Morphological Changes In Hippocampus Research Articles

PKR Inhibitor C16 Regulates HIV-gp120 Induced Neuronal Injury and Cognitive Impairment in Vivo and in Vitro Models.

To study the neuronal protective effect and its potential mechanism of C16 against gp120-induced cognitive impairment in vitro and in vivo. The NORT method was used to evaluate the short-term memory abilities of rats, the morphological changes in hippocampus were observed by Nissl staining. Cell viability and damage degree were detected by MTT and LDH. The cell living/apoptosis status of PC12 cells was determined by AO/EB double staining and the relative mRNA expressions of PKR, IRE1α, JNK, GRP78, and CHOP were detected by RT-qPCR. In comparison with the gp120 + Memantine and gp120 + C16 groups, the rats in the gp120 group showed a significantly decreased discrimination index (P < 0.001), with disordered CA1 region cells and reduced neuron numbers. AO/EB double staining revealed morphological changes in the gp120 and NMDA groups, while cells in the gp120 + C16 and NMDA + C16 groups resembled the control group. And C16 can significantly down-regulate the mRNA expression levels of PKR, IRE1α, JNK, GRP78, and CHOP. (P < 0.05). C16 can reduce the cognitive impairment stimulated by gp120 or NMDA, the protective mechanism may be correlated with inhibiting the upregulation of PKR/IRE1α/JNK pathway and suppressing apoptosis induced by downstream proteins GRP78 and CHOP.

Hybrid-feature based spherical quasi-conformal registration for AD-induced hippocampal surface morphological changes

Background and objectiveEstablishing accurate one-to-one morphological correspondence between different hippocampal surfaces is a solid foundation for the analysis of AD-induced hippocampal morphological changes. However, owing to the large variations between hippocampal surfaces, exiting registration work either fails to obtain the accurate matching of local and overall morphological features or does not preserve the bijectivity during parametric mapping. For this reason, this study proposes a hybrid-feature based spherical quasi-conformal registration (HSQR) method that can effectively maintain the diffeomorphic property while meeting the hybrid-feature matching constraints in the spherical parameter domain. MethodsThe HSQR algorithm is primarily achieved through hippocampal surface hybrid feature extraction and spherical quasi-conformal registration. First, hybrid features for a comprehensive morphological description of the hippocampal surface were established, which included essential anatomical features (landmarks) and mean curvature (intensity) features to ensure the accuracy of surface morphology alignment. Second, spherical parameterization was applied to genus-0 closed surfaces, such as the hippocampus, which maximized the preservation of the original local surface morphology through area-preserving properties. Third, a novel spherical quasi-conformal registration algorithm that can handle large deformations is established. It transforms a 3D spherical parameter domain into a 2D plane parameter domain using iterative local stereo projection to improve the efficiency of the registration algorithm. Subsequently, by controlling the Beltramin coefficient, the hybrid morphological features could be aligned while ensuring bijection before and after registration. ResultsUsing a cohort including 161 patients with amyloid-β (Aβ) positive Alzheimer disease (AD), 234 Aβ positive mild cognitive impairment (MCI) and 266 Aβ negative cognitively unimpaired (CU) individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, we set up the experiment which indicated that the HSQR-based whole bilateral hippocampal atrophy features demonstrated the stronger statistical power for group morphological differences of CU vs. MCI with q-value: 0.0453 for left hippocampus and 0.0401 for right hippocampus and group morphological differences of AD vs. MCI with q-value: 0.0282 for left hippocampus and 0.0421 for right hippocampus. ConclusionsOur registration algorithm may provide a solid foundation for the accurate quantification of hippocampal surface morphological changes for the differential diagnosis and tracking of AD.

Chronic exposure to PM10 induces anxiety-like behavior via exacerbating hippocampal oxidative stress

As one of the most environmental concerns, inhaled particulate matter (PM10) causes numerous health problems. However, the associations between anxiety behavior and toxicity caused by PM10 have rarely been reported so far. To investigate the changes of behavior after PM10 exposure and to identify the potential mechanisms of toxicity, PM10 samples (with doses of 15 mg/kg and 30 mg/kg) were intratracheally instilled into rats to simulate inhalation of polluted air by the lungs. After instillation for eight weeks, anxiety-like behavior was evaluated, levels of oxidative stress and morphological changes of hippocampus were measured. The behavioral results indicated that PM10 exposure induced obvious anxiety-like behavior in the open field and elevated plus maze tests. Both PM10 concentrations tested could increase whole blood viscosity and trigger hippocampal neuronal damage and oxidative stress by increasing superoxide dismutase (SOD) activities and malondialdehyde levels, and decreasing the expressions of antioxidant-related proteins (e.g., nuclear factor erythroid 2-related factor 2 (Nrf2), SOD1 and heme oxygenase 1). Furthermore, through collecting and analyzing questionnaires, the data showed that the participants experienced obvious anxiety-related emotions and negative somatic responses under heavily polluted environments, especially PM10 being the main pollutant. These results show that PM10 exposure induces anxiety-like behavior, which may be related to suppressing the Nrf2/Keap1-SOD1 pathway.

State of the Hippocampus and Frontal Brain in Rats with Experimental Hypothyroidism

Introduction. Despite the fact that today patients with hypothyroidism manage to correct their hormonal profile, perfect control is not always achieved during the course of the disease. This was noted in a study of 22 people with hypothyroidism according to medical records for 8.24±0.76 years: the average TSH level was 7.14±2.37 mIU∕l, T4 was 23.01±4.38 pmol/l, although at the start of the study TSH was 3.72±0.76 mIU∕l and T4 was 13.8±1.96 pmol/l. Ultimately, this affected cognitive functions, including attention, speech and memory, despite the fact that cognitive impairment with drug compensation of hypothyroidism is considered reversible.&#x0D; The results of a morphological study of the hippocampus and frontal lobe of the brain in rats with experimental hypothyroidism at an early stage can serve as a prototype for changes in the corresponding structures responsible for cognitive functions in individuals with hypothyroidism, even against the background of relative compensation with a long course of the disease.&#x0D; Objective. To study morphology of the brain areas responsible for cognitive functions, in particular the hippocampus and anterior-frontal cortex in rats in the early stages of experimental hypothyroidism.&#x0D; Materials and methods. The study included 12 white outbred sexually mature male rats. Hypothyroidism was modelled in 7 rats using the drug “Mercazolil” (“Zdorovye”, Ukraine). After 28 days, the animals underwent light-optical study of the histological structure of CA1, CA3 fields of the hippocampus, dentate gyrus and anterior-frontal cortex. Five animals were intact and, accordingly, served as controls.&#x0D; Results. The light-optical examination revealed the sequence and depth of the violations: the most pronounced dystrophic changes with vacuolation of structures occur in the dentate gyrus; in the hippocampus itself, the CA1 field is the most vulnerable; lateralisation of hippocampal morphological changes with left-sided dominance was detected; minor morphological changes were detected in the anterior-frontal cortex. It is important that neuro-glial changes occur in parallel with vascular disorders.&#x0D; Conclusions. Under the conditions of simulated hypothyroidism, changes occur in all studied brain components with their left-sided dominance, except for the anterior-frontal cortex.

Infection with COVID-19 is no longer a public emergency: But what about degenerative dementia?

Although no longer considered a public health threat, post-COVID cognitive syndrome continues to impact on a considerable proportion of individuals who were infected with COVID-19. Recent studies have also suggested that COVID may be represent a critical risk factor for the development of Alzheimer's disease (AD). We compared 17 COVID patients with 20 controls and evaluated the effects of COVID-19 on general cognitive performance, hippocampal volume, and connections using structural and seed-based connectivity analysis. We showed that COVID patients exhibited considerably worse cognitive functioning and increased hippocampal connectivity supported by the strong correlation between hippocampal connectivity and cognitive scores. Our findings of higher hippocampal connectivity with no observable hippocampal morphological changes even in mild COVID cases may be represent evidence of a prestructural compensatory mechanism for stimulating additional neuronal resources to combat cognitive dysfunction as recently shown for the prodromal stages of degenerative cognitive disorders. Our findings may be also important in light of recent data showing that other viral infections as well as COVID may constitute a critical risk factor for the development of AD. To our knowledge, this is the first study that investigated network differences in COVID patients, with a particular focus on compensatory hippocampal connectivity.

MR-based spatiotemporal anisotropic atrophy evaluation of hippocampus in Alzheimer's disease progression by multiscale skeletal representation.

Increasing evidence has shown a higher sensitivity of Alzheimer's disease (AD) progression by local hippocampal atrophy rather than the whole volume. However, existing morphological methods based on subfield-volume or surface in imaging studies are not capable to describe the comprehensive process of hippocampal atrophy as sensitive as histological findings. To map histological distinctive measurements onto medical magnetic resonance (MR) images, we propose a multiscale skeletal representation (m-s-rep) to quantify focal hippocampal atrophy during AD progression in longitudinal cohorts from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The m-s-rep captures large-to-small-scale hippocampal morphology by spoke interpolation over label projection on skeletal models. To enhance morphological correspondence within subjects, we align the longitudinal m-s-reps by surface-based transformations from baseline to subsequent timepoints. Cross-sectional and longitudinal measurements derived from m-s-rep are statistically analyzed to comprehensively evaluate the bilateral hippocampal atrophy. Our findings reveal that during the early AD progression, atrophy primarily affects the lateral-medial extent of the hippocampus, with a difference of 1.8 mm in lateral-medial width in 2 years preceding conversion (p < .001), and the medial head exhibits a maximum difference of 3.05%/year in local atrophy rate (p = .011) compared to controls. Moreover, progressive mild cognitive impairment (pMCI) exhibits more severe and widespread atrophy in the head and body compared to stable mild cognitive impairment (sMCI), with a maximum difference of 1.21 mm in thickness in the medial head 1 year preceding conversion (p = .012). In summary, our proposed method can quantitatively measure the hippocampal morphological changes on 3T MR images, potentially assisting the pre-diagnosis and prognosis of AD.

Sleep deprivation aggravates cognitive impairment in septic rats by activating neuronal glycolytic isoenzyme PFKFB3

To evaluate the effect of sleep deprivation on cognitive function in septic rats and its relationship with neuronal glycolysis isoenzyme phosphofructokinase-2/fructose-2, 6-diphosphatase 3 (PFKFB3). Fifty-six healthy male Sprague-Dawley (SD) rats were randomly divided into 4 groups (n = 14): control group (Con group), sepsis group (LPS group), sepsis+sleep deprivation group (LPS+SD group), sepsis+sleep deprivation+glycolysis inhibitor 3-PO treatment group (LPS+SD+3-PO group). The sepsis model was established by intraperitoneal injection of lipopolysaccharide (LPS) 10 mg/kg. Rats in LPS+SD group were treated with sleep deprivation using a sleep deprivation instrument 24 hours after LPS injection. The LPS+SD+3-PO group was intraperitoneally injected with LPS for 24 hours, and then injected with 3-PO 50 mg/kg, followed by sleep deprivation. Novel object recognition experiments were performed 72 hours after LPS injection. Subsequently, blood and brain tissue samples were collected. The contents of lactate (Lac), reactive oxygen species (ROS) and serum tumor necrosis factor-α (TNF-α), neuron-specific enolase (NSE), pyruvate in brain tissue were detected by enzyme-linked immunosorbent assay (ELISA). Then, the lactate/pyruvate ratio was calculated. Na+-K+-ATPase activity in brain tissue was detected by colorimetry. Morphological changes in hippocampus were detected by hematoxylin-eosin (HE) staining. And the protein expression levels of PFKFB3, ZO-1 and cleaved caspase-3 were measured by Western blotting. Compared with Con group, the novel object recognition index of LPS group was decreased, the levels of NSE, TNF-α, lactate/pyruvate ratio in serum and the levels of Lac, ROS and dry-wet weight ratio in brain tissue were significantly increased, Na+-K+-ATPase activity in brain tissue was decreased, the protein expressions of PFKFB3, caspase-3 were up-regulated, ZO-1 expression was down-regulated, and the neurons in hippocampus were slightly degenerated. Compared with LPS group, the novel object recognition index of LPS+SD group was further decreased [(39.4±5.3)% vs. (54.5±7.6)%)], serum NSE, TNF-α, lactate/pyruvate ratio and brain tissue Lac, ROS, dry-wet weight ratio were further increased [NSE (μg/L): 3.21±0.42 vs. 2.55±0.36, TNF-α (ng/L): 139.4±19.7 vs. 92.2±13.5, lactate/pyruvate ratio: 29.7±5.5 vs. 19.2±4.2, Lac (μmol/g): 19.51±2.33 vs. 11.34±1.52, ROS (kU/g): 117.4±18.7 vs. 78.2±11.8, dry-wet weight ratio: (81.3±9.2)% vs. (64.3±6.6)%], and Na+-K+-ATPase activity was further decreased (mmol×L-1×h-1: 1.88±0.34 vs. 2.91±0.39), the protein expressions of PFKFB3, caspase-3 were further up-regulated and ZO-1 expression was further down-regulated (PFKFB3/β-actin: 0.80±0.11 vs. 0.45±0.07, caspase-3/β-actin: 0.71±0.09 vs. 0.37±0.05, ZO-1/β-actin: 0.31±0.05 vs. 0.61±0.08). The differences were statistically significant (all P < 0.05). HE staining showed that the degeneration of neurons in hippocampus was significantly aggravated. Compared with LPS+SD group, the novel object recognition index of LPS+SD+3-PO group was increased [(50.8±5.9)% vs. (39.4±5.3)%], NSE, TNF-α, lactate/pyruvate ratio of serum and Lac, ROS, dry-wet weight ratio of brain tissue were significantly decreased [NSE (μg/L): 2.60±0.33 vs. 3.21±0.42, TNF-α (ng/L): 103.7±18.3 vs. 139.4±19.7, lactate/pyruvate ratio: 17.4±5.1 vs. 29.7±5.5, Lac (μmol/g): 13.68±2.02 vs. 19.51±2.33, ROS (kU/g): 86.9±14.5 vs. 117.4±18.7, dry-wet weight ratio: (67.7±6.9)% vs. (81.3±9.2)%], and Na+-K+-ATPase activity was increased (mmol×L-1×h-1: 2.82±0.44 vs. 1.88±0.34). The protein expressions of PFKFB3, caspase-3 were down-regulated and ZO-1 expression was up-regulated (PFKFB3/β-actin: 0.50±0.06 vs. 0.80±0.11, caspase-3/β-actin: 0.43±0.06 vs. 0.71±0.09, ZO-1/β-actin: 0.52±0.06 vs. 0.31±0.05). The differences were statistically significant (all P < 0.05). HE staining showed that the degeneration of neurons in hippocampus was significantly improved. Sleep deprivation could aggravate neuroinflammation, neuronal degeneration and apoptosis in septic rats, resulting in destruction of blood-brain barrier and cognitive impairment. 3-PO treatment significantly alleviate the injury and degeneration of hippocampal neurons in septic rats, inhibit neuroinflammation and apoptosis, and improve cognitive dysfunction, which may be related to the inhibition of glycolytic isoenzyme PFKFB3.

Effects of acupuncture on regulating the hippocampal inflammatory response in rats exposed to post-traumatic stress disorder

Data from clinical and experimental studies have verified the efficacy and safety of acupuncture in the treatment of post-traumatic stress disorder (PTSD). However, the concrete mechanism has not been well elucidated. The stress-induced activation of inflammatory response is involved in the development and pathogenesis of PTSD. Here, we aimed to investigate the effects of acupuncture on regulating the hippocampal inflammatory response in rats exposed to PTSD. Forty male rats were randomly divided into control, model, acupuncture and sertraline group. Within 1 day after adaptive feeding, all rats were exposed to single prolonged stress (SPS), except for the rats in the control group. Rats in acupuncture group were exposed to acupuncture intervention at the acupoints of Baihui (GV20) and Yintang (GV29), 20 min once per day for 15 days. Rats in sertraline group were exposed to a suspension of sertraline and distilled water (0.2 mg/ml), once per day for 15 days continuously. Body weight and elevated plus maze experiment were detected at different time-points to evaluate the behavioral changes of rats. HE staining method was used to observe the basic pathological morphological changes in hippocampus. Immunofluorescence staining method was used to observe the activation of hippocampal microglia. The content of IL-6 and IL-1β in serum were detected by ELISA method. Compared with the control group, the body weight of rats in model group significantly decreased on 8 days, and the percentage of time in open arms and open arm entries decreased significantly on 15 days after SPS procedures, which indicated that SPS induced PTSD-like behavior in rats. Acupuncture exerted therapeutic effect. Simultaneously, the result of HE staining confirmed that SPS induced hippocampal morphological changes in SPS rats. Notably, acupuncture reversed the reduction and pathological injury to some extent. The results have also shown that acupuncture intervention effectively reversed the activated microglia of the hippocampus in rats. Moreover, the expression of IL-1β in serum was significantly decreased by acupuncture intervention. In summary, the present study demonstrated that the role of acupuncture in eliminating PTSD-like behavior might be connected with reversing the pathological process of the inflammatory response mediated by the activation of microglia induced by SPS.

GATA-binding protein 4 promotes neuroinflammation and cognitive impairment in Aβ1-42 fibril-infused rats through small nucleolar RNA host gene 1/miR-361-3p axis.

Aging with dysregulated metabolic and immune homeostasis stimulates pyroptosis, neuroinflammation, and cellular senescence, thus contributing to etiopathogenesis of Alzheimer's disease. GATA-binding protein 4 (GATA4) functions as a transcriptional factor in response to DNA damage, and is associated with neuroinflammation and cellular senescence. The role of GATA4 in Alzheimer's disease was investigated. GATA4 was elevated in hippocampus of Aβ1-42 fibril-infused rats. Injection with shRNA targeting GATA4 reduced escape latency with increase of time in target quadrant and number of platform crossings in Aβ1-42 fibril-infused rats. Moreover, knockdown of GATA4 ameliorated morphological changes of hippocampus and reduced amyloid plaque deposition in Aβ1-42 fibril-infused rats. Silence of GATA4 repressed neuroinflammation and apoptosis in Aβ1-42 fibril-infused rats. Loss of GATA4 in Aβ1-42 fibril-infused rats reduced the expression of specificity protein 1 (Sp1) to downregulate long noncoding RNA small nucleolar RNA host gene 1 (SNHG1) and upregulated miR-361-3p. Loss of SNHG1 ameliorated learning and memory impairments in Aβ1-42 fibril-infused rats. Overexpression of Sp1 attenuated GATA4 silence-induced decrease of escape latency, increase of time in target quadrant, and number of platform crossings in Aβ1-42 fibril-infused rats. In conclusion, silence of GATA4 ameliorated cognitive dysfunction and inhibited hippocampal inflammation and cell apoptosis through regulation of Sp1/SNHG1/miR-361-3p.

Effects Of Aerobic Exercise On Synaptic Plasticity And PKA Expression In Hippocampus Of Aging Rats

PURPOSE: To investigate the Effects of aerobic exercise on synaptic plasticity and PKA expression in hippocampus of aging rats. METHODS: Sixty male SD rats were divided into 3 group at random: saline control group(SC), aging model group(S), aerobic exercise intervention on aging group(SE). Aging model was established by injecting low galactose via peritoneal, 100 mg / kg, once a day for 6 weeks in S and SE. And S were injected the same dosage of saline. D-gal were injected in S and SE and were simultaneously administered for a 6-week swimming exercise intervention, 6 days a week for 1 hour a day. And the general state of rats was observed weekly. At the end of modeling and swimming, Morris water maze was used to evaluate the spatial learning and memory ability. HE staining was used to observe Morphological changes of Hippocampus. The expression of PKA was tested by western blotting. The expression of BDNF and SYN in Hippocampus was tested by immunofluorescence. The experimental data was reported as mean ± SE. level of significance was set at α = 0.05. RESULTS: 1) Compared with SC and SE, S showed obvious signs of aging, such as loss of weight, decrease of activity, loss hair and neurons significantly reducing, the cell morphology was incomplete and the chromatin was unevenly colored. 2) The Morris water maze test was showed that: Compared with SC, the escape latency of S was significantly increased (P < 0.01); the number of crossing the platform was significantly reduced (P < 0.01). Compared with S, the escape latency of SE was significantly decreased (P < 0.05), and the number of crossing the platform was significantly increased (P < 0.01). 3) Compared with S, the expression of PKA was significantly increased in SC and SE (1.30 ± 0.03 vs. 0.77 ± 0.07, P < 0.01; 1.22 ± 0.11 vs. 0.77 ± 0.07, P < 0.05). 4) Compared to S, the immunofluorescence density values of BDNF and SYN significantly increasing was observed in SC and SE (25.52 ± 1.34 vs. 16.83 ± 1.30, P < 0.01; 23.15 ± 1.26 vs. 16.83 ± 1.30, P < 0.05); (53.85 ± 6.14 vs. 25.68 ± 1.36, P < 0.01; 51.18 ± 1.26 vs. 25.68 ± 1.36, P < 0.01). CONCLUSIONS: 6 weeks of aerobic exercise effectively reverses brain injury and learning and memory impairment in aging rats. The mechanism may be related to significantly up-regulate the expression of PKA in hippocampus to promote synaptic plasticity and improve learning and memory ability.

Studying APOE ɛ4 Allele Dose Effects witha Univariate Morphometry Biomarker.

A univariate neurodegeneration biomarker (UNB) based on MRI with strong statistical discrimination power would be highly desirable for studying hippocampal surface morphological changes associated with APOE ɛ4 genetic risk for AD in the cognitively unimpaired (CU) population. However, existing UNB work either fails to model large group variances or does not capture AD induced changes. We proposed a subspace decomposition method capable of exploiting a UNB to represent the hippocampal morphological changes related to the APOE ɛ4 dose effects among the longitudinal APOE ɛ4 homozygotes (HM, N = 30), heterozygotes (HT, N = 49) and non-carriers (NC, N = 61). Rank minimization mechanism combined with sparse constraint considering the local continuity of the hippocampal atrophy regions is used to extract group common structures. Based on the group common structures of amyloid-β (Aβ) positive AD patients and Aβ negative CU subjects, we identified the regions-of-interest (ROI), which reflect significant morphometry changes caused by the AD development. Then univariate morphometry index (UMI) is constructed from these ROIs. The proposed UMI demonstrates a more substantial statistical discrimination power to distinguish the longitudinal groups with different APOE ɛ4 genotypes than the hippocampal volume measurements. And different APOE ɛ4 allele load affects the shrinkage rate of the hippocampus, i.e., HM genotype will cause the largest atrophy rate, followed by HT, and the smallest is NC. The UMIs may capture the APOE ɛ4 risk allele-induced brain morphometry abnormalities and reveal the dose effects of APOE ɛ4 on the hippocampal morphology in cognitively normal individuals.

The analysis of structural magnetic resonance imaging manifestation of hippocampus based on voxel and spherical harmonic surface morphometry in mesial temporal lobe epilepsy

Objective: To compare the hippocampal volume and local surface morphology changes in patients with mesial temporal lobe (mTLE) using the voxel-based morphometry and spherical harmonic methods respectively. Methods: A total of 66 patients (31 males and 35 females, age range from 17 to 48 (28±8) years) with mTLE and 80 age-and gender-matched controls (38 males and 42 females, age range from 19 to 46 (27±7) years) were retrospectively collected from July 2009 to February 2019 at Jinling hospital.. High resolution structural MRI of the whole brain, three-dimensional T1-weighted data(3DT1) were acquired from each subject. The changes of hippocampal volume and surface morphology were evaluated between mTLE groups and controls for observing the hippocampal atrophy pattern by using voxel-based morphometry and spherical harmonic shape descriptions point distribution model respectively. Pearson correlation analysis was conducted for observing the relationship between the morphological changes of hippocampus and disease duration. Results: Compared with the controls, hippocampal volume on the affected side in patients with mTLE was significantly reduced (Z-score:-1.55±0.57 vs 0.38±0.58, P<0.001) and negatively correlated with disease duration (r=-0.297, P=0.016). Furthermore, surface morphology analysis subtly showed that the atrophy of the affected hippocampus in patients with mTLE mainly located in the head, mesial lateral part and posterior tail of the hippocampus. Their displacement values were negatively correlated with disease duration (r=-0.336, P=0.006) and positively associated with the hippocampal grey matter volume (r=0.336, P=0.006). Conclusions: Voxel-based morphometry analysis reveals a global reduction in hippocampal volume, while the morphological measurement method based on surface shape can describe the local morphological changes of hippocampal atrophy.

Proteomic study on the damage of learning and memory ability of rat offspring caused by chronic stress during pregnancy

Objective: To study the differential protein and signal pathway related to the impairment of learning and memory ability of offspring caused by chronic stress during pregnancy and explore the possible mechanism. Methods: From July to October 2019, sixteen SPF free female SD rats aged 80-90 days, weighing (200±20) g. Twelve SPF grade male SD rats aged 90-100 days, weighing (220±20) g. After a week of adaptive feeding, the female rats were randomly divided into control group and model group (8 rats in each group) , male rats were divided into control mating group (n=8) and model mating group (n=4) . Chronic unpredictable mild stress (CUMS) model was established and stimulated continuously for 21 days. One day before stress, the first, seventh, fourteenth and 21th day after stress, the blood was collected from the inner canthus vein of the female rats, and the content of corticosterone was determined. Morris water maze test was used to detect the spatial learning and memory ability of offspring rats. The morphological changes of hippocampus were observed by HE and Nissl staining. The proteomic correlation analysis of offspring rats' hippocampus was performed by isobaric tags for relative and absolute quantification (iTRAQ) technique. Results: Compared with the control group, the content of plasma corticosterone in the model group was significantly higher (F=7.717, P<0.05) , and the model was successfully established. In Morris water maze test, compared with the control offspring group, the escape latency was longer, the average swimming speed was lower, the number of crossing platform was less, and the target quadrant run was shorter in the model offspring group (P<0.05) . The pathological results showed that the morphology of cells in the hippocampal tissue of the model offspring group was irregular, the number of neurons was small, Nissl body was unevenly distributed, the volume was small and the number was small. Mass spectrometry analysis showed that a total of 5065 proteins were screened out in the two offspring groups, and 26 proteins were differentially expressed (P<0.05) , of which 19 proteins were up-regulated and 7 proteins were down regulated. The differential proteins were mainly involved in 23 biological processes, 14 cellular components and 9 molecular functions. Kyoto Encyclopedia of genes and genomes (KEGG) enrichment analysis showed that 57 pathways were enriched, of which 8 signaling pathways were significantly enriched (P<0.05) . There were 5 signaling pathways that might be involved in the impairment of learning and memory ability of offspring, including neuroactive ligand receptor interaction, cGMP-PKG signaling pathway, adhesion and connection, adhesion and connection FoxO signaling pathway and Notch signaling pathway, mainly including tyrosine protein kinase receptor, tyrosine kinase receptor and Notch signaling pathway, and α2A adrenergic receptor, cGMP dependent protein kinase and other differential proteins may be involved in the injury process. Conclusion: The damage of learning and memory ability of offspring may be caused by chronic stress during pregnancy rats. The enriched signal pathway and key differential proteins of proteomics may play an important role in the process of damage.

Neuroprotective role of Glycyrrhiza glabra on chronic noise induced changes in Hippocampal morphology and its functions in wistar albino rats

Background: Noise has become inexorable stress due to the increase in urbanization, automobile usage, and lifestyle modification.Aim: The study aims to investigate the effect of chronic noise stress on hippocampal morphology and the neuroprotective effect of Glycyrrhiza glabra (GG) on stress-induced male Wistar albino rats. Methods: Adult albino rats were randomly divided into four groups. Each group contained six animals. Rats exposed to chronic noise stress (100 dB/4 h – 30Days), Noise + GG (150 mg/kg Bw/Oral), and GG alone were compared with control animal and assessed for behaviour using the hole-board test, marble burying test, the morphology of hippocampus by histology, DNA fragmentation and assessed the Phytochemical constitutes in GG. Results: The rats exposed to chronic noise stress showed significance (p&lt;0.05) of behavioral alterations such as increased fear and anxiety, obsessive-compulsive behaviour, enlarged lateral ventricle, and reduced hippocampal volume. Conclusion: The results reported that chronic noise stress affects the neurobehavioral due to reduced hippocampal volume.

Hypermethioninemia induces memory deficits and morphological changes in hippocampus of young rats: implications on pathogenesis.

The aim of this study was to investigate the effect of the chronic administration of methionine (Met) and/or its metabolite, methionine sulfoxide (MetO), on the behavior and neurochemical parameters of young rats. Rats were treated with saline (control), Met (0.2-0.4g/kg), MetO (0.05-0.1g/kg), and/or a combination of Met + MetO, subcutaneously twice a day from postnatal day 6 (P6) to P28. The results showed that Met, MetO, and Met + MetO impaired short-term and spatial memories (P < 0.05), reduced rearing and grooming (P < 0.05), but did not alter locomotor activity (P > 0.05). Acetylcholinesterase activity wasincreased in the cerebral cortex, hippocampus, and striatum following Met and/or MetO (P < 0.05) treatment, while Na+,K+-ATPaseactivity wasreduced in the hippocampus (P < 0.05). There was an increase in the level of thiobarbituric acid reactive substances (TBARS) in the cerebral cortex in Met-, MetO-, and Met + MetO-treated rats (P < 0.05). Met and/or MetO treatment reduced superoxide dismutase, catalase, and glutathione peroxidase activity, total thiol content, and nitrite levels, and increased reactive oxygen species and TBARS levels in the hippocampus and striatum (P < 0.05). Hippocampal brain-derived neurotrophic factor was reduced by MetO and Met + MetO compared with the control group. The number of NeuN-positive cellswas decreased in the CA3 in Met + MetO group and in the dentate gyrus in the Met, MetO, and Met + MetO groups compared to control group (P < 0.05). Taken together, these findings further increase our understanding of changes in the brain in hypermethioninemia by elucidating behavioral alterations, biological mechanisms, and the vulnerability of brain function to high concentrations of Met and MetO.

Deformation-based shape analysis of the hippocampus in the semantic variant of primary progressive aphasia and Alzheimer’s disease

BackgroundIncreasing evidence shows that the semantic variant of primary progressive aphasia (svPPA) is characterized by hippocampal atrophy. However, less is known about disease-related morphological hippocampal changes. The goal of the present study is to conduct a detailed characterization of the impact of svPPA on global hippocampus volume and morphology compared with control subjects and patients with Alzheimer’s disease (AD). MethodsWe measured hippocampal volume and deformation-based shape differences in 22 patients with svPPA compared with 99 patients with AD and 92 controls. Multiple Automatically Generated Templates Brain Segmentation Algorithm (MAGeT-Brain) was used on MRI images obtained at the diagnostic visit. ResultsComparable left and right hippocampal atrophy were observed in svPPA and AD. Deformation-based shape analysis showed a common pattern of morphological deformation in svPPA and AD compared with controls. More specifically, both svPPA and AD showed inward deformations in the dorsal surface of the hippocampus, from head to tail on the left side, and more limited to the anterior portion of the body in the right hemisphere. These results also pointed out that both diseases are characterized by a lateral displacement of the central part (body) of the hippocampus. DiscussionOur study provides critical new evidence of hippocampal morphological changes in svPPA, similar to those found in AD. These findings highlight the importance of considering morphological hippocampal changes as part of the anatomical profile of patients with svPPA.

The Cannabinoid Receptor Agonist WIN55,212-2 Ameliorates Hippocampal Neuronal Damage After Chronic Cerebral Hypoperfusion Possibly Through Inhibiting Oxidative Stress and ASK1-p38 Signaling.

Chronic cerebral hypoperfusion (CCH) is a major contributor to cognitive decline and degenerative processes leading to Alzheimer's disease, vascular dementia, and aging. However, the delicate mechanism of CCH-induced neuronal damage, and therefore proper treatment, remains unclear. WIN55,212-2 (WIN) is a nonselective cannabinoid receptor agonist that has been shown to have effects on hippocampal neuron survival. In this study, we investigated the potential roles of WIN, as well as its underlying mechanism in a rat CCH model of bilateral common carotid artery occlusion. Hippocampal morphological changes and mitochondrial ultrastructure were detected using hematoxylin and eosin staining and electron microscopy, respectively. Various biomarkers, such as reactive oxidative species (ROS), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) were used to assess the level of oxidative stress in the hippocampus. Furthermore, the expression levels of neuronal nuclei (NeuN), apoptosis signal-regulating kinase 1 (ASK1)-p38 signaling proteins, cleaved Caspase-9 and -3, and cytochrome-c (Cyt-C) were accessed by western blotting. CCH decreased the levels of NeuN, Cyt-C (mitochondrial), SOD, and CAT, and increased the levels of MDA, phosphorylated ASK1 and phosphorylated p38, cleaved Caspase-9 and -3, and Cyt-C (cytoplasm), which were reversed by WIN treatment. Chronic treatment with WIN also improved CCH-induced neuronal degeneration and mitochondrial fragmentation. These findings indicated that WIN may be a potential therapeutic agent for ischemic neuronal damage, involving a mechanism associated with the suppression of oxidative stress and ASK1-p38 signaling.

Carvacrol suppresses learning and memory dysfunction and hippocampal damages caused by chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion (CCH) is a common phenomenon in many neurological diseases such as vascular dementia and Alzheimer's disease. Several drugs have been investigated to prevent and treat the CCH. The carvacrol (CAR) has been shown to have beneficial effects on various neurodegenerative and neuropsychiatric disorders. Accordingly, the present study was designed to evaluate the effect of CAR on neuronal damages in hippocampus in a well-defined model for CCH. Forty-eight male Wistar rats were equally divided into four groups of sham (A), CCH (B), CCH+ CAR 25, and 50 mg/kg/daily (C and D). The animals were subjected to permanent bilateral occlusion of the carotid arteries (2-vessel occlusion, 2VO) to induce CCH model. Cognitive function was evaluated by Morris water maze test. Morphological changes of hippocampus were assessed using Nissl staining. Free radical scavenging activity was measured by 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Moreover, catalase (CAT) and superoxide dismutase (SOD) activities and lipid peroxidation levels were measured using biochemical analysis. CAR significantly improved the spatial learning and memory deficits assessed using the Morris water maze test. CAR also significantly attenuated neuronal necrosis as well as malondialdehyde (MDA) and elevated the levels of SOD and CAT activity in the hippocampus. The results indicate that CAR produces significant neuroprotective effects on neuronal damages induced by CCH. Protective effect of CAR may be mediated by antioxidative effect of this drug.

Effect of triptolide on cognitive dysfunction in vascular dementia rats through SIRT1/NF-κB signaling pathway

To investigate the effect of triptolide on cognitive dysfunction in vascular dementia rats and its effect on SIRT1/NF-κB pathway,fifty healthy male Sprague-Dawley rats were randomly divided into 5 groups: Sham operation group( Sham group),vascular dementia model group( 2 VO group),triptolide intraperitoneal injection group( TR group),triptolide intraperitoneal injection + EX527 intracerebroventricular administration group( T+E group),EX527 intracerebroventricular administration group( EX527 group). After 4 weeks of modeling,Morris water maze test and object recognition test were used to evaluate the learning and memory ability of rats. The morphological changes of hippocampus in each group were observed in brain tissue. The chemical colorimetry was used to detect the activities of SOD and MDA in hippocampus. IL-6 and TNF-α levels were detected by ELISA. Western blot was used to detect the expression of SIRT1,NF-κB,IκBα and caspase 3 in hippocampus. The results showed that compared with the Sham group,the learning and memory ability of the vascular dementia model rats was reduced,the SOD activity in the hippocampus was decreased,the MDA activity and IL-6 level were increased,the neuronal degeneration changed significantly,the expression of SIRT1 and IκBα was decreased and the expression of caspase 3 and NF-κB was significantly increased. After intervention by triptolide,the level of oxidative stress and the degenerative changes in hippocampus were significantly slowed down. The expression of SIRT1 and IκBα protein was increased and the expression of caspase 3 and NF-κB was significantly decreased. While,after intervention by triptolide and EX527,the expression of SIRT1 was decreased,the levels of oxidative stress and neuronal degeneration in the hippocampus were aggravated,and the learning and memory ability was reduced. The results showed that triptolide could improve cognitive impairment in vascular dementia rats and its mechanism may be related to SIRT1/NF-κB signaling pathway.

Effects of metformin on depressive behavior in chronic stress rats

To detect the effects of metformin on the depressive-like behaviors in rats. Forty male SD rats were randomly divided into four groups: control group (CON group), metformin group (MET group), model group (CUMS group), model + metformin group (CUMS + MET group), 10 rats in each group. Chronic unpredictable mild stress (CUMS) method was used to establish rat depression model in three weeks. After the model was established successfully, two metformin groups were intraperitoneally injected with metformin (100 mg/kg), while the control group and the model group were injected with the same amount of saline once a day for two weeks. After that, the changes of weight gain, sucrose water preference experiment, forced swimming test, tail suspension immobility test and open field test were detected. The morphological changes of hippocampus were observed by Nissl staining. Compared with the control group, the weight gain of rats in CUMS group was significantly slowed down (P＜0.05), the sucrose preference rate and the spontaneous activity were significantly reduced (P＜0.05), and the immobility time in forced swimming and tail suspension immobility test was significantly prolonged (P＜0.05), and the morphological structure of hippocampus was changed, which confirmed the success of CUMS depression model. Compared with CUMS group, metformin treatment had no significant effect on body weight of rats, but it could significantly improve sucrose water intake, immobility time and spontaneous activity of CUMS depression model rats (P＜0.05), and improve the abnormal morphological changes of hippocampus in CUMS rats. Metformin has a therapeutic benefit against CUMS-induced depression, which provides a new treatment for patients with diabetes mellitus complicated with depression.