Spatial Learning In Mice Research Articles

Resveratrol Improves Paclitaxel-Induced Cognitive Impairment in Mice by Activating SIRT1/PGC-1α Pathway to Regulate Neuronal State and Microglia Cell Polarization.

This study aimed to investigate the effect of resveratrol (Res) on paclitaxel (PTX)-induced cognitive impairment and elucidate the underlying molecular mechanisms. Morris Water Maze (MWM) test was used to evaluate the mice's spatial learning and memory abilities. Western blotting was applied to detect protein expression of receptor-interacting protein (RIP3), mixed lineage kinase domain-like protein (MLKL), silencing information regulator 2 related enzyme 1 (SIRT1), peroxisome proliferator activated receptor coactivator-1 (PGC-1α), NADPH oxidase 2 (NOX2), NOX4, postsynaptic density zone 95 (PSD95), arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS). Immunofluorescence of RIP3, MLKL, Arg-1, Iba-1 and iNOS was conducted to observe the apoptosis of hippocampal cells and the polarization of microglia. qRT-PCR was performed to detect BDNF mRNA expressions. DHE staining was used to assess the level of oxidative stress response. Golgi-Cox staining and dendritic spine counting were applied to visualize synaptic structural plasticity. Postsynaptic density was performed by transmission electron microscope. ELISA was used to detect the contents of tumour necrosis factor alpha (TNF-α), IL-1β, IL-4, and IL-10. PTX-induced cognitive impairment model was constructed after the application of PTX, represented as longer latency to platform and less platform crossing times over the whole period in PTX group. After Res treatment, the above indicators were reversed, indicating that cognitive function was improved. Moreover, Res reduced neuronal apoptosis and oxidative stress through SIRT1/PGC-1α pathway in mice, manifesting as down-regulated expression of RIP3, MLKL, NOX2 and NOX4. Meanwhile, Res increased the density of dendritic spines and the expression of PSD95 and BDNF, thereby ameliorating the PTX induced synaptic damage. Besides, M2 microglia was in the majority, eliciting the expression of anti-inflammatory cytokines IL-4 and IL-10 after Res treatment in PTX+Res group, while immunofluorescence images results demonstrated an decrease in the proportion of M2 microglia a following SIRT1 inhibitor EX-527. Res improves PTX-induced cognitive impairment in mice by activating SIRT1/PGC-1α pathways to regulate neuronal state and microglia cell polarization.

Efecto del estímulo masticatorio y estrés agudo sobre la interleuquina 6, la memoria y el aprendizaje espacial en ratones Balb/c

Introduction. Acute stress alters memory and spatial learning and the expression of interleukin 6, the chewing stimulus would prevent these effects. Objective. To determine the effect of chewing stimulation and acute stress on the expression of interleukin 6 and memory and spatial learning in mice. Methods. Experiment where 70 male albino mice of the Balb/c of age 2 month were randomly distributed into: Group A1: acute stress 1 hour; Group A2: acute stress 1 hour + chewing stimulus 1 hour; Group B1: acute stress 2 hours; Group B2: acute stress 2 hours + chewing stimulus 2 hours; Group C1: acute stress 3 hours; C2: acute stress 3 hours + chewing stimulus 3 hours; Group D: without intervention. For 3 days, spatial memory and learning were tested in the Morris water maze. Interleukin 6 (IL-6) was analyzed by ELISA test. Results. IL-6 was higher in the B2 group vs the other groups (p<0.0001). In addition, on the first day of evaluation, the acquisition of spatial memory and spatial was lower in the A1 vs. A2 group (p=0.042). Conclusión. Only on the first day of evaluation, we found that the masticatory stimulus prevented the decrease in memory acquisition and spatial learning in mice subjected to low-intensity acute stress. The results were generally inconclusive on the effect of masticatory stimulation. In addition, IL-6 was higher in the stress + masticatory stimulus (group B2) over the rest.

Overexpressing lnc240 Rescues Learning and Memory Dysfunction in Hepatic Encephalopathy Through miR-1264-5p/MEF2C Axis.

Hepatic encephalopathy (HE) is a nervous system disease caused by severe liver diseases and different degrees of learning and memory dysfunction. Long non-coding RNA (lncRNA) is highly expressed in the brain and plays important roles in central nervous system diseases like Alzheimer's disease. In the present work, we found that the expression of lnc240 in the hippocampus of HE mice was significantly downregulated, but its pathogenesis in HE has not been clarified. This study aimed to explore the effects of lnc240 on the cognitive function of HE. The expression of lnc240, miR-1264-5p, and MEF2C was analyzed with RNA-seq and further determined by qRT-PCR in HE mouse. Double luciferase reporter gene testing confirmed the relationship between lnc240, MEF2C, and miR-1264-5p. The functional role of lnc240 and MEF2C in vitro and in vivo was evaluated by qRT-PCR, western blot analysis, immunofluorescence staining, Golgi staining, electrophysiology, and Morris water maze. The expression of lnc240 was decreased in HE mice. The overexpression of lnc240 could significantly downregulate miR-1264-5p and upregulate MEF2C, also increasing the amplitude and frequency of mEPSC in primary cultured hippocampal neurons. The overexpression of miR-1264-5p reversed the effect of lnc240 on MEF2C. Moreover, in vivo experiments have shown that the overexpression of lnc240 could improve HE mice's spatial learning and memory functions. Golgi staining suggested that overexpression of lnc240 could increase the density and maturity of dendritic spines in hippocampal neurons of HE mice. Lnc240 can regulate the expression of MEF2C through miR-1264-5p and regulate the synaptic plasticity of hippocampal neurons, thereby saving the learning and memory dysfunction in HE mice, suggesting that lnc240 might be a potential therapeutic target for the treatment of HE.

Protocol for Exploring the Role of Irisin in the Enhancement of Spatial Learning Mediated by Aerobic Physical Exercise in Adult Mice

Introduction: Age-related cognitive decline decreases with aerobic physical exercise in many animal models and humans. Irisin, a myokine and its’ precursor FNDC5, has increased hippocampal development to improve learning and memory. This study aims to determine the association between irisin, physical activity and enhancement of spatial learning in adult mice. Methods: Three experimental studies will be conducted to explore the role of FNDC5/irisin in spatial learning. Study 1 will test the spatial learning ability in C57BL/6 mice using Morris Water Maze (MWM) task in WT, FNDC5+/- and FNDC5-/- mice strains. Study 2 will test the changes in the MWM task due to exogenous administration of FNDC5/irisin in the hippocampus, specifically in the dentate gyrus region. Study 3 aims to test the effect of aerobic physical activity on irisin levels in the dentate gyrus region and the changes in the MWM task. Anticipated Results: Study 1 results are expected to show that WT mice perform better compared to the FNDC5+/- and FNDC5-/- in completing the MWM task. Study 2 is anticipated to show that hippocampal administration of FNDC5/irisin can rescue the spatial learning phenotype. Study 3 is expected to show that PE improves spatial learning in all mice strains by regulating FNDC5/irisin levels. Discussion: FNDC5/irisin play a role in enhancing neurogenesis and synaptic plasticity by regulating downstream signalling pathways that are involved in cognitive functions. Aerobic PE enhances this mechanism, resulting in improved spatial learning. Conclusion: Aerobic PE is expected to significantly regulates hippocampal FNDC5/irisin, which is associated with enhancing spatial learning and cognitive functions.

Synaptic loss in a mouse model of euthyroid Hashimoto\u2019s thyroiditis: possible involvement of the microglia

BackgroundHashimoto’s thyroiditis (HT) is an autoimmune illness that renders individuals vulnerable to neuropsychopathology even in the euthyroid state, the mechanisms involved remain unclear. We hypothesized that activated microglia might disrupt synapses, resulting in cognitive disturbance in the context of euthyroid HT, and designed the present study to test this hypothesis.MethodsExperimental HT model was induced by immunizing NOD mice with thyroglobulin and adjuvant twice. Morris Water Maze was measured to determine mice spatial learning and memory. The synaptic parameters such as the synaptic density, synaptic ultrastructure and synaptic-markers (SYN and PSD95) as well as the interactions of microglia with synapses were also determined.ResultsHT mice had poorer performance in Morris Water Maze than controls. Concurrently, HT resulted in a significant reduction in synapse density and ultrastructure damage, along with decreased synaptic puncta visualized by immunostaining with synaptophysin and PSD-95. In parallel, frontal activated microglia in euthyroid HT mice showed increased engulfment of PSD95 and EM revealed that the synaptic structures were visible within the microglia. These functional alterations in microglia corresponded to structural increases in their attachment to neuronal perikarya and a reduction in presynaptic terminals covering the neurons.ConclusionOur results provide initial evidence that HT can induce synaptic loss in the euthyroid state with deficits might be attributable to activated microglia, which may underlie the deleterious effects of HT on spatial learning and memory.

Evidence for the interaction of COX-2 with mGluR5 in the regulation of EAAT1 and EAAT3 protein levels in the mouse hippocampus. The influence of oxidative stress mechanisms

Since we found that inhibition of cyclooxygenase-2 (COX-2) with concomitant application of a metabotropic glutamate receptor subtype 5 (mGluR5) antagonist (MTEP) down-regulates mGluR7 in the hippocampus (HC) and changes behavior of mice, our team decided to investigate the mechanism responsible for the observed changes. The amino acid glutamate (Glu) is a major excitatory neurotransmitter in the brain. Glu uptake is regulated by excitatory amino acid transporters (EAAT). There are five transporters with documented expression in neurons and glia in the central nervous system (CNS). EAATs, maintain the correct transmission of the Glu signal and prevent its toxic accumulation by removing Glu from the synapse. It has been documented that the toxic level of Glu is one of the main causes of mental and cognitive abnormalities.Given the above mechanisms involved in the functioning of the Glu synapse, we hypothesized modification of Glu uptake, involving EAATs as the cause of the observed changes. This study investigated the level of selected EAATs in the HC after chronic treatment with mGluR5 antagonist MTEP, NS398, and their combination using Western blot. Concomitant MTEP treatment with NS398 or a single administration of the above causes changes in LTP and modulation of EAAT levels in mouse HC. As EAATs are cellular markers of oxidative stress mechanisms, the E. coli lipopolysaccharide (LPS) challenge was performed. The modified Barnes maze test (MBM) revealed alterations in the mouse spatial learning abilities.This study reports an interaction between the mGluR5 and COX-2 in the HC, with EAAT1 and EAAT3 involvement.

CSE-Derived H2S Inhibits Reactive Astrocytes Proliferation and Promotes Neural Functional Recovery after Cerebral Ischemia/Reperfusion Injury in Mice Via Inhibition of RhoA/ROCK2 Pathway.

The effect of cystathionine-γ-lyase (CSE)-derived hydrogen sulfide (H2S) on the reactive proliferation of astrocytes and neural functional recovery over 30 d after acute cerebral ischemia and reperfusion (I/R) was determined by applying wild-type (WT) and CSE knockout (KO) mice. The changes of glial fibrillary acidic protein (GFAP) expression in hippocampal tissues was tested. Besides, we assessed the changes of mice spatial learning memory ability, neuronal damage, RhoA, Rho kinase 2 (ROCK2), and myelin basic protein (MBP) expressions in hippocampal tissues. The results revealed that cerebral I/R resulted in obvious increase of GFAP expression in hippocampal tissues. Besides, we found the neuronal damage, learning, and memory deficits of mice induced by cerebral I/R as well as revealed the upregulation of RhoA and ROCK2 expressions and reduced MBP expression in hipppcampal tissues of mice following cerebral I/R. Not surprisingly, the GFAP expression and cerebral injury as well as the upregulation of the RhoA/ROCK2 pathway were more remarkable in CSE KO mice, compared with those in WT mice over 30 d following acute cerebral I/R, which could be blocked by NaHS treatment, a donor of exogenous H2S. In addition, the ROCK inhibitor Fasudil also inhibited the reactive proliferation of astrocytes and ameliorated the recovery of neuronal function over 30 d after cerebral I/R. For the purpose of further confirmation of the role of H2S on the astrocytes proliferation following cerebral I/R, the immunofluorescence double staining: bromodeoxyuridine (BrdU) and GFAP was evaluated. There was a marked upregulation of BrdU-labeled cells coexpressed with GFAP in hippocampal tissues at 30 d after acute cerebral I/R; however, the increment of astrocytes proliferation could be ameliorated by both NaHS and Fasudil. These findings indicated that CSE-derived H2S could inhibit the reactive proliferation of astrocytes and promote the recovery of mice neural functional deficits induced by a cerebral I/R injury via inhibition of the RhoA/ROCK2 signal pathway.

The Role of Smad2 in Adult Neuroplasticity as Seen through Hippocampal-Dependent Spatial Learning/Memory and Neurogenesis.

Adult neural plasticity is an important and intriguing phenomenon in the brain, and adult hippocampal neurogenesis is directly involved in modulating neural plasticity by mechanisms that are only partially understood. We have performed gain-of-function and loss-of-function experiments to study Smad2, a transcription factor selected from genes that are demethylated after exercise through the analysis of an array of physical activity-induced factors, and their corresponding gene expression, and an efficient inducer of plasticity. In these studies, changes in cell number and morphology were analyzed in the hippocampal dentate gyrus (cell proliferation and survival, including regional distribution, and structural maturation/differentiation, including arborization, dendritic spines, and neurotransmitter-specific vesicles) of sedentary male mice, after evaluation in a battery of behavioral tests. As a result, we reveal a role for Smad2 in the balance of proliferation versus maturation of differentiating immature cells (Smad2 silencing increases both the proliferation and survival of cycling cells in the dentate granule cell layer), and in the plasticity of both newborn and mature neurons in mice (by decreasing dendritic arborization and dendritic spine number). Moreover, Smad2 silencing specifically compromises spatial learning in mice (through impairments of spatial tasks acquisition both in long-term learning and working memory). These data suggest that Smad2 participates in adult neural plasticity by influencing the proliferation and maturation of dentate gyrus neurons.SIGNIFICANCE STATEMENT Smad2 is one of the main components of the transforming growth factor-β (TGF-β) pathway. The commitment of cell fate in the nervous system is tightly coordinated by SMAD2 signaling, as are further differentiation steps (e.g., dendrite and axon growth, myelination, and synapse formation). However, there are no studies that have directly evaluated the role of Smad2 gene in hippocampus of adult animals. Modulation of these parameters in the adult hippocampus can affect hippocampal-dependent behaviors, which may shed light on the mechanisms that regulate adult neurogenesis and behavior. We demonstrate here a role for Smad2 in the maturation of differentiating immature cells and in the plasticity of mature neurons. Moreover, Smad2 silencing specifically compromises the spatial learning abilities of adult male mice.

D-Aspartate consumption selectively promotes intermediate-term spatial memory and the expression of hippocampal NMDA receptor subunits

d-Aspartate (d-Asp) and d-serine (d-Ser) have been proposed to promote early-phase LTP in vitro and to enhance spatial memory in vivo. Here, we investigated the behavioural effects of chronic consumption of d-Asp and d-Ser on spatial learning of mice together with the expression of NMDA receptors. We also studied the alterations of neurogenesis by morphometric analysis of bromo-deoxyuridine incorporating and doublecortin expressing cells in the hippocampus. Our results specify a time period (3–4 h post-training), within which the animals exposed to d-Asp (but not d-Ser) show a more stable memory during retrieval. The cognitive improvement is due to elimination of transient bouts of destabilization and reconsolidation of memory, rather than to enhanced acquisition. d-Asp also protracted reversal learning probably due to reduced plasticity. Expression of GluN1 and GluN2A subunits was elevated in the hippocampus of d-Asp (but not d-Ser) treated mice. d-Asp or d-Ser did not alter the proliferation of neuronal progenitor cells in the hippocampus. The observed learning-related changes evoked by d-Asp are unlikely to be due to enhanced proliferation and recruitment of new neurones. Rather, they are likely associated with an upregulation of NMDA receptors, as well as a reorganization of receptor subunit assemblies in existing hippocampal/dentate neurons.

Flexibility as a marker of early cognitive decline in humanized apolipoprotein E ε4 (ApoE4) mice

To test the hypothesis that ApoE4 may be involved in cognitive deficits associated with aging, we investigated the impact of APOE4 status and aging on the flexibility and memory components of spatial learning in mice. Young adult (6 months) and middle-aged (14 months) ApoE4, ApoE3 and C57BL/6 male mice were tested for flexibility in an aquatic Y-maze, and for spatio-temporal memory acquisition in the Starmaze. Our results revealed a flexibility deficit of the 6-month-old ApoE4 mice compared to controls. However, this deficit was not associated with spatio-temporal memory deficit at the same age. Importantly, the ApoE4 flexibility deficit did not increase with age, nor turn into memory deficit, or was able to predict individual variations of memory performance at 14 months. By contrast, control ApoE3 mice showed a decline of flexibility at 14 months resulting in performance similar to that of ApoE4. Overall, our results suggest that ApoE4 could be associated with an acceleration of the flexibility decrease otherwise observed in normal aging.

Human Cerebral Organoid Implantation Alleviated the Neurological Deficits of Traumatic Brain Injury in Mice.

Traumatic brain injury (TBI) causes a high rate of mortality and disability, and its treatment is still limited. Loss of neurons in damaged area is hardly rescued by relative molecular therapies. Based on its disease characteristics, we transplanted human embryonic stem cell- (hESC-) derived cerebral organoids in the brain lesions of controlled cortical impact- (CCI-) modeled severe combined immunodeficient (SCID) mice. Grafted organoids survived and differentiated in CCI-induced lesion pools in mouse cortical tissue. Implanted cerebral organoids differentiated into various types of neuronal cells, extended long projections, and showed spontaneous action, as indicated by electromyographic activity in the grafts. Induced vascularization and reduced glial scar were also found after organoid implantation, suggesting grafting could improve local situation and promote neural repair. More importantly, the CCI mice's spatial learning and memory improved after organoid grafting. These findings suggest that cerebral organoid implanted in lesion sites differentiates into cortical neurons, forms long projections, and reverses deficits in spatial learning and memory, a potential therapeutic avenue for TBI.

Hashimoto's Thyroiditis Induces Hippocampus-Dependent Cognitive Alterations by Impairing Astrocytes in Euthyroid Mice.

Background: Although studies have reported an increased risk for cognitive disorders in Hashimoto's thyroiditis (HT) patients, even in the euthyroid state, the mechanisms involved remain unclear. The hippocampus is a classic brain region associated with cognitive function, among which the formation of long-term potentiation (LTP) in the Schaffer collateral-CA1 pathway plays an important role in the process of learning and memory. Therefore, this study established a euthyroid HT model in mice and investigated whether and how HT itself has the ability to trigger LTP alterations accompanied by learning and memory abnormality. Methods: An experimental euthyroid HT model was established in NOD mice through immunization with porcine thyroglobulin (Tg). Morris water maze was measured to determine mice spatial learning and memory. We investigated the effect of HT on synaptic transmission and high-frequency stimulation-induced LTP in the Schaffer collateral-CA1 synapse of mice hippocampus in vivo. Then, animals were sacrificed for thyroid-related parameter measure as well as detection of cellular and molecular events associated with the induction of LTP. Results: HT mice showed intrathyroidal lymphocyte infiltration and rising serum thyroid autoantibody levels accompanied by normal thyroid function. The HT mice had poorer performance in Morris water maze than controls. These alterations were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral-CA1 synapses of the hippocampus in vivo. The integrity of the synaptic structure is the premise for the production of LTP. As detected by transmission electron microscopy, the ultrastructure of synapse and astrocyte in the hippocampus were impaired in euthyroid HT mice. Additionally, Western blot and real-time polymerase chain reaction analyses confirmed that in HT mice, GS, GLAST, and GLT-1, key elements in glutamate-glutamine circulation located in astrocyte, were downregulated, accompanied by elevated levels of glutamate in the hippocampus, which impaired the material basis for LTP induction. NMDR2B expression in the hippocampus was also downregulated. Conclusion: HT can induce damage of LTP in the hippocampal Schaffer collateral-CA1 pathway in the euthyroid state, and this can be attributed, at least partly, to astrocytes impairment, which may underlie the deleterious effects of HT itself on hippocampal-dependent learning and memory function.

Neuronal and astroglial monocarboxylate transporters play key but distinct roles in hippocampus-dependent learning and memory formation.

Brain lactate formation, intercellular exchange and utilization has been implicated in memory formation. However, the individual role of either neuronal or astroglial monocarboxylate transporters for the acquisition and consolidation of information remains incomplete. Using novel transgenic mice and a viral vector approach to decrease the expression of each transporter in a cell-specific manner within the dorsal hippocampus, we show that both neuronal MCT2 and astroglial MCT4 are required for spatial information acquisition and retention (at 24 h post-training) in distinct hippocampus-dependent tasks. Intracerebral infusion of lactate rescued spatial learning in mice with reduced levels of astroglial MCT4 but not of neuronal MCT2, suggesting that lactate transfer from astrocytes and utilization in neurons contribute to hippocampal-dependent learning. In contrast, only neuronal MCT2 was shown to be required for long-term (7 days post training) memory formation. Interestingly, reduced MCT2 expression levels in mature neurons result in a heterologous effect as it blunts hippocampal neurogenesis associated with memory consolidation. These results suggest important but distinct contributions of both neuronal MCT2 and astroglial MCT4 in learning and memory processes, going beyond a simple passive role as alternative energy substrate suppliers or in waste product disposal.

A modified Barnes maze for an accurate assessment of spatial learning in mice

BackgroundThe Morris water maze (MWM) and the Barnes maze (BM) are among the most widely-used paradigms for assessing spatial learning in rodents, with specific advantages and disadvantages for each apparatus. Compared with the intense water-related stress exerted during the MWM, the BM exhibits a milder light-induced stress, while suffering from biasing animals towards non-spatial strategies such as serial search, a heuristic non-spatial search strategy. To overcome this problem, we have developed a modified Barnes maze (MBM) apparatus that recapitulates natural environments more accurately without inducing undesirable exploration strategy bias. New methodApparatus. A circular 122 cm-wide table with 40 randomly placed holes. One target hole is leading to an escape chamber. Task. Three target locations were examined, varying in their distance from the center. C57BL6/j male mice were given three trials per day to find the target. Following acquisition, a probe test was performed by removing the escape chamber. ResultsSpatial-encoding-depended reduction in latency to reach the target was observed, along with improvement in path efficiency with test progress. Mice tested with peripheral and distal targets outperformed mice tested with a central target. A robust exploration pattern was identified in the probe test. Comparison with existing methodThe MBM mimics natural environment to a higher degree of accuracy than the BM, without eliciting bias towards non-spatial searching strategies. ConclusionsSpatial learning in the MBM is a target-location sensitive process, providing flexibility in task difficulty. Along with overcoming biases towards non-spatial strategies, the MBM represents an improvement over the well-validated BM.

Loss of MsrB1 perturbs spatial learning and long-term potentiation/long-term depression in mice.

MsrB1 belongs to the methionine sulfoxide reductase family, it is also known as selenoprotein R for the sake of possessing a selenocysteine residue. It has been reported that MsrB1 could interact with actin, TRPM6, clusterin, and amyloid-beta in vitro. Thus, we presumed that MsrB1 may play an important role in central nervous system. To examine whether MsrB1 knockout has any effects on brain development or learning behavior, we carried out histological study on brains of MsrB1 deficient mice, and further tested spatial learning ability and long-term synaptic plasticity of these mice by using Morris water maze and electrophysiological methods. It was observed that loss of MsrB1 did not perturb the overall development of central nervous system except for the astrogliosis in hippocampus, however, it led mice to be incapable in spatial learning and severe impairments in LTP/LTD expression in CA1 of brain slices, along with the down-regulation of the synaptic proteins including PSD95, SYP, GluN2A and GluN2B, as well as the dramatic decrease of CaMKIIs phosphorylation at 286(287) compared with wild type mice. Taken together, these results suggest that MsrB1 is essential for mice spatial learning and LTP/LTD induction, and the MsrB1 related redox homeostasis may be involved in regulating the phosphorylation of CaMKIIs.

Interleukine-17 Administration Modulates Adult Hippocampal Neurogenesis and Improves Spatial Learning in Mice.

Adult hippocampal neurogenesis plays an important role in health and disease. Regulating neurogenesis may be a key mechanism in the pathophysiology and treatment of several neurobehavioral disorders such as schizophrenia, depression, autism spectrum disorders and Alzheimer's disease. Cytokines are known to affect adult neurogenesis, but conflicting studies have been reported with regard to their actual role. Interleukine-17 (IL-17), a potent pro-inflammatory cytokine, has been shown to inhibit proliferation of neuroprogenitors and thus reduce hippocampal neurogenesis, while other studies suggested it can promote neurite outgrowth. In the present study we sought to explore the possible effect of a single dose administration of IL-17 on neurogenesis related behavior, i.e. spatial learning. Surprisingly, ICR mice injected with IL-17 (8μg) had a significant slight improvement in spatial learning in the Morris water maze paradigm, without any changes in general locomotion compared with control mice. Indeed, the expression of neurogenesis related genes was down regulated following IL-17 treatment. However, we detected an upregulation in the expression of FGF-13, a gene promoting microtubule polymerization and neurite outgrowth, thus supporting neuronal maturation. We thus suggest that IL-17 has a complex role in regulating adult neurogenesis: inhibiting neuroprogenitors proliferation on one hand, while promoting maturation of already formed neuroblasts on the other hand. Our findings suggest that these roles can potentially affect neurogenesis related behavior. Its actual role in health and disease is yet to be determined.

Downregulation of sonic hedgehog signaling in the hippocampus leads to neuronal apoptosis in high-fat diet-fed mice

Background/aimsObesity induces hippocampal neuronal apoptosis and leads to cognitive function deficits. Sonic hedgehog (SHH) signaling is crucial during nervous system development and is neuroprotective in many neurologic diseases. This study assessed the role of SHH signaling in the cognitive deficits in high-fat diet (HFD)-induced obese mice. MethodsFlow cytometry assay was used to examine cell apoptosis. Tissue pathology was evaluated by Nissl staining. Immunofluorescent staining and western blotting were used to detect SHH signaling molecules and apoptosis-related proteins. The Morris water maze test was performed to evaluate mouse spatial learning and memory. ResultsAfter HFD feeding for 24 weeks, the expression of SHH signaling molecules was downregulated in the mouse hippocampus. In vitro, GANT61 inhibited SHH signaling and induced apoptosis in HT22 mouse hippocampal cells. Smoothened agonist (SAG), an agonist of SHH signaling, reduced apoptosis in GANT61-treated HT22 cells by regulating caspase-9 and caspase-3 activation. In vivo, 12-week SAG treatment also inhibited the apoptosis of hippocampal neurons in HFD-fed mice by increasing mitofusin 2 (Mfn2) and B-cell lymphoma 2 (Bcl-2) levels and decreasing dynamin-related protein 1 (Drp1) and Bcl-2 homologous antagonist/killer (Bak) levels. Behavioral testing showed that SAG administration ameliorated the cognitive impairment in HFD-fed mice. ConclusionDownregulation of hippocampal SHH signaling leads to neuronal apoptosis and cognitive deficits in HFD-fed mice. These findings provide useful information for the identification of potential targets for research and therapeutic interventions for cognitive impairment in obesity.

Levocarnitine Improves AlCl3-Induced Spatial Working Memory Impairment in Swiss albino Mice.

Background: Aluminum, a neurotoxic substance, causes oxidative stress induced-neurodegenerative diseases. Several lines of evidence suggest that levocarnitine has an antioxidant effect and also plays an important role in beta-oxidation of fatty acids. However, the role of levocarnitine in aluminum-induced neurotoxicity has not been well documented. Here we aimed to investigate the effect of levocarnitine on aluminum chloride (AlCl3)-induced oxidative stress and memory dysfunction.Methods: Male Swiss albino mice (n = 30) were treated with either control (saline) or AlCl3 or AlCl3 plus levocarnitine or levocarnitine or astaxanthin plus AlCl3 or astaxanthin alone. The spatial working memory was determined by radial arm maze (RAM). In addition, we measured the lipid peroxidation (MDA), glutathione (GSH), advanced oxidation of protein products (AOPP), nitric oxide (NO) and activity of superoxide dismutase (SOD) in the various brain regions including prefrontal cortex (PFC), striatum (ST), parietal cortex (PC), hippocampus (HIP) hypothalamus (HT) and cerebellum (CB). We used astaxanthin as a standard antioxidant to compare the antioxidant activity of levocarnitine.Results: The RAM data showed that AlCl3 treatment (50 mg/kg) for 2 weeks resulted in a significant deficit in spatial learning in mice. Moreover, aluminum exposure significantly (p < 0.05) increased the level of oxidative stress markers such as MDA, GSH, AOPP and NO in the various brain regions compared to the controls. In addition, combined administration of levocarnitine and AlCl3 significantly (p < 0.05) lowered the MDA, AOPP, GSH and NO levels in mice.Conclusion: Our results demonstrate that levocarnitine could serve as a potential therapeutic agent in the treatment of oxidative stress associated diseases as well as in memory impairment.

Somatic Accumulation of GluA1-AMPA Receptors Leads to Selective Cognitive Impairments in Mice.

The GluA1 subunit of the L-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) plays a crucial, but highly selective, role in cognitive function. Here we analyzed AMPAR expression, AMPAR distribution and spatial learning in mice (Gria1R/R), expressing the “trafficking compromised” GluA1(Q600R) point mutation. Our analysis revealed somatic accumulation and reduction of GluA1(Q600R) and GluA2, but only slightly reduced CA1 synaptic localization in hippocampi of adult Gria1R/R mice. These immunohistological changes were accompanied by a strong reduction of somatic AMPAR currents in CA1, and a reduction of plasticity (short-term and long-term potentiation, STP and LTP, respectively) in the CA1 subfield following tetanic and theta-burst stimulation. Nevertheless, spatial reference memory acquisition in the Morris water-maze and on an appetitive Y-maze task was unaffected in Gria1R/R mice. In contrast, spatial working/short-term memory during both spontaneous and rewarded alternation tasks was dramatically impaired. These findings identify the GluA1(Q600R) mutation as a loss of function mutation that provides independent evidence for the selective role of GluA1 in the expression of short-term memory.

Staufen2 deficiency leads to impaired response to novelty in mice.

Staufen2 (Stau2) is a double-stranded RNA-binding protein (RBP) involved in posttranscriptional gene expression control in neurons. In flies, staufen contributes to learning and long-term memory formation. To study the impact of mammalian Stau2 on behavior, we generated a novel gene-trap mouse model that yields significant constitutive downregulation of Stau2 (Stau2GT). In order to investigate the effect of Stau2 downregulation on hippocampus-dependent behavior, we performed a battery of behavioral assays, i.e. open field, novel object recognition/location (NOR/L) and Barnes maze. Stau2GT mice displayed reduced locomotor activity in the open field and altered novelty preference in the NOR and NOL paradigms. Adult Stau2GT male mice failed to discriminate between familiar and newly introduced objects but showed enhanced spatial novelty detection. Additionally, we observed deficits in discriminating different spatial contexts in a Barnes maze assay. Together, our data suggest that Stau2 contributes to novelty preference and explorative behavior that is a driver for proper spatial learning in mice.