Voluntary Wheel Running in Old C57BL/6 Mice Reduces Age-Related Inflammation in the Colon but Not in the Brain

Inflammation is considered a possible cause of cognitive decline during aging. This study investigates the influence of physical activity and social isolation in old mice on their cognitive functions and inflammation. The Barnes maze task was performed to assess spatial learning and memory in 3, 9, 15, 24, and 28 months old male C57BL/6 mice as well as following voluntary wheel running (VWR) and social isolation (SI) in 20 months old mice. Inflammatory gene expression was analyzed in hippocampal and colonic samples by qPCR. Cognitive decline occurs in mice between 15 and 24 months of age. VWR improved cognitive functions while SI had negative effects. Expression of inflammatory markers changed during aging in the hippocampus ( Il1a / Il6 / S100b / Iba1 / Adgre1 / Cd68 / Itgam ) and colon ( Tnf / Il6 / Il1ra / P2rx7 ). VWR attenuates inflammaging specifically in the colon ( Ifng / Il10 / Ccl2 / S100b / Iba1 ), while SI regulates intestinal Il1b and Gfap . Inflammatory markers in the hippocampus were not altered following VWR and SI. The main finding of our study is that both the hippocampus and colon exhibit an increase in inflammatory markers during aging, and that voluntary wheel running in old age exclusively attenuates intestinal inflammation. Based on the existence of the gut-brain axis, our results extend therapeutic approaches preserving cognitive functions in the elderly to the colon

Adult and Embryonic GAD Transcripts Are Spatiotemporally Regulated during Postnatal Development in the Rat Brain

GABA (gamma-aminobutyric acid), the main inhibitory neurotransmitter in the brain, is synthesized by glutamic acid decarboxylase (GAD). GAD exists in two adult isoforms, GAD65 and GAD67. During embryonic brain development at least two additional transcripts exist, I-80 and I-86, which are distinguished by insertions of 80 or 86 bp into GAD67 mRNA, respectively. Though it was described that embryonic GAD67 transcripts are not detectable during adulthood there are evidences suggesting re-expression under certain pathological conditions in the adult brain. In the present study we systematically analyzed for the first time the spatiotemporal distribution of different GADs with emphasis on embryonic GAD67 mRNAs in the postnatal brain using highly sensitive methods. hybridizations confirmed the occurrence of embryonic GAD67 transcripts in the olfactory bulb and furthermore detected their localization mainly in the subventricular zone and the rostral migratory stream.Embryonic GAD67 transcripts can hardly be detected in the adult brain, except for specific regions associated with neurogenesis and high synaptic plasticity. Therefore a functional role in processes like proliferation, migration or synaptogenesis is suggested

Identification of Ischemic Regions in a Rat Model of Stroke

Investigations following stroke first of all require information about the spatio-temporal dimension of the ischemic core as well as of perilesional and remote affected tissue. Here we systematically evaluated regions differently impaired by focal ischemia.Wistar rats underwent a transient 30 or 120 min suture-occlusion of the middle cerebral artery (MCAO) followed by various reperfusion times (2 h, 1 d, 7 d, 30 d) or a permanent MCAO (1 d survival). Brains were characterized by TTC, thionine, and immunohistochemistry using MAP2, HSP72, and HSP27. TTC staining reliably identifies the infarct core at 1 d of reperfusion after 30 min MCAO and at all investigated times following 120 min and permanent MCAO. Nissl histology denotes the infarct core from 2 h up to 30 d after transient as well as permanent MCAO. Absent and attenuated MAP2 staining clearly identifies the infarct core and perilesional affected regions at all investigated times, respectively. HSP72 denotes perilesional areas in a limited post-ischemic time (1 d). HSP27 detects perilesional and remote impaired tissue from post-ischemic day 1 on. Furthermore a simultaneous expression of HSP72 and HSP27 in perilesional neurons was revealed.TTC and Nissl staining can be applied to designate the infarct core. MAP2, HSP72, and HSP27 are excellent markers not only to identify perilesional and remote areas but also to discriminate affected neuronal and glial populations. Moreover markers vary in their confinement to different reperfusion times. The extent and consistency of infarcts increase with prolonged occlusion of the MCA. Therefore interindividual infarct dimension should be precisely assessed by the combined use of different markers as described in this study

Attenuated Inflammatory Response in Aged Mice Brains following Stroke

Background: Increased age is a major risk factor for stroke incidence, post-ischemic mortality, and severe and long-term disability. Stroke outcome is considerably influenced by post-ischemic mechanisms. We hypothesized that the inflammatory response following an ischemic injury is altered in aged organisms. Methods and Results: To that end, we analyzed the expression pattern of pro-inflammatory cytokines (TNF, IL-1a, IL-1b, IL-6), anti-inflammatory cytokines (IL-10, TGFb1), and chemokines (Mip-1a, MCP-1, RANTES) of adult (2 months) and aged (24 months) mice brains at different reperfusion times (6 h, 12 h, 24 h, 2 d, 7 d) following transient occlusion of the middle cerebral artery. The infarct size was assessed to monitor possible consequences of an altered inflammatory response in aged mice. Our data revealed an increased neuro-inflammation with age. Above all, we found profound age-related alterations in the reaction to stroke. The response of pro-inflammatory cytokines (TNF, and IL-1b) and the level of chemokines (Mip-1a, and MCP-1) were strongly diminished in the aged post-ischemic brain tissue. IL-6 showed the strongest age-dependent decrease in its post-ischemic expression profile. Anti-inflammatory cytokines (TGFb1, and IL-10) revealed no significant age dependency after ischemia. Aged mice brains tend to develop smaller infarcts. Conclusion: The attenuated inflammatory response to stroke in aged animals may contribute to their smaller infarcts. The results presented here highlight the importance of using aged animals to investigate age-associated diseases like stroke

Impact of an online guided physical activity training on cognition and gut-brain axis interactions in older adults: protocol of a randomized controlled trial

IntroductionBy 2050, the worldwide percentage of people 65 years and older is assumed to have doubled compared to current numbers. Therefore, finding ways of promoting healthy (cognitive) aging is crucial. Physical activity is considered an effective approach to counteract not only physical but also cognitive decline. However, the underlying mechanisms that drive the benefits of regular physical activity on cognitive function are not fully understood. This randomized controlled trial aims to analyze the effect of an eight-week standardized physical activity training program in older humans on cognitive, brain, and gut-barrier function as well as the relationship between the resulting changes.Methods and analysisOne-hundred healthy participants aged 60 to 75 years will be recruited. First, participants will undergo an extensive baseline assessment consisting of neurocognitive tests, functional and structural brain imaging, physical fitness tests, and gut-microbiome profiling. Next, participants will be randomized into either a multi-component physical activity group (experimental condition) or a relaxation group (active control condition), with each training lasting 8 weeks and including an equal number and duration of exercises. The whole intervention will be online-based, i.e., participants will find their intervention schedule and all materials needed on the study website. After the intervention phase, participants will have their post-intervention assessment, which consists of the same measures and tests as the baseline assessment. The primary outcome of this study is the change in the cognitive parameter of visual processing speed from baseline to post-measurement, which will on average take place 10 weeks after the randomization. Secondary outcomes related to cognitive, brain, and microbiome data will be analyzed exploratory.Clinical trial registration:https://drks.de/search/de/trial/DRKS0002802

Presence of γ-aminobutyric acid transporter mRNA in interneurons and principal cells of rat hippocampus

After release, neurotransmitters are removed from the extracellular space by high-af®nity uptake. Speci®c sodiumdependent transporters serve this function for the inhibitory transmitter g-aminobutyric acid (GABA). However, it is largely unknown to which proportion GABA is taken up by GABAergic interneurons, glia cells or principal neurons. We analyzed the distribution of mRNA for the main GABA-transporter subtype in the hippocampus, GAT-1, in adult rats. Most interneurons were strongly stained for GAT-1 mRNA, indicating re-uptake by the GABA-releasing cells. Surprisingly, prominent signals for GAT-1 were also found throughout the principal cell layers (granule and pyramidal cells). These data indicate that GABA transporters may be present in non-GABAergic projection cells of the rat hippocampus which contribute to the clearance of GABA from the extracellular spaceSFB 515/B

Ef®cacy of background GABA uptake in rat hippocampal slices

GABA uptake is crucial for the termination of inhibitory synaptic events. In addition, GABA transporters may also control the level of diffusely distributed GABA in the extracellular space. We analysed this function by superfusing rat hippocampal slices with different concentrations of GABA. Whole-cell patch clamp recordings of CA1 pyramidal cells revealed small increases in chloride conductance at 5-10 microM GABA which increased dramatically upon addition of the GABA uptake blocker tiagabine. Tiagabine alone induced a significant chloride conductance indicating that spontaneous release of GABA in hippocampal slices is neutralized by GAT-1, the main hippocampal GABA transporter. Thus, GAT-1 clears the extracellular space in the hippocampus from diffusely distributed GABA with high efficacy.SFB 515-B