Hippocampal Differences Research Articles

Signature of paraoxonases in the altered redox homeostasis in Alzheimer's disease

Paraoxonase (PON) enzymes (PON1, PON2 and PON3) exert antioxidant properties through arylesterase, lactonase and paraoxonase activities. Increasing findings suggested their potential involvement, particularly PON1 and PON2, in Alzheimer's disease (AD), a neurodegenerative pathology characterized by early oxidative stress. Specifically, decreased serum PON1-arylesterase and lactonase activities seem to be associated with an increased brain oxidative damage in early AD, leading to hypothesize that PON activity alterations might be an early event in AD. To address this hypothesis, the levels of 4-hydroxynonenal (4-HNE; i.e. a marker of oxidative stress damage) along with the protein expression and enzymatic activity of PON1 and PON2 have been investigated in the brain and serum of young [Postnatal day (PD)8–10, 20–25 and 60–65] asymptomatic 3xTg-AD female mice, one of the most used transgenic models of AD.At PD 8–10, there were no differences in hippocampus and prefrontal cortex (PFC) 4-HNE expression levels between 3xTg-AD mice compared to controls (Non-Tg mice). On the other hand, significant increased levels of 4-HNE were detected in PD 20–30 3xTg-AD mice hippocampus, while a significant reduction was observed in 3xTg-AD group at PD 60–65. In the PFC, 4-HNE levels were significantly reduced in 3xTg-AD mice brain at PD 20–30, while no differences in 4-HNE levels were detected at PD 60–65.No significant differences in arylesterase and lactonase activities were observed in the plasma of 3xTg-AD and Non-Tg mice at the different considered ages. Compared to Non-Tg mice, a reduction of brain arylesterase activity was found in 3xTg-AD female at PD 20–30 and PD 60–65, but it was significant only in the younger group. Finally, a similar trend was observed also for PON1 and PON2 protein levels, with both significantly, and solely, decreased in 3xTg-AD mice brain at PD 20–30.Overall, these findings suggest that the altered oxidative stress homeostasis in the 3xTg-AD female mice may be related to an early reduction in activity and expression of PONs enzymes most likely via a reduced brain arylesterases activity.

Setting boundaries: Development of neural and behavioral event cognition in early childhood.

The ongoing stream of sensory experience is so complex and ever-changing that we tend to parse this experience at "event boundaries," which structures and strengthens memory. Memory processes undergo profound change across early childhood. Whether young children also divide their ongoing processing along event boundaries, and if those boundaries relate to memory, could provide important insight into the development of memory systems. In Study 1, 4-7-year-old children and adults segmented a cartoon, and we tested their memory. Children's event boundaries were more variable than adults' and differed in location and consistency of agreement. Older children's event segmentation was more adult-like than younger children's, and children who segmented events more like adults had better memory for those events. In Study 2, we asked whether these developmental differences in event segmentation had their roots in distinct neural representations. A separate group of 4-8-year-old children watched the same cartoon while undergoing an fMRI scan. In the right hippocampus, greater pattern dissimilarity across event boundaries compared to within events was evident for both child and adult behavioral boundaries, suggesting children and adults share similar event cognition. However, the boundaries identified by a data-driven Hidden Markov Model found that a different brain region-the left and right angular gyrus-aligned only with event boundaries defined by children. Overall, these data suggest that children's event cognition is reasonably well-developed by age 4 but continues to become more adult-like across early childhood. RESEARCH HIGHLIGHTS: Adults naturally break their experience into events, which structures and strengthens memory, but less is known about children's event perception and memory. Study 1 had adults and children segment and remember events from an animated show, and Study 2 compared those segmentations to other children's fMRI data. Children show better recognition and temporal order memory and more adult-like event segmentation with age, and children who segment more like adults have better memory. Children's and adults' behavioral boundaries mapped onto pattern similarity differences in hippocampus, and children's behavioral boundaries matched a data-driven model's boundaries in angular gyrus.

Proteomic differences in hippocampus and cortex of sudden unexplained death in childhood

Sudden unexplained death in childhood (SUDC) is death of a child over 1 year of age that is unexplained after review of clinical history, circumstances of death, and complete autopsy with ancillary testing. Multiple etiologies may cause SUDC. SUDC and sudden unexpected death in epilepsy (SUDEP) share clinical and pathological features, suggesting some similarities in mechanism of death and possible abnormalities in hippocampus and cortex. To identify molecular signaling pathways, we performed label-free quantitative mass spectrometry on microdissected frontal cortex, hippocampal dentate gyrus (DG), and cornu ammonis (CA1-3) in SUDC (n = 19) and pediatric control cases (n = 19) with an explained cause of death. At a 5% false discovery rate (FDR), we found differential expression of 660 proteins in frontal cortex, 170 in DG, and 57 in CA1-3. Pathway analysis of altered proteins identified top signaling pathways associated with activated oxidative phosphorylation (p = 6.3 × 10–15, z = 4.08) and inhibited EIF2 signaling (p = 2.0 × 10–21, z = − 2.56) in frontal cortex, and activated acute phase response in DG (p = 8.5 × 10–6, z = 2.65) and CA1-3 (p = 4.7 × 10–6, z = 2.00). Weighted gene correlation network analysis (WGCNA) of clinical history indicated that SUDC-positive post-mortem virology (n = 4/17) had the most significant module in each brain region, with the top most significant associated with decreased mRNA metabolic processes (p = 2.8 × 10–5) in frontal cortex. Additional modules were associated with clinical history, including fever within 24 h of death (top: increased mitochondrial fission in DG, p = 1.8 × 10–3) and febrile seizure history (top: decreased small molecule metabolic processes in frontal cortex, p = 8.8 × 10–5) in all brain regions, neuropathological hippocampal findings in the DG (top: decreased focal adhesion, p = 1.9 × 10–3). Overall, cortical and hippocampal protein changes were present in SUDC cases and some correlated with clinical features. Our studies support that proteomic studies of SUDC cohorts can advance our understanding of the pathogenesis of these tragedies and may inform the development of preventive strategies.

The role of hippocampus and amygdala morphology in memory bias of learned fear in youth with chronic pain

Exaggerated recall of pain may pose a risk for pain persistence and elevated pain-related distress. In adults with chronic pain, such discrepancy (or memory bias) has been correlated to hippocampal morphology. However, this has not been examined in youth with chronic pain nor applied to the recall of fear and negative affect, and to amygdala morphology, considering its involvement in threat processing. This study therefore aims to examine whether hippocampal and amygdala shape is related to a biased recall of threat-safety learning in youth with chronic pain. T1-weighted MR images of 85 youth were analyzed (age M=15.6±0.9), of which 54 had chronic pain. The Screaming Lady paradigm was used for threat conditioning. Follow-up memory interviews assessed recalled fear and unpleasantness of conditioned stimuli (threat/CS+, safe/CS-). A discrepancy score was calculated between actual and recalled fear/negative affect (n=60, including n=37 patients). Permutation-based statistics focused on group differences in hippocampus and amygdala morphology using vertex-based shape analysis, as well as on correlations with discrepancy scores (voxel-based thresholding, corrected for multiple comparisons). We found an overall negative memory bias only for unpleasantness of the CS+. On an individual level, 20% had a negatively-biased recall for unpleasantness of the CS+, and 35% for fear of the CS+. Analyses showed no group differences in hippocampal or amygdala shape displacement. Nevertheless, there was a negative correlation between memory bias in fear for the CS+ and right amygdala shape displacement, indicating that a more negative fear-related memory bias is associated with thinning of this region. No other correlations were observed. Our findings revealed that a recall bias for learned fear is related to amygdala morphology in youth. Youth with chronic pain, however, did not differ in amygdala morphology compared to controls. NIH R01HD083270 to LE Simons.

The importance of identifying functional Val158Met polymorphism in catechol-O- Methyltransferase when assessing MRI-based volumetric measurements in major depressive disorder.

Many studies have shown volumetric differences in the hippocampus between COMT gene polymorphisms and other studies have shown differences between depressed patients and controls; yet, few studies have been completed to identify the volumetric differences when taking both factors into consideration. Using voxel-based morphology (VBM) we investigated, in major depressive disorder (MDD) patients and healthy controls, the relationship between COMT gene polymorphism and volumetric abnormalities. Data from 60 MDD patients and 25 healthy controls were included in this study. Volumetric measurements and genotyping of COMTval158met polymorphism were conducted to determine its impact on gray matter volume (GMV) in the hippocampus and amygdala using a Met dominant model (Val/Val vs Met/Val & Met/Met). In the analysis, a significant difference in the right hippocampus (p = 0.015), right amygdala (p = 0.003) and entire amygdala (p = 0.019) was found between the interaction of diagnosis and genotype after MRI scanner, age and sex correction. Healthy controls (HC) with the Met dominant genotype exhibited a larger right hippocampal, right amygdalar and entire amydgalar volume than MDD patients with the Met dominant genotype. Conversely, HC with the Val/Val genotype displayed a lower right hippocampal, right amygdalar and entire amygdalar volume than their MDD counterparts. This study shows that COMT polymorphism and depression may have a confounding effect on neuroimaging studies.

Sex difference in CHI3L1 expression levels in human brain aging and in Alzheimer’s disease

Several genetic sexual dimorphisms have been identified in animal and human brains, which may form a neural basis for sex-specific predisposition to neurological diseases. In the last years, clinical studies have observed that Alzheimer’s disease (AD) disproportionately affects women compared with men. Chitinase-3-Like 1 protein (CHI3L1) has been frequently investigated in body fluids as a surrogate marker of neuroinflammation in AD and other neurological disorders. Nevertheless, the sex-related differences in CHI3L1 expression in the human brain has not yet been investigated. Here we aimed to evaluate the specificity of increase of CHI3L1 in five brain regions (cerebellum, dorsolateral prefrontal cortex, prefrontal cortex, hippocampus, and visual cortex) of male and female controls during normal aging, as well as in AD patients. We selected ten microarray datasets from NCBI, representing normal aging (n = 1290) and AD (n = 992), and stratified the brain specimens according to age, gender and brain region. The expression levels of CHI3L1 were correlated with age and gender. Female control brain specimens showed higher CHI3L1 expression than male brains. The expression differences between men and women were most obvious in older subjects. The expression analysis of CHI3L1 in the different brain regions of AD subjects also showed sex differences; females with AD had greater expression in the cerebellum than males. Notably, sex-associated CHI3L1 expression differences in hippocampus disappeared in AD. These findings demonstrate that the expression of CHI3L1 in the brains of cognitively unimpaired subjects and AD patients is closely linked to age and sex, which was most obvious in the cerebellum. Further studies are needed to confirm our results.

UHPLC-QTOFMS-Based Metabolomic Analysis of the Hippocampus in Hypoxia Preconditioned Mouse

Background: Hypoxia appears in a number of extreme environments, including high altitudes, the deep sea, and during aviation, and occurs in cancer, cardiovascular disease, respiratory failures and neurological disorders. Though it is well recognized that hypoxic preconditioning (HPC) exerts endogenous neuroprotective effect against severe hypoxia, the mediators and underlying molecular mechanism for the protective effect are still not fully understood. This study established a hippocampus metabolomics approach to explore the alterations associated with HPC.Methods: In this study, an animal model of HPC was established by exposing the adult BALB/c mice to acute repetitive hypoxia four times. Ultra-high liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOFMS) in combination with univariate and multivariate statistical analyses was employed to deciphering metabolic changes associated with HPC in hippocampus tissue. MetaboAnalyst 3.0 was used to construct HPC related metabolic pathways.Results: The significant metabolic differences in hippocampus between the HPC groups and control were observed, indicating that HPC mouse model was successfully established and HPC could caused significant metabolic changes. Several key metabolic pathways were found to be acutely perturbed, including phenylalanine, tyrosine and tryptophan biosynthesis, taurine and hypotaurine metabolism, phenylalanine metabolism, glutathione metabolism, alanine, aspartate and glutamate metabolism, tyrosine metabolism, tryptophan metabolism, purine metabolism, citrate cycle, and glycerophospholipid metabolism.Conclusion: The results of the present study provided novel insights into the mechanisms involved in the acclimatization of organisms to hypoxia, and demonstrated the neuroprotective mechanism of HPC.

Morphological changes in subregions of hippocampus and amygdala in major depressive disorder patients.

Despite many neuroimaging studies in the past years, the neuroanatomical substrates of major depressive disorder (MDD) subcortical structures are still not well understood. Since hippocampus and amygdala are the two vital subcortical structures that most susceptible to MDD, finding the evidence of morphological changes in their subregions may bring some new insights for MDD research. Combining structural magnetic resonance imaging (MRI) with novel morphometry analysis methods, we recruited 25 MDD patients and 28 healthy controls (HC), and investigated their volume and morphological differences in hippocampus and amygdala. Relative to volumetric method, our methods detected more significant global morphological atrophies (p<0.05). More precisely, subiculum and cornu ammonis (CA) 1 subregions of bilateral hippocampus, lateral (LA) and basolateral ventromedial (BLVM) of left amygdala and LA, BLVM, central (CE), amygdalostriatal transition area (ASTR), anterior cortical (ACO) and anterior amygdaloid area (AAA) of right amygdala were demonstrated prone to atrophy. Correlation analyses between each subject's surface eigenvalues and Hamilton Depression Scale (HAMD) were then performed. Correlation results showed that atrophy areas in hippocampus and amygdala have slight tendencies of expanding into other subregions with the development of MDD. Finally, we performed group morphometric analysis and drew the atrophy and expansion areas between MDD-Medicated group (only 19 medicated subjects in MDD group were included) and HC group, found some preliminary evidence about subregional morphological resilience of hippocampus and amygdala. These findings revealed new pathophysiologic patterns in the subregions of hippocampus and amygdala, which can help with subsequent smaller-scale MDD research.

Neuroimaging Studies of Suicidal Behavior and Non-suicidal Self-Injury in Psychiatric Patients: A Systematic Review.

Background: With around 800,000 people taking their own lives every year, suicide is a growing health concern. Understanding the factors that underlie suicidality and identifying specific variables associated with increased risk is paramount for increasing our understanding of suicide etiology. Neuroimaging methods that enable the investigation of structural and functional brain markers in vivo are a promising tool in suicide research. Although a number of studies in clinical samples have been published to date, evidence about neuroimaging correlates for suicidality remains controversial.Objective: Patients with mental disorders have an increased risk for both suicidal behavior and non-suicidal self-injury. This manuscript aims to present an up-to-date overview of the literature on potential neuroimaging markers associated with SB and NSSI in clinical samples. We sought to identify consistently reported structural changes associated with suicidal symptoms within and across psychiatric disorders.Methods: A systematic literature search across four databases was performed to identify all English-language neuroimaging articles involving patients with at least one psychiatric diagnosis and at least one variable assessing SB or NSSI. We evaluated and screened evidence in these articles against a set of inclusion/exclusion criteria and categorized them by disease, adhering to the PRISMA guidelines.Results: Thirty-three original scientific articles investigating neuroimaging correlates of SB in psychiatric samples were found, but no single article focusing on NSSI alone. Associations between suicidality and regions in frontal and temporal cortex were reported by 15 and 9 studies across four disorders, respectively. Furthermore, differences in hippocampus were reported by four studies across three disorders. However, we found a significant lack of replicability (consistency in size and direction) of results across studies.Conclusions: Our systematic review revealed a lack of neuroimaging studies focusing on NSSI in clinical samples. We highlight several potential sources of bias in published studies, and conclude that future studies should implement more rigorous study designs to minimize bias risk. Despite several studies reporting associations between SB and anatomical differences in the frontal cortex, there was a lack of consistency across them. We conclude that better-powered samples, standardized neuroimaging and analytical protocols are needed to continue advancing knowledge in this field.

Sex Dimorphism Profile of Alzheimer's Disease-Type Pathologies in an APP/PS1 Mouse Model.

Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by parenchymal and vascular beta-amyloid (Aβ) burden, tau pathology, neuroinflammation, and loss of neurons and synapses. There is a clear sex difference in the prevalence of AD. However, sex differences in AD-type pathologies have not been systematically documented. Applying 12-month-old female and male APP/PS1 mice as a model, we investigated the sex dimorphism in these major pathological indices. Compared with male APP/PS1 mice, the females exhibited higher parenchymal Aβ burdens, with the sex difference in hippocampus being the most significant. Female APP/PS1 mice had more severe cerebral amyloid angiopathy and subsequent microhemorrhage. In addition, female APP/PS1 mice also showed higher levels of phosphorylated tau and proinflammatory cytokines, more severe astrocytosis and microgliosis, and greater neuronal and synaptic degenerations. The present study systematically described a sex dimorphism in AD-type pathologic indices, suggesting that gender should be taken into account in designing studies involving these pathological indices and when interpreting the relevant findings in those studies.

Altered Hippocampal-Parahippocampal Function During Stimulus Encoding

Declarative memory-the ability to learn, store, and retrieve information-has been consistently reported to be altered in schizophrenia, and hippocampal-parahippocampal dysfunction has been implicated in this deficit. To elucidate the possible role of genetic risk factors in such findings, it is necessary to study healthy relatives of patients with schizophrenia who carry risk-associated genes but not the confounding factors related to the disorder. To investigate whether altered brain responses, particularly in the hippocampus and parahippocampus, during the encoding phase of a simple declarative memory task are also observed in unaffected siblings who are at increased genetic risk for schizophrenia. Functional magnetic resonance imaging was used with a simple visual declarative memory paradigm to test for differences in neural activation across normal control participants, patients with schizophrenia, and their healthy siblings. This study was conducted at a research center and included a total of 308 participants (181 normal control participants, 65 healthy siblings, and 62 patients with schizophrenia); all participants were white of European ancestry. All participants completed a declarative memory task involving incidental encoding of neutral visual scenes interleaved with crosshair fixation while undergoing functional magnetic resonance imaging. Differences in hippocampus and parahippocampus activation and coupling across groups and correlations with accuracy were analyzed. Analyses were repeated in pairwise-matched samples. Both patients with schizophrenia and their healthy siblings showed reduced parahippocampal activation (bilaterally) and hippocampal-parietal (BA 40) coupling during the encoding of novel stimuli when compared with normal control participants. There was a significant positive correlation between parahippocampal activation during encoding and the visual-memory score. These results suggest that altered hippocampal-parahippocampal function during encoding is an intermediate biologic phenotype related to increased genetic risk for schizophrenia. Therefore, measuring hippocampal-parahippocampal function with neuroimaging represents a potentially useful approach to understanding genetic mechanisms that confer risk for schizophrenia.

FKBP5 and Attention Bias for Threat

The FKBP5 gene product regulates glucocorticoid receptor (GR) sensitivity and hypothalamic-pituitary-adrenal axis functioning and has been associated with many stress-related psychiatric disorders. The study of intermediate phenotypes, such as emotion-processing biases and their neural substrates, provides a way to clarify the mechanisms by which FKBP5 dysregulation mediates risk for psychiatric disorders. To examine whether allelic variations for a putatively functional single-nucleotide polymorphism associated with FKBP5 gene regulation (rs1360780) would relate differentially to attention bias for threat. this was measured through behavioral response on a dot probe task and hippocampal activation during task performance. Morphologic substrates of differential hippocampal response were also measured. Cross-sectional study conducted from 2010 to 2012 examining associations between genotype, behavioral response, and neural response (using functional magnetic resonance imaging [fMRI]) on the dot probe; voxel-based morphometry and global and local shape analyses were used to measure structural differences in hippocampi between genotype groups. Participants were recruited from primary care clinics of a publicly funded hospital in Atlanta, Georgia. An African American cohort of adults (N = 103) was separated into 2 groups by genotype: one genotype group included carriers of the rs1360780 T allele, which has been associated with increased risk for posttraumatic stress disorder and affective disorders; the other group did not carry this allele. Behavioral data included both sexes (N = 103); the MRI cohort (n = 36) included only women. Behavioral and fMRI (blood oxygen level-dependent) response, voxel-based morphometry, and shape analyses. Carriers of the rs1360780 T allele showed an attention bias toward threat compared with individuals without this allele (F1,90 = 5.19, P = .02). Carriers of this allele demonstrated corresponding increases in hippocampal activation and differences in morphology; global and local shape analyses revealed alterations in hippocampal shape for TT/TC compared with CC genotype groups. Genetic variants of FKBP5 may be associated with risk for stress-related psychiatric disorders via differential effects on hippocampal structure and function, resulting in altered attention response to perceived threat.

Differences in Brain Activity during a Verbal Associative Memory Encoding Task in High- and Low-fit Adolescents

Aerobic fitness is associated with better memory performance as well as larger volumes in memory-related brain regions in children, adolescents, and elderly. It is unclear if aerobic exercise also influences learning and memory functional neural circuitry. Here, we examine brain activity in 17 high-fit (HF) and 17 low-fit (LF) adolescents during a subsequent memory encoding paradigm using fMRI. Despite similar memory performance, HF and LF youth displayed a number of differences in memory-related and default mode (DMN) brain regions during encoding later remembered versus forgotten word pairs. Specifically, HF youth displayed robust deactivation in DMN areas, including the ventral medial PFC and posterior cingulate cortex, whereas LF youth did not show this pattern. Furthermore, LF youth showed greater bilateral hippocampal and right superior frontal gyrus activation during encoding of later remembered versus forgotten word pairs. Follow-up task-dependent functional correlational analyses showed differences in hippocampus and DMN activity coupling during successful encoding between the groups, suggesting aerobic fitness during adolescents may impact functional connectivity of the hippocampus and DMN during memory encoding. To our knowledge, this study is the first to examine the influence of aerobic fitness on hippocampal function and memory-related neural circuitry using fMRI. Taken together with previous research, these findings suggest aerobic fitness can influence not only memory-related brain structure, but also brain function.

Hippocampal metabolic dysfunction in juvenile myoclonic epilepsy: 3D multivoxel spectroscopy study

Purpose To investigate the metabolic differences in hippocampi of patients with juvenile myoclonic epilepsy (JME) and healthy controls using magnetic resonance spectroscopy (MRS). Methods A 3D multivoxel SE 135 MRS study on 1.5 T scanner of both hippocampi was performed in 17 patients with JME and normal brain MRI and in 19 age and sex matched controls. Three dominant signals were measured: Choline (Cho), Creatine (tCr) and N-Acetylaspartate (NAA) and expressed as ratios of Cho:tCr, NAA:tCr, NAA:Cho and NAA:(Cho + tCr). Metabolite ratios in head, body and tail of each hippocampus in the JME group of patients were compared with ratios from corresponding structures in the control group. Results We found a significant difference in metabolite ratios of both hippocampi between the JME and the control groups. We detected significant differences of Cho:tCr in the head, NAA:tCr in the head, body and tail, NAA:Cho and NAA:(Cho + tCr) in the body and tail of the left hippocampus, and NAA:Cho and NAA:(Cho + tCr) in the body and tail of the right hippocampus. Discussion Although not previously recognized as a part of the epileptogenic network, our results suggest that the hippocampus, well recognized as a key player in focal epilepsies , may have a certain role in the pathogenesis of JME.

Novel oximes as blood–brain barrier penetrating cholinesterase reactivators

The US Army utilizes pralidoxime (2-PAM) for the reactivation of OP-inhibited AChE. While 2-PAM effectively reactivates acetylcholinesterase (AChE) in the body, it does not cross the blood–brain barrier (BBB) at therapeutically relevant levels. To address this problem of central nervous system AChE reactivation, novel sugar–oxime conjugates were utilized. These ‘sugar–oximes’ would potentially be transported across the BBB because they contain a sugar moiety which would be recognized by the facilitative glucose transporters. Eight previously reported, but understudied sugar–oximes, as well as six novel sugar–oximes were synthesized, and their ability to reactivate both human red blood cell AChE and plasma butyrylcholinesterase poisoned with DFP, paraoxon, sarin and VX were tested. The results show that the novel sugar–oxime 13c was more active than the other compounds with a reactivation potential similar to 2-PAM. The sugar–oxime 8b had low toxicity with a LD 50 of 1590 mg/kg from a single IM dose in the guinea pig and >2000 mg/kg IP in the mouse. Histopathological analysis showed that there were no apparent differences in hippocampus, heart, liver, kidney sciatic nerve, or skeletal muscle between treated and untreated animals. These results show that sugar–oximes can be effective reactivators and suggest that high treatment doses may be possible.

Differential expression of MAPKs subgroup in the hippocampus of rats exposed to chronic unpredictable stress

Objective To examine the cognitive function and the differential expression of mitogen-activated protein kinase (MAPK) subgroup in the hippocampus of rats exposed to chronic unpredictable stress. Methods Thirty-two SD rats were divided into chronic unpredictable stress (CUS) group and controls. CUS rats were exposed to 21 days chronic unpredictable stressors,and the controls were stress-free. Immediately after the last stressor,the cognitive function was tested using Morris water maze,and the protein levels of MAPK subgroup in hippocampus were detected by immunohistochemistry and western blot. Results The latencies of CUS and control rats differed significantly on the first 5 trial (F=5.258～10.225,P 0.05),and the number of times that rats crossed the removed hidden platform in CUS group was significantly fewer than that in the control group (1.8±0.5 VS 7.0±3.9,t=3.741,P<0.05). Immunohistochemistry showed that the labeling index of P-CREB was reduced in the dentate gyrus in CUS group compared with that in the control group. Western blot showed that CREB,ERK1/2,P-ERK1/2,P38,P-P38 and JNK levels had no statistical difference in hippocampus between the two groups. However,CUS significantly decreased P-CREB level [(13.6±8.3) % VS (36.0±14.5)%,t=3.792,P<0.05] and P-JNK level [(30.8±7.8) % VS (113.8±55.3) %,t=4.204,P<0.05] in the hippocampus. Conclusions Abnormal JNK-CREB cascade played important roles in the CUS,and the spatial memory of the CUS rats was reduced compared to control rats,but can be restored to the comparable level through training. Key words: Chronic unpredictable stress (CUS); Mitogen-activated protein kinase (MAPK); cAMP response element-binding protein (CREB); Hippocampus

Hippocampal signaling protein levels are different in early and late metestrus in the rat

Early and late metestrus in the rat differ by progesterone levels. As it is known that progesterone shows a potential negative effect on cognitive performances and can counteract the estradiol-induced neural effects, we intended to study signaling proteins in the hippocampus, a structure representing a main brain area of cognitive function. Female OFA Sprague–Dawley rats were used in the studies and estrous phases were determined using vaginal smears. Hippocampal tissue was taken, proteins extracted, run on two-dimensional gel electrophoresis and proteins were identified by mass spectrometry methods (MALDI-TOF-TOF and nano-LC-ESI-MS/MS). Individual signaling protein levels quantified by specific software were shown to vary between the two phases, including NG,NG-dimethylarginine dimethylaminohydrolase 1 for nitric oxide signaling, guanine nucleotide-binding proteins, septin 6, septin 11, G-septin alpha, and 14-3-3 protein gamma. Results from this study indicate that early and late metestrus show differences in signaling pathways, that may help to design further investigations at the protein level and may assist to interpret literature on protein expression and brain protein levels in female rats. Moreover, signaling differences in hippocampus are challenging cognitive studies during these two metestrus phases probably revealing cognitive differences between early and late metestrus.

Carbamazepine treatment recovered low N-acetylaspartate+N-acetylaspartylglutamate (tNAA) levels in the megencephaly mouse BALB/cByJ-Kv1.1

Megencephaly mice (BALB/cByJ-Kv1.1(mceph/mceph)) display excessive brain growth and seizures related to a mutation within the potassium channel gene Kv1.1 producing a malfunctioning protein. (1)H Magnetic resonance spectroscopy (MRS) provides means to study brain transmitters and metabolites in vivo. We applied MRS to pinpoint differences in hippocampus between mceph/mceph and wild type (wt) mice. Carbamazepine (CBZ) protects against brain overgrowth in mceph/mceph. Therefore, the effects of durable oral CBZ treatment on the MR spectra were investigated. LCModel was used for spectra quantification and multivariate data analysis applied to detect group differences. mceph/mceph mice had lower levels of N-acetylaspartate+N-acetylaspartylglutamate (tNAA) and choline-containing (tCho) compounds compared to wt mice. Glutamate, glutamine, taurine and myo-inositol levels were similar in wt and mceph/mceph. Furthermore, CBZ treatment recovered tCho and tNAA levels in mceph/mceph. Thus, distinct differences in MRS spectra between mceph/mceph and wt mice were depicted and treatment effects of CBZ were monitored using MRS.

Serial analysis of gene expression predicts structural differences in hippocampus of long attack latency and short attack latency mice

The genetically selected long attack latency (LAL) and short attack latency (SAL) mice differ in a wide variety of behavioural traits and display differences in the serotonergic system and the hypothalamus-pituitary-adrenocortical (HPA)-axis. Serial analysis of gene expression (SAGE) was used to generate a hippocampal expression profile of almost 30 000 genes in LAL and SAL mice. Using SAGE, we found differential expression of 191 genes. Among these were genes involved in growth, signal transduction, and cell metabolism. The SAGE study was supported by GeneChip analysis (Affymetrix). Strikingly, both SAGE and GeneChips showed a higher expression of numerous cytoskeleton genes, such as cofilin and several tubulin isotypes in LAL mice. LAL mice also showed a higher expression of several calmodulin-related genes and genes encoding components of a MAPK cascade, namely raf-related oncogene and ERK2. The findings were confirmed by in situ hybridization. Our results of differential expression of cytoskeleton and signal transduction genes therefore suggest differential regulation of the raf/ERK pathway that may be related to structural differences in the hippocampus of LAL and SAL mice. As stress-related disorders, such as depression, are also linked to differential regulation of the HPA-axis and the serotonergic system and are associated with altered hippocampal morphology, differential regulation of these genes may be involved in the pathogenesis of these diseases.

Volumetric magnetic resonance imaging evidence of bilateral hippocampal atrophy in mesial temporal lobe epilepsy.

We measured absolute volumes and volume differences of hippocampi in patients with mesial temporal lobe epilepsy (MTLE) using volumetric magnetic resonance imaging (MRI) to determine the extent of bilateral atrophy in MTLE and to relate hippocampal volumes (HV) to outcome of temporal lobectomy. HV and hippocampal differences (HD) were measured in 40 patients with MTLE determined by pathology of hippocampal sclerosis (HS) and compared with those of age-matched controls. Results were matched with surgical outcome. Hippocampi contralateral to lobectomy (right hippocampi 2.96 +/- 0.49 cm3, left 3.14 +/- 0.51 cm3) were significantly smaller than those of controls (right hippocampi 3.73 +/- 0.52 cm3, left 3.60 +/- 0.51 cm3) but were significantly larger than hippocampi ipsilateral to lobectomy (right hippocampi 2.63 +/- 0.61 cm3, 2.18 cm3) as compared across groups by analysis of variance (ANOVA: F = 27.2, p < 0.0001). The smaller hippocampus was ipsilateral to lobectomy in 39 of 40 cases. Seven of 40 MTLE patients (18%) had bilateral atrophy, defined by volumes of each hippocampi 2 SD lower than control means. Surgical outcome was independent of hippocampal asymmetry and bilateral atrophy measured by chi-square and Fisher's exact tests. We determined that most patients with MTLE have some degree of bilateral, asymmetric hippocampal pathology. However, asymmetry and bilateral atrophy have no clear relation to surgical outcome.