Spontaneous Alternation In Y-maze Research Articles

Pharmacological intervention of behavioural traits and brain histopathology of prenatal valproic acid-induced mouse model of autism.

Autism spectrum disorder (ASD) is one of the leading causes of distorted social communication, impaired speech, hyperactivity, anxiety, and stereotyped repetitive behaviour. The aetiology of ASD is complex; therefore, multiple drugs have been suggested to manage the symptoms. Studies with histamine H3 receptor (H3R) blockers and acetylcholinesterase (AchE) blockers are considered potential therapeutic agents for the management of various cognitive impairments. Therefore, the aim of this study was to evaluate the neuro-behavioural effects of Betahistine, an H3R antagonist, and Donepezil, an acetylcholinesterase inhibitor on Swiss albino mouse model of autism. The mice were intraperitoneally injected with valproic acid (VPA) on the embryonic 12.5th day to induce autism-like symptoms in their offspring. This induced autism-like symptoms persists throughout the life. After administration of different experimental doses, various locomotor tests: Open Field, Hole-Board, Hole Cross and behavioural tests by Y-Maze Spontaneous Alternation and histopathology of brain were performed and compared with the control and negative control (NC1) groups of mice. The behavioural Y-Maze test exhibits significant improvement (p <0.01) on the short term memory of the test subjects upon administration of lower dose of Betahistine along with MAO-B inhibitor Rasagiline once compared with the NC1 group (VPA-exposed mice). Furthermore, the tests showed significant reduction in locomotion in line crossing (p <0.05), rearing (p <0.001) of the Open Field Test, and the Hole Cross Test (p <0.01) with administration of higher dose of Betahistine. Both of these effects were observed upon administration of acetylcholinesterase inhibitor, Donepezil. Brain-histopathology showed lower neuronal loss and degeneration in the treated groups of mice in comparison with the NC1 VPA-exposed mice. Administration of Betahistine and Rasagiline ameliorates symptoms like memory deficit and hyperactivity, proving their therapeutic effects. The effects found are dose dependent. The findings suggest that H3R might be a viable target for the treatment of ASD.

Photoperiod, food restriction and memory for objects and places in mice

The suprachiasmatic nucleus (SCN) contains a population of cell-autonomous circadian oscillators essential for entrainment to daily light–dark (LD) cycles. Synchrony among SCN oscillators is modified by photoperiod and determines functional properties of SCN clock cycling, including its amplitude, phase angle of entrainment, and free running periodicity (τ). For many species, encoding of daylength in SCN output is critical for seasonal regulation of metabolism and reproduction. C57BL/6 mice do not show seasonality in these functions, yet do show photoperiodic modulation of SCN clock output. The significance of this for brain systems and functions downstream from the SCN in these species is largely unexplored. C57BL/6 mice housed in a long-day photoperiod have been reported to perform better on tests of object, spatial and fear memory compared to mice in a standard 12 h photoperiod. We previously reported that encoding of photoperiod in SCN output, evident in τ in constant dark (DD), can be blocked by limiting food access to a 4 h mealtime in the light period. To determine whether this might also block the effect of long days on memory, mice entrained to 18 h:6 h (L18) or 6 h:18 h (L6) LD cycles were tested for 24 h object memory (novel object preference, NOP) and spatial working memory (Y-maze spontaneous alternation, SA), at 4 times of day, first with food available ad libitum and then during weeks 5–8 of daytime restricted feeding. Photoperiod modified τ as expected, but did not affect performance on the NOP and SA tests, either before or during restricted feeding. NOP performance did improve in the restricted feeding condition in both photoperiods, eliminating a weak time of day effect evident with food available ad-libitum. These results highlight benefits of restricted feeding on cognitive function, and suggest a dose–response relationship between photoperiod and memory, with no benefits at daylengths up to 18 h.

Neuroinflammation and Neurometabolomic Profiling in Fentanyl Overdose Mouse Model Treated with Novel β-Lactam, MC-100093, and Ceftriaxone.

Opioid-related deaths are attributed to overdoses, and fentanyl overdose has been on the rise in many parts of the world, including the USA. Glutamate transporter 1 (GLT-1) has been identified as a therapeutic target in several preclinical models of substance use disorders, and β-lactams effectively enhance its expression and function. In the current study, we characterized the metabolomic profile of the nucleus accumbens (NAc) in fentanyl-overdose mouse models, and we evaluated the protective effects of the functional enhancement of GLT-1 using β-lactams, ceftriaxone, and MC-100093. BALB/c mice were divided into four groups: control, fentanyl, fentanyl/ceftriaxone, and fentanyl/MC-100093. While the control group was intraperitoneally (i.p.) injected with normal saline simultaneously with other groups, all fentanyl groups were i.p. injected with 1 mg/kg of fentanyl as an overdose after habituation with four repetitive non-consecutive moderate doses (0.05 mg/kg) of fentanyl for a period of seven days. MC-100093 (50 mg/kg) and ceftriaxone (200 mg/kg) were i.p. injected from days 5 to 9. Gas chromatography-mass spectrometry (GC-MS) was used for metabolomics, and Western blotting was performed to determine the expression of target proteins. Y-maze spontaneous alternation performance and the open field activity monitoring system were used to measure behavioral manifestations. Fentanyl overdose altered the abundance of about 30 metabolites, reduced the expression of GLT-1, and induced the expression of inflammatory mediators IL-6 and TLR-4 in the NAc. MC-100093 and ceftriaxone attenuated the effects of fentanyl-induced downregulation of GLT-1 and upregulation of IL-6; however, only ceftriaxone attenuated fentanyl-induced upregulation of TRL4 expression. Both of the β-lactams attenuated the effects of fentanyl overdose on locomotor activities but did not induce significant changes in the overall metabolomic profile. Our findings revealed that the exposure to a high dose of fentanyl causes alterations in key metabolic pathways in the NAc. Pretreatment with ceftriaxone and MC-100093 normalized fentanyl-induced downregulation of GLT-1 expression with subsequent attenuation of neuroinflammation as well as the hyperactivity, indicating that β-lactams may be promising drugs for treating fentanyl use disorder.

Circulating IGF-1 related exercise associated with improved spatial memory in elderly mice

This study examined the correlation between the circulating and hippocampal IGF-1 levels in elderly mice after exercise intervention and evaluated the relationship between circulating and hippocampal IGF-1 levels in improving the spatial memory function of elderly mice. Methods: Nine-month-old female mice were divided into treadmill, swimming, and control groups, each consisting of ten mice. Exercises were carried out for six weeks, five times a week. Before and after training, Y-maze spontaneous alternation tests were carried out for spatial working memory. After six weeks of exercise, hippocampal and circulating IGF-1 levels were measured with the ELISA method. ANOVA was performed to analyze differences between groups. Pearson’s or Spearman’s correlation analysis was performed to assess the correlation of hippocampal and circulating IGF-1 levels with spatial working memory and the correlation between circulating IGF-1 levels and hippocampal IGF-1 levels. Results: The circulating IGF-1 levels significantly increased (p &lt; 0.05) in the treadmill and swimming groups compared to the control, while the hippocampal IGF-1 levels only significantly increased (p &lt; 0.05) in the swimming group. There was a significant correlation between spatial memory and blood IGF-1 levels (p = 0.002), but no significant correlation (p = 0.122) existed between spatial memory and hippocampal IGF-1 levels. There was a significant correlation between serum IGF-1 levels and hippocampal IGF-1 levels (p = 0.028). Conclusion: Circulating IGF-1 levels were correlated with hippocampal IGF-1 levels. However, hippocampal IGF-1 levels had yet to demonstrate any significant correlation with improved memory function Keywords: IGF-1, exercise, ageing, memory, hippocampus

Protective Effects and Mechanism of Heracleum moellendorffii Hance on Alcohol-Induced Cognitive Decline in Mice.

Chronic and continuous alcohol consumption increases the risk of cognitive decline and may lead to alcohol-related dementia. We investigated the potential of Heracleum moellendorffii Hance root extract (HME) for treating alcohol-related cognitive impairment. Behavioral tests evaluated the effects of HME on cognitive function and depression. Changes in hippocampus and liver tissues were evaluated by Western blotting and H&E staining. The group treated with HME 200 mg/kg showed a significant increase in spontaneous alternation in Y-maze and a decrease in immobility in a forced swimming test (FST) compared to the vehicle-treated group. These results suggest that HME can restore memory deficits and reverse depressive symptoms caused by chronic alcohol consumption. The HME-treated group also upregulated brain-derived neurotrophic factor (BDNF), phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2), and phosphorylated cAMP response element-binding protein (CREB) in the hippocampus. Additionally, it reduced lipid vacuolation in the liver and increased the expression of aldehyde dehydrogenase 1 (ADH1). The administration of HME improves cognitive impairment and reverses depressive symptoms due to alcohol consumption, restoring neural plasticity in the hippocampus and alcohol metabolism in the liver. These findings suggest that HME is a promising treatment for alcohol-related brain disorders. Molecular mechanisms underlying the therapeutic effects of HME and its active ingredients should be investigated further.

MDPV (3,4-methylenedioxypyrovalerone) administered to mice during development of the central nervous system produces persistent learning and memory impairments

BackgroundSynthetic cathinones (SC) constitute the second most frequently abused class of new psychoactive substances. They serve as an alternative to classic psychostimulatory drugs of abuse, such as methamphetamine, cocaine, or 3,4-methylenedioxymethamphetamine (MDMA). Despite the worldwide prevalence of SC, little is known about their long-term impact on the central nervous system. Here, we examined the effects of repeated exposure of mice during infancy, to 3,4-methylenedioxypyrovalerone (MDPV), a SC potently enhancing dopaminergic neurotransmission, on learning and memory in young adult mice.MethodsAll experiments were performed on C57BL/6J male and female mice. Animals were injected with MDPV (10 or 20 mg/kg) and BrdU (bromodeoxyuridine, 25 mg/kg) during postnatal days 11–20, which is a crucial period for the development of their hippocampus. At the age of 12 weeks, mice underwent an assessment of various types of memory using a battery of behavioral tests. Afterward, their brains were removed for detection of BrdU-positive cells in the dentate gyrus of the hippocampal formation with immunohistochemistry, and for measurement of the expression of synaptic proteins, such as synaptophysin and PSD95, in the hippocampus using Western blot.ResultsExposure to MDPV resulted in impairment of spatial working memory assessed with Y-maze spontaneous alternation test, and of object recognition memory. However, no deficits in hippocampus-dependent spatial learning and memory were found using the Morris water maze paradigm. Consistently, hippocampal neurogenesis and synaptogenesis were not interrupted. All observed MDPV effects were sex-independent.ConclusionsMDPV administered repeatedly to mice during infancy causes learning and memory deficits that persist into adulthood but are not related to aberrant hippocampal development.

Aquaporin-4 inhibition attenuates Pentylenetetrazole-induced behavioral seizures and cognitive impairments in kindled rats

Epilepsy is a neurological condition distinguished by recurrent and unexpected seizures. Astrocytic channels and transporters are essential for maintaining normal neuronal functionality. The astrocytic water channel, aquaporin-4 (AQP4), which plays a pivotal role in regulating water homeostasis, is a potential target for epileptogenesis. In present study, we examined the effect of different doses (10, 50, 100 μM and 5 mM) of AQP4 inhibitor, 2-nicotinamide-1, 3, 4-thiadiazole (TGN-020), during kindling acquisition, on seizure parameters and seizure-induced cognitive impairments. Animals were kindled by injection of pentylenetetrazole (PTZ: 37.5 mg/kg, i.p.). TGN-020 was administered into the right lateral cerebral ventricle 30 min before PTZ every alternate day. Seizure parameters were assessed 20 min after PTZ administration. One day following the last PTZ injection, memory performance was investigated using spontaneous alternation in Y-maze and novel object recognition (NOR) tests. The inhibition of AQP4 during the kindling process significantly decreased the maximal seizure stage and seizure duration (two-way ANOVA, P = 0.0001) and increased the latency of seizure onset and the number of PTZ injections required to induce different seizure stages (one-way ANOVA, P = 0.0001). Compared to kindled rats, the results of the NOR tests showed that AQP4 inhibition during PTZ-kindling prevented recognition memory impairment. Based on these results, AQP4 could be involved in seizure development and seizure-induced cognitive impairment. More investigation is required to fully understand the complex interactions between seizure activity, water homeostasis, and cognitive dysfunction, which may help identify potential therapeutic targets for these conditions.

The effects of chronic morphine administration on spatial memory and microtubule dynamicity in male mice's brain

The examination of the influence of morphine on behavioral processes, specifically learning and memory, holds significant importance. Additionally, microtubule proteins play a pivotal role in cellular functions, and the dynamics of microtubules contribute to neural network connectivity, information processing, and memory storage. however, the molecular mechanism of morphine on microtubule dynamics, learning, and memory remains uncovered. In the present study, we examined the effects of chronic morphine administration on memory formation impairment and the kinetic alterations in microtubule proteins induced by morphine in mice. Chronic morphine administration at doses of 5 and 10 mg/kg dose-dependently decreased subjects' performance in spatial memory tasks, such as the Morris Water Maze and Y-maze spontaneous alternation behavior. Furthermore, morphine was found to stabilize microtubule structure, and increase polymerization, and total polymer mass. However, it simultaneously impaired microtubule dynamicity, stemming from structural changes in tubulin dimer structure. These findings emphasize the need for careful consideration of different doses when using morphine, urging a more cautious approach in the administration of this opioid medication.

6-Shogaol attenuates natural aging-induced locomotive and cognitive declines through suppression of p75 neurotrophin receptor in vivo

The present study aimed to investigate the effect of 6-shogaol (6S) treatment on brain senescence. Mice were naturally aged until 25-month-old and treated with 10 mg/kg of 6S for a month. Behavioral tests were performed to measure locomotion and cognitive function. Neuronal damage, synaptic plasticity, neuroinflammation, neurogenesis and p75 neurotrophin receptor (p75NTR) expression were examined by immunohistochemistry or immunofluorescence. 6S treatment improved locomotion during open field test in the aged mice and spontaneous alternation in Y-maze. These data are in line with that 6S administration improved dopaminergic neuronal loss and dopamine signaling and attenuated hippocampal synaptic plasticity in the aged brain. Additionally, 6S treatment reduced striatal and hippocampal microgliosis and astrocytosis but promoted neurogenesis in subventricular zone. Furthermore, 6S treatment reversed the p75NTR expression in the senescent brain. The current findings suggest that 6S can be a functional food for successful aging through brain rejuvenation at the molecular level.

Combination strategy employing BACE1 inhibitor and memantine to boost cognitive benefits in Alzheimer's disease therapy.

The β-secretase BACE1 initiates amyloid-β (Aβ) generation and represents a long-standing prime therapeutic target for the treatment of Alzheimer's disease (AD). However, BACE1 inhibitors tested to date in clinical trials have yielded no beneficial outcomes. In fact, prior BACE1 inhibitor trials targeted at ~ 50-90% Aβ reductions in symptomatic or prodromal AD stages have ended in the discontinuation due to futility and/or side effects, including cognitive worsening rather than expected improvement at the highest dose. We tested whether a combination strategy with the selective BACE1 inhibitor GRL-8234 and the FDA-approved symptomatic drug memantine may provide synergistic cognitive benefits within their safe dose range. The drug effects were evaluated in the advanced symptomatic stage of 5XFAD mice that developed extensive cerebral Aβ deposition. Chronic combination treatment with 33.4-mg/kg GRL-8234 and 10-mg/kg memantine, but not either drug alone, rescued cognitive deficits in 5XFAD mice at 12months of age (the endpoint after 60-day drug treatment), as assessed by the contextual fear conditioning, spontaneous alternation Y-maze and nest building tasks. Intact baseline performances of wild-type control mice on three cognitive paradigms demonstrated that combination treatment did not augment potential cognitive side effects of individual drugs. Biochemical and immunohistochemical examination showed that combination treatment did not synergistically reduce the β-amyloidogenic processing of amyloid precursor protein or Aβ levels in 5XFAD mouse brains. A combination strategy with BACE1 inhibitors and memantine may be able to increase the effectiveness of individual drugs within their safe dose range in AD therapy.

SAT600 Absent LH Signaling Rescues The Anxiety Phenotype In Aging Female Mice

Abstract Disclosure: S. Sims: None. O. Barak: None. V. Ryu: None. S. Miyashita: None. H.S. Kannangara: None. F. Korkmaz: None. A. Macdonald: None. A. Gumerova: None. K. Goosens: None. M. Zaidi: None. T. Yuen: None. D. Lizneva: None. T. Frolinger: None. Clinical studies and experimental data together support a role for pituitary gonadotropins, including luteinizing hormone (LH), otherwise considered solely as a fertility hormones, in age-related cognitive decline. Furthermore, rising levels of LH in post-menopausal women have been implicated in the high prevalence of mood disorders. This study was designed to examine the effect of deficient LH signaling, using the global Lhcgr-/- mouse, on both cognitive and emotional behavior in 12-month-old mice. For this, we established and validated a battery of five tests, including Dark-Light Box (DLB), Y-Maze Spontaneous Alternation, Novel Object Recognition (NOR) and contextual and cued Fear Conditioning (FCT) tests. We found that 12-month-old female mice display a prominent anxiety phenotype on DLB and FCT. This phenotype was not seen in female Lhcgr-/- mice, indicating full phenotypic rescue. Furthermore, there was no effect of depleting LHCGRs on recognition memory or working spatial memory on NOR and Y-maze testing, respectively, in 12-month-old mice, notwithstanding the absence of a basal phenotype in wild type littermates. The latter data do not exclude an effect of LH on cognition documented in previous studies. Finally, male mice and 3-month-old male and female mice did not consistently display deficits on any test. The data collectively document, for the first time, that loss of LH signaling reverses age-related emotional disturbances, a prelude to future targeted therapies that block LH action. Presentation: Saturday, June 17, 2023

CD137L Inhibition Ameliorates Hippocampal Neuroinflammation and Behavioral Deficits in a Mouse Model of Sepsis-Associated Encephalopathy

Anxiety manifestations and cognitive dysfunction are common sequelae in patients with sepsis-associated encephalopathy (SAE). Microglia-mediated inflammatory signaling is involved in anxiety, depression, and cognitive dysfunction during acute infection with bacterial lipopolysaccharide (LPS). However, the molecular mechanisms underlying microglia activation and behavioral and cognitive deficits in sepsis have not been in fully elucidated. Based on previous research, we speculated that the CD137 receptor/ligand system modulates microglia function during sepsis to mediate classical neurological SAE symptoms. A murine model of SAE was established by injecting male C57BL/6 mice with LPS, and cultured mouse BV2 microglia were used for in vitro assays. RT-qPCR, immunofluorescence staining, flow cytometry, and ELISA were used to assess microglial activation and the expression of CD137L and inflammation-related cytokines in the mouse hippocampus and in cultured BV2 cells. In addition, behavioral tests were conducted in assess cognitive performance and behavioral distress. Immunofluorescence and RT-qPCR analyses showed that hippocampal expression of CD137L was upregulated in activated microglia following LPS treatment. Pre-treatment with the CD137L neutralizing antibody TKS-1 significantly reduced CD137L levels, attenuated the expression of M1 polarization markers in microglia, and inhibited the production of TNF-α, IL-1β, and IL-6 in both LPS-treated mice and BV2 cells. Conversely, stimulation of CD137L signaling by recombinant CD137-Fc fusion protein activated the synthesis and release of pro-inflammatory cytokines in cultures BV2 microglia. Importantly, open field, elevated plus maze, and Y-maze spontaneous alternation test results indicated that TKS-1 administration alleviated anxiety-like behavior and spatial memory decline in mice with LPS-induced SAE. These findings suggest that CD137L upregulation in activated microglia critically contributes to neuroinflammation, anxiety-like behavior, and cognitive dysfunction in the mouse model of LPS-induced sepsis. Therefore, therapeutic modulation of the CD137L/CD137 signaling pathway may represent an effective way to minimize brain damage and prevent cognitive and emotional deficits associated with SAE.

Supraphysiologic doses of 17β-estradiol aggravate depression-like behaviors in ovariectomized mice possibly via regulating microglial responses and brain glycerophospholipid metabolism

Background17β-Estradiol (E2) is generally considered neuroprotective in humans. However, the current clinical use of estrogen replacement therapy (ERT) is based on the physiological dose of E2 to treat menopausal syndrome and has limited therapeutic efficacy. The efficacy and potential toxicity of superphysiological doses of ERT for menopausal neurodegeneration are unknown.MethodsIn this study, we investigated the effect of E2 with a supraphysiologic dose (0.5 mg/kg, sE2) on the treatment of menopausal mouse models established by ovariectomy. We performed the open field, Y-maze spontaneous alternation, forced swim tests, and sucrose preference test to investigate behavioral alterations. Subsequently, the status of microglia and neurons was detected by immunohistochemistry, HE staining, and Nissl staining, respectively. Real-time PCR was used to detect neuroinflammatory cytokines in the hippocampus and cerebral cortex. Using mass spectrometry proteomics platform and LC–MS/ MS-based metabolomics platform, proteins and metabolites in brain tissues were extracted and analyzed. BV2 and HT22 cell lines and primary neurons and microglia were used to explore the underlying molecular mechanisms in vitro.ResultssE2 aggravated depression-like behavior in ovariectomized mice, caused microglia response, and increased proinflammatory cytokines in the cerebral cortex and hippocampus, as well as neuronal damage and glycerophospholipid metabolism imbalance. Subsequently, we demonstrated that sE2 induced the pro-inflammatory phenotype of microglia through ERα/NF-κB signaling pathway and downregulated the expression of cannabinoid receptor 1 in neuronal cells, which were important in the pathogenesis of depression.ConclusionThese data suggest that sE2 may be nonhelpful or even detrimental to menopause-related depression, at least partly, by regulating microglial responses and glycerophospholipid metabolism.

A quantitative analysis of spontaneous alternation behaviors on a Y-maze reveals adverse effects of acute social isolation on spatial working memory

Animals tend to alternate between different choices, which requires the ability to remember recent choices. The Y-maze spontaneous alternation test is widely used in various animal models for assessing short-term memory, and its precise evaluation depends upon the accurate determination of the arm visit sequence. However, an objective method for defining arm visits is lacking owing to uncertainty regarding the extent to which an animal must go into the arm to be considered visited. Here, we conducted quantitative analyses on mice behavior in the Y-maze while systematically varying the arm visit threshold and assessed the effect of acute social isolation on spatial working memory. Our results revealed that 24-h social isolation significantly reduced spontaneous alternation rate when the arm threshold was set at the distal part of the arm. Furthermore, the memory of the recently visited arms faded away faster in the socially isolated mice. However, other behavioral factors were comparable to those of the group-housed mice, indicating a specific impairment of short-term memory. Our findings suggest that the location of arm visit threshold is critical for the precise evaluation of short-term memory, and our study provides a method for comprehensively and systematically assessing spontaneous alternation behavior in the Y-maze.

Dual administration of lipopolysaccharide induces behavioral changes in rats relevant to psychotic disorders.

We previously reported that dual injections of lipopolysaccharide (LPS) in mice constitute a valuable tool for investigating the contribution of inflammation to psychotic disorders. The present study investigated how immune activation affects the kynurenine pathway and rat behavior of relevance for psychotic disorders. Male Sprague Dawley rats were treated with either dual injections of LPS (0.5 mg/Kg + 0.5 mg/Kg, i.p.) or dual injections of saline. Twenty-four hours after the second injection, behavioral tests were carried out, including locomotor activity test, fear conditioning test, spontaneous alternation Y-maze test, and novel object recognition test. In a separate batch of animals, in vivo striatal microdialysis was performed, and tryptophan, kynurenine, quinolinic acid (QUIN), and kynurenic acid (KYNA) in the dialysate were measured using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Dual-LPS treatment decreased spontaneous locomotion, exaggerated d-amphetamine-induced locomotor activity, and impaired recognition memory in male Sprague-Dawley rats. In vivo microdialysis showed that dual-LPS treatment elicited metabolic disturbances in the kynurenine pathway with increased extracellular levels of kynurenine and KYNA in the striatum. The present study further supports the feasibility of using the dual-LPS model to investigate inflammation-related psychotic disorders and cognitive impairments.

Transcranial ultrasound neuromodulation facilitates isoflurane-induced general anesthesia recovery and improves cognition in mice

Delayed arousal and cognitive dysfunction are common, especially in older patients after general anesthesia (GA). Elevating central nervous system serotonin (5-HT) levels can promote recovery from GA and increase synaptic plasticity to improve cognition. Ultrasound neuromodulation has become a noninvasive physical intervention therapy with high spatial resolution and penetration depth, which can modulate neuronal excitability to treat psychiatric and neurodegenerative diseases. This study aims to use ultrasound to noninvasively modulate the brain 5-HT levels of mice to promote recovery from GA and improve cognition in mice. The dorsal raphe nucleus (DRN) of mice during GA was stimulated by the 1.1 MHz ultrasound with a negative pressure of 356 kPa, and the liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) method was used to measure the DRN 5-HT concentrations. The mice’s recovery time from GA was assessed, and the cognition was evaluated through spontaneous alternation Y-maze and novel object recognition (NOR) tests. After ultrasound stimulation, the mice’s DRN 5-HT levels were significantly increased (control: 554.0 ± 103.2 ng/g, anesthesia + US: 664.2 ± 84.1 ng/g, *p = 0.0389); the GA recovery time (return of the righting reflex (RORR) emergence latency time) of mice was significantly reduced (anesthesia: 331.6 ± 70 s, anesthesia + US: 223.2 ± 67.7 s, *p = 0.0215); the spontaneous rotation behavior score of mice was significantly increased (anesthesia: 59.46 ± 5.26 %, anesthesia + US: 68.55 ± 5.24 %; *p = 0.0126); the recognition index was significantly increased (anesthesia: 55.02 ± 6.23 %, anesthesia + US: 78.52 ± 12.21 %; ***p = 0.0009). This study indicates that ultrasound stimulation of DRN increases serotonin levels, accelerates recovery from anesthesia, and improves cognition, which could be an important strategy for treating delayed arousal, postoperative delirium, or even lasting cognitive dysfunction after GA.

Absent LH signaling rescues the anxiety phenotype in aging female mice.

Clinical studies and experimental data together support a role for pituitary gonadotropins, including luteinizing hormone (LH), otherwise considered solely as fertility hormones, in age-related cognitive decline. Furthermore, rising levels of LH in post-menopausal women have been implicated in the high prevalence of mood disorders. This study was designed to examine the effect of deficient LH signaling on both cognitive and emotional behavior in 12-month-old Lhcgr-/- mice. For this, we established and validated a battery of five tests, including Dark-Light Box (DLB), Y-Maze Spontaneous Alternation, Novel Object Recognition (NOR), and contextual and cued Fear Conditioning (FCT) tests. We found that 12-month-old female wild type mice display a prominent anxiety phenotype on DLB and FCT. This phenotype was not seen in 12-month-old female Lhcgr-/- mice, indicating full phenotypic rescue. Furthermore, there was no effect of LHCGR depletion on recognition memory or working spatial memory on NOR and Y-maze testing, respectively, in 12-month-old mice, notwithstanding the absence of a basal phenotype in wild type littermates. The latter data do not exclude an effect of LH on cognition documented in previous studies. Finally, 12-month-old male mice and 3-month-old male and female mice did not consistently display deficits on any test. The data collectively document, for the first time, that loss of LH signaling reverses age-related emotional disturbances, a prelude to future targeted therapies that block LH action.

Novel Phenylethanoid Glycosides Improve Hippocampal Synaptic Plasticity via the Cyclic Adenosine Monophosphate-CREB-Brain-Derived Neurotrophic Growth Factor Pathway in APP/PS1 Transgenic Mice

Introduction: Alzheimer’s disease (AD) is a major public health concern worldwide, but there are still no drugs available that treat it effectively. Previous studies have shown that phenylethanoid glycosides have pharmacological effects, which include anti-AD properties, but the underlying mechanisms by which they ameliorate AD symptoms remain unknown. Methods: In this study, we used an APP/PS1 AD mouse model to explore the function and mechanisms underlying savatiside A (SA) and torenoside B (TB) in the treatment of AD. SA or TB (100 mg·kg-1·d-1) was orally administered to 7-month-old APP/PS1 mice for 4 weeks. Cognitive and memory functions were measured using behavioral experiments (including the Morris water maze test and the Y-maze spontaneous alternation test). Molecular biology experiments (including Western blotting, immunofluorescence, and enzyme-linked immunosorbent assays) were used to detect any corresponding changes in signaling pathways. Results: The results showed that SA or TB treatment could significantly reduce cognitive impairment in APP/PS1 mice. We also showed that chronic treatment with SA/TB could prevent spine loss, synaptophysin immunoreactivity, and neuronal loss in mice, thereby improving synaptic plasticity and moderating learning and memory deficits. SA/TB administration also promoted the expression of synaptic proteins in APP/PS1 mouse brains and upregulated phosphorylation of proteins in the cyclic adenosine monophosphate (cAMP)/CREB/brain-derived neurotrophic growth factor (BDNF) pathway that are responsible for synaptic plasticity. Additionally, chronic SA/TB treatment increased the levels of BDNF and nerve growth factor (NGF) in the brains of APP/PS1 mice. Both astrocyte and microglia volumes, as well as the generation of amyloid β, were also decreased in SA/TB-treated APP/PS1 mice compared to control APP/PS1 mice. Conclusion: In summary, SA/TB treatment was associated with activation of the cAMP/CREB/BDNF pathway and increased BDNF and NGF expression, indicating that SA/TB improves cognitive functioning via nerve regeneration. SA/TB is a promising candidate drug for the treatment of AD.

Neuroprotective Effect of White Nelumbo nucifera Gaertn. Petal Tea in Rats Poisoned with Mancozeb.

Nelumbo nucifera Gaertn. (N. nucifera) tea is used as food and folk medicine to reduce toxicity in Southeast Asia. Mancozeb (Mz) is used for controlling fungi in agriculture and contains heavy metals. This study aimed to examine the effect of white N. nucifera petal tea on cognitive behavior, hippocampus histology, oxidative stress, and amino acid metabolism in rats poisoned with mancozeb. Seventy-two male Wistar rats were divided into nine groups (n = 8 in each). Y-maze spontaneous alternation test was used to assess cognitive behavior, and amino acid metabolism was investigated by nuclear magnetic resonance spectroscopy (1H-NMR) from blood. There was a significant increase in relative brain weight in the Mz co-administered with the highest dose (2.20 mg/kg bw) of white N. nucifera group. The levels of tryptophan, kynurenine, picolinic acid, and serotonin in blood showed a significant decrease in the Mz group and a significant increase in the Mz co-administered with low dose (0.55 mg/kg bw) of white N. nucifera group. However, there was no significant difference in cognitive behavior, hippocampus histology, oxidative stress, and corticosterone. This study demonstrated that a low dose of white N. nucifera petal tea has a neuroprotective effect against mancozeb.

Dapagliflozin Ameliorates Cognitive Impairment in Aluminum-Chloride-Induced Alzheimer's Disease via Modulation of AMPK/mTOR, Oxidative Stress and Glucose Metabolism.

Alzheimer's disease (AD) is a progressive neurological illness characterized by memory loss and cognitive deterioration. Dapagliflozin was suggested to attenuate the memory impairment associated with AD; however, its mechanisms were not fully elucidated. This study aims to examine the possible mechanisms of the neuroprotective effects of dapagliflozin against aluminum chloride (AlCl3)-induced AD. Rats were distributed into four groups: group 1 received saline, group 2 received AlCl3 (70 mg/kg) daily for 9 weeks, and groups 3 and 4 were administered AlCl3 (70 mg/kg) daily for 5 weeks. Dapagliflozin (1 mg/kg) and dapagliflozin (5 mg/kg) were then given daily with AlCl3 for another 4 weeks. Two behavioral experiments were performed: the Morris Water Maze (MWM) and the Y-maze spontaneous alternation (Y-maze) task. Histopathological alterations in the brain, as well as changes in acetylcholinesterase (AChE) and amyloid β (Aβ) peptide activities and oxidative stress (OS) markers, were all evaluated. A western blot analysis was used for the detection of phosphorylated 5' AMP-activated protein kinase (p-AMPK), phosphorylated mammalian target of Rapamycin (p-mTOR) and heme oxygenase-1 (HO-1). Tissue samples were collected for the isolation of glucose transporters (GLUTs) and glycolytic enzymes using PCR analysis, and brain glucose levels were also measured. The current data demonstrate that dapagliflozin represents a possible approach to combat AlCl3-induced AD in rats through inhibiting oxidative stress, enhancing glucose metabolism and activating AMPK signaling.