ABSTRACT
High-fat diet (HFD) can induce deficits in neural function, oxidative stress, and decrease hippocampal neurogenesis. Hypericum (H.) scabrum extract (Ext) contains compounds that could treat neurological disorders. This study aimed to examine the neuroprotective impacts of the H. scabrum Ext on hippocampal synaptic plasticity in rats that were fed HFD. Fifty-four male Wistar rats (220 ± 10 g) were randomly arranged in six groups: (1) HFD group; (2) HFD + Ext300 group; (3) HFD + Ext100 group; (4) Control group; (5) Ext 300 mg/kg group; (6) Ext 100 mg/kg group. These protocols were administrated for 3 months. After this stage, a stimulating electrode was implanted in the perforant pathway (PP), and a bipolar recording electrode was embedded into the dentate gyrus (DG). Long-term potentiation (LTP) was provoked by high-frequency stimulation (HFS) of the PP. Field excitatory postsynaptic potentials (EPSP) and population spikes (PS) were recorded at 5, 30, and 60 min after HFS. The HFD group exhibited a large and significant decrease in their PS amplitude and EPSP slope as compared to the control and extract groups. In reverse, H. scabrum administration in the HFD + Ext rats reversed the effect of HFD on the PS amplitude and EPSP slope. The results of the study support that H. scabrum Ext can inhibit diminished synaptic plasticity caused by the HFD. These effects are probably due to the extreme antioxidant impacts of the Ext and its capability to scavenge free radicals.
Subject(s)
Brain/drug effects , Dentate Gyrus/drug effects , Diet, High-Fat/adverse effects , Hypericum/chemistry , Neuronal Plasticity/drug effects , Plant Extracts/pharmacology , Animals , Antioxidants/pharmacology , Brain/physiology , Dentate Gyrus/physiology , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/physiology , Long-Term Potentiation , Male , Neuronal Plasticity/physiology , Rats , Rats, WistarABSTRACT
Diabetes mellitus (DM) is associated with impaired hippocampal synaptic plasticity. Coenzyme Q10 (CoQ10) acts as an antioxidant and exerts neuroprotective effects. Accordingly, this study aimed at evaluating the effects of CoQ10 on hippocampal long-term potentiation (LTP) and paired-pulse facilitation (PPF) in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were randomly divided into six groups (nâ¯=â¯8 per group) as follows and treated for 90â¯days: the control, controlâ¯+â¯low dose of CoQ10 (100â¯mg/kg), controlâ¯+â¯high dose of CoQ10 (600â¯mg/kg), diabetic, diabeticâ¯+â¯low dose of CoQ10, and diabeticâ¯+â¯high dose of CoQ10 groups. Diabetes was induced by a single intraperitoneal injection of 50â¯mg/kg STZ. The population spike (PS) amplitude and slope of excitatory post synaptic potentials (EPSPs) were measured in dentate gyrus (DG) area in response to the stimulation applied to the perforant path (PP). The results showed that the STZ-induced diabetes impaired LTP induction in the PP-DG synapses. This finding is supported by the decreased EPSP slope and PS amplitude of LTP (Pâ¯<â¯0.05). Both low- and high-dose CoQ10 supplementation in the control and diabetic animals enhanced EPSP slope and PS amplitude of LTP in the granular cells of DG (Pâ¯<â¯0.05). PPF was affected by LTP induction in diabetic animals receiving the high dose of CoQ10 (Pâ¯<â¯0.05). It is suggested that CoQ10 administration could attenuate deteriorative effect of STZ-induced diabetes on in vivo LTP in the DG. The enhanced transmitter release can be partly one of the possible underlying mechanism(s) responsible for the LTP induction in the diabetic animals treated with CoQ10.
Subject(s)
Antioxidants/administration & dosage , Dentate Gyrus/drug effects , Diabetes Mellitus/physiopathology , Long-Term Potentiation/drug effects , Neurons/drug effects , Neuroprotective Agents/administration & dosage , Ubiquinone/analogs & derivatives , Animals , Dentate Gyrus/physiology , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/physiopathology , Male , Neurons/physiology , Rats, Wistar , Streptozocin/administration & dosage , Ubiquinone/administration & dosageABSTRACT
Episodic memories typically comprise multiple elements. A defining characteristic of episodic retrieval is holistic recollection, i.e., comprehensive recall of the elements a memorized event encompasses. A recent study implicated activity in the human hippocampus with holistic recollection of multi-element events based on cues (Horner et al., 2015). Here, we obtained ultra-high resolution functional neuroimaging data at 7 tesla in 30 younger adults (12 female) using the same paradigm. In accordance with anatomically inspired computational models and animal research, we found that metabolic activity in hippocampal subfield CA3 (but less pronounced in dentate gyrus) correlated with this form of mnemonic pattern completion across participants. Our study provides the first evidence in humans for a strong involvement of hippocampal subfield CA3 in holistic recollection via pattern completion.SIGNIFICANCE STATEMENT Memories of daily events usually involve multiple elements, although a single element can be sufficient to prompt recollection of the whole event. Such holistic recollection is thought to require reactivation of brain activity representing the full event from one event element ("pattern completion"). Computational and animal models suggest that mnemonic pattern completion is accomplished in a specific subregion of the hippocampus called CA3, but empirical evidence in humans was lacking. Here, we leverage the ultra-high resolution of 7 tesla neuroimaging to provide first evidence for a strong involvement of the human CA3 in holistic recollection of multi-element events via pattern completion.
Subject(s)
CA3 Region, Hippocampal/physiology , Mental Recall/physiology , Pattern Recognition, Visual/physiology , Adult , Brain Mapping , CA3 Region, Hippocampal/diagnostic imaging , CA3 Region, Hippocampal/metabolism , Cues , Dentate Gyrus/physiology , Female , Functional Neuroimaging , Humans , Magnetic Resonance Imaging , Male , Memory, Episodic , Photic Stimulation , Psychomotor Performance/physiology , Reading , Temporal Lobe/physiology , Young AdultABSTRACT
Post-weaning social isolation (PWSI) is known to induce exaggerated and abnormal aggression in male rats. Here we aimed to assess the effects of PWSI on aggressiveness and social behavior in both male and female rats. Furthermore, we evaluated how PWSI affects the central oxytocin (OXT) and vasopressin (AVP) systems in both sexes. Wistar rats were isolated (IS) or group housed (GH) in same-sex groups immediately after weaning. After seven weeks, rats underwent an intruder test to assess aggression. In one group, brains were immediately dissected afterwards for in situ hybridization and receptor autoradiography. The other group underwent additional anxiety-like and social behavior tests. PWSI induced increased (abnormal) aggression and impaired social memory in both sexes. Especially IS females exhibited abnormal aggression towards juveniles. Furthermore, PWSI increased OXT mRNA expression in the paraventricular nucleus of the hypothalamus (PVN) and decreased OXTR binding in the anterior portion of the nucleus accumbens (NAcc), independent of the sex. V1a receptor binding was decreased in the lateral hypothalamus (LH) and dentate gyrus (DG) in IS rats, regardless of sex. However, V1a receptor binding in the anterior portion of the bed nucleus of stria terminalis (BNSTa) was decreased in IS females but increased in IS males. Taken together, our data support PWSI as a reliable model to exacerbate aggression not only in male but also in female rats. In addition, OXT receptors in the NAcca and V1a receptors in the LH, DG, and BNSTa may play a role in the link between PWSI and aggression. This article is part of the Special Issue entitled 'Current status of the neurobiology of aggression and impulsivity'.
Subject(s)
Aggression/physiology , Arginine Vasopressin/physiology , Brain/physiology , Oxytocin/physiology , Social Isolation , Animals , Arginine Vasopressin/metabolism , Dentate Gyrus/physiology , Female , Hypothalamus/physiology , Male , Nucleus Accumbens/physiology , Oxytocin/metabolism , RNA, Messenger/metabolism , Rats, Wistar , Receptors, Oxytocin/metabolism , Receptors, Vasopressin/metabolism , Septal Nuclei/physiology , Sex CharacteristicsABSTRACT
Calretinin (CR), a calcium-binding protein from EF-hand family, is localised in non-pyramidal GABA-ergic interneurons of the hippocampus. CR takes part in maintaining calcium binding homeostasis, which suggests its neuroprotective role. Hippocampal neurons contain membrane transient receptor potential vanilloid 1 (TRPV1) which binds to capsaicin (CAP) contained in habanero pepper fruits. Few in vivo studies have revealed the effect of CAP on interneurons containing CR. The aim of the present study was to investigate the CR immunoreac- tivity in interneurons of the hippocampal CA1 field and dentate gyrus (DG) in adult rats after intragastric admin- istration of the habanero pepper fruits. Wistar rats received a peanut oil - control group (C), and oil suspension of habanero pepper fruits at doses of 0.025 g dm/kg b.w. - group I and 0.08 g dm/kg b.w. - group II for 28 days. After euthanasia, the brains were collected and embedded in paraffin blocks using a routine histological tech- nique. Frontal hippocampal sections were immunohistochemically stained for CR by using a peroxidase-antiper- oxidase method. CR immunoreactive (CR-IR) interneurons were morphologically and morphometrically ana- lyzed under a light microscope. The results showed similar shapes and distribution of cells in both areas of the brain in group C and I of animals. However, CR-IR interneurons in the hippocampal CA1 field and in DG were occasionally observed in the group II of rats. The results of morphometric studies did not reveal statistically significant differences in the surface area and shape index of cells between examined brain regions from groups I and II compared to group C. Only in group II of rats, an increase in the digital immunostaining intensity of CR-IR interneurons was found in DG. Low number of CR-IR interneurons in the hippocampal CA1 field and in the DG, under the influence of a large dose of habanero pepper fruits containing CAP, may be caused by the activation of TRPV1 receptors and the increase in Ca2+ ions in these cells. This phenomenon may ultimately lead to neuronal death and may disturb neuronal conduction.
Subject(s)
CA1 Region, Hippocampal/cytology , Calbindin 2/metabolism , Capsicum , Dentate Gyrus/cytology , Interneurons/physiology , Animals , CA1 Region, Hippocampal/physiology , Dentate Gyrus/physiology , Male , Rats , Rats, WistarABSTRACT
Rhynchophylline (RIN) is a significant active component isolated from the Chinese herbal medicine Uncaria rhynchophylla. The overproduction of soluble amyloid ß protein (Aß) oligomers in the hippocampus is closely involved in impairments in cognitive function at the early stage of Alzheimer's disease (AD). Growing evidences show that RIN possesses neuroprotective effects against Aß-induced neurotoxicity. However, whether RIN can prevent soluble Aß1-42-induced impairments in spatial cognitive function and synaptic plasticity is still unclear. Using the combined methods of behavioral tests, immunofluorescence and electrophysiological recordings, we characterized the key neuroprotective properties of RIN and its possible cellular and molecular mechanisms against soluble Aß1-42-related impairments in rats. Our findings are as follows: (1) RIN efficiently rescued the soluble Aß1-42-induced spatial learning and memory deficits in the Morris water maze test and prevented soluble Aß1-42-induced suppression in long term potentiation (LTP) in the entorhinal cortex (EC)-dentate gyrus (DG) circuit. (2) Excessive activation of extrasynaptic GluN2B-NMDAR and subsequent Ca2+ overload contributed to the soluble Aß1-42-induced impairments in spatial cognitive function and synaptic plasticity. (3) RIN prevented Aß1-42-induced excessive activation of extrasynaptic NMDARs by reducing extrasynaptic NMDARs -mediated excitatory postsynaptic currents and down regulating GluN2B-NMDAR expression in the DG region, which inhibited Aß1-42-induced Ca2+ overload mediated by extrasynanptic NMDARs. The results suggest that RIN could be an effective therapeutic candidate for cognitive impairment in AD.
Subject(s)
Memory Disorders/drug therapy , Oxindoles/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Spatial Learning/drug effects , Amyloid beta-Peptides/pharmacology , Animals , Dentate Gyrus/physiology , Down-Regulation/drug effects , Entorhinal Cortex/physiology , Excitatory Postsynaptic Potentials/drug effects , Long-Term Potentiation/drug effects , Male , Maze Learning/drug effects , Neuronal Plasticity/drug effects , Neuroprotective Agents/pharmacology , Oxindoles/therapeutic use , Peptide Fragments/pharmacology , Rats , Receptors, N-Methyl-D-Aspartate/biosynthesisABSTRACT
Modafinil is a wake promoting drug approved for clinical use and also has cognitive enhancing properties. Its enantiomer R-Modafinil (R-MO) is not well studied in regard to cognitive enhancing properties. Hence we studied its effect in a spatial memory paradigm and its possible effects on dentate gyrus long-term potentiation (DG-LTP). Clinically relevant doses of R-MO, vehicle dimethyl sulfoxide (DMSO) or saline were administered for three days during the hole-board test and in in vivo DG-LTP. Synaptic levels of dopamine receptors D1R, D2R, dopamine transporter (DAT), and its phosphorylated form (ph-DAT) in DG tissue 4 h after LTP induction were quantified by western blot analysis. Monoamine reuptake and release assays were performed by using transfected HEK-293 cells. Possible neurotoxic side effects on general behaviour were also studied. R-MO at both doses significantly enhanced spatial reference memory during the last training session and during memory retrieval compared to DMSO vehicle but not when compared to saline treated rats. Similarly, R-MO rescues DG-LTP from impairing effects of DMSO. DMSO reduced memory performance and LTP magnitude when compared to saline treated groups. The synaptic DR1 levels in R-MO groups were significantly decreased compared to DMSO group but were comparable with saline treated animals. We found no effect of R-MO in neurotoxicity tests. Thus, our results support the notion that LTP-like synaptic plasticity processes could be one of the factors contributing to the cognitive enhancing effects of spatial memory traces. D1R may play an important regulatory role in these processes.
Subject(s)
Benzhydryl Compounds/pharmacology , Dentate Gyrus/drug effects , Learning/drug effects , Long-Term Potentiation/drug effects , Nootropic Agents/pharmacology , Spatial Memory/drug effects , Animals , Dentate Gyrus/physiology , Dimethyl Sulfoxide/pharmacology , Dopamine/metabolism , Dopamine Plasma Membrane Transport Proteins/metabolism , Drug Evaluation, Preclinical , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , HEK293 Cells , Humans , Learning/physiology , Long-Term Potentiation/physiology , Male , Modafinil , Rats, Sprague-Dawley , Receptors, Dopamine/metabolism , Spatial Memory/physiologyABSTRACT
Adult hippocampal neurogenesis can be modulated by various physiological and pathological conditions, including stress, affective disorders, and several neurological conditions. Given the proposed role of this form of structural plasticity in the functioning of the hippocampus (namely learning and memory and affective behaviors), it is believed that alterations in hippocampal neurogenesis might underlie some of the behavioral deficits associated with these psychiatric and neurological conditions. Thus, the search for compounds that can reverse these deficits with minimal side effects has become a recognized priority. In the present study we tested the pro-neurogenic effects of isoxazole 9 (Isx-9), a small synthetic molecule that has been recently identified through the screening of chemical libraries in stem cell-based assays. We found that administration of Isx-9 for 14days was able to potentiate cell proliferation and increase the number of immature neurons in the hippocampal DG of adult rats. In addition, Isx-9 treatment was able to completely reverse the marked reduction in these initial stages of the neurogenic process observed in vehicle-treated animals (which were submitted to repeated handling and exposure to daily intraperitoneal injections). Based on these results, we recommend that future neurogenesis studies that require repeated handling and manipulation of animals should include a naïve (non-manipulated) control to determine the baseline levels of hippocampal cell proliferation and neuronal differentiation. Overall, these findings demonstrate that Isx-9 is a promising synthetic compound for the mitigation of stress-induced deficits in adult hippocampal neurogenesis. Future studies are thus warranted to evaluate the pro-neurogenic properties of Isx-9 in animal models of affective and neurological disorders associated with impaired hippocampal structural plasticity.
Subject(s)
Cell Proliferation/drug effects , Central Nervous System Agents/pharmacology , Dentate Gyrus/drug effects , Isoxazoles/pharmacology , Neurogenesis/drug effects , Neurons/drug effects , Thiophenes/pharmacology , 2-Hydroxypropyl-beta-cyclodextrin , Animals , Central Nervous System Agents/chemical synthesis , Corticosterone/blood , Dentate Gyrus/cytology , Dentate Gyrus/physiology , Drug Evaluation, Preclinical , Immunohistochemistry , Isoxazoles/chemical synthesis , Male , Molecular Structure , Neurons/cytology , Neurons/physiology , Rats, Sprague-Dawley , Stress, Psychological/drug therapy , Stress, Psychological/pathology , Stress, Psychological/physiopathology , Thiophenes/chemical synthesis , beta-Cyclodextrins/pharmacologyABSTRACT
Sideritis plants and their extracts have been used in traditional medicine as sedatives, anxiolytics and anticonvulsant agents. Pinenes are the most prevalent of the volatile aroma components in Siderites extracts and the pinene metabolites myrtenol and verbenol have been identified as the most potent positive allosteric modulators of synaptic GABAA receptors composed of α1ß2 and α1ß2γ2 subunits. In view of their therapeutic spectrum, we wondered whether these two terpenoids would also augment tonic GABA currents mediated by extrasynaptic GABAA receptors containing the δ subunit. When we expressed α4ß2δ receptors in HEK293 cells, we found that co-application of myrtenol or verbenol enhanced whole-cell current responses to GABA by up to 100%. Consistent with their effects on heterologous α1ß2γ2 receptors, we found that myrtenol and verbenol, when co-applied with GABA via local perfusion, increased the amplitude and area of miniature inhibitory postsynaptic potentials (mIPSCs) recorded in whole-cell voltage-clamp recordings from granule cells in the dentate gyrus of mouse hippocampal brain slices. In addition, co-application of terpenoids with GABA was also able to enhance tonic GABA current, measured from the change in baseline current and current noise, compared to GABA perfusion alone. Our results suggest that myrtenol and verbenol act as positive allosteric modulators at synaptic and extrasynaptic GABAA receptors, thereby augmenting phasic and tonic GABAergic inhibition. Thus, our study reveals an important pharmacological and therapeutic target of bicyclic monoterpenoids.
Subject(s)
Dentate Gyrus/physiology , Inhibitory Postsynaptic Potentials , Monoterpenes/pharmacology , Neurons/physiology , Receptors, GABA-A/physiology , Animals , Bicyclic Monoterpenes , Dentate Gyrus/drug effects , Female , HEK293 Cells , Humans , Male , Mice , Mice, Inbred C57BL , Miniature Postsynaptic Potentials , Neurons/drug effects , gamma-Aminobutyric Acid/pharmacologyABSTRACT
Aging is associated with reduced hippocampal neurogenesis, which may in turn contribute to cognitive impairment. We assessed the effect of Ginkgo biloba (Gb) on hippocampal neurogenesis in elderly male mice using immunohistochemistry. We used anti-caspase-3 as a marker of apoptosis, anti-GFAP as a marker of neural stem cells, anti-Ki-67 as a specific marker for cellular proliferation and anti-doublecortin (DCX) to detect newly born neurons in the hippocampal dentate gyrus (DG) of aged male mice. The 24-month-old male mice were divided into two groups: a control group treated with distilled water and a group fed with Gb at a dose of 100 mg/kg once daily for 28 days. A sharp decrease in apoptotic cells in Gb-treated compared to nontreated mice was observed by anti-csapase-3 immunostaining. A large number of GFAP+ve cells was found in the subgranular zone of the DG of Gb-treated mice, suggesting an increase in the pool of neural stem cells by Gb treatment. There was also an increase in Ki-67 immunoreactive cells, indicating increased cell proliferation in the DG in the Gb-treated compared to nontreated group. A significant increase in newborn DCX+ve neurons with well-developed tertiary dendrites was also found in the Gb-treated compared to nontreated group. Using Western blot analysis, the expression of DCX protein in the Gb group was also significantly increased compared to the control. The results support a beneficial role of Gb on hippocampal neurogenesis in the context of brain aging.
Subject(s)
Aging/pathology , Aging/physiology , Dentate Gyrus/cytology , Dentate Gyrus/physiology , Ginkgo biloba/chemistry , Neurogenesis/drug effects , Plant Extracts/pharmacology , Plant Leaves/chemistry , Administration, Ophthalmic , Animals , Cell Proliferation/drug effects , Dentate Gyrus/drug effects , Doublecortin Protein , Male , Mice , Plant Extracts/administration & dosage , Plant Extracts/isolation & purification , Stimulation, ChemicalABSTRACT
Alzheimer's disease (AD) is characterized by amyloid ß (Aß) peptide aggregation and cholinergic neurodegeneration. Therefore, in this paper, we examined silibinin, a flavonoid extracted from Silybum marianum, to determine its potential as a dual inhibitor of acetylcholinesterase (AChE) and Aß peptide aggregation for AD treatment. To achieve this, we used molecular docking and molecular dynamics simulations to examine the affinity of silibinin with Aß and AChE in silico. Next, we used circular dichroism and transmission electron microscopy to study the anti-Aß aggregation capability of silibinin in vitro. Moreover, a Morris Water Maze test, enzyme-linked immunosorbent assay, immunohistochemistry, 5-bromo-2-deoxyuridine double labeling, and a gene gun experiment were performed on silibinin-treated APP/PS1 transgenic mice. In molecular dynamics simulations, silibinin interacted with Aß and AChE to form different stable complexes. After the administration of silibinin, AChE activity and Aß aggregations were down-regulated, and the quantity of AChE also decreased. In addition, silibinin-treated APP/PS1 transgenic mice had greater scores in the Morris Water Maze. Moreover, silibinin could increase the number of newly generated microglia, astrocytes, neurons, and neuronal precursor cells. Taken together, these data suggest that silibinin could act as a dual inhibitor of AChE and Aß peptide aggregation, therefore suggesting a therapeutic strategy for AD treatment.
Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/etiology , Amyloid beta-Peptides/metabolism , Cholinesterase Inhibitors , Phytotherapy , Protein Aggregation, Pathological/metabolism , Silymarin/pharmacology , Silymarin/therapeutic use , Alzheimer Disease/physiopathology , Animals , Dentate Gyrus/metabolism , Dentate Gyrus/physiology , Female , Male , Mice, Transgenic , Silybum marianum/chemistry , Nerve Regeneration/drug effects , Rats, Sprague-Dawley , Silybin , Silymarin/isolation & purificationABSTRACT
In the current study, we investigated whether electroacupuncture (EA) can inhibit pathological reductions in neurogenesis. Zucker diabetic fatty (ZDF) rats at 7 weeks of age were anesthetized with zoletil, and sham-acupuncture or EA at the Zusanli (ST36) and Baihui (GV20) acupoints was administered once a day for 5 weeks. In the ZDF group that received sham-EA (ZDF-Sham group), the blood glucose level was significantly increased together with age as compared to the control littermates [Zucker lean control (ZLC) rat]. In contrast, proliferating cells and differentiated neuroblasts were significantly decreased in the ZDF-Sham group compared to the ZLC group. Although EA treatment decreased blood glucose levels, this was not statistically significant when compared to blood glucose levels changes in the ZDF-Sham group. However, proliferating cells and differentiated neuroblasts were significantly increased with EA in ZDF rats as compared to those in the ZDF-Sham group. Brain-derived neurotrophic factor (BDNF) levels were significantly decreased in hippocampal homogenates of ZDF-Sham group compared to those in the ZLC group. The EA treatment significantly increased the BDNF levels compared to those in the ZDF-Sham group, and BDNF levels in this group were similar to those in the ZLC group. These results suggest that EA at ST36 and GV20 can ameliorate the reductions in proliferating cells and differentiated neuroblasts in the dentate gyrus induced by type-2 diabetes without significantly reducing blood glucose levels with increasing BDNF levels.
Subject(s)
Acupuncture Therapy/methods , Brain-Derived Neurotrophic Factor/metabolism , Dentate Gyrus/physiology , Diabetes Mellitus, Type 2/metabolism , Electric Stimulation , Neurons/physiology , Animals , Blood Glucose , Brain-Derived Neurotrophic Factor/genetics , Cell Differentiation , Cell Proliferation , Dentate Gyrus/cytology , Female , Male , Neurons/cytology , Rats , Rats, ZuckerABSTRACT
In the present study, the orthosteric GABAA receptor (GABAAR) ligand 4,5,6,7-tetrahydroisothiazolo[5,4-c]pyridin-3-ol (Thio-THIP) was found to possess a highly interesting functional profile at recombinant human GABAARs and native rat GABAARs. Whereas Thio-THIP displayed weak antagonist activity at α1,2,5ß2,3γ2S and ρ1 GABAARs and partial agonism at α6ß2,3δ GABAARs expressed in Xenopus oocytes, the pronounced agonism exhibited by the compound at α4ß1δ and α4ß3δ GABAARs was contrasted by its negligible activity at the α4ß2δ subtype. To elucidate to which extent this in vitro profile translated into functionality at native GABAARs, we assessed the effects of 100 µm Thio-THIP at synaptic and extrasynaptic receptors in principal cells of four different brain regions by slice electrophysiology. In concordance with its α6ß2,3δ agonism, Thio-THIP evoked robust currents through extrasynaptic GABAARs in cerebellar granule cells. In contrast, the compound did not elicit significant currents in dentate gyrus granule cells or in striatal medium spiny neurons (MSNs), indicating predominant expression of extrasynaptic α4ß2δ receptors in these cells. Interestingly, Thio-THIP evoked differential degrees of currents in ventrobasal thalamus neurons, a diversity that could arise from differential expression of extrasynaptic α4ßδ subtypes in the cells. Finally, whereas 100 µm Thio-THIP did not affect the synaptic currents in ventrobasal thalamus neurons or striatal MSNs, it reduced the current amplitudes recorded from dentate gyrus granule cells, most likely by targeting perisynaptic α4ßδ receptors expressed at distal dendrites of these cells. Being the first published ligand capable of discriminating between ß2- and ß3-containing receptor subtypes, Thio-THIP could be a valuable tool in explorations of native α4ßδ GABAARs.
Subject(s)
Brain/drug effects , Brain/metabolism , GABA-A Receptor Agonists/pharmacology , Isoxazoles/pharmacology , Neural Inhibition/drug effects , Neural Inhibition/physiology , Receptors, GABA-A/metabolism , Animals , Brain/cytology , Cerebellum/drug effects , Cerebellum/physiology , Corpus Striatum/drug effects , Corpus Striatum/physiology , Dentate Gyrus/drug effects , Dentate Gyrus/physiology , Dose-Response Relationship, Drug , Humans , Membrane Potentials/drug effects , Membrane Potentials/physiology , Neurons/drug effects , Neurons/physiology , Protein Subunits/agonists , Protein Subunits/antagonists & inhibitors , Protein Subunits/metabolism , Rats , Receptors, GABA-A/chemistry , Recombinant Proteins/drug effects , Thalamus/drug effects , Thalamus/physiology , XenopusABSTRACT
The dentate gyrus (DG) is a region in the hippocampal formation whose function declines in association with human aging and is therefore considered to be a possible source of age-related memory decline. Causal evidence is needed, however, to show that DG-associated memory decline in otherwise healthy elders can be improved by interventions that enhance DG function. We addressed this issue by first using a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related DG dysfunction and to develop a cognitive task whose function localized to this anatomical site. Then, in a controlled randomized trial, we applied these tools to study healthy 50-69-year-old subjects who consumed either a high or low cocoa flavanol-containing diet for 3 months. A high-flavanol intervention was found to enhance DG function, as measured by fMRI and by cognitive testing. Our findings establish that DG dysfunction is a driver of age-related cognitive decline and suggest non-pharmacological means for its amelioration.
Subject(s)
Cacao , Cognition/physiology , Dentate Gyrus/physiology , Diet/methods , Flavanones/administration & dosage , Acoustic Stimulation/methods , Aged , Exercise Test/methods , Exercise Test/psychology , Female , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Time FactorsABSTRACT
Chong-Myung-Tang (CMT) is a multi-herbal formula that has been used to improve memory. However, the potential mechanism remains unknown. The present study investigated the effects of CMT (50, 100, and 200 mg/kg) on spatial memory of aged mice. The behavioral training tests indicated that 200 mg/kg CMT treatment can significantly improve spatial memory of aged mice in the Morris water maze. Moreover, cell survival was examined by injecting bromodeoxyuridine (BrdU) on the first three days. The result showed that 200 mg/kg CMT treatment significantly increased cell survival in the dentate gyrus. Cell proliferation was determined by injecting BrdU 2 h before the mice were killed. The result suggested that CMT treatments had no influence on cell proliferation in the dentate gyrus. Thus, an increase in cell survival in the dentate gyrus stimulated by CMT may be involved in the effect of CMT on spatial memory improvement.
Subject(s)
Aging/physiology , Dentate Gyrus/cytology , Dentate Gyrus/drug effects , Neurogenesis/drug effects , Plant Extracts/pharmacology , Spatial Memory/drug effects , Animals , Behavior, Animal/drug effects , Behavior, Animal/physiology , Cell Proliferation/drug effects , Cell Survival/drug effects , Chemistry, Pharmaceutical , Dentate Gyrus/physiology , Male , Maze Learning/drug effects , Mice , Mice, Inbred ICR , Plant Extracts/chemistryABSTRACT
BACKGROUND: Cynomorium songaricum Rupr. (CS) has been used as a medicine to treat many diseases as well as to alleviate age-related issues, such as memory impairment, dementia, and stress. In this study, we assessed the effects of Cynomorium songaricum extract (CSE) on the novel object recognition, cell proliferation and neuroblast differentiation in the dentate gyrus of mice by using 5-bromodeoxyuridine (BrdU) and polysialylated neural cell adhesion molecule (PSA-NCAM). We also measured serum corticosterone levels to assess its correlation with neurogenesis and stress. METHODS: Male C57BL/6 J mice were divided into 3 groups: vehicle-treated, 40 mg/kg CSE-treated, and 100 mg/kg CSE-treated. The vehicle and CSE were given to mice once a day for 3 weeks. BrdU was injected twice a day for 3 days to label newly generated cells. RESULTS: Administration of CSE significantly increased the preferential exploration of new objects in these mice. In addition, administration of CSE decreased serum levels of corticosterone. BrdU-positive cells as well as brain-derived neurotrophic factor (BDNF) mRNA expression in the dentate gyrus were higher in the CSE-treated groups than in the vehicle-treated group. PSA-NCAM-positive neuroblasts and their well-developed tertiary dendrites were also significantly increased by the treatment of CSE. These effects were prominent at the higher dosage than at the lower dosage. CONCLUSION: These results suggest that administration of CSE increases cell proliferation and neuroblast differentiation in the dentate gyrus of mice by reducing serum corticosterone levels and increasing BDNF levels in this area.
Subject(s)
Cynomorium/chemistry , Dentate Gyrus/drug effects , Neurogenesis/drug effects , Plant Extracts/pharmacology , Recognition, Psychology/drug effects , Animals , Brain-Derived Neurotrophic Factor/genetics , Cell Proliferation/drug effects , Corticosterone/blood , Dendrites/drug effects , Dentate Gyrus/cytology , Dentate Gyrus/physiology , Male , Mice , Mice, Inbred C57BL , Neural Stem Cells/cytology , Neural Stem Cells/drug effects , RNA, Messenger/analysis , RNA, Messenger/genetics , Stress, PsychologicalABSTRACT
A number of major inventions in history have been based on bionic imitation. Heuristics, by applying biological systems to the creation of artificial devices and machines, might be one of the most critical processes in scientific innovation. In particular, prototype heuristics propositions that innovation may engage automatic activation of a prototype such as a biological system to form novel associations between a prototype's function and problem-solving. We speculated that the cortical dissociation between the automatic activation and forming novel associations in innovation is critical point to heuristic creativity. In the present study, novel and old scientific innovations (NSI and OSI) were selected as experimental materials in using learning-testing paradigm to explore the neural basis of scientific innovation induced by heuristic prototype. College students were required to resolve NSI problems (to which they did not know the answers) and OSI problems (to which they knew the answers). From two fMRI experiments, our results showed that the subjects could resolve NSI when provided with heuristic prototypes. In Experiment 1, it was found that the lingual gyrus (LG; BA18) might be related to prototype heuristics in college students resolving NSI after learning a relative prototype. In Experiment 2, the LG (BA18) and precuneus (BA31) were significantly activated for NSI compared to OSI when college students learned all prototypes one day before the test. In addition, the mean beta-values of these brain regions of NSI were all correlated with the behavior accuracy of NSI. As our hypothesis indicated, the findings suggested that the LG might be involved in forming novel associations using heuristic information, while the precuneus might be involved in the automatic activation of heuristic prototype during scientific innovation.
Subject(s)
Behavior/physiology , Dentate Gyrus/physiology , Gyrus Cinguli/physiology , Learning/physiology , Problem Solving/physiology , Thalamus/physiology , Adult , Artificial Intelligence , Brain Mapping , Dentate Gyrus/anatomy & histology , Female , Gyrus Cinguli/anatomy & histology , Humans , Inventions , Magnetic Resonance Imaging , Male , Thalamus/anatomy & histologyABSTRACT
Acupuncture, a traditional Chinese therapeutic method, has been widely used in clinical practice to treat diseases such as stroke, Bell's palsy, Alzheimer disease, Parkinson diseases, dysmenorrhea and chronic pain. Mounting lab data had suggested that electro-acupuncture could alleviate dementia and restore long term potentiation of hippocampus in rat. Clinical data also indicated that electro-acupuncture could improve electrical activity of brain in vascular dementia patients. However, its biological basis and acute effects on hippocampal long term potentiation (LTP) remain not well understood. Therefore, we sought to investigate whether acute electro-acupuncture (acupoints: ST36 and SP6; continuous wave, 2 mV, 2Hz; lasted 20 min) could enhance LTP of perforant path-dentate gyrus granule cells in anesthetized rat and explore its underlying mechanisms. We found that electro-acupuncture could significantly increase PS2/PS 1 in pair pulse test (P <0.05, inter-pulse interval: 20ms and 90ms). When compared to control group, electro-acupuncture could significantly enhance LTP to about 234% which was about 143% of that in control group (P <0.05). It suggested that electro-acupuncture could modulate the function of interneurons in hippocampus hence increase LTP.
Subject(s)
Dentate Gyrus/physiology , Electroacupuncture , Hippocampus/physiology , Long-Term Potentiation , Memory , Perforant Pathway/physiology , Synapses/physiology , Animals , Humans , Male , Rats , Rats, WistarABSTRACT
Melatonin modulates adult hippocampal neurogenesis in adult mice. Also, plasma melatonin levels and new neuron formation decline during aging probably causing cognitive alterations. In this study, we analyzed the impact of exogenous supplementation with melatonin in three key events of hippocampal neurogenesis during normal aging of mice. The analysis was performed in rodents treated with melatonin during 3, 6, 9 or 12 months. We found an increase in cell proliferation in the dentate gyrus of the hippocampus after 3, 6 and 9 months of treatment (>90%). Additionally, exogenous melatonin promoted survival of new cells in the dentate gyrus (>50%). Moreover, melatonin increased the number of doublecortin-labeled cells after 6 and 9 months of treatment (>150%). In contrast, melatonin administered during 12 months did not induce changes in hippocampal neurogenesis. Our results indicate that melatonin also modulates the neurogenic process in the hippocampus during normal aging of mice. Together, the data support melatonin as one of the positive endogenous regulators of neurogenesis during aging.
Subject(s)
Aging/physiology , Dentate Gyrus/cytology , Dentate Gyrus/drug effects , Melatonin/pharmacology , Neurogenesis/drug effects , Animals , Cell Proliferation/drug effects , Cell Survival/drug effects , Cell Survival/physiology , Central Nervous System Depressants/pharmacology , Cognition/physiology , Dentate Gyrus/physiology , Doublecortin Domain Proteins , Male , Melatonin/physiology , Mice , Mice, Inbred BALB C , Microtubule-Associated Proteins/metabolism , Neurogenesis/physiology , Neurons/cytology , Neurons/metabolism , Neuropeptides/metabolismABSTRACT
Omega-3 fatty acid deprivation during development reduces performance in learning tasks, and dietary DHA supplementation improves learning ability and enhances long term memory in both young and old animals. However, little attention has been paid to the effect of maternal intake of Omega-3 fatty acids on hippocampal function in their pups. Randomly some of the pregnant dams were supplemented with Omega-3 essential fatty acid, others with tap-water, during pregnancy and breast-feeding by gavage daily. Spatial learning and memory was tested in Morris water maze. Field potentials from the dentate gyrus were recorded in response to medial perforant pathway in urethane-anesthetized pups. Omega-3-treated rats found the platform less traveled and closer to platform than control animals. However the pups from both groups show the same performance in retrieval task. No differences were found between corresponding animal groups in the input-output curves of the field potential slopes, suggesting no effect of Omega-3 supplementation on basal synaptic efficacy. Potentiation of population spike amplitude was much higher in pups of Omega-3 treated dams than control. Up to now Omega 3 fatty acid has been shown to be beneficial on the synaptic plasticity only under some pathological conditions. For the first time, we showed improved dentate gyrus-LTP and enhanced Morris water maze performance in healthy pups from healthy dams treated with Omega-3 fatty acids during pregnancy and breast-feeding period. Molecular studies are needed to explain Omega-3 effect on hippocampal synaptic plasticity.