Low Levels In Brain Research Articles

Knockdown of C-C Chemokine Receptor 5 (CCR5) is Protective Against Cerebral Ischemia and Reperfusion Injury.

Stroke is the second leading cause of death and a major cause of disability of adults worldwide. Inflammatory processes are known to contribute to the pathophysiology of cerebral ischemia, especially following reperfusion. Chemokines and their receptors are involved in migration of leukocytes and have been implicated in the pathogenesis of ischemic stroke. In the present study, we investigated the effects of C-C chemokine receptor type 5 (CCR5) deficiency on neurological outcome, brain damage and expression of pro-inflammatory chemokines: chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine (CC motif) ligand 3 (CCL3) and chemokine (C-C motif) ligand 5 (CCL5), and the brain-derived neurotrophic factor (BDNF). Adult male C57BL/6 (wild-type) (WT) and CCR5 deficient mice were subjected to transient cerebral ischemia induced by 25 min of bilateral common carotid artery occlusion (BCCAO) followed by 24 hours of reperfusion. Mice were divided into four groups: WT sham group, which underwent sham operation; WT ischemic group, which was subjected to transient bilateral common carotid artery occlusion, CCR5-/- sham group, which underwent sham operation, and CCR5-/- ischemic group, which was subjected to transient BCCAO. In CCR5 deficiency, we observed a significant improvement in the neurological deficits associated with decreased brain infarcted area as evaluated by triphenyltetrazolium chloride (TTC). Moreover, CCR5 deficiency revealed decreased percentage of necrotic cavities areas and frequency of ischemic neurons by histometric analysis. In addition, CCR5-/- ischemic animals showed lower brain levels of the chemokine CXCL1 and higher levels of BDNF by ELISA, compared with WT BCCAo mice. Taken together, our results suggest a potential neuroprotection in the absence of CCR5 receptor during global brain ischemia and reperfusion injury.

Systematic analysis of the achaete-scute complex-like gene signature in clinical cancer patients.

The achaete-scute complex-like (ASCL) family, also referred to as ‘achaete-scute complex homolog’ or ‘achaete-scute family basic helix-loop-helix transcription factor’, is critical for proper development of the nervous system and deregulation of ASCL plays a key role in psychiatric and neurological disorders. The ASCL family consists of five members, namely ASCL1, ASCL2, ASCL3, ASCL4 and ASCL5. The ASCL1 gene serves as a potential oncogene during lung cancer development. There is a correlation between increased ASCL2 expression and colon cancer development. Inhibition of ASCL2 reduced cellular proliferation and tumor growth in xenograft tumor experiments. Although previous studies demonstrated involvement of ASCL1 and ASCL2 in tumor development, little is known on the remaining ASCL family members and their potential effect on tumorigenesis. Therefore, a holistic approach to investigating the expression of ASCL family genes in diverse types of cancer may provide new insights in cancer research. In this study, we utilized a web-based microarray database (Oncomine; www.oncomine.org) to analyze the transcriptional expression of the ASCL family in clinical cancer and normal tissues. Our bioinformatics analysis revealed the potential involvement of multiple ASCL family members during tumor onset and progression in multiple types of cancer. Compared to normal tissue, ASCL1 exhibited a higher expression in cancers of the lung, pancreas, kidney, esophagus and head and neck, whereas ASCL2 exhibited a high expression in cancers of the breast, colon, stomach, lung, head and neck, ovary and testis. ASCL3, however, exhibited a high expression only in breast cancer. Interestingly, ASCL1 expression was downregulated in melanoma and in cancers of the bladder, breast, stomach and colon. ASCL2 exhibited low expression levels in sarcoma, melanoma, brain and prostate cancers. Reduction in the expression of ASCL3 was detected in lymphoma, bladder, cervical, kidney and epithelial cancers. Similarly, ASCL5 exhibited low expression in the majority of brain cancer subtypes, such as glioblastoma and oligodendroglioma. This analysis supports the hypothesis that specific ASCL members may play an important role in cancer development. Collectively, our data suggest that alterations in the expression of ASCL gene family members are correlated with cancer development. Furthermore, ASCL family members were categorized according to cancer subtype. The aim of this report was to provide novel insights to the significance of the ASCL family in various cancers and our findings suggested that the ASCL gene family may be an ideal target for future cancer studies.

Interferon gamma modulation of disease manifestation and the local antibody response to alphavirus encephalomyelitis

Infection of mice with Sindbis virus (SINV) produces encephalomyelitis and provides a model for examination of the central nervous system (CNS) immune response to alphavirus infection. Clearance of infectious virus is accomplished through a cooperative effort between SINV-specific antibody and IFN-γ, but the regulatory interactions are poorly understood. To determine the effects of IFN-γ on clinical disease and the antiviral immune response, C57BL/6 mice lacking IFN-γ (Ifng-/-) or IFN-γ receptor (Ifngr1-/-) were studied in comparison to WT mice. Maximum production of Ifng mRNA and IFN-γ protein in the CNS of WT and Ifngr1-/- mice occurred 5-7 days after infection, with higher levels of IFN-γ in Ifngr1-/- mice. Onset of clinical disease was earlier in mice with impaired IFN-γ signalling, although Ifngr1-/- mice recovered more rapidly. Ifng-/- and Ifngr1-/- mice maintained body weight better than WT mice, associated with better food intake and lower brain levels of inflammatory cytokines. Clearance of infectious virus from the spinal cords was slower, and CNS, but not serum, levels of SINV-specific IgM, IgG2a and IgG2b were lower in Ifngr1-/- and Ifng-/- mice compared to WT mice. Decreased CNS antiviral antibody was associated with lower expression of mRNAs for B-cell attracting chemokines CXCL9, CXCL10 and CXCL13 and fewer B cells in the CNS. Therefore, IFN-γ signalling increases levels of CNS pro-inflammatory cytokines, leading to clinical disease, but synergistically clears virus with SINV-specific antibody at least in part by increasing chemokine production important for infiltration of antibody-secreting B cells into the CNS.

Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism.

ApoE on high-density lipoproteins is primarily responsible for lipid transport and cholesterol homeostasis in the central nervous system (CNS). Normally produced mostly by astrocytes, apoE is also produced under neuropathologic conditions by neurons. ApoE on high-density lipoproteins is critical in redistributing cholesterol and phospholipids for membrane repair and remodeling. The 3 main structural isoforms differ in their effectiveness. Unlike apoE2 and apoE3, apoE4 has markedly altered CNS metabolism, is associated with Alzheimer disease and other neurodegenerative disorders, and is expressed at lower levels in brain and cerebrospinal fluid. ApoE4-expressing cultured astrocytes and neurons have reduced cholesterol and phospholipid secretion, decreased lipid-binding capacity, and increased intracellular degradation. Two structural features are responsible for apoE4 dysfunction: domain interaction, in which arginine-61 interacts ionically with glutamic acid-255, and a less stable conformation than apoE3 and apoE2. Blocking domain interaction by gene targeting (replacing arginine-61 with threonine) or by small-molecule structure correctors increases CNS apoE4 levels and lipid-binding capacity and decreases intracellular degradation. Small molecules (drugs) that disrupt domain interaction, so-called structure correctors, could prevent the apoE4-associated neuropathology by blocking the formation of neurotoxic fragments. Understanding how to modulate CNS cholesterol transport and metabolism is providing important insights into CNS health and disease.

Alternative promoters of Peg3 with maternal specificity.

Peg3 (paternally expressed gene 3) is an imprinted gene localized within an evolutionarily conserved 500-kb domain in human chromosome 19q13.4 and mouse proximal chromosome 7. In the current study, we have identified three alternative promoters for mouse Peg3 and one alternative promoter for human PEG3. These alternative promoters are localized within the 200-kb upstream region of human and mouse PEG3, which is well conserved and thus predicted to harbor several cis-regulatory elements for the PEG3 domain. In the mouse, two of these alternative promoters drive maternal-specific expression of Peg3 specifically in the hypothalamus of the adult brain, while the remaining third promoter drives bi-allelic expression of Peg3 with a paternal bias only in the neonatal-stage brain. In human, an alternative transcript is also detected at relatively very low levels in adult brain and placenta. Overall, the identification of alternative promoters in both mouse and human models suggests that these alternative promoters may be functionally selected features for the PEG3 imprinted domain during mammalian evolution.

Partial Amelioration of Peripheral and Central Symptoms of Huntington's Disease via Modulation of Lipid Metabolism.

Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder characterized by uncontrollable dance-like movements, as well as cognitive deficits and mood changes. A feature of HD is a metabolic disturbance that precedes neurological symptoms. In addition, brain cholesterol synthesis is significantly reduced, which could hamper synaptic transmission. Alterations in lipid metabolism as a potential target for therapeutic intervention in the R6/2 mouse model of HD were examined. Electrophysiological recordings in vitro examined the acute effects of cholesterol-modifying drugs. In addition, behavioral testing, effects on synaptic activity, and measurements of circulating and brain tissue concentrations of cholesterol and the ketone β-hydroxybutyrate (BHB), were examined in symptomatic R6/2 mice and littermate controls raised on normal chow or a ketogenic diet (KD). Whole-cell voltage clamp recordings of striatal medium-sized spiny neurons (MSNs) from symptomatic R6/2 mice showed increased frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) compared with littermate controls. Incubation of slices in cholesterol reduced the frequency of large-amplitude sIPSCs. Addition of BHB or the Liver X Receptor (LXR) agonist T0901317 reduced the frequency and amplitude of sIPSCs. Surprisingly, incubation in simvastatin to reduce cholesterol levels also decreased the frequency of sIPSCs. HD mice fed the KD lost weight more gradually, performed better in an open field, had fewer stereotypies and lower brain levels of cholesterol than mice fed a regular diet. Lipid metabolism represents a potential target for therapeutic intervention in HD. Modifying cholesterol or ketone levels acutely in the brain can partially rescue synaptic alterations, and the KD can prevent weight loss and improve some behavioral abnormalities.

Maternal transfer of dechloranes and their distribution among tissues in contaminated ducks

The tissue concentrations of dechlorane plus and its analogues were determined in ducks collected from several e-waste recycling villages of Taizhou, China. Compared with the published literature, the relatively high concentrations of these compounds were detected in ducks, indicating serious DP contamination. Since both the duck meat and eggs were important components for diet, this result reminded us of keeping a watchful eye on human dietary exposure to DP and its analogues in this study area. The wet-weight concentrations of DP and its analogues were significantly related to tissue lipid content (p < 0.05), indicating that the lipid pools predominantly impacted the distribution of DPs in ducks. On the basis of lipid adjustment, the significantly lower levels in brain than those in liver and blood, displayed the occurrence of liver sequestration and blood–brain barrier to DP and its analogues in the duck (p < 0.05). The maternal transfer of DP and Mirex was not obviously limited, and the transferring extent of Dec 602 was over one. The stereo-selected accumulation of two DP isomers occurred among tissues with preference to syn-DP in blood, and to anti-DP in brain. The values of lipid-adjusted monodechlorinated products mainly originated from the exterior environment in ducks.

Radioiodinated PARP1 tracers for glioblastoma imaging

BackgroundAlthough the understanding of the genetic and molecular basis of cancer has advanced significantly over the past several decades, imaging and treatment options for glioblastoma patients have been more limited (N Engl J Med 359:492-507, 2008). This is in part due to difficulties in diagnosing this disease early, combined with its diffuse, infiltrative growth. This study was aimed at the development of a novel diagnostic tool for glioblastoma through the synthesis of a small molecule based on radioiodinated poly(ADP-ribose)polymerase 1 (PARP1) targeted tracers. This PARP1 is a biomarker that is overexpressed in glioblastoma tissue, but has only low expression levels in the healthy brain (Neoplasia 16:432-40, 2014).MethodsA library of PARP1 inhibitors (iodo-PARPis) was synthesized. Based on their pharmacokinetic properties and nuclear PARP1 binding, the most successful inhibitor was radiolabeled with 131I and 124I. Biodistribution as well as imaging experiments were performed in orthotopic and subcutaneous mouse models of glioblastoma.ResultsOne member of our iodo-poly(ADP-ribose)polymerase 1 (PARP1) inhibitor library, I2-PARPi, shows promising biophysical properties for in vivo application. All synthesized tracers have IC50 values in the nanomolar range (9 ± 2–107 ± 4 nM) and were able to inhibit the uptake of a fluorescent PARP1 inhibitor analog (PARPi-FL). I2-PARPi was able to reduce the uptake of PARPi-FL by 78 ± 4 % in vivo. In mouse models of glioblastoma, we show that the radioiodinated inhibitor analog has high uptake in tumor tissue (U251 MG xenograft, tumor, 0.43 ± 0.06 %ID/g; brain, 0.01 ± 0.00 %ID/g; muscle, 0.03 ± 0.01 %ID/g; liver, 2.35 ± 0.57 %ID/g; thyroid, 0.24 ± 0.06 %ID/g). PET and SPECT imaging performed in orthotopic glioblastoma models with [124I]- and [131I]-I2-PARPi showed selective accumulation in the tumor tissue. These results were also verified using autoradiography of tumor sections, which displayed focal selective uptake of the tracer in the tumor regions as confirmed by histology. The uptake could be blocked through pre-injection of excess unlabeled PARP1 inhibitor (Olaparib).ConclusionsWe have successfully synthesized and radioiodinated the PARP1 selective tracer I2-PARPi. The novel tracer shows selective binding to tumor tissue, both in vitro and in models of glioblastoma, and has the potential to serve as a selective PET imaging agent for brain tumors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-015-0123-1) contains supplementary material, which is available to authorized users.

Rapid Recovery of Vesicular Dopamine Levels in Methamphetamine Users in Early Abstinence.

We previously reported very low levels of dopamine in post-mortem striatum of chronic methamphetamine users, raising the possibility that restoration of normal dopamine levels could help in this addiction and perhaps prevent early relapse. To establish relevance of this finding to the living brain, we tested whether striatal [(11)C]-(+)-dihydrotetrabenazine binding, a vesicular monoamine transporter probe sensitive to changes in (stored) vesicular dopamine, is elevated in methamphetamine users. Chronic methamphetamine users underwent [(11)C]-(+)-dihydrotetrabenazine positron emission tomography scans during early (mean 2.6 days) and later (~10 days) abstinence. Striatal [(11)C]-(+)-dihydrotetrabenazine binding was elevated (suggesting low stored dopamine) in methamphetamine users (n=28; 2.6 days after last use) relative to controls (n=22) (+28%, p<0.0001) and correlated with severity and recency of drug use and with cognitive impairment and withdrawal symptoms. Mean [(11)C]-(+)-dihydrotetrabenazine binding levels in the subgroup of methamphetamine users who could remain abstinent ~10 days following last use (n=17) were normal at the follow-up scan. Our imaging data support post-mortem findings and suggest that chronic methamphetamine users have low brain levels of stored dopamine during very early abstinence from MA, which could contribute to behavioral and cognitive deficits. Findings also suggest a rapid recovery of stored dopamine in some methamphetamine users who become abstinent and who therefore might not benefit from dopamine replacement medication (eg, levodopa). Further study is necessary to establish whether those users who could not maintain abstinence for the second scan might have a more severe and persistent dopamine deficiency and who could benefit from this medication.

The Impact of Docosahexaenoic Acid on Alzheimer's Disease: Is There a Role of the Blood-Brain Barrier?

There currently is no cure or established preventative treatment for Alzheimer's disease (AD). Considering the increasing aging population and the subsequent high prevalence of AD worldwide, identifying a cost-effective way to prevent AD is an essential unmet medical need. Relative to healthy human brain samples, postmortem AD brain samples have been shown to exhibit lower docosahexaenoic acid (DHA) levels, an essential polyunsaturated fatty acid required for normal neuronal function. However, findings from different studies are controversial and it is not clear whether this alteration in DHA brain levels is a cause or consequence of AD. Animal studies have also demonstrated that administration of DHA can alleviate the underlying pathophysiology of AD, including but not limited to amyloid pathology, tau pathology, and neuroinflammation. Moreover, DHA has been suggested to exert cognitive-enhancing effects and epidemiological studies have suggested that regular consumption of fish or omega-3 fatty acid enriched diets can attenuate the cognitive decline in AD and/or lower the risk of developing AD. However, the beneficial effects of DHA in AD have not been clearly demonstrated by current human randomised-control trials. In addition, the underlying reasons for the lower brain levels of DHA in AD remain to be fully characterised. However, given that the brain has limited capacity to produce DHA de novo and obtains DHA from the plasma, one plausible explanation for the lower brain levels of DHA in AD is reduced bloodbrain barrier (BBB) transport of this fatty acid in AD, as has been reported in one mouse model of AD. Unfortunately, the actual mechanisms governing the BBB transport of DHA in healthy conditions are not clearly understood, complicating the relationship between reduced BBB transport of DHA, attenuated DHA brain levels and AD pathology. The purpose of this review, therefore, is to summarise the findings of the biochemical, functional and epidemiological studies assessing the impact of DHA on the progression of AD, with a focus on how brain DHA levels alter in AD, the mechanisms thought to be held responsible for the apparent protective effects of DHA in AD, and the factors governing BBB transport of DHA in AD.

Olive oil-enriched diet reduces brain oxidative damages and ameliorates neurotrophic factor gene expression in different life stages of rats

Our aim was to assess the influence of maternal diet rich in monounsaturated fatty acids on oxidative and molecular parameters in brains of mouse pups as well as their body weight during their lifetime. Female rats received a diet containing 20% of olive oil-enriched diet (OOED) and a standard diet control diet (CD) in different periods: pregnancy, lactation and after weaning until pups' adulthood. On the last prenatal day (Group 1), embryos from OOED group showed smaller body weight, brain weight and lower levels of sulphydryl groups glutathione reduced (GSH) in the brain. On postnatal delay-21 (PND21) (Group 2), pups from OOED group showed higher body weight and brain weight, reduced brain weight/body weight ratio and lower brain lipid peroxidation (LP). On PND70 (Group 3), pups from OOED group showed lower brain LP and higher levels of GSH in prefrontal cortex and lower brain levels of reactive species in the hippocampus. Interestingly, the group of animals whose diet was modified from OOED to CD on PND21 showed greater weight gain compared to the group that remained in the same original diet (OOED) until adulthood. Furthermore, OOED consumption during pregnancy and lactation significantly increased BDNF only, as well as its main transcripts exon IV and VI mRNA levels in the prefrontal cortex. In addition, OOED significantly up-regulated FGF-2 mRNA levels in the prefrontal cortex. These findings open a pioneering line of investigation about dietary adjunctive therapeutic strategies and the potential of healthy dietary habits to prevent neonatal conditions and their influence on adulthood.

Optimized Quantification of Translocator Protein Radioligand ¹⁸F-DPA-714 Uptake in the Brain of Genotyped Healthy Volunteers.

Translocator protein (TSPO) is expressed at a low level in healthy brain and is upregulated during inflammatory processes that may occur in neurodegenerative diseases. Thus, TSPO may be a suitable in vivo indicator of neurodegeneration. Here, we quantified the (18)F-DPA-714 radioligand in healthy TSPO-genotyped volunteers and developed a method to eliminate the need for invasive arterial blood sampling. Ten controls (7 high-affinity binders [HABs] and 3 mixed-affinity binders [MABs]) underwent (18)F-DPA-714 PET with arterial and venous sampling. (18)F-DPA-714 binding was quantified with a metabolite-corrected arterial plasma input function, using the 1- and 2-tissue-compartment models (TCMs) as well as the Logan analysis to estimate total volume distribution (V(T)) in the regions of interest. Alternative quantification methods were tested, including tissue-to-plasma ratio or population-based input function approaches normalized by late time points of arterial or venous samples. The distribution pattern of (18)F-DPA-714 was consistent with the known distribution of TSPO in humans, with the thalamus displaying the highest binding and the cerebellum the lowest. The 2-TCM best described the regional kinetics of (18)F-DPA-714 in the brain, with good identifiability (percentage coefficient of variation < 5%). For each region of interest, V(T) was 47.6% ± 6.3% higher in HABs than in MABs, and estimates from the 2-TCM and the Logan analyses were highly correlated. Equilibrium was reached at 60 min after injection. V(T) calculated with alternative methods using arterial samples was strongly and significantly correlated with that calculated by the 2-TCM. Replacement of arterial with venous sampling in these methods led to a significant but lower correlation. Genotyping of subjects is a prerequisite for a reliable quantification of (18)F-DPA-714 PET images. The 2-TCM and the Logan analyses are accurate methods to estimate (18)F-DPA-714 V(T) in the human brain of both HAB and MAB individuals. Population-based input function and tissue-to-plasma ratio with a single arterial sample are promising alternatives to classic arterial plasma input function. Substitution with venous samples is promising but still requires methodologic improvements.

Sequencing and Gene Expression of HC‐9, an Aquaporin‐9 Homolog, in Freeze‐tolerant Cope's Gray Treefrog

Cope's gray treefrogs, Hyla chrysoscelis, accumulate glycerol in response to cold as part of their freeze tolerance mechanism. The glycerol is suspected to derive from glucose that is stored in the liver before it is exported to the bloodstream for distribution to other tissues. We therefore hypothesized that tissues from H. chrysoscelis, including hepatocytes, would express a homolog of aquaporin 9 (AQP9), a transmembrane protein from the aquaglyceroporin family that facilitates glycerol transport in mammalian liver. We also hypothesized that AQP9 would be up-regulated during cold acclimation to promote glycerol permeability. To test this hypothesis, we designed primers based on published AQP9 sequences, generated cDNA from mRNA extracted from liver, and identified a 945 base pair gene, HC-9, with high homology (69%) to human AQP9. Quantitative PCR analysis revealed HC-9 expression in liver, stomach, bladder, kidney, eye, lung, muscle, and skin (and at low levels in intestine, brain, heart, fat, and red blood cells). In tissues from frogs that had been cold acclimated, HC-9 was not up-regulated in any tissue and was down regulated in muscle and stomach, contrary to our hypothesis. In frozen and thawed animals, expression of HC-9 RNA mRNA was down-regulated in most tissues. Ongoing studies are characterizing the transport properties of HC-9 and the pattern of HC-9 protein expression in cold acclimation and freezing. Supported by NSF IOS-1121457.

Glutamic acid decarboxylase 1 alternative splicing isoforms: characterization, expression and quantification in the mouse brain.

BackgroundGABA has important functions in brain plasticity related processes like memory, learning, locomotion and during the development of the nervous system. It is synthesized by the glutamic acid decarboxylase (GAD). There are two isoforms of GAD, GAD1 and GAD2, which are encoded by different genes. During embryonic development the transcription of GAD1 mRNA is regulated by alternative splicing and several alternative transcripts were distinguished in human, mouse and rat. Despite the fact that the structure of GAD1 gene has been extensively studied, knowledge of its exact structural organization, alternative promoter usage and splicing have remained incomplete.ResultsIn the present study we report the identification and characterization of novel GAD1 splicing isoforms (GenBank: KM102984, KM102985) by analyzing genomic and mRNA sequence data using bioinformatics, cloning and sequencing. Ten mRNA isoforms are generated from GAD1 gene locus by the combined actions of utilizing different promoters and alternative splicing of the coding exons. Using RT-PCR we found that GAD1 isoforms share similar pattern of expression in different mouse tissues and are expressed early during development. Quantitative RT-PCR was used to investigate the expression of GAD1 isoforms and GAD2 in olfactory bulb, cortex, medial and lateral striatum, hippocampus and cerebellum of adult mouse. Olfactory bulb showed the highest expression of GAD1 transcripts. Isoforms 1/2 are the most abundant forms. Their expression is significantly higher in the lateral compared to the medial striatum. Isoforms 3/4, 5/6, 7/8 and 9/10 are barely detectable in all investigated regions except of the high expression in olfactory bulb. When comparing GAD1 expression with GAD2 we found that Isoforms 1/2 are the predominant isoforms. In situ hybridization confirmed the predominant expression of Isoforms 7/8 and 9/10 in the olfactory bulb and revealed their weak expression in hippocampus, cerebellum and some other areas known to express GAD1.ConclusionsGeneration of ten splicing isoforms of GAD1 was described including two so far uncharacterized transcripts. GAD1 splicing isoforms producing the shorter, enzymatically inactive GAD25 protein are expressed at very low level in adult mouse brain except in the olfactory bulb that is associated with neurogenesis and synaptic plasticity even during adulthood.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2202-15-114) contains supplementary material, which is available to authorized users.

P059: Influence of perceived social support on cognitive decline in rural community-dwelling seniors

magnetic-resonance-spectroscopy (MRS) is 92.7% of Control level (p =0.0252) (8 studies). Conclusion: These data indicate that the lower brain levels of choline-containing compounds as measured by MRS, may reflect lower plasma availability of choline-containing lipids in AD. This suggests that patients with AD have specific nutritional requirements for choline to increase plasma choline-containing phospholipids, leading to increased choline availability for the brain.

Photoperiodic responses of depression-like behavior, the brain serotonergic system, and peripheral metabolism in laboratory mice

Seasonal affective disorder (SAD) is characterized by depression during specific seasons, generally winter. The pathophysiological mechanisms underlying SAD remain elusive due to a limited number of animal models with high availability and validity. Here we show that laboratory C57BL/6J mice display photoperiodic changes in depression-like behavior and brain serotonin content. C57BL/6J mice maintained under short-day conditions, as compared to those under long-day conditions, demonstrated prolonged immobility times in the forced swimming test with lower brain levels of serotonin and its precursor l-tryptophan. Furthermore, photoperiod altered multiple parameters reflective of peripheral metabolism, including the ratio of plasma l-tryptophan to the sum of other large neutral amino acids that compete for transport across the blood-brain barrier, responses of circulating glucose and insulin to glucose load, sucrose intake under restricted feeding condition, and sensitivity of the brain serotonergic system to peripherally administered glucose. These data suggest that the mechanisms underlying SAD involve the brain-peripheral tissue network, and C57BL/6J mice can serve as a powerful tool for investigating the link between seasons and mood.

Tissue distribution and thyroid hormone effects on mRNA abundance for membrane transporters Mct8, Mct10, and organic anion-transporting polypeptides (Oatps) in a teleost fish

Many of the actions of thyroid hormones (THs) occur via TH binding to intracellular receptors. Although it was long thought that THs diffused passively across plasma membranes, it is now recognized that cellular entry is mediated by a variety of membrane transporter proteins. In this study, we identified cDNAs encoding the TH transporters monocarboxylate transferases 8 (mct8) and 10 (mct10) as well as eight distinct organic anion-transporting polypeptide (oatp) proteins from fathead minnow (Pimephales promelas). Analysis of the tissue distribution of transporter mRNAs revealed that mct8 and mct10 transcripts were both abundant in liver, but also present at lower levels in brain, gonad and other tissues. Transcripts encoding oatp1c1 were highly abundant in brain, liver and gonad, and exhibited significant sex differences in the liver and gonad. Treatment of adult male minnows with 3,5,3′-triiodothyronine (T3) or the goitrogen methimazole altered gene transcript abundance for several transporters. Fish given exogenous T3 had reduced mct8 and oapt1c1 mRNA levels in the liver compared to methimazole-treated fish. In the brain, transcripts for mct8, mct10, oatp2b1, and oatp3a1 were each reduced in abundance in fish with elevated T3. As a whole, these results provide evidence that TH status influences the transcriptional dynamics of mct8, mct10 and several Oatp genes including oatp1c1 in teleost fish.

Gene structure and expression of leptin in Chinese perch

Leptin is an important hormone involved in regulation of food intake, energy expenditure and reproduction in mammals, but its role in acanthomorph fishes remains scant. In the present study, we characterized leptin gene structure and its tissue expression in Chinese perch (Siniperca chuatsi). In contrast to typical leptin gene organization of 3 exons and 2 introns in other vertebrates, Chinese perch leptin gene consisted of 2 exons and 1 intron. This is the first leptin gene characterized in Perciformes, and is also the first leptin gene lacking an intron reported in Perciformes. The unique gene structure, the conservation of both cysteines that form the single disulfide bridge in leptin, and stable clustering in phylogenetic analyses substantiate the unambiguous orthology of mammalian and fish leptins, despite low amino acid identity. Polymorphism of leptin gene was examined in wild and cultivated populations of Chinese perch by direct sequencing of 120 fish. No SNP was found in leptin gene. Leptin mRNA of Chinese perch was highly expressed in liver, and expressed at low levels in brain, visceral adipose tissue, intestine, spleen and muscle.

Matrix Metalloproteinase-2 and Metalloproteinase-9 Activities are Associated with Blood–Brain Barrier Dysfunction in an Animal Model of Severe Sepsis

There is no description on the mechanisms associated with blood-brain barrier (BBB) disruption during sepsis development. Thus, we here determined changes in permeability of the BBB in an animal model of severe sepsis and the role of matrix metalloproteinase (MMP)-2 and MMP-9 in the dysfunction of the BBB. Sepsis was induced in Wistar rats by cecal ligation and perforation. BBB permeability was assessed using the Evans blue dye method. The content of MMP-2 and MMP-9 in the cerebral microvessels was determined by western blot. The activity of MMP-2 and MMP-9 was determined using zymography. An inhibitor of MMP-2 and MMP-9 or specific inhibitors of MMP-2 or MMP-9 were administered to define the role of MMPs on BBB permeability, brain inflammatory response, and sepsis-induced cognitive alterations. The increase of BBB permeability is time-related to the increase of MMP-9 and MMP-2 in the microvessels, both in cortex and hippocampus. Using an MMP-2 and MMP-9 inhibitor, or specific MMP-2 or MMP-9 inhibitors, the increase in the permeability of the BBB was reversed. This was associated with lower brain levels of interleukin (IL)-6 and lower oxidative damage. In contrast, only the inhibition of both MMP-9 and MMP-2 was able to improve acute cognitive alterations associated with sepsis. In conclusion, MMP-2 and MMP-9 activation seems to be a major step in BBB dysfunction, but BBB dysfunction seems not to be associated with acute cognitive dysfunction during sepsis development.

Expression of the G72/G30 gene in transgenic mice induces behavioral changes

The G72/G30 gene complex is a candidate gene for schizophrenia and bipolar disorder. However, G72 and G30 mRNAs are expressed at very low levels in human brain, with only rare splicing forms observed. We report here G72/G30 expression profiles and behavioral changes in a G72/G30 transgenic mouse model. A human BAC clone containing the G72/G30 genomic region was used to establish the transgenic mouse model, on which gene expression studies, Western blot and behavioral tests were performed. Relative to their minimal expression in humans, G72 and G30 mRNAs were highly expressed in the transgenic mice, and had a more complex splicing pattern. The highest G72 transcript levels were found in testis, followed by cerebral cortex, with very low or undetectable levels in other tissues. No LG72 (the long putative isoform of G72) protein was detected in the transgenic mice. Whole-genome expression profiling identified 361 genes differentially-expressed in transgenic mice compared to wild-type, including genes previously implicated in neurological and psychological disorders. Relative to wild-type mice, the transgenic mice exhibited fewer stereotypic movements in the open field test, higher baseline startle responses in the course of the prepulse inhibition test, and lower hedonic responses in the sucrose preference test. The transcriptome profile changes and multiple mouse behavioral effects suggest that the G72 gene may play a role in modulating behaviors relevant to psychiatric disorders.