Pharmacologically-Induced Neurovascular Uncoupling is Associated with Cognitive Impairment in Mice

There is increasing evidence that vascular risk factors, including aging, hypertension, diabetes mellitus, and obesity, promote cognitive impairment; however, the underlying mechanisms remain obscure. Cerebral blood flow (CBF) is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism is known to be impaired in the aforementioned pathophysiologic conditions. To establish a direct relationship between impaired NVC and cognitive decline, we induced neurovascular uncoupling pharmacologically in mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH), the NO synthase inhibitor l-NG-Nitroarginine methyl ester (L-NAME), and the COX inhibitor indomethacin decreased NVC by over 60% mimicking the aging phenotype, which was associated with significantly impaired spatial working memory (Y-maze), recognition memory (Novel object recognition), and impairment in motor coordination (Rotarod). Blood pressure (tail cuff) and basal cerebral perfusion (arterial spin labeling perfusion MRI) were unaffected. Thus, selective experimental disruption of NVC is associated with significant impairment of cognitive and sensorimotor function, recapitulating neurologic symptoms and signs observed in brain aging and pathophysiologic conditions associated with accelerated cerebromicrovascular aging.

Download Full-text

The Differential Effects of Acute Right- vs. Left-Sided Vestibular Deafferentation on Spatial Cognition in Unilateral Labyrinthectomized Mice

Frontiers in Neurology ◽

10.3389/fneur.2021.789487 ◽

2021 ◽

Vol 12 ◽

Author(s):

Thanh Tin Nguyen ◽

Gi-Sung Nam ◽

Jin-Ju Kang ◽

Gyu Cheol Han ◽

Ji-Soo Kim ◽

...

Keyword(s):

Spatial Cognition ◽

Motor Coordination ◽

Spatial Working Memory ◽

Spatial Navigation ◽

Vestibular Stimulation ◽

Current Data ◽

Control Group ◽

Y Maze ◽

Lesion Side ◽

Unilateral Labyrinthectomy

This study aimed to investigate the disparity in locomotor and spatial memory deficits caused by left- or right-sided unilateral vestibular deafferentation (UVD) using a mouse model of unilateral labyrinthectomy (UL) and to examine the effects of galvanic vestibular stimulation (GVS) on the deficits over 14 days. Five experimental groups were established: the left-sided and right-sided UL (Lt.-UL and Rt.-UL) groups, left-sided and right-sided UL with bipolar GVS with the cathode on the lesion side (Lt.-GVS and Rt.-GVS) groups, and a control group with sham surgery. We assessed the locomotor and cognitive-behavioral functions using the open field (OF), Y maze, and Morris water maze (MWM) tests before (baseline) and 3, 7, and 14 days after surgical UL in each group. On postoperative day (POD) 3, locomotion and spatial working memory were more impaired in the Lt.-UL group compared with the Rt.-UL group (p < 0.01, Tamhane test). On POD 7, there was a substantial difference between the groups; the locomotion and spatial navigation of the Lt.-UL group recovered significantly more slowly compared with those of the Rt.-UL group. Although the differences in the short-term spatial cognition and motor coordination were resolved by POD 14, the long-term spatial navigation deficits assessed by the MWM were significantly worse in the Lt.-UL group compared with the Rt.-UL group. GVS intervention accelerated the vestibular compensation in both the Lt.-GVS and Rt.-GVS groups in terms of improvement of locomotion and spatial cognition. The current data imply that right- and left-sided UVD impair spatial cognition and locomotion differently and result in different compensatory patterns. Sequential bipolar GVS when the cathode (stimulating) was assigned to the lesion side accelerated recovery for UVD-induced spatial cognition, which may have implications for managing the patients with spatial cognitive impairment, especially that induced by unilateral peripheral vestibular damage on the dominant side.

Download Full-text

Galvanic Vestibular Stimulation Improves Spatial Cognition After Unilateral Labyrinthectomy in Mice

Frontiers in Neurology ◽

10.3389/fneur.2021.716795 ◽

2021 ◽

Vol 12 ◽

Author(s):

Thanh Tin Nguyen ◽

Gi-Sung Nam ◽

Jin-Ju Kang ◽

Gyu Cheol Han ◽

Ji-Soo Kim ◽

...

Keyword(s):

Spatial Memory ◽

Spatial Cognition ◽

Motor Coordination ◽

Spatial Working Memory ◽

Vestibular Stimulation ◽

Galvanic Vestibular Stimulation ◽

Control Group ◽

Y Maze ◽

Unilateral Labyrinthectomy

Objectives: To investigate the deficits of spatial memory and navigation from unilateral vestibular deafferentation (UVD) and to determine the efficacy of galvanic vestibular stimulation (GVS) for recovery from these deficits using a mouse model of unilateral labyrinthectomy (UL).Methods: Thirty-six male C57BL/6 mice were allocated into three groups that comprise a control group and two experimental groups, UVD with (GVS group) and without GVS intervention (non-GVS group). In the experimental groups, we assessed the locomotor and cognitive behavioral function before (baseline) and 3, 7, and 14 days after surgical UL, using the open field (OF), Y maze, and Morris water maze (MWM) tests. In the GVS group, the stimulations were applied for 30 min daily from postoperative day (POD) 0–4 via the electrodes inserted subcutaneously close to both bony labyrinths.Results: Locomotion and spatial cognition were significantly impaired in the mice with UVD non-GVS group compared to the control group. GVS significantly accelerated recovery of locomotion compared to the control and non-GVS groups on PODs 3 (p < 0.001) and 7 (p < 0.05, Kruskal–Wallis and Mann–Whitney U tests) in the OF and Y maze tests. The mice in the GVS group were better in spatial working memory assessed with spontaneous alternation performance and spatial reference memory assessed with place recognition during the Y maze test than those in the non-GVS group on POD 3 (p < 0.001). In addition, the recovery of long-term spatial navigation deficits during the MWM, as indicated by the escape latency and the probe trial, was significantly better in the GVS group than in the non-GVS group 2 weeks after UVD (p < 0.01).Conclusions: UVD impairs spatial memory, navigation, and motor coordination. GVS accelerated recoveries in short- and long-term spatial memory and navigation, as well as locomotor function in mice with UVD, and may be applied to the patients with acute unilateral vestibular failure.

Download Full-text

2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione Ameliorates Diabetic Cognitive Impairment Through Inhibiting Hif3α and Apoptosis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.708141 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lihui Wang ◽

Jinjin Cao ◽

Qianqian Xu ◽

Xiaomei Lu ◽

Xin Yang ◽

...

Keyword(s):

Cognitive Impairment ◽

Object Recognition ◽

Neuronal Apoptosis ◽

Spatial Working Memory ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Ht22 Cells ◽

Beneficial Effects ◽

Y Maze ◽

Associated Proteins

Diabetes mellitus (DM) is an independent risk factor for cognitive impairment. Although the etiology of diabetic cognitive impairment is complex and multifactorial, the hippocampus neuronal apoptosis is recognized as a main cause of diabetes-induced cognitive impairment. 2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) was purified from the roots of Averrhoa carambola L. Previous research demonstrated that DMDD was safe and effective in delaying some diabetic complications. However, the efficacy of DMDD to ameliorate diabetic cognitive impairment in type 2 diabetes mice has not been reported. In the present study, the behavioral evaluation was performed by Y maze and novel object recognition in db/db mice. Gene expression profiles were detected using mouse lncRNA microarray analysis in the hippocampi of db/db mice. Changes in the neurodegeneration-associated proteins and the apoptosis-related proteins were determined in both db/db mice and high glucose-treated HT22 cells by Western blotting. We observed that DMDD treatment significantly ameliorated the spatial working memory and object recognition memory impairment in db/db mice. Further study showed that neurodegeneration-associated protein tau was decreased after DMDD treatment in the hippocampi of db/db mice. Eleven lncRNAs and four mRNAs including pro-apoptotic gene Hif3a were significantly differently expressed after DMDD treatment in the hippocampi of db/db mice. The expression of Hif3a, cleaved parp, and caspase 3 proteins was significantly increased in the hippocampi of diabetic db/db mice compared with db/m control mice and then decreased after DMDD treatment. Similar beneficial effects of DMDD were observed in HG-treated HT22 cells. These data indicate that DMDD can alleviate cognitive impairment by inhibiting neuronal apoptosis through decreasing the expression of pro-apoptotic protein Hif3a. In conclusion, our study suggests that DMDD has great potential to be a new preventive and therapeutic compound for diabetic cognitive impairment.

Download Full-text

New Study in Rats Matches Genetic Influences and Cognitive Impairment, Offers More Complex Model of Brain Aging

PsycEXTRA Dataset ◽

10.1037/e301302003-001 ◽

2003 ◽

Author(s):

Keyword(s):

Cognitive Impairment ◽

Brain Aging ◽

Complex Model ◽

Genetic Influences

Download Full-text

Effect of alkaloid extracted from Huperzia phlegmaria on cognitive deficits scopolamine-induced in mice

Current Bioactive Compounds ◽

10.2174/1573407216999200520082046 ◽

2020 ◽

Vol 16 ◽

Author(s):

Dang Kim Thu ◽

Dao Thi Vui ◽

Nguyen Thi Ngoc Huyen ◽

Nguyen Thi Thanh Binh ◽

Nguyen Thi Huyen ◽

...

Keyword(s):

Cognitive Impairment ◽

Mouse Brain ◽

Cognitive Deficits ◽

Inhibitory Activity ◽

Water Maze ◽

Ache Activity ◽

Y Maze ◽

Ache Inhibitory Activity ◽

Kinetic Inhibition ◽

Brain Tissues

Background: Huperzia phlegmaria has been used for the treatment of neurological disorder. Alkaloids are main bioactive compounds found in Huperzia phlegmaria. We aimed to investigate the acetylcholinesterase (AChE) inhibitory activity in vitro of Huperzia phlegmaria alkaloid extract (HpAE) and protective effects on mice which were induced cognitive deficits by scopolamine. Methods: AChE inhibitory activity and kinetic inhibition mechanism was investigated by Ellman's assay. Mice were administrated orally HpAE (30 mg/kg and 60 mg/kg) for fourteen days, and injected scopolamine at a dose of 1 mg/kg intraperitoneally for four days to induce cognitive impairment. The Y-maze and the Morris water maze were used for evaluating the memory behaviors. Acetylcholine (ACh) levels and AChE activity were measured in brain tissue. Glutathione peroxidase (GPx), superoxide dismutase (SOD) activities, and malondialdehyde (MDA) groups were also evaluated in the mouse brain tissues. Results: Our data showed that HpAE had the strong AChE inhibitory activity with an IC50 value of 5.12 ± 0.48 μg/mL in a concentration-dependent manner. Kinetic inhibition analysis demonstrated that HpPAE inhibited AChE followed the mixed inhibition type with Ki (representing the affinity of the enzyme and inhibitor) was 4.37 ± 0.35 µg/mL. Scopolamine induced the cognitive impairment in Morris Water Maze and Y-maze test along with reduced brain levels of ACh and antioxidant enzyme and increased AChE activity in mouse brain tissues. Treatment with HpAE at both dose (30 mg/kg and 60 mg/kg) decreased the SCP-induced cognitive impairment in both behavioral tests along with decreased acetylcholinesterase activity and MDA level, and increased ACh level and antioxidant enzyme in mouse brain tissues. Conclusion: Our results suggested that the HpAE at both dose (30 mg/kg and 60 mg/kg) may be used for prevent and treatment of Alzheimer’s disease.

Download Full-text

The Oxford Handbook of Adult Cognitive Disorders

10.1093/oxfordhb/9780190664121.001.0001 ◽

2019 ◽

Keyword(s):

Cognitive Impairment ◽

Cognitive Function ◽

Neurodevelopmental Disorders ◽

Brain Aging ◽

Cognitive Disorders ◽

Diverse Range ◽

Medical Specialties ◽

Psychiatric Illnesses ◽

Medical Disorders ◽

The Impact

The prevalence of cognitive impairment caused by neurodegenerative diseases and other neurologic disorders associated with aging is expected to rise dramatically between now and year 2050, when the population of Americans aged 65 or older will nearly double. Cognitive impairment also commonly occurs in other neurologic conditions, as well as in non-neurologic medical disorders (and their treatments), idiopathic psychiatric illnesses, and adult neurodevelopmental disorders. Cognitive impairment can thus infiltrate all aspects of healthcare, making it necessary for clinicians and clinical researchers to have an integrated knowledge of the spectrum of adult cognitive disorders. The Oxford Handbook of Adult Cognitive Disorders is meant to serve as an up-to-date, scholarly, and comprehensive volume covering most diseases, conditions, and injuries resulting in impairments in cognitive function in adults. Topics covered include normal cognitive and brain aging, the impact of medical disorders (e.g., cardiovascular, liver, pulmonary) and psychiatric illnesses (e.g., depression and bipolar disorder) on cognitive function, adult neurodevelopmental disorders (e.g., Down Syndrome, Attention Deficit/Hyperactivity Disorder), as well as the various neurological conditions (e.g., Alzheimer’s disease, chronic traumatic encephalopathy, concussion). A section of the Handbook is also dedicated to unique perspectives and special considerations for the clinicians and clinical researchers, covering topics such as cognitive reserve, genetics, diversity, and neuroethics. The target audience of this Handbook includes: (1) clinicians, particularly psychologists, neuropsychologists, neurologists (including behavioral and cognitive neurologists), geriatricians, and psychiatrists (including neuropsychiatrists), who provide clinical care and management for adults with a diverse range of cognitive disorders; (2) clinical researchers who investigate cognitive outcomes and functioning in adult populations; and (3) graduate level students and post-doctoral trainees studying psychology, clinical neuroscience, and various medical specialties.

Download Full-text

Intranasal insulin rescues repeated anesthesia-induced deficits in synaptic plasticity and memory and prevents apoptosis in neonatal mice via mTORC1

Scientific Reports ◽

10.1038/s41598-021-94849-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Patricia Soriano Roque ◽

Mehdi Hooshmandi ◽

Laura Neagu-Lund ◽

Shelly Yin ◽

Noosha Yousefpour ◽

...

Keyword(s):

Cognitive Impairment ◽

Synaptic Plasticity ◽

General Anesthesia ◽

Preventive Treatment ◽

Intranasal Insulin ◽

Translational Repressor ◽

Beneficial Effects ◽

Underlying Mechanisms ◽

Induced Apoptosis ◽

Preclinical And Clinical Studies

AbstractLong-lasting cognitive impairment in juveniles undergoing repeated general anesthesia has been observed in numerous preclinical and clinical studies, yet, the underlying mechanisms remain unknown and no preventive treatment is available. We found that daily intranasal insulin administration to juvenile mice for 7 days prior to repeated isoflurane anesthesia rescues deficits in hippocampus-dependent memory and synaptic plasticity in adulthood. Moreover, intranasal insulin prevented anesthesia-induced apoptosis of hippocampal cells, which is thought to underlie cognitive impairment. Inhibition of the mechanistic target of rapamycin complex 1 (mTORC1), a major intracellular effector of insulin receptor, blocked the beneficial effects of intranasal insulin on anesthesia-induced apoptosis. Consistent with this finding, mice lacking mTORC1 downstream translational repressor 4E-BP2 showed no induction of repeated anesthesia-induced apoptosis. Our study demonstrates that intranasal insulin prevents general anesthesia-induced apoptosis of hippocampal cells, and deficits in synaptic plasticity and memory, and suggests that the rescue effect is mediated via mTORC1/4E-BP2 signaling.

Download Full-text

Pharmacological rescue of cognitive function in a mouse model of chemobrain

Molecular Neurodegeneration ◽

10.1186/s13024-021-00463-2 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Lien D. Nguyen ◽

Tom T. Fischer ◽

Barbara E. Ehrlich

Keyword(s):

Cognitive Impairment ◽

Prefrontal Cortex ◽

Calcium Oscillations ◽

Neuronal Morphology ◽

Post Injection ◽

Object Recognition Test ◽

Cognitive Changes ◽

Memory Acquisition ◽

Underlying Mechanisms ◽

Trisphosphate Receptor

Abstract Background After chemotherapy, many cancer survivors suffer from long-lasting cognitive impairment, colloquially known as “chemobrain.” However, the trajectories of cognitive changes and the underlying mechanisms remain unclear. We previously established paclitaxel-induced inositol trisphosphate receptor (InsP3R)-dependent calcium oscillations as a mechanism for peripheral neuropathy, which was prevented by lithium pretreatment. Here, we investigated if a similar mechanism also underlay paclitaxel-induced chemobrain. Method Mice were injected with 4 doses of 20 mg/kg paclitaxel every other day to induced cognitive impairment. Memory acquisition was assessed with the displaced object recognition test. The morphology of neurons in the prefrontal cortex and the hippocampus was analyzed using Golgi-Cox staining, followed by Sholl analyses. Changes in protein expression were measured by Western blot. Results Mice receiving paclitaxel showed impaired short-term spatial memory acquisition both acutely 5 days post injection and chronically 23 days post injection. Dendritic length and complexity were reduced in the hippocampus and the prefrontal cortex after paclitaxel injection. Concurrently, the expression of protein kinase C α (PKCα), an effector in the InsP3R pathway, was increased. Treatment with lithium before or shortly after paclitaxel injection rescued the behavioral, cellular, and molecular deficits observed. Similarly, memory and morphological deficits could be rescued by pretreatment with chelerythrine, a PKC inhibitor. Conclusion We establish the InsP3R calcium pathway and impaired neuronal morphology as mechanisms for paclitaxel-induced cognitive impairment. Our findings suggest lithium and PKC inhibitors as candidate agents for preventing chemotherapy-induced cognitive impairment.

Download Full-text

Effects of Pueraria candollei var mirifica (Airy Shaw and Suvat.) Niyomdham on Ovariectomy-Induced Cognitive Impairment and Oxidative Stress in the Mouse Brain

Molecules ◽

10.3390/molecules26113442 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3442

Author(s):

Yaowared Chulikhit ◽

Wichitsak Sukhano ◽

Supawadee Daodee ◽

Waraporn Putalun ◽

Rakvajee Wongpradit ◽

...

Keyword(s):

Oxidative Stress ◽

Cognitive Impairment ◽

Morris Water Maze Test ◽

Object Recognition Test ◽

Pueraria Mirifica ◽

Beneficial Effects ◽

Maze Test ◽

Y Maze ◽

Tnf Α ◽

17Β Estradiol

The effects of the phytoestrogen-enriched plant Pueraria mirifica (PM) extract on ovari-ectomy (OVX)-induced cognitive impairment and hippocampal oxidative stress in mice were investigated. Daily treatment with PM and 17β-estradiol (E2) significantly elevated cognitive behavior as evaluated by using the Y maze test, the novel object recognition test (NORT), and the Morris water maze test (MWM), attenuated atrophic changes in the uterus and decreased serum 17β-estradiol levels. The treatments significantly ameliorated ovariectomy-induced oxidative stress in the hippocampus and serum by a decrease in malondialdehyde (MDA), an enhancement of superoxide dismutase, and catalase activity, including significantly down-regulated expression of IL-1β, IL-6 and TNF-α proinflammatory cytokines, while up-regulating expression of PI3K. The present results suggest that PM extract suppresses oxidative brain damage and dysfunctions in the hippocampal antioxidant system, including the neuroinflammatory system in OVX animals, thereby preventing OVX-induced cognitive impairment. The present results indicate that PM exerts beneficial effects on cognitive deficits for which menopause/ovariectomy have been implicated as risk factors.

Download Full-text