulata extract (RCE), containing a potent antioxidant salidroside, promotes neurogenesis in the hippocampus of depressive rats. The current study was designed to further investigate the protective effect of the RCE on neurogenesis in a rat model of Alzheimer's disease (AD) induced by an intracerebroventricular injection of streptozotocin (STZ), and to determine whether this neuroprotective effect is induced by the antioxidative activity of salidroside. Our results showed that pretreatment with the RCE significantly improved the impaired neurogenesis and simultaneously reduced the oxidative stress in the hippocampus of AD rats. In vitro studies revealed that (1) exposure of neural stem cells (NSCs) from the hippocampus to STZ strikingly increased intracellular reactive oxygen species (ROS) levels, induced cell death and perturbed cell proliferation and differentiation, (2) hydrogen peroxide induced similar cellular activities as STZ, (3) pre-incubation of STZ-treated NSCs with catalase, an antioxidant, suppressed all these cellular activities induced by STZ, and (4) likewise, pre-incubation of STZ-treated NSCs with salidroside, also an antioxidant, suppressed all these activities as catalase: reduction of ROS levels and NSC death with simultaneous increases in proliferation and differentiation. Our findings indicated that the RCE improved the impaired hippocampal neurogenesis in the rat model of AD through protecting NSCs by its main ingredient salidroside which scavenged intracellular ROS.

Chronic administration of the neurotrophic agent cerebrolysin ameliorates the behavioral and morphological changes induced by neonatal ventral hippocampus lesion in a rat model of schizophrenia.

Neonatal ventral hippocampal lesion (nVHL) in rats has been widely used as a neurodevelopmental model to mimic schizophrenia-like behaviors. Recently, we reported that nVHLs result in dendritic retraction and spine loss in prefrontal cortex (PFC) pyramidal neurons and medium spiny neurons of the nucleus accumbens (NAcc). Cerebrolysin (Cbl), a neurotrophic peptide mixture, has been reported to ameliorate the synaptic and dendritic pathology in models of aging and neurodevelopmental disorder such as Rett syndrome. This study sought to determine whether Cbl was capable of reducing behavioral and neuronal alterations in nVHL rats. The behavioral analysis included locomotor activity induced by novel environment and amphetamine, social interaction, and sensoriomotor gating. The morphological evaluation included dendritic analysis by using the Golgi-Cox procedure and stereology to quantify the total cell number in PFC and NAcc. Behavioral data show a reduction in the hyperresponsiveness to novel environment- and amphetamine-induced locomotion, with an increase in the total time spent in social interactions and in prepulse inhibition in Cbl-treated nVHL rats. In addition, neuropathological analysis of the limbic regions also showed amelioration of dendritic retraction and spine loss in Cbl-treated nVHL rats. Cbl treatment also ameliorated dendritic pathology and neuronal loss in the PFC and NAcc in nVHL rats. This study demonstrates that Cbl promotes behavioral improvements and recovery of dendritic neuronal damage in postpubertal nVHL rats and suggests that Cbl may have neurotrophic effects in this neurodevelopmental model of schizophrenia. These findings support the possibility that Cbl has beneficial effects in the management of schizophrenia symptoms.

Microscopic magnetic resonance elastography of traumatic brain injury model.

Traumatic brain injury (TBI) is a major cause of death and disability for which there is no cure. One of the issues inhibiting clinical trial success is the lack of targeting specific patient populations due to inconsistencies between clinical diagnostic tools and underlying pathophysiology. The development of reliable, noninvasive markers of TBI severity and injury mechanisms may better identify these populations, thereby improving clinical trial design. Magnetic resonance elastography (MRE), by assessing tissue mechanical properties, can potentially provide such marker. MRE synchronizes mechanical excitations with a phase contrast imaging pulse sequence to noninvasively register shear wave propagation, from which local values of tissue viscoelastic properties can be deduced. The working hypothesis of this study is that TBI involves a compression of brain tissue large enough to bring the material out of its elastic range, sufficiently altering mechanical properties to generate contrast on MRE measurements. To test this hypothesis, we combined microscopic MRE with brain tissue collected from adult male rats subjected to a controlled cortical impact injury. Measurements were made in different regions of interest (somatosensory cortex, hippocampus, and thalamus), and at different time points following the injury (immediate, 24 h, 7 days, 28 days). Values of stiffness in the somatosensory cortex were found to be 23-32% lower in the injured hemisphere than in the healthy one, when no significant difference was observed in the case of sham brains. A preliminary in vivo experiment is also presented, as well as alternatives to improve the faithfulness of stiffness recovery.

[Effect of active site of Xiangsha Liujunzitang on behavior and injury of hippocampal neurons in depression model mice].

OBJECTIVE: To observe the effect of the active site of Xiangshia Liujunzitang on behavior, injury of hippocampal neurons and Ca2+ ion in hippocampal synaptic in the depression model mice. METHOD: Sixty male Kunming mice were randomly divided into 5 group, the control group, the model group and the active site of Xiangshia Liujunzitang groups (400, 600, 800 mg x kg(-1) body weight). The model was established by separation and chronic unpredictable mild stimulation. The increased weight and crossing scores, rearing scores were measured by open-field and sweet water consumption of mice. Cone cell and configuration of neuron in CA1, CA3 region of hippocampus were observed by Nissl. The concentration of Hippocampal synaptic Ca2+ was detected by fluorimetry. RESULT: Comparing with the mice of control, the increased weight was slowed (P < 0.001), the scores of rearing and crossing were decreased (P < 0.001), sweet water consumption were decreased, too. Numbers of cone cells in CA3 region of hippocampus were decreased obviously (P < 0.001), and Ca2+ ion in hippocampal synaptic was increased obviously. Comparing with the mice of model, the active site of Xiangshia Liujunzitang could increase the increased weight on the 14 th and 21 st day obviously. The active site of Xiangshia Liujunzitang could increase the scores of crossing obviously (P < 0.05), with no dose-effect relationship. The active site of Xiangshia Liujunzitang (800 mg x kg(-1)) could increase the scores of rearing obviously (P < 0.001); The active site of Xiangshia Liujunzitang (400, 600, 800 mg x kg(-1)) could increase sweet water consumption obviously (P < 0.01, P < 0.01, P < 0.001); The active site of Xiangshia Liujunzitang (600, 800 mg x kg(-1)) could increase numbers of cone cell in CA3 region of hippocampus obviously (P < 0.001); The active site of Xiangshia Liujunzitang (600, 800 mg x kg(-1)) could decreased Ca2+ in hippocampal synaptic with dose-effect relationship (P < 0.01, P < 0.001). CONCLUSION: The active site of Xiangshia Liujunzitang can improve all the symptoms of the depression model mice and protect the injury of hippocampal neurons in the depression model mice. The possible mechanism of action is to restrict Ca2+ ion overfreight.

Selective reorganization of GABAergic transmission in neonatal ventral hippocampal-lesioned rats.

Post-mortem studies suggested a disturbance of the GABAergic system in schizophrenia. Neonatal ventral hippocampal-lesioned (NVHL) rats were used as a neurodevelopmental model of schizophrenia. Here, we characterized the GABAergic system, focusing on the GABA-synthesizing enzyme, GAD67, GABAergic interneuron characteristic proteins, and the GABA transporter, gat-1. As the GABAergic system is crucial to brain excitability, the sensitivity to pentylenetetrazol (PTZ) administration, an antagonist of GABAA receptors, was also evaluated in such rats. Male pups were lesioned with ibotenic acid at postnatal day 7. As adults, they were submitted to standard behavioural tests, i.e. prepulse inhibition of the startle reflex and increased locomotion under apomorphine, to assess the effectiveness of the lesions and the PTZ infusion test before immunohistochemistry of the GABAergic neuron markers. We found a widespread perturbation of the enzyme responsible for GABA synthesis, GAD67 and a decrease of specific interneurons, restricted to the hippocampus, entorhinal and prefrontal cortex, but no alteration of gat-1-positive fibres. The usual behavioural properties of the model, such as hyperlocomotion under apomorphine and a deficit in sensorimotor gating were confirmed. NVHL rats showed changes in cortical excitability reflected by higher susceptibility than sham-operated rats to spike wave discharges and decreased susceptibility to clonic seizures, induced by increasing the dose of PTZ. These findings indicate that a neonatal lesion of the ventral hippocampus elicits alterations in the GABAergic system leading to functional consequences on brain excitability, lending support to the idea that GABAergic systems could be involved in the pathophysiology of schizophrenia.