Acquisition Of Spatial Memory Research Articles

Retrieval of allocentric spatial memories is preserved up to thirty days and does not require higher brain metabolic demands

Spatial orientation is a cognitive ability that is indispensable for survival. Several visual distal cues present in the context can be integrated, establishing a cognitive map. Although there is cumulative evidence about the neural substrate involved in spatial memory acquisition, the brain networks mediating the processes involved in the retrieval of allocentric spatial memories have been studied less. Here, we aimed to explore the role of neuronal oxidative metabolism in the retrieval of allocentric spatial memories through cytochrome c oxidase (CCO) histochemistry seven, 15, 30, 45, and 60 days after task acquisition. Our behavioural results show that spatial memory retrieval in male and female rats is preserved seven, 15, and 30 days post-acquisition, but there is forgetfulness after this time, with subjects not being able to remember the position of the hidden platform after 45 and 60 dfearays. Regarding the study of male brain metabolism, we observed reduced CCO activity in the medial prefrontal cortex, the parietal, retrosplenial, rhinal cortex, and the hippocampal regions in all the groups that failed to solve the task. Similar results were found for female brain oxidative metabolism, in addition to certain differences between succefearssful-retrieval female groups. In conclusion, our work adds information about the behavioural retrieval of an allocentric spatial reference task, suggesting that recovering spatial information seven, 15, and 30days after acquisition is a simple task that does not require a high metabolic demand, in both male and female rats.

Pharmacological inhibition of sphingosine-1-phosphate lyase partially reverses spatial memory impairment in streptozotocin-diabetic rats

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid with strong neuroprotective properties that is important for normal excitability and synaptic transmission in the hippocampal neurons. Considering the above, the aim of the present study was to determine whether increasing brain S1P level is able to reverse spatial memory impairment in streptozotocin-diabetic rats. The experiment was carried out on diabetic (n = 22) and nondiabetic (n = 10) male Wistar rats. Diabetes was induced by a single injection of streptozotocin. Eleven weeks later, 11 diabetic animals received injections of THI (S1P lyase inhibitor) for seven days. During the last five days of the experiment spatial reference memory acquisition and retention were tested in the Morris water maze task. The animals were then anaesthetized and samples of the hippocampus, prefrontal cortex, striatum, and cerebellum were excised. The content of S1P and related sphingolipids was measured using a HPLC method. Diabetes induced a depletion of ceramide in the hippocampus and cerebellum that was associated with impaired spatial memory and learning. Administration of THI to the diabetic animals prevented ceramide depletion in the hippocampus and cerebellum, and induced an increase in S1P content in all examined brain structures. These effects were associated with an improvement in spatial memory. We conclude that pharmacological inhibition of S1P lyase partially reverses the impairment in spatial memory induced by chronic hyperglycemia, and that this effect may be related to the prevention of ceramide depletion in the hippocampus and cerebellum, the increase in brain S1P level, or both.

Perinatal Exposure to Triclosan Results in Abnormal Brain Development and Behavior in Mice.

Triclosan (TCS) is one of the most common endocrine-disrupting chemicals (EDCs) present in household and personal wash products. Recently, concerns have been raised about the association between abnormal behavior in children and exposure to EDC during gestation. We hypothesized that exposure to TCS during gestation could affect brain development. Cortical neurons of mice were exposed in vitro to TCS. In addition, we examined in vivo whether maternal TCS administration can affect neurobehavioral development in the offspring generation. We determined that TCS can impair dendrite and axon growth by reducing average length and numbers of axons and dendrites. Additionally, TCS inhibited the proliferation of and promoted apoptosis in neuronal progenitor cells. Detailed behavioral analyses showed impaired acquisition of spatial learning and reference memory in offspring derived from dams exposed to TCS. The TCS-treated groups also showed cognition dysfunction and impairments in sociability and social novelty preference. Furthermore, TCS-treated groups exhibited increased anxiety-like behavior, but there was no significant change in depression-like behaviors. In addition, TCS-treated groups exhibited deficits in nesting behavior. Taken together, our results indicate that perinatal exposure to TCS induces neurodevelopment disorder, resulting in abnormal social behaviors, cognitive impairment, and deficits in spatial learning and memory in offspring.

Small lesions of the dorsal or ventral hippocampus subregions are associated with distinct impairments in working memory and reference memory retrieval, and combining them attenuates the acquisition rate of spatial reference memory.

The importance of the hippocampus in spatial learning is well established, but the precise relative contributions by the dorsal (septal) and ventral (temporal) subregions remain unresolved. One debate revolves around the extent to which the ventral hippocampus contributes to spatial navigation and learning. Here, separate small subtotal lesions of dorsal hippocampus or ventral hippocampus alone (destroying 18.9 and 28.5% of total hippocampal volume, respectively) spared reference memory acquisition in the water maze. By contrast, combining the two subtotal lesions significantly reduced the rate of acquisition across days. This constitutes evidence for synergistic integration between dorsal and ventral hippocampus in mice. Evidence that ventral hippocampus contributes to spatial/navigation learning also emerged early on during the retention probe test as search preference was reduced in mice with ventral lesions alone or combined lesions. The small ventral lesions also led to anxiolysis in the elevated plus maze and over-generalization of the conditioned freezing response to a neutral context. Similar effects of comparable magnitudes were seen in mice with combined lesions, suggesting that they were largely due to the small ventral damage. By contrast, small dorsal lesions were uniquely associated with a severe spatial working memory deficit in the water maze. Taken together, both dorsal and ventral poles of the hippocampus contribute to efficient spatial navigation in mice: While the integrity of dorsal hippocampus is necessary for spatial working memory, the acquisition and retrieval of spatial reference memory are modulated by the ventral hippocampus. Although the impairments following ventral damage (alone or in combination with dorsal damage) were less substantial, a wider spectrum of spatial learning, including context conditioning, was implicated. Our results encourage the search for integrative mechanism between dorsal and ventral hippocampus in spatial learning. Candidate neural substrates may include dorsoventral longitudinal connections and reciprocal modulation via overlapping polysynaptic networks beyond hippocampus.

Age-dependent effects of testosterone on spatial memory in male rats

Decreased spatial memory is common in aging populations and reduces their quality of life. Although its role is still controversial, low testosterone (T) may contribute to impaired cognition in aged men. This study aimed to identify the role of T in age-related deficiencies in spatial memory among male rats. Young adult (3 months old) and aged (21 months old) Wistar rats were assigned to independent groups: intact, orchidectomized, or orchidectomized + subcutaneous pellets of T propionate. The phases of spatial memory acquisition (4 daily trials/4 days) and spatial memory retention (1 trial/day, 3 and 12 days after acquisition) were evaluated using the Barnes maze. Compared with young adults, aged intact rats took longer to find the goal, made more mistakes, and showed only slight improvements in goal sector exploration across the acquisition period. The young orchidectomized rats showed no improvement in performance over the days during the acquisition phase. T treatment in hormonally deprived old rats produced a small improvement in goal sector exploration and number of errors during the acquisition phase. Meanwhile, in young adults, this treatment improved the goal sector searching in the retention phase (12 days after acquisition training). Our results suggested that age-related spatial memory deficits cannot be entirely explained by the decline in T levels; however, this androgen produced subtle and mild beneficial effects on spatial memory in young and old males. Taken together, our findings suggest age differences in the role of T on spatial memory in males.

Neuroprotective Effects of Lithium in Chemotherapy‐induced Cognitive Impairments

Chemotherapy, a life‐saving treatment for cancer patients, is often associated with debilitating, sometimes irreversible, side effects. Approximately 40% of cancer survivors suffer from cognitive impairments, with symptoms including memory lapses, learning difficulties, and troubles with focusing, planning, multi‐tasking, and verbal communication. However, essential questions concerning the specific cognitive functions affected, the trajectories of cognitive changes, and the underlying mechanisms remain unclear. We aimed to investigate these questions by developing a mouse model of paclitaxel‐induced cognitive impairments. We also examined the potential neuroprotective effects of lithium, a compound previously shown to be beneficial in multiple neuropsychiatric and neurodegenerative disorders. Mice receiving four intraperitoneal injections of paclitaxel showed impaired short‐term spatial memory acquisition within a week of the last injection, which persisted for at least three weeks. Using Golgi‐Cox staining, we observed reduced dendritic arborization and spine density in the hippocampus and the cortex following paclitaxel injection, suggesting that these regions were particularly vulnerable. Importantly, lithium pretreatment completely rescued the behavioral and cellular deficits observed. Subsequently, we showed that paclitaxel treatment resulted in the upregulation of protein kinase C (PKC) both acutely and chronically, suggesting that dysregulated PKC signaling contributed to the neurological dysfunctions observed. In conclusion, we establish a molecular and cellular basis for paclitaxel‐induced cognitive impairments. Our findings also suggest a role for lithium as a protective agent to prevent cognitive impairments induced by paclitaxel and other chemotherapeutics.

Chronic Pain Impairs Memory Formation via Disruption of Neurogenesis Mediated by Mesohippocampal Brain-Derived Neurotrophic Factor Signaling

BackgroundChronic pain patients often complain of their poor memory. The mechanisms underlying chronic pain–related memory impairment remain elusive, and there are few clinical therapeutic strategies available for this condition. MethodsIn a neuropathic pain model induced by chronic constrictive injury of the sciatic nerve in male mice, we used circuit-specific electrophysiological recording, combined with chemogenetic, molecular, and pharmacologic methods, to examine the circuit and molecular mechanisms underlying chronic pain–related memory impairment. ResultsOur current results show that chronic neuropathic pain impaired the acquisition of spatial memory and, meanwhile, reduced adult neurogenesis in the dentate gyrus. Experimentally reducing dentate gyrus neurogenesis mimicked this pain-induced effect on spatial memory formation in naïve mice. Furthermore, pain-associated impairments of both hippocampal neurogenesis and memory formation were rescued or mimicked by chemogenetic activation or deactivation, respectively, of the ventral tegmental area dopaminergic projection, through which ventral tegmental area–released brain-derived neurotrophic factor was required. Importantly, we found that chronic, but not acute, systematic administration of subanesthetic doses of ketamine, while without relieving pain, ameliorated chronic pain–related impairment of spatial memory formation, potentially by rescuing brain-derived neurotrophic factor–mediated dentate gyrus neurogenesis. ConclusionsThese findings provide a novel, circuit-based mechanistic link between chronic pain and memory formation deficit, and potential new therapeutic options for chronic pain–related learning deficit and memory impairment.

N-Methyl-d-Aspartate Receptor Modulation by Nicotinamide Adenine Dinucleotide Phosphate Oxidase Type 2 Drives Synaptic Plasticity and Spatial Memory Impairments in Rats Exposed Pre- and Postnatally to Ethanol.

Aims: Pre- and/or early postnatal ethanol exposure (prenatal alcohol exposure [PAE]) impairs synaptic plasticity as well as memory formation, but the mechanisms underlying these effects remain unclear. Both long-term potentiation (LTP) and spatial memory formation in the hippocampus involve the nicotinamide adenine dinucleotide phosphate oxidase type 2 (NOX2) enzyme. Previous studies have reported that N-methyl-d-aspartate receptor (NMDAR) activation increases NOX2-mediated superoxide generation, resulting in inhibition of NMDAR function, but whether NOX2 impacts NMDAR function in PAE animals leading to impaired LTP and memory formation remains unknown. We aim to evaluate whether the NOX2-NMDAR complex is involved in the long-lasting deleterious effects of PAE on hippocampal LTP and memory formation. Results: Here we provide novel evidence that PAE animals display impaired NMDAR-dependent LTP in the cornus ammonis field 1 (CA1) and NMDAR-mediated LTP in the dentate gyrus (DG). Moreover, PAE rats displayed increased NMDAR-mediated transmission in both hippocampal areas. Interestingly, NOX2 pharmacological inhibition restored NMDAR-mediated transmission and LTP in the CA1, but not in the DG. PAE also induced overexpression of NOX2 and CaMKII isoforms, but did not modify the content or the redox state of the N-methyl-d-aspartate receptor subunit-1 (NR1) subunit of NMDAR in both areas of the hippocampus. In addition, adolescent PAE rats orally fed the antioxidant and free radical scavenger apocynin exhibited significantly improved spatial memory acquisition. Innovation and Conclusion: By showing in PAE animals NOX2 overexpression and increased NMDAR-mediated transmission, which might lead to impaired synaptic plasticity and memory formation in a region-specific manner, we provide an important advance to our current understanding of the cellular mechanisms underlying PAE-dependent defective hippocampal function.

Decreased hippocampal efficiency in obese rats is expressed by impaired cognition, neurogenesis and proteomic changes

AbstractObesity associates with plethora of dysfunctions including changes in the brain structures, like hippocampus which is particularly susceptible to metabolic or inflammatory alterations. The is a need to expand knowledge about the obesity related brain changes in order to enable development of new therapeutic interventions, that would support not only weight loss but also could help to restore the after-effects of obesity in the brain. In the present report we evaluated the hippocampal efficiency of obese rats. In order to induce obesity 4 weeks old male rats were fed with a chow that mimics human western diet for 12 weeks (model of diet induced obesity). Then the cognitive functions (water maze), neurogenesis (BrdU detection) and global proteomic changes (MS/MS analysis) were analyzed in separate cohorts of animals. Obese rats had worsen cognitive flexibility than normal rats, but the spatial learning and long term memory were unaffected. The number of BrdU/NeuN positive cells was lowered in obese animals suggesting decreased hippocampal neurogenesis. The analysis of proteins revealed that about 120 proteins significantly differed between hippocampi of obese and normal rats. Neuronal calcium sensor 1 (NCS-1) which participates in mechanisms involving synaptic plasticity and acquisition of spatial memory was decreased in obese rats. Neuromodulin and vinculin, required for synaptic plasticity also decreased in these animals. Impaired neurogenesis was associated with decreased level of: receptor-type tyrosine-protein phosphatase zeta and cytoplasmic dynein 1 light intermediate chain 2, which play crucial roles in controlling axonal growth and neuronal migration. Altogether the data show that proteomic changes related to obesity associate with impaired hippocampal functioning. The same set of experiments was performed on the additional cohort of obese animals subsequent to weight loss to examine if the observed brain changes persist if obesity is reversed. This research is supported by Nutricia Foundation, grant no. RG 1/2017.

P.102 Long-term efficacy of lurasidone in antipsychotic-naïve vs. antipsychotic-exposed adolescents with schizophrenia: Post-hoc analysis of a two year, open-label study

Spatial orientation is a cognitive ability that is indispensable for survival. Several visual distal cues present in the context can be integrated, establishing a cognitive map. Although there is cumulative evidence about the neural substrate involved in spatial memory acquisition, the brain networks mediating the processes involved in the retrieval of allocentric spatial memories have been studied less. Here, we aimed to explore the role of neuronal oxidative metabolism in the retrieval of allocentric spatial memories through cytochrome c oxidase (CCO) histochemistry seven, 15, 30, 45, and 60 days after task acquisition. Our behavioural results show that spatial memory retrieval in male and female rats is preserved seven, 15, and 30 days post-acquisition, but there is forgetfulness after this time, with subjects not being able to remember the position of the hidden platform after 45 and 60 dfearays. Regarding the study of male brain metabolism, we observed reduced CCO activity in the medial prefrontal cortex, the parietal, retrosplenial, rhinal cortex, and the hippocampal regions in all the groups that failed to solve the task. Similar results were found for female brain oxidative metabolism, in addition to certain differences between succefearssful-retrieval female groups. In conclusion, our work adds information about the behavioural retrieval of an allocentric spatial reference task, suggesting that recovering spatial information seven, 15, and 30days after acquisition is a simple task that does not require a high metabolic demand, in both male and female rats.

Effects of mercuric chloride on spatial memory deficit-induced by beta-amyloid and evaluation of mitochondrial function markers in the hippocampus of rats.

Mercury is a highly poisonous heavy metal abundantly found in the environment in its inorganic form. Although evidence have been provided about the possible role of inorganic mercury in the pathology of Alzheimer's disease (AD), its effect on cognitive and mitochondrial functions have not yet been completely understood. Thus, the purpose of the present study was to examine the effects of the chronic exposure to mercuric chloride (0.4, 0.8 and 1.6 mg kg-1 per day for 3 weeks) through drinking water (by gavage) on spatial learning and memory and hippocampal mitochondrial function in beta-amyloid treated rats (1 μg per μL per side, intrahippocampally). The acquisition and retention of spatial memory were evaluated by the Morris water maze (MWM) test. Several parameters of hippocampal mitochondrial function were also measured. The results indicated that mercury impaired spatial learning and memory as well as aggravated Aβ-induced memory impairments in a concentration-dependent manner. Furthermore, mercury exposure resulted in a significant increase in ROS generation, MMP collapse, mitochondrial swelling, glutathione oxidation, lipid peroxidation, and outer membrane damage. In addition, a reduced cytochrome c oxidase (complex IV) activity and elevated ADP/ATP ratio in the rats' hippocampus was also observed. The findings of the current study revealed that chronic mercury exposure led to mitochondrial dysfunction, which resulted in spatial memory impairments. The results also showed that mercury can exacerbate the toxic effects of Aβ on spatial memory and hippocampal mitochondrial function.

Pro-cognitive effect of upregulating cyclic guanosine monophosphate signalling during memory acquisition or early consolidation is mediated by increased AMPA receptor trafficking.

Background:Episodic memory consists of different mnemonic phases, including acquisition and early and late consolidation. Each of these phases is characterised by distinct molecular processes. Although both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are implicated in the acquisition phase, early consolidation only depends on cGMP, whereas late consolidation is mediated by cAMP. Accordingly, the cGMP-selective phosphodiesterase 5 (PDE5) inhibitor vardenafil or the cAMP-selective PDE4 inhibitor rolipram can improve memory acquisition or consolidation when applied during their respective time windows.Aims:Considering the important role of glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) during normal memory function, we aimed to investigate whether the differential actions of these PDE inhibitors are mediated through AMPAR dynamics.Methods:For biochemical analysis, mice were treated with either vardenafil or rolipram and sacrificed shortly after injection. For the behavioural studies, mice received either of the inhibitors during the different mnemonic phases, while their spatial memory was tested using the object location task, and they were sacrificed 24 hours later.Results:Administration of either vardenafil or rolipram causes rapid changes in AMPARs. Moreover, treatment with vardenafil during the acquisition or early consolidation of spatial memory resulted in increased surface levels of AMPARs which were still augmented 24 hours after learning. Membrane levels of AMPARs were not affected anymore 24 hours after learning when rolipram was administrated at either the acquisition or late consolidation phase.Conclusions:These results suggest that dissociative molecular mechanisms could mediate the pro-cognitive function of different classes of PDE inhibitors, and in the case of vardenafil, this phenomenon could be explained by changes in AMPAR dynamics.

Gpr158 Deficiency Impacts Hippocampal CA1 Neuronal Excitability, Dendritic Architecture, and Affects Spatial Learning.

G-protein-coupled receptor 158 (Gpr158) is highly expressed in striatum, hippocampus and prefrontal cortex. It gained attention as it was implicated in physiological responses to stress and depression. Recently, Gpr158 has been shown to act as a pathway-specific synaptic organizer in the hippocampus, required for proper mossy fiber-CA3 neurocircuitry establishment, structure, and function. Although rodent Gpr158 expression is highest in CA3, considerable expression occurs in CA1 especially after the first postnatal month. Here, we combined hippocampal-dependent behavioral paradigms with subsequent electrophysiological and morphological analyses from the same group of mice to assess the effects of Gpr158 deficiency on CA1 physiology and function. We demonstrate deficits in spatial memory acquisition and retrieval in the Morris water maze paradigm, along with deficits in the acquisition of extinction memory in the passive avoidance test in Gpr158 KO mice. Electrophysiological recordings from CA1 pyramidal neurons revealed normal basal excitatory and inhibitory synaptic transmission, however, Schaffer collateral stimulation yielded dramatically reduced post-synaptic currents. Interestingly, intrinsic excitability of CA1 pyramidals was found increased, potentially acting as a compensatory mechanism to the reductions in Schaffer collateral-mediated drive. Both ex vivo and in vitro, neurons deficient for or with lowered levels of Gpr158 exhibited robust reductions in dendritic architecture and complexity, i.e., reduced length, surface, bifurcations, and branching. This effect was localized in the apical but not basal dendrites of adult CA1 pyramidals, indicative of compartment-specific alterations. A significant positive correlation between spatial memory acquisition and extent of complexity of CA1 pyramidals was found. Taken together, we provide first evidence of significant disruptions in hippocampal CA1 neuronal dendritic architecture and physiology, driven by Gpr158 deficiency. Importantly, the hippocampal neuronal morphology deficits appear to support the impairments in spatial memory acquisition observed in Gpr158 KO mice.

Individual differences of rats and effects of d-Cycloserine on the acquisition of spatial memory

Individual differences of rats and effects of d-Cycloserine on the acquisition of spatial memory

Neurosteroid and benzodiazepine combination therapy reduces status epilepticus and long-term effects of whole-body sarin exposure in rats.

ObjectiveOur objective was to evaluate the protective efficacy of the neurosteroid pregnanolone (3α‐hydroxy‐5β pregnan‐20‐one), a GABAA receptor‐positive allosteric modulator, as an adjunct to benzodiazepine therapy against the chemical warfare nerve agent (CWNA) sarin (GB), using whole‐body exposure, an operationally relevant route of exposure to volatile GB.MethodsRats implanted with telemetry transmitters for the continuous measurement of cortical electroencephalographic (EEG) activity were exposed for 60 minutes to 3.0 LCt50 of GB via whole‐body exposure. At the onset of toxic signs, rats were administered an intramuscular injection of atropine sulfate (2 mg/kg) and the oxime HI‐6 (93.6 mg/kg) to increase survival rate and, 30 minutes after seizure onset, treated subcutaneously with diazepam (10 mg/kg) and intravenously with pregnanolone (4 mg/kg) or vehicle. Animals were evaluated for GB‐induced status epilepticus (SE), spontaneous recurrent seizures (SRS), impairment in spatial memory acquisition, and brain pathology, and treatment groups were compared.ResultsDelayed dual therapy with pregnanolone and diazepam reduced time in SE in GB‐exposed rats compared to those treated with delayed diazepam monotherapy. The combination therapy of pregnanolone with diazepam also prevented impairment in the Morris water maze and reduced the neuronal loss and neuronal degeneration, evaluated at one and three months after exposure.SignificanceNeurosteroid administration as an adjunct to benzodiazepine therapy offers an effective means to treat benzodiazepine‐refractory SE, such as occurs following delayed treatment of GB exposure. This study is the first to present data on the efficacy of delayed pregnanolone and diazepam dual therapy in reducing seizure activity, performance deficits and brain pathology following an operationally relevant route of exposure to GB and supports the use of a neurosteroid as an adjunct to standard anticonvulsant therapy for the treatment of CWNA‐induced SE.

Acute and chronic effects of single dose memantine after controlled cortical impact injury in adult rats.

Altered glutamatergic neurotransmission after traumatic brain injury (TBI) contributes to excitotoxic cell damage and death. Prevention or suppression of such changes is a desirable goal for treatment of TBI. Memantine (3,5-dimethyl-1-adamantanamine), an uncompetitive NMDA receptor antagonist with voltage-dependent open channel blocking kinetics, was reported to be neuroprotective in preclinical models of excitotoxicity, brain ischemia, and in TBI when administered prophylactically, immediately, or within minutes after injury. The current study examined effects of memantine administered by single intraperitoneal injection to adult male rats at a more clinically relevant delay of one hour after moderate-severe controlled cortical impact (CCI) injury or sham surgery. Histopathology was assessed on days 1, 7, 21, and 90, vestibulomotor function (beam balance and beam walk) was assessed on days 1-5 and 71-75, and spatial memory (Morris water maze test, MWM) was assessed on days 14-21 and 83-90 after CCI injury or sham surgery. When administered at 10 mg/kg, but not 2.5 or 5 mg/kg, memantine preserved cortical tissue and reduced neuronal degeneration 1 day after injury, and attenuated loss of synaptophysin immunoreactivity in the hippocampus 7 days after injury. No effects of 10 mg/kg memantine were observed on histopathology at 21 and 90 days after CCI injury or sham surgery, or on vestibulomotor function and spatial memory acquisition assessed during any of the testing periods. However, 10 mg/kg memantine resulted in trends for improved search strategy in the MWM memory retention probe trial. Administration of memantine at a clinically-relevant delay after moderate-severe CCI injury has beneficial effects on acute outcomes, while more significant improvement on subacute and chronic outcomes may require repeated drug administration or its combination with another therapy.

Behavioral and molecular effects of intrahippocampal infusion of auraptene, resveratrol, and curcumin on H-89-induced deficits on spatial memory acquisition and retention in Morris water maze.

Our aim was to investigate the effects of resveratrol, auraptene, and curcumin on the spatial learning and spatial memory retention in the Morris water maze (MWM). The effects of 4-day bilateral intrahippocampal (i.h.) infusions of dimethyl sulfoxide (DMSO), H-89 as a protein kinase AII inhibitor, auraptene/H-89, resveratrol/H-89, and curcumin/H-89 were investigated on spatial memory acquisition in MWM. The rats were trained for 4 days; each day included one block of four trials. Post-training probe tests were performed on day 5 in acquisition test. For retention assessments, different animals were trained for 4 days and then infused (i.h.) with either DMSO, H-89, auraptene/H-89, resveratrol/H-89, or curcumin/H-89. The retention test was performed 48 h after the last training trial. The bilateral infusion of H-89 led to a significant impairment in spatial memory in acquisition and retention tests accompanied with a significant decrease in expressions of cAMP response-element binding (CREB) and pCREB proteins in hippocampus. Resveratrol and curcumin reversed the H-89-induced spatial memory acquisition and retention impairments with significant increases in both CREB and pCREB proteins expressions compared to H-89-treated animals. Auraptene showed significant effects in reversing H-89-induced impairments in spatial memory retention but not spatial memory acquisition.

Impact of Gold Nanoparticles on Amyloid β-Induced Alzheimer's Disease in a Rat Animal Model: Involvement of STIM Proteins.

Alzheimer's disease (AD) is the most common type of neurodegenerative amyloid disorder causing progressive cognitive decline and memory loss. A considerable number of therapies for AD rely on inhibition/delay/dissociation of amyloid beta (Aβ) oligomers and fibrils. In this case, nanoparticles (NPs) demonstrated substantial effects on the Aβ fibrillation process; however, their effects on progressive cognitive decline and memory have been poorly investigated in vivo. In this study, acquisition and retention of spatial learning and memory are studied in a rat animal model of AD after intrahippocampal (IH) and intraperitoneal (IP) injections of a model NP, i.e., gold NPs (AuNPs). The outcomes revealed that the AuNPs could improve the acquisition and retention of spatial learning and memory in Aβ treated rats as indicated by decreased time (Aβ: 39.60 ± 3.23 s vs Aβ+AuNPs: 25.78 ± 2.80 s) and distance (Aβ: 917.98 ± 50.81 cm vs Aβ+AuNPs: 589.09 ± 65.96 cm) of finding the hidden platform during training days and by increased time spent in the target quadrant (Aβ: 19.40 ± 0.98 s vs Aβ+AuNPs: 29.36 ± 1.14 s) in the probe test in Morris water maze (MWM). Expression of brain-derived neurotrophic factor, BDNF, cAMP response element binding protein, CREB, and stromal interaction molecules, e.g., STIM1 and STIM2 was also increased, supporting improved neural survival. Our outcomes may pave a way for mechanistic insights toward the role of NPs on retrieval of the deteriorated behavioral functions in brain tissue after AD outbreak.

Pharmacological Manipulation of Trk, p75NTR, and NGF Balance Restores Memory Deficit in Global Ischemia/Reperfusion Model in Rats.

Long-term memory impairment is reported in more than 50% of cardiac arrest survivors. Monosialoganglioside (GM1) provided neuroprotection in experimental models of stroke but failed to replicate its promise clinically for unknown reasons. GM1 stimulates the release of nerve growth factor (NGF), which is synthesized as a precursor protein (pro-NGF) that either mediates apoptosis through the p75 neurotrophin receptor (p75NTR) or is cleaved by the protease furin (FUR) to yield mature NGF, the latter supporting survival through tropomyosin kinase receptor (Trk). The flavanol epicatechin (EPI) inhibits p75NTR-mediated signaling and apoptosis by pro-NGF. The aim of the current work is to test whether these two drugs affect, or communicate with, each other in the setting of CNS injuries. Using the two-vessel occlusion model of global ischemia/reperfusion (I/R), we tested if pharmacological modulation of Trk, p75NTR, and NGF balance with GM1, EPI, and their combination, can correct the memory deficit that follows this insult. Finally, we tested if FUR insufficiency and/or p75NTR-mediated apoptosis negatively affect the neurotherapeutic effect of GM1. Key proteins for Trk and p75NTR, FUR, and both forms of NGF were assessed. All treatment regiments successfully improved spatial memory retention and acquisition. A week after the insult, most Trk and p75NTR proteins were normal, but pro/mature NGF ratio remained sharply elevated and was associated with the poorest memory performance. Pharmacological correction of this balance was achieved by reinforcing Trk and p75NTR signaling. GM1 increased FUR levels, while concomitant administration of EPI weakened GM1 effect on pro-survival Trk and p75NTR mediators. GM1 neuroprotection is therefore not limited by FUR but could be dependent on p75NTR. Graphical Abstract "."

Ferroptosis Contributes to Neuronal Death and Functional Outcome After Traumatic Brain Injury.

Traumatic brain injury triggers multiple cell death pathways, possibly including ferroptosis-a recently described cell death pathway that results from accumulation of 15-lipoxygenase-mediated lipid oxidation products, specifically oxidized phosphatidylethanolamine containing arachidonic or adrenic acid. This study aimed to investigate whether ferroptosis contributed to the pathogenesis of in vitro and in vivo traumatic brain injury, and whether inhibition of 15-lipoxygenase provided neuroprotection. Cell culture study and randomized controlled animal study. University research laboratory. HT22 neuronal cell line and adult male C57BL/6 mice. HT22 cells were subjected to pharmacologic induction of ferroptosis or mechanical stretch injury with and without administration of inhibitors of ferroptosis. Mice were subjected to sham or controlled cortical impact injury. Injured mice were randomized to receive vehicle or baicalein (12/15-lipoxygenase inhibitor) at 10-15 minutes postinjury. Pharmacologic inducers of ferroptosis and mechanical stretch injury resulted in cell death that was rescued by prototypical antiferroptotic agents including baicalein. Liquid chromatography tandem-mass spectrometry revealed the abundance of arachidonic/adrenic-phosphatidylethanolamine compared with other arachidonic/adrenic acid-containing phospholipids in the brain. Controlled cortical impact resulted in accumulation of oxidized phosphatidylethanolamine, increased expression of 15-lipoxygenase and acyl-CoA synthetase long-chain family member 4 (enzyme that generates substrate for the esterification of arachidonic/adrenic acid into phosphatidylethanolamine), and depletion of glutathione in the ipsilateral cortex. Postinjury administration of baicalein attenuated oxidation of arachidonic/adrenic acid-containing-phosphatidylethanolamine, decreased the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling positive cells in the hippocampus, and improved spatial memory acquisition versus vehicle. Biomarkers of ferroptotic death were increased after traumatic brain injury. Baicalein decreased ferroptotic phosphatidylethanolamine oxidation and improved outcome after controlled cortical impact, suggesting that 15-lipoxygenase pathway might be a valuable therapeutic target after traumatic brain injury.