Development and validation of prechiasmatic mouse model of subarachnoid hemorrhage to measure long-term neurobehavioral impairment.

Controllable and reproducible animal models of aneurysmal subarachnoid hemorrhage (SAH) are crucial for the systematic study of the pathophysiology and treatment of this debilitating condition. Despite the variety of animal models of SAH currently available, attempts to translate promising therapeutic strategies from preclinical studies to humans have largely failed. This failure is likely due, at least in part, to poor replication of pathology and disabilities in these preclinical models, especially the long-term neurocognitive deficits that drive poor quality of life / return to work in SAH survivors. Therefore, there is an unmet need to develop experimental models that reliably replicate the long-term clinical ramifications of SAH - especially in mice where genetic manipulations are straightforward and readily available. To address this need, we developed a standardized mouse model of SAH that reproducibly produced significant and trackable long-term neurobehavioral deficits. SAH was induced by performing double blood injections into the prechiasmatic cistern - a simple modification to the well-characterized single prechiasmatic injection mouse model of SAH. Following SAH, mice recapitulated key characteristics of SAH patients including long-term cognitive impairment as observed by a battery of behavioral testing and delayed pathophysiologic processes assayed by neuroinflammatory markers. We believe that this new SAH mouse model will be an ideal paradigm for investigating the complex pathophysiology of SAH and identifying novel druggable therapeutic targets for treating SAH-associated long-term neurocognitive deficits in patients.

Repeated multi-domain cognitive training prevents cognitive decline, anxiety and amyloid pathology found in a mouse model of Alzheimer disease.

Education, occupation, and an active lifestyle, comprising enhanced social, physical, and mental components are associated with improved cognitive functions in aged people and may delay the progression of various neurodegenerative diseases including Alzheimer's disease. To investigate this protective effect, 3-month-old APPNL-G-F/NL-G-F mice were exposed to repeated single- or multi-domain cognitive training. Cognitive training was given at the age of 3, 6, & 9 months. Single-domain cognitive training was limited to a spatial navigation task. Multi-domain cognitive training consisted of a spatial navigation task, object recognition, and fear conditioning. At the age of 12 months, behavioral tests were completed for all groups. Then, mice were sacrificed, and their brains were assessed for pathology. APPNL-G-F/NL-G-F mice given multi-domain cognitive training compared to APPNL-G-F/NL-G-F control group showed an improvement in cognitive functions, reductions in amyloid load and microgliosis, and a preservation of cholinergic function. Additionally, multi-domain cognitive training improved anxiety in APPNL-G-F/NL-G-F mice as evidenced by measuring thigmotaxis behavior in the Morris water maze. There were mild reductions in microgliosis in the brain of APPNL-G-F/NL-G-F mice with single-domain cognitive training. These findings provide causal evidence for the potential of certain forms of cognitive training to mitigate the cognitive deficits in Alzheimer disease.

Propofol Affords No Protection against Delayed Cerebral Ischemia in a Mouse Model of Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) is an important contributor to poor outcomes in aneurysmal subarachnoid hemorrhage (SAH) patients. We previously showed that volatile anesthetics such as isoflurane, sevoflurane and desflurane provided robust protection against SAH-induced DCI, but the impact of a more commonly used intravenous anesthetic agent, propofol, is not known. The goal of our current study is to examine the neurovascular protective effects of propofol on SAH-induced DCI. Twelve-week-old male wild-type mice were utilized for the study. Mice underwent endovascular perforation SAH or sham surgery followed one hour later by propofol infusion through the internal jugular vein (2 mg/kg/min continuous intravenous infusion). Large artery vasospasm was assessed three days after SAH. Neurological outcome assessment was performed at baseline and then daily until animal sacrifice. Statistical analysis was performed via one-way ANOVA and two-way repeated measures ANOVA followed by the Newman-Keuls multiple comparison test with significance set at p < 0.05. Intravenous propofol did not provide any protection against large artery vasospasm or sensory-motor neurological deficits induced by SAH. Our data show that propofol did not afford significant protection against SAH-induced DCI. These results are consistent with recent clinical studies that suggest that the neurovascular protection afforded by anesthetic conditioning is critically dependent on the class of anesthetic agent.

Isoflurane Conditioning-Induced Delayed Cerebral Ischemia Protection in Subarachnoid Hemorrhage-Role of Inducible Nitric Oxide Synthase.

Background Recent evidence implicates inflammation as a key driver in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH). Inducible nitric oxide synthase (iNOS) is one of the known major mediators of inflammation. We previously showed that an inhalational anesthetic, isoflurane, provides strong protection against delayed cerebral ischemia after SAH. Our current study aims to define the role of iNOS in isoflurane conditioning-induced protection against delayed cerebral ischemia in a mouse model of SAH. Methods and Results The experiments used 10- to 14-week-old male wild-type (C57BL/6) and iNOS global knockout mice. Anesthetic conditioning was initiated 1 hour after SAH with isoflurane 2% for 1 hour. Isoflurane-induced changes in iNOS expression were measured. N-(3-(aminomethyl) benzyl) acetamidine, a highly selective iNOS inhibitor, was injected intraperitoneally immediately after SAH and then daily. Vasospasm, microvessel thrombosis, and neurological assessment was performed. Data were analyzed by 1-way ANOVA and 2-way repeated measures ANOVA followed by Student Newman Keuls comparison test. Statistical significance was set at P<0.05. Isoflurane conditioning downregulated iNOS expression in naïve and SAH mice. N-(3-(aminomethyl) benzyl) acetamidine attenuated large artery vasospasm and microvessel thrombosis and improved neurological deficits in wild-type animals. iNOS knockout mice were significantly resistant to vasospasm, microvessel thrombosis, and neurological deficits induced by SAH. Combining isoflurane with N-(3-(aminomethyl) benzyl) acetamidine did not offer extra protection, nor did treating iNOS knockout mice with isoflurane. Conclusions Isoflurane conditioning-induced delayed cerebral ischemia protection appears to be mediated by downregulating iNOS. iNOS is a potential therapeutic target to improve outcomes after SAH.

Isoflurane Conditioning Provides Protection against Subarachnoid Hemorrhage Induced Delayed Cerebral Ischemia through NF-kB Inhibition.

Delayed cerebral ischemia (DCI) is the largest treatable cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-kB), a transcription factor known to function as a pivotal mediator of inflammation, is upregulated in SAH and is pathologically associated with vasospasm. We previously showed that a brief exposure to isoflurane, an inhalational anesthetic, provided multifaceted protection against DCI after SAH. The aim of our current study is to investigate the role of NF-kB in isoflurane-conditioning-induced neurovascular protection against SAH-induced DCI. Twelve-week-old wild type male mice (C57BL/6) were divided into five groups: sham, SAH, SAH + Pyrrolidine dithiocarbamate (PDTC, a selective NF-kB inhibitor), SAH + isoflurane conditioning, and SAH + PDTC with isoflurane conditioning. Experimental SAH was performed via endovascular perforation. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. Three doses of PDTC (100 mg/kg) were injected intraperitoneally. NF-kB and microglial activation and the cellular source of NF-kB after SAH were assessed by immunofluorescence staining. Vasospasm, microvessel thrombosis, and neuroscore were assessed. NF-kB was activated after SAH; it was attenuated by isoflurane conditioning. Microglia was activated and found to be a major source of NF-kB expression after SAH. Isoflurane conditioning attenuated microglial activation and NF-kB expression in microglia after SAH. Isoflurane conditioning and PDTC individually attenuated large artery vasospasm and microvessel thrombosis, leading to improved neurological deficits after SAH. The addition of isoflurane to the PDTC group did not provide any additional DCI protection. These data indicate isoflurane-conditioning-induced DCI protection after SAH is mediated, at least in part, via downregulating the NF-kB pathway.

Dramatic impacts on brain pathology, anxiety, and cognitive function in the knock-in APPNL-G-F mouse model of Alzheimer disease following long-term voluntary exercise.

BACKGROUND: An active lifestyle is associated with improved cognitive functions in aged people and may prevent or slow down the progression of various neurodegenerative diseases including Alzheimer's disease (AD). To investigate these protective effects, male APPNL-G-F mice were exposed to long-term voluntary exercise. METHODS: Three-month-old AD mice were housed in a cage supplemented with a running wheel for 9 months for long-term exercise. At the age of 12 months, behavioral tests were completed for all groups. After completing behavioral testing, their brains were assessed for amyloid pathology, microgliosis, and cholinergic cells. RESULTS: The results showed that APPNL-G-F mice allowed to voluntarily exercise showed an improvement in cognitive functions. Furthermore, long-term exercise also improved anxiety in APPNL-G-F mice as assessed by measuring thigmotaxis in the Morris water task. We also found reductions in amyloid load and microgliosis, and a preservation of cholinergic cells in the brain of APPNL-G-F mice allowed to exercise in their home cages. These profound reductions in brain pathology associated with AD are likely responsible for the observed improvement of learning and memory functions following extensive and regular exercise. CONCLUSION: These findings suggest the potential of physical exercise to mitigate the cognitive deficits in AD.

Status Analysis of Herbal Drug Therapies in Epilepsy: Advancements in the Use of Medicinal Plants with Anti-inflammatory Properties.

BACKGROUND: The use of plants and plant products in health care has shown an exponential increase in the past two decades. INTRODUCTION: In-spite of the availability of well-established pharmacotherapy for epilepsy, a large no of the population still explores alternative treatments due to refractory seizures, adverse effects of drugs, chronic treatment, inaccessibility of standard therapies in rural areas and the social stigma attached to the disease. Various studies on medicinal plants showed the protective effect of herbals in animal models of epilepsy. METHODS: In the present review, a status analysis of the traditional use of various medicinal plants in epilepsy with a special focus on plats having anti-inflammatory potential is recorded. RESULT AND CONCLUSION: The shortcomings of research on medicinal plants which need to be explored further in order to tackle the growing need for safer and effective drugs for epilepsy are discussed. Overall, there is a huge scope of herbal drugs in CNS disorders, especially epilepsy, either as an adjunct by reducing the dose and thus side effects of standard anti-epileptic drugs or as a standalone agent. Although, there is still an urgent need of well planned randomized controlled clinical trials to validate their efficacy and safety.

STAT3 inhibitor mitigates cerebral amyloid angiopathy and parenchymal amyloid plaques while improving cognitive functions and brain networks.

Previous reports indicate a potential role for signal transducer and activator of transcription 3 (STAT3) in amyloid-ß (Aß) processing and neuritic plaque pathogenesis. In the present study, the impact of STAT3 inhibition on cognition, cerebrovascular function, amyloid pathology, oxidative stress, and neuroinflammation was studied using in vitro and in vivo models of Alzheimer's disease (AD)-related pathology. For in vitro experiments, human brain vascular smooth muscle cells (HBVSMC) and human brain microvascular endothelial cells (HBMEC) were used, and these cultured cells were exposed to Aß peptides followed by measurement of activated forms of STAT3 expression and reactive oxygen species (ROS) generation. Further, 6 months old 5XFAD/APOE4 (5XE4) mice and age-matched negative littermates were used for in vivo experiments. These mice were treated with STAT3 specific inhibitor, LLL-12 for 2 months followed by neurobehavioral and histopathological assessment. In vitro experiments showed exposure of cerebrovascular cells to Aß peptides upregulated activated forms of STAT3 and produced STAT3-mediated vascular oxidative stress. 5XE4 mice treated with the STAT3-specific inhibitor (LLL-12) improved cognitive functions and functional connectivity and augmented cerebral blood flow. These functional improvements were associated with a reduction in neuritic plaques, cerebral amyloid angiopathy (CAA), oxidative stress, and neuroinflammation. Reduction in amyloid precursor protein (APP) processing and attenuation of oxidative modification of lipoprotein receptor related protein-1 (LRP-1) were identified as potential underlying mechanisms. These results demonstrate the broad impact of STAT3 on cognitive functions, parenchymal and vascular amyloid pathology and highlight the therapeutic potential of STAT3 specific inhibition for treatment of AD and CAA.

Anesthetic and subanesthetic doses of isoflurane conditioning provides strong protection against delayed cerebral ischemia in a mouse model of subarachnoid hemorrhage.

Delayed cerebral ischemia (DCI) is identified as one of the significant contributors to poor patient outcome after aneurysmal subarachnoid hemorrhage (SAH). We previously reported that a supratherapeutic dose of isoflurane conditioning (2%) provided robust protection against SAH-induced DCI. The aim of our current study is to compare the efficacy of the supratherapeutic dose of isoflurane to that typically used to establish general anesthesia or sedation. After IRB approval for animal studies, ten to fourteen-week-old wild-type male mice (C57BL/6) were divided into five groups - sham, SAH alone, or SAH with isoflurane conditioning (0.5%, 1%, and 2%). Conditioning was performed with one-hour of isoflurane initiated one-hour after induction of SAH via endovascular perforation technique. Vasospasm measurement in the middle cerebral artery was assessed 72 h after SAH. Neurological assessment was performed at baseline and for next three days after SAH. It was identified that all tested doses of isoflurane conditioning (0.5%, 1%, and 2%) significantly attenuated large artery vasospasm and markedly improved neurological deficits following SAH. No significant differences in neurovascular outcome were noted between the three doses of isoflurane conditioning. Our data show that isoflurane dosing typically used for general anesthesia (1%) or sedation (0.5%) provide similar levels of DCI protection in SAH as that provided by a supratherapeutic dose (2%). This result has important implications for future translational studies. Additional studies examining the therapeutic potential of anesthetic conditioning for SAH are therefore warranted.

Traffic noise exposure, cognitive decline, and amyloid-beta pathology in an AD mouse model.

Concerns are growing that exposure to environmental pollutants, such as traffic noise, might cause cognitive impairments and predispose individuals toward the development of Alzheimer's disease (AD) dementia. In this study in a knock-in mouse model of AD, we investigated how chronic traffic noise exposure (CTNE) impacts cognitive performance and amyloid-beta (Aß) pathology. A group of APPNL-G-F/NL-G-F mice was exposed to CTNE (70 dBA , 8 hr/day for 1 month) and compared with nonexposed counterparts. Following CTNE, an increase in hypothalamic-pituitary-adrenal (HPA) axis responsivity was observed by corticosterone assay of the blood. One month after CTNE, the CTNE group demonstrated impairments in cognitive and motor functions, and indications of anxiety-like behavior, relative to the control animals. The noise-exposed group also showed elevated Aß aggregation, as inferred by a greater number of plaques and larger average plaque size in various regions of the brain, including regions involved in stress regulation. The results support that noise-associated dysregulation of the neuroendocrine system as a potential risk factor for developing cognitive impairment and Aß pathology, which should be further investigated in human studies.

Indian Medicinal Herbs and Formulations for Alzheimer's Disease, from Traditional Knowledge to Scientific Assessment.

Cognitive impairment, associated with ageing, stress, hypertension and various neurodegenerative disorders including Parkinson's disease and epilepsy, is a major health issue. The present review focuses on Alzheimer's disease (AD), since it is the most important cause of cognitive impairment. It is characterized by progressive memory loss, language deficits, depression, agitation, mood disturbances and psychosis. Although the hallmarks of AD are cholinergic dysfunction, ß-amyloid plaques and neurofibrillary tangle formation, it is also associated with derangement of other neurotransmitters, elevated levels of advanced glycation end products, oxidative damage, neuroinflammation, genetic and environmental factors. On one hand, this complex etiopathology makes a response to commonly used drugs such as donepezil, rivastigmine, galantamine and memantine less predictable and often unsatisfactory. On the other hand, it supports the use of herbal medicines due to their nonspecific antioxidant and anti-inflammatory activity and specific cholinesterase inhibitory activity. The popularity of herbal medicines is also increasing due to their perceived effectiveness, safety and affordability. In the present article, the experimental and clinical evidence have been reviewed for various Indian herbal medicines such as Centella asiatica, Bacopa monnieri, Curcuma longa, Clitoria ternatea, Withania somnifera, Celastrus paniculatus, Evolvulus alsinoides, Desmodium gangeticum, Eclipta alba, Moringa oleifera and Convolvulus pluricaulis, which have shown potential in cognitive impairment. Some commonly available herbal formulations for memory impairment in India have also been reviewed.

Increased processing of SINE B2 ncRNAs unveils a novel type of transcriptome deregulation in amyloid beta neuropathology.

The functional importance of many non-coding RNAs (ncRNAs) generated by repetitive elements and their connection with pathologic processes remains elusive. B2 RNAs, a class of ncRNAs of the B2 family of SINE repeats, mediate through their processing the transcriptional activation of various genes in response to stress. Here, we show that this response is dysfunctional during amyloid beta toxicity and pathology in the mouse hippocampus due to increased levels of B2 RNA processing, leading to constitutively elevated B2 RNA target gene expression and high Trp53 levels. Evidence indicates that Hsf1, a master regulator of stress response, mediates B2 RNA processing in hippocampal cells and is activated during amyloid toxicity, accelerating the processing of SINE RNAs and gene hyper-activation. Our study reveals that in mouse, SINE RNAs constitute a novel pathway deregulated in amyloid beta pathology, with potential implications for similar cases in the human brain, such as Alzheimer's disease (AD).

Prenatal noise stress aggravates cognitive decline and the onset and progression of beta amyloid pathology in a mouse model of Alzheimer's disease.

Environmental distresses occurring during the sensitive periods of early life may exacerbate the vulnerability to develop physical and mental diseases in old age. Studies have shown the impact of prenatal stress (PS) on the endocrine development and reprogramming of hypothalamic-pituitary-adrenal axis functions in association with cognitive development and susceptibility to neuropsychiatric diseases. Long-term exposure to glucocorticoids can damage the brain and intensify the progression of Alzheimer's disease (AD)-like neuropathological changes, especially in females. There is, however, less information as to the link between PS and the risk of developing AD pathology throughout the lifespan. In the present study, male and female APPNL-G-F/NL-G-F offspring of dams exposed to gestational noise stress were compared with the control offspring in corticosterone alternations, cognitive and motor performances, and the onset age and development of amyloid beta (Aß) plaques across age. The hyperactivity of the hypothalamic-pituitary-adrenal axis, spatial learning, and Aß development were sex specific, showing persistent high levels of stress and further memory loss in females than males, especially in PS mice. The Aß deposition was started earlier, by 2-3 months, and exhibited a heightened progression in PS animals. The PS also created a long-lasting anxiety-like behavior and impairment in cognitive function and motor coordination. Our results suggested PS as a risk to exacerbate AD-like neuropathological changes during the lifespan, with higher susceptibility of females. The findings were discussed in line with the most likely mechanisms for the PS effects, that is, dysregulation of the neuroendocrine system and the placenta by the PS.

Looking beyond the standard version of the Morris water task in the assessment of mouse models of cognitive deficits.

Most studies investigating hippocampal-dependent learning and memory in mouse models of disease use the standard version of the Morris water task (MWT), in which a place is learned over several days. While useful in determining if there are learning and memory deficits, often it is not clear if memory acquisition, consolidation, or retrieval is affected. For rats, we developed a variant of the task in which we added a single-massed training session to a new location after the standard distributed version of the MWT. Using this version of the task, competition between these two spatial representations can then be assessed in a probe trial. We have found in rat models of Alzheimer's disease that this paradigm can detect subtle impairments that are often missed in the standard version of the MWT. To the best of our knowledge, MWT paradigm with a single-massed training session have never been used for mice. We sought to validate this paradigm for the use of assessing mouse models of disease. In the first two experiments, control mice did not have a preference for the new platform location, but instead with extensive training in the massed session displayed a preference for both the old and new locations. In the third experiment, a novel mouse model of Alzheimer's disease was impaired in the standard version of the MWT, but not in the massed training phase of this paradigm. Importantly, these data demonstrate that our paradigm is more informative in characterizing spatial learning and memory in mouse models of disease.

Age-dependent behavioral and biochemical characterization of single APP knock-in mouse (APPNL-G-F/NL-G-F) model of Alzheimer's disease.

Saito et al developed a novel amyloid precursor protein (APP) knock-in mouse model (APPNL-G-F) for Alzheimer's disease (AD) to overcome the problem of overexpression of APP in available transgenic mouse models. However, this new mouse model for AD is not fully characterized age-dependently with respect to behavioral and biochemical changes. Therefore, in the present study, we performed an age-dependent behavioral and biochemical characterization of this newly developed mouse model. Here, we used 3-, 6-, 9-, and 12-month-old APPNL-G-F and C57BL/6J mice. We used a separate cohort of animals at each age point. Morris water maze, object recognition, and fear-conditioning tests were used for the assessment of learning and memory functions and open-field test to measure the general locomotor activity of mice. After each testing point, we perfused the mice and collected the brain for immunostaining. We performed the immunostaining for amyloid burden (4G8), glial fibrillary acidic protein, choline acetyltransferase, and tyrosine hydroxylase. The results of the present study indicate that APPNL-G-F mice showed age-dependent memory impairments with maximum impairment at the age of 12 months. These mice showed memory impairment in Morris water maze and fear conditioning tests when they were 6 months old, whereas, in object recognition test, memory deficit was found in 9-month-old mice. APPNL-G-F mice age dependently showed an increase in amyloid load in different brain regions. However, no amyloid pathology was found in 3-month-old APPNL-G-F mice. Choline acetyltransferase neurons in medial septum-diagonal band complex and tyrosine hydroxylase neurons in locus coeruleus were decreased significantly in APPNL-G-F mice. This mouse model also indicated an age-dependent increase in glial fibrillary acidic protein load. It can be concluded from the results that the APPNL-G-F mouse model may be used to explore the Aß hypothesis, molecular, and cellular mechanisms involved in AD pathology and to screen the therapeutic potential compounds for the treatment of AD.

Gestational Stress Augments Postpartum ß-Amyloid Pathology and Cognitive Decline in a Mouse Model of Alzheimer's Disease.

Besides well-known risk factors for Alzheimer's disease (AD), stress, and in particular noise stress (NS), is a lifestyle risk factor common today. It is known that females are at a significantly greater risk of developing AD than males, and given that stress is a common adversity in females during pregnancy, we hypothesized that gestational noise exposure could exacerbate the postpartum development of the AD-like neuropathological changes during the life span. Pregnant APPNL-G-F/NL-G-F mice were randomly assigned to either the stress condition or control group. The stress group was exposed to the NS on gestational days 12-16, which resulted in a markedly higher hypothalamic-pituitary-adrenal (HPA) axis responsivity during the postpartum stage. Higher amyloid-ß (Aß) deposition and larger Aß plaque size in the olfactory area were the early onset impacts of the gestational stress (GS) seen at the age of 4 months. This pattern of increased Aß aggregation and larger plaque size were observed in various brain areas involved in both AD and stress regulation, especially in limbic structures, at the age of 6 months. The GS also produced anxiety-like behavior, deficits in learning and memory, and impaired motor coordination. The findings suggest that environmental stresses during pregnancy pose a potential risk factor in accelerating postpartum cognitive decline and AD-like neuropathological changes in the dams (mothers) later in life.

Gradual Cerebral Hypoperfusion Impairs Fear Conditioning and Object Recognition Learning and Memory in Mice: Potential Roles of Neurodegeneration and Cholinergic Dysfunction.

In the present study, male C57BL/6J mice were subjected to gradual cerebral hypoperfusion by implanting an ameroid constrictor (AC) on the left common carotid artery (CCA) and a stenosis on the right CCA. In the sham group, all surgical procedures were kept the same except no AC was implanted and stenosis was not performed. One month following the surgical procedures, fear conditioning and object recognition tests were conducted to evaluate learning and memory functions and motor functions were assessed using a balance beam test. At the experimental endpoint, mice were perfused and brains were collected for immunostaining and histology. Learning and memory as well as motor functions were significantly impaired in the hypoperfusion group. The immunoreactivity to choline acetyltransferase was decreased in dorsal striatum and basal forebrain of the hypoperfusion group indicating that cholinergic tone in these brain regions was compromised. In addition, an increased number of Fluoro-Jade positive neurons was also found in cerebral cortex, dorsal striatum and hippocampus indicating neurodegeneration in these brain regions. Based on this pattern of data, we argued that this mouse model would be a useful tool to investigate the therapeutic interventions for the treatment of vascular dementia. Additionally, this model could be employed to exploit the effect of microvascular occlusions on cognitive impairment in the absence and presence of Alzheimer's disease pathology.

Prenatal noise stress impairs HPA axis and cognitive performance in mice.

Noise stress is a common environmental pollutant whose adverse effect on offspring performance has been less studied. This study was novel in terms of using "noise" as a prenatal stress compared with physical stress to explore the effect of stress during gestation on HPA axis activation, cognitive performance, and motor coordination, as well as in investigating the effect of behavioral assessments on the corticosterone (CORT) levels. Three groups of C57BL/6 mice with a gestational history of either noise stress (NS), physical stress (PS), or no stress were examined in several behavioral tests. Plasma CORT level was significantly higher before starting the behavioral tests in NS group than the two other groups. It was significantly increased after the behavioral tests in both prenatal stressed groups relative to the controls. Stress caused anxiety-like behavior and reduced learning and memory performance in both stressed groups compared to the controls, as well as decreased motor coordination in the NS group relative to the other groups. The findings suggested that: prenatal NS severely changes the HPA axis; both prenatal stressors, and particularly NS, negatively impair the offspring's cognitive and motor performance; and, they also cause a strong susceptibility to interpret environmental experiences as stressful conditions.

Corticosterone response to gestational stress and postpartum memory function in mice.

Maternal stress is a common adversity during pregnancy. Gestational corticosterone alternations are thought to contribute to the etiology of postpartum behavioral disturbances. However, the impact of stress during pregnancy, in particular noise exposure, on gestational corticosterone fluctuations and spatial cognition in postpartum mice has not been fully understood yet. We hypothesized that noise exposure during pregnancy negatively affects gestational corticosterone levels and postpartum memory function in the dams similar to the physical stressors. Pregnant C57BL/6 mice were randomly assigned to either one of two stress conditions or a control condition. The noise stress (NS) was induced by presenting a loud intermittent 3000 Hz frequency on gestational days (GDs) 12, 14, and 16 for 24 hours, whereas the physical stress (PS) consisted of restraint and exposure to an elevated platform on GDs 12-16. Plasma corticosterone level was collected on GDs 11 and 17, and Morris water task (MWT) was carried out 30 days after parturition. Compared to the control group, the level of corticosterone in the stressed groups was significantly increased on GD17 relative to GD11. Significantly longer swim time and lower swim speed were observed in both stressed groups relative to the control group. Probe time was significantly shorter in the NS group than the other groups. The delta corticosterone level was significantly correlated with the swim time as well as the probe time in the three groups. Given the results, the adverse effects of gestational noise exposure on the hypothalamic pituitary-adrenal (HPA) axis activation and postpartum spatial learning and memory function were as large as/ or a bit stronger than the physical stresses. The findings suggest the significance of conservation against loud noise exposure in daily living, as well as need to further notice to the different aspects of gestational stress in mothers' behavior like offspring.

Experimental induction of type 2 diabetes in aging-accelerated mice triggered Alzheimer-like pathology and memory deficits.

Alzheimer's disease (AD) is an age-dependent neurodegenerative disease constituting ~95% of late-onset non-familial/sporadic AD, and only ~5% accounting for early-onset familial AD. Availability of a pertinent model representing sporadic AD is essential for testing candidate therapies. Emerging evidence indicates a causal link between diabetes and AD. People with diabetes are >1.5-fold more likely to develop AD. Senescence-accelerated mouse model (SAMP8) of accelerated aging displays many features occurring early in AD. Given the role played by diabetes in the pre-disposition of AD, and the utility of SAMP8 non-transgenic mouse model of accelerated aging, we examined if high fat diet-induced experimental type 2 diabetes in SAMP8 mice will trigger pathological aging of the brain. Results showed that compared to non-diabetic SAMP8 mice, diabetic SAMP8 mice exhibited increased cerebral amyloid-ß, dysregulated tau-phosphorylating glycogen synthase kinase 3ß, reduced synaptophysin immunoreactivity, and displayed memory deficits, indicating Alzheimer-like changes. High fat diet-induced type 2 diabetic SAMP8 mice may represent the metabolic model of AD.