Essential role of ROS - 8-Nitro-cGMP signaling in long-term memory of motor learning and cerebellar synaptic plasticity.

Although reactive oxygen species (ROS) are known to have harmful effects in organisms, recent studies have demonstrated expression of ROS synthases at various parts of the organisms and the controlled ROS generation, suggesting possible involvement of ROS signaling in physiological events of individuals. However, physiological roles of ROS in the CNS, including functional roles in higher brain functions or neuronal activity-dependent ROS production, remain to be elucidated. Here, we demonstrated involvement of ROS - 8-NO2-cGMP signaling in motor learning and synaptic plasticity in the cerebellum. In the presence of inhibitors of ROS signal or ROS synthases, cerebellar motor learning was impaired, and the stimulus inducing long-term depression (LTD), cellular basis for the motor learning, failed to induce LTD but induced long-term potentiation (LTP)-like change at cerebellar synapses. Furthermore, ROS was produced by LTD-inducing stimulus in enzyme-dependent manner, and excess administration of the antioxidant vitamin E impaired cerebellar motor learning, suggesting beneficial roles of endogenous ROS in the learning. As a downstream signal, involvement of 8-NO2-cGMP in motor learning and cerebellar LTD were also revealed. These findings indicate that ROS - 8-NO2-cGMP signal is activated by neuronal activity and is essential for cerebellum-dependent motor learning and synaptic plasticity, demonstrating involvement of the signal in physiological function of brain systems.

Coenzyme Q10 supplementation improves the motor function of middle-aged mice by restoring the neuronal activity of the motor cortex.

Physiological aging causes motor function decline and anatomical and biochemical changes in the motor cortex. We confirmed that middle-aged mice at 15-18 months old show motor function decline, which can be restored to the young adult level by supplementing with mitochondrial electron transporter coenzyme Q10 (CoQ10) as a water-soluble nanoformula by drinking water for 1 week. CoQ10 supplementation concurrently improved brain mitochondrial respiration but not muscle strength. Notably, we identified an age-related decline in field excitatory postsynaptic potential (fEPSP) amplitude in the pathway from layers II/III to V of the primary motor area of middle-aged mice, which was restored to the young adult level by supplementing with CoQ10 for 1 week but not by administering CoQ10 acutely to brain slices. Interestingly, CoQ10 with high-frequency stimulation induced NMDA receptor-dependent long-term potentiation (LTP) in layer V of the primary motor cortex of middle-aged mice. Importantly, the fEPSP amplitude showed a larger input‒output relationship after CoQ10-dependent LTP expression. These data suggest that CoQ10 restores the motor function of middle-aged mice by improving brain mitochondrial function and the basal fEPSP level of the motor cortex, potentially by enhancing synaptic plasticity efficacy. Thus, CoQ10 supplementation may ameliorate the age-related decline in motor function in humans.

Cognitive, physical, and mental profiles of older adults with misplaced self-evaluation of hearing loss.

BACKGROUND: Although inconsistency between objective and subjective hearing loss among older adults has been suggested, a systematic examination of the cognitive and physical functioning among such older adults is lacking. Our objective was to assess the cognitive, physical, and mental profiles associated with the discrepancy. METHODS: The auditory acuity of 696 community-dwelling older adults was evaluated using a pure-tone average of hearing thresholds at 1.0 and 4.0 kHz in the better-hearing ear. Participants were then stratified as follows: normal hearing ≤ 25 dB, mild loss >25 dB and ≤40 dB, and moderate loss >40 dB and ≤70 dB. Global cognition, gait speed, and depressive symptoms were also assessed. RESULTS: Among older adults, 63.5% of those with mild hearing loss and 22.2% of those with moderate hearing loss did not recognize hearing difficulties. Significantly lower cognition and gait performance were observed in those with moderate hearing loss without subjective hearing loss (i.e., overestimation of hearing acuity) than in those with subjective hearing loss. Furthermore, older adults with subjective hearing loss showed a higher tendency toward depression than those without subjective hearing loss, irrespective of objective hearing loss. CONCLUSIONS: Our results suggest that failure to recognize a high level of age-related hearing loss may be related to impaired cognition and gait performance among older adults. Subjective hearing loss may indicate a tendency toward depression.

Long-term D-Allose Administration Favorably Alters the Intestinal Environment in Aged Male Mice.

D-Allose, a C3 epimer of D-glucose, has potential to improve human health as a functional food. However, its effect on the intestinal environment remains unknown. Aged humans progressively express changes in the gut, some of which deleteriously affect gastrointestinal health. In this study, we profiled the intestinal microbiome in aged mice and analyzed organic acids produced by bacteria in cecum contents after long-term ingestion of D-allose. D-Allose did not significantly change organic acid concentration. However, long-term ingestion did significantly increase the relative abundance of Actinobacteria and reduce the relative abundance of Proteobacteria. These results suggest that oral D-allose improves the proportion of favorable intestinal flora in aged mice. D-Allose significantly decreased the relative abundance of Lachnospiraceae bacteria, but increased the relative abundance of Bacteroides acidifaciens and Akkermansia muciniphila. Thus, D-allose might serve as a nutraceutical capable of improving the balance of gut microbiome during aging.

Reversal of spatial memory impairment by phosphodiesterase 3 inhibitor cilostazol is associated with reduced neuroinflammation and increased cerebral glucose uptake in aged male mice.

The nucleotide second messenger 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP) mediate fundamental functions of the brain, including learning and memory. Phosphodiesterase 3 (PDE3) can hydrolyze both cAMP and cGMP and appears to be involved in the regulation of their contents in cells. We previously demonstrated that long-term administration of cilostazol, a PDE3 inhibitor, maintained good memory performance in aging mice. Here, we report on studies aimed at determining whether cilostazol also reverses already-impaired memory in aged male mice. One month of oral 1.5% cilostazol administration in 22-month-old mice reversed age-related declines in hippocampus-dependent memory tasks, including the object recognition and the Morris water maze. Furthermore, cilostazol reduced neuroinflammation, as evidenced by immunohistochemical staining, and increased glucose uptake in the brain, as evidence by positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG). These results suggest that already-expressed memory impairment in aged male mice that depend on cyclic nucleotide signaling can be reversed by inhibition of PDE3. The reversal of age-related memory impairments may occur in the central nervous system, either through cilostazol-enhanced recall or strengthening of weak memories that otherwise may be resistant to recall.

Gait and Age-Related Hearing Loss Interactions on Global Cognition and Falls.

OBJECTIVES: Age-related hearing loss (ARHL) is considered a risk factor for cognitive impairment and falls. The association may be modulated by gait performance because ARHL is related to mobility decline, which strongly contributes to cognitive impairment and falls. We investigated the interactive effects of gait and ARHL on global cognition and falls among older adults. STUDY DESIGN: Retrospective cohort study. METHODS: The auditory acuity of 810 community-dwelling older adults was measured using a pure-tone average of hearing thresholds at 1,000 and 4,000 Hz in the better-hearing ear. Participants were then stratified as follows: normal hearing, ≤25 dB; mild hearing loss (HL), >25 and ≤40 dB; and moderate to severe HL, >40 dB. Gait speed was assessed as an indicator of gait performance and fall occurrence within the previous year. Global cognition was determined using the Montreal Cognitive Assessment (MoCA) test. RESULTS: A total of 320 (39.5%) and 233 (28.8%) participants had mild and moderate to severe HL, respectively. Hierarchical multiple and logistic regression analyses showed interactions between gait performance and moderate hearing loss on both global cognition and the occurrence of falls. Specifically, older adults with moderate hearing loss who walked slowly showed lower MoCA scores and a higher incidence of falls, whereas those with decent gait speed did not show such a tendency. CONCLUSION: Our results suggest that poor gait performance might modulate the effects of ARHL, leading to cognitive decline and falls. Poor cognitive performance and falls may be prevalent in older adults with ARHL, especially in those with slower gait and moderate hearing loss. LEVEL OF EVIDENCE: 3 Laryngoscope, 132:857-863, 2022.

Tocotrienols reach the brain and play roles in the attenuation of body weight gain and improvement of cognitive function in high-fat diet-treated mice.

Obesity induces severe disorders such as type 2 diabetes and cardiovascular events, and the number of people with obesity is increasing all over the world. Furthermore, it is possible that obesity increases the risk of cognitive dysfunction via the acceleration of oxidative damage. Tocotrienols, which are part of the vitamin E family, have antioxidant and anti-obesity effects. However, the effects of tocotrienols on high-fat diet-treated mice have not been completely elucidated. In this study, we assessed changes in body weight, spatial reference memory acquisition, liver lipid droplet size, blood brain barrier-related protein expressions and antioxidative defense systems in high-fat diet-treated mice in the presence or absence of tocotrienols. The results showed that tocotrienols significantly inhibited body weight gain and lipid droplet synthesis. Although the amount was very small, it was confirmed that tocotrienols surely reached the brain in the perfused brain. Treatment with tocotrienols was tended to improve cognitive function in the control mice. However, tocotrienols did not modulate blood brain barrier-related protein expressions or antioxidative defense systems. These results indicate that treatment with tocotrienols could be effective for the prevention of obesity and cognitive dysfunction. Further extended research is needed to elucidate the relationship between anti-obesity and antioxidant effects of tocotrienols, especially in the brain.

Functional Aging in Male C57BL/6J Mice Across the Life-Span: A Systematic Behavioral Analysis of Motor, Emotional, and Memory Function to Define an Aging Phenotype.

Aging is characterized generally by progressive and overall physiological decline of functions and is observed in all animals. A long line of evidence has established the laboratory mouse as the prime model of human aging. However, relatively little is known about the detailed behavioral and functional changes that occur across their lifespan, and how this maps onto the phenotype of human aging. To better understand age-related changes across the life-span, we characterized functional aging in male C57BL/6J mice of five different ages (3, 6, 12, 18, and 22 months of age) using a multi-domain behavioral test battery. Spatial memory and physical activities, including locomotor activity, gait velocity, and grip strength progressively declined with increasing age, although at different rates; anxiety-like behaviors increased with aging. Estimated age-related patterns showed that these functional alterations across ages are non-linear, and the patterns are unique for each behavioral trait. Physical function progressively declines, starting as early as 6 months of age in mice, while cognitive function begins to decline later, with considerable impairment present at 22 months of age. Importantly, functional aging of male C57BL/6J mouse starts at younger relative ages compared to when it starts in humans. Our study suggests that human-equivalent ages of mouse might be better determined on the basis of its functional capabilities.

Splenic artery aneurysm rupture during pregnancy: A case report of maternal and fetal survival.

INTRODUCTION: Pregnancy has been demonstrated as a significant risk factor of splenic artery aneurysm (SAA) formation and rupture. However, prompt diagnosis of SAA rupture in a pregnant patient showing acute abdomen has been practically challenging in light of its rarity and vague initial presentation. PRESENTATION OF CASE: A 40-year-old woman (gravida 1, para 0) at 35 weeks' gestation presented to the emergency department with upper abdominal pain and nausea. Because of fetal dysfunction, emergency caesarian section was performed by a Pfannenstiel incision. Following delivery, 400 g of hemorrhage was removed from the upper abdominal cavity. Computed tomography showed a 37-mm SAA associated with copious adjacent fluid. Although selective angiography did not demonstrate active extravasation, interventional isolation of the SAA was not performed because of multiple surrounding arteries. Relaparotomy with an upper midline incision was then performed. Sudden cardiac arrest occurred upon opening the lesser sac to irrigate clots, and cardiac massage and proximal and distal clamping of the SAA were required. Eventually, splenectomy with excision of the SAA and pancreatic tail was successfully performed, but gauze packing of the open surgical wound was required because of severe coagulopathy. Following removal of the packs and closure of the abdomen 2 days after splenectomy, the patient and infant satisfactorily recovered without sequelae. DISCUSSION: Given continual awareness of abdominal vascular collapse during pregnancy, undelayed diagnosis and safer intervention might be achieved. CONCLUSION: Awareness at initial presentation and multidisciplinary efforts might be essential to achieve maternal and fetal survival in SAA rupture during pregnancy.

8-Nitro-cGMP attenuates context-dependent fear memory in mice.

We previously reported that 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) is endogenously produced via nitric oxide/reactive oxygen species signaling pathways and it reacts with protein thiol residues to add cGMP structure to proteins through S-guanylation. S-Guanylation occurs on synaptosomal-associated protein 25 (SNAP-25), which is a part of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex that regulates exocytosis. However, the biological relevance of 8-nitro-cGMP in the nervous system remains unclear. Here, we investigated the effects of intracerebroventricular (icv) infusion of 8-nitro-cGMP on mouse brain functions. The results of an open-field test and fear-conditioning task revealed that icv infusion of 8-nitro-cGMP decreased the vertical activity and context-dependent fear memory of mice, which are both associated with the hippocampus. Immunohistochemical analysis revealed increased c-Fos-positive cells in the dentate gyrus in 8-nitro-cGMP-infused mice. Further, biochemical analyses showed that icv infusion of 8-nitro-cGMP increased S-guanylated proteins including SNAP-25 and SNARE complex formation as well as decreased complexes containing complexin, which regulates exocytosis by binding to the SNARE complex, in the hippocampus. These findings suggest that accumulation of 8-nitro-cGMP in the hippocampus affects its functions, including memory, via S-guanylation of hippocampal proteins such as SNAP-25.

Vitamin C and vitamin E double-deficiency increased neuroinflammation and impaired conditioned fear memory.

BACKGROUND: Vitamin C (l-ascorbic acid, VC) and vitamin E (α-tocopherol, VE) play important physiological roles as endogenous antioxidants in many tissues and organs. However, their roles in the brain remain entirely elusive. We established senescence marker protein 30 (SMP30)/α-tocopherol transfer protein (αTTP) double knockout (DKO) mice as a novel VC and VE double-deficiency model and examined the effect of VC and VE double-deficiency on brain functions. METHODS: DKO and wild-type (WT) mice were divided into the following two groups: mice in the CE (+) group were supplied with sufficient amounts of VC and VE and mice in the CE (-) group were deficient in both VC and VE. After 8 weeks of CE (+) or CE (-) treatments, a battery of behavioral experiments was conducted to analyze cognitive functions, including memory, through the Morris water maze and Pavlovian fear conditioning tasks. RESULTS: The plasma VC and VE levels in DKO-CE (-) mice and VE level in WT-CE (-) mice were almost completely depleted after 8 weeks of the deficient treatment. The behavioral study revealed that the general behaviors, including locomotor activity and anxiety level, were not influenced by the CE (-) treatment in DKO and WT mice. However, in the Pavlovian fear conditioning task, DKO-CE (-) mice showed impaired conditioned fear memory compared with that of DKO-CE (+) mice. Furthermore, increased mRNA expression was observed in inflammatory-related genes, such as IL-6, TNFα, F4/80, and Mcp-1, in the hippocampus of DKO-CE (-) mice. CONCLUSIONS: The findings of this study provide evidence that VC and VE deficiency led to impaired conditioned fear memory possibly caused by neuroinflammation in the brain.

PDE3 Inhibitors Repurposed as Treatments for Age-Related Cognitive Impairment.

As the population of older individuals grows worldwide, researchers have increasingly focused their attention on identifying key molecular targets of age-related cognitive impairments, with the aim of developing possible therapeutic interventions. Two such molecules are the intracellular cyclic nucleotides, cAMP and cGMP. These second messengers mediate fundamental aspects of brain function relevant to memory, learning, and cognitive function. Consequently, phosphodiesterases (PDEs), which hydrolyze cAMP and cGMP, are promising targets for the development of cognition-enhancing drugs. Inhibitors that target PDEs work by elevating intracellular cAMP. In this review, we provide an overview of different PDE inhibitors, and then we focus on pharmacological and physiological effects of PDE3 inhibitors in the CNS and peripheral tissues. Finally, we discuss findings from experimental and preliminary clinical studies and the potential beneficial effects of the PDE3 inhibitor cilostazol on age-related cognitive impairments. In the innovation pipeline of pharmaceutical development, the antiplatelet agent cilostazol has come into the spotlight as a novel treatment for mild cognitive impairment. Overall, the repurposing of cilostazol may represent a potentially promising way to treat mild cognitive impairment, Alzheimer's disease, and vascular dementia. In this review, we present a brief summary of cAMP signaling and different PDE inhibitors, followed by a discussion of the pharmacological and physiological role of PDE3 inhibitors. In this context, we discuss the repurposing of a PDE3 inhibitor, cilostazol, as a potential treatment for age-related cognitive impairment based on recent research.

Long-term cilostazol administration prevents age-related decline of hippocampus-dependent memory in mice.

Phosphodiesterases (PDEs) are enzymes that hydrolyze and inactivate 3', 5'-cyclic adenosine monophosphate (cAMP) and/or 3', 5'-cyclic guanosine monophosphate (cGMP). The regulation of intracellular signaling pathways mediated by cyclic nucleotides is imperative to synaptic plasticity and memory in animals. Because PDEs play an important role in this regulation, PDE inhibitors are considered as candidate compounds for treating cognitive and memory disorders. In the present study, we tested whether cilostazol, a selective PDE3 inhibitor, prevents the cognitive deterioration that occurs during the course of normal aging in mice. Ten months of cilostazol administration (1.5%) in 13-month-old mice improved spatial memory when tested at 23 months of age. First, it prevented the decline in the ability of these aged mice to recognize a change in an object's location in the object recognition task. Second, spatial memory of these cilostazol-treated aged mice in the Morris water maze was comparable to that of untreated middle-aged mice (13 months old). Cilostazol administration had no effect on the emotional states and physical ability of aged mice. Thus, long-term cilostazol administration prevented hippocampus-dependent memory decline in aged mice, allowing them to achieve a level of cognitive performance similar to middle-aged mice and without negative behavioral side effects. Considering its well-established safety in other medical contexts, cilostazol may be a potential therapeutic candidate drug for staving off cognitive decline in the aging human population.

Coffee consumption in aged mice increases energy production and decreases hepatic mTOR levels.

OBJECTIVE: Coffee, one of the world's most consumed beverages, has many benefits. Some studies have reported the effects of coffee on aging. The aim of this study was to investigate the locomotor activity, energy metabolism, and lipid metabolism of aged (20-mo-old) mice given coffee. METHODS: Aged C57 BL/6 NCr mice were divided into three groups: controls that were not given coffee (n = 9), a group that received 0.1% caffeinated coffee (n = 9), and a group that received 0.1% decaffeinated coffee (n = 9). This regimen continued for 17 wk until mice reached the age of 24 mo. RESULTS: Regular and decaffeinated coffee consumption decreased plasma-free fatty acid levels, increased hepatic adenosine triphosphate content, and decreased total mammalian target of rapamycin (mTOR) and phosphorylated mTOR (p-mTOR) protein content in the liver. However, no differences were found in the protein or activity levels of Akt, adenosine monophosphate-activated protein kinase (AMPK), p70 S6 kinase, or sterol regulatory element-binding protein 1, proteins that are upstream or downstream of the mTOR complex 1 (mTORC1)-related pathways. Regular coffee consumption increased food and water intake, locomotor activity, the volume of carbon dioxide production, and the respiration exchange ratio. CONCLUSION: Regular and decaffeinated coffee consumption decreased hepatic total mTOR and p-mTOR levels independently of Akt and AMPK pathways in aged mice. Because decreased mTORC1 activity is known to have antiaging effects, coffee consumption during old age may retard aging. Moreover, coffee consumption by the aged population had a positive effect on behavioral energy and lipid metabolism.

Long-term cilostazol administration ameliorates memory decline in senescence-accelerated mouse prone 8 (SAMP8) through a dual effect on cAMP and blood-brain barrier.

Phosphodiesterases (PDEs), which hydrolyze and inactivate 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP), play an important role in synaptic plasticity that underlies memory. Recently, several PDE inhibitors were assessed for their possible therapeutic efficacy in treating cognitive disorders. Here, we examined how cilostazol, a selective PDE3 inhibitor, affects brain functions in senescence-accelerated mouse prone 8 (SAMP8), an animal model of age-related cognitive impairment. Long-term administration of cilostazol restored the impaired context-dependent conditioned fear memory of SAMP8 to match that in normal aging control substrain SAMR1. Cilostazol also increased the number of cells containing phosphorylated cAMP-responsive element binding protein (CREB), a downstream component of the cAMP pathway. Finally, cilostazol improves blood-brain barrier (BBB) integrity, demonstrated by reduced extravasation of 2-deoxy-2-18F-fluoro-d-glucose and Evans Blue dye in the brains of SAMP8. This improvement in BBB integrity was associated with an increased amount of zona occludens protein 1 (ZO-1) and occludin proteins, components of tight junctions integral to the BBB. The results suggest that long-term administration of cilostazol exerts its beneficial effects on age-related cognitive impairment through a dual mechanism: by enhancing the cAMP system in the brain and by maintaining or improving BBB integrity.

Preclinical and first-in-man studies of [(11)C]CB184 for imaging the 18-kDa translocator protein by positron emission tomography.

OBJECTIVE: We performed preclinical and first-in-man clinical positron emission tomography (PET) studies in human brain using N,N-di-n-propyl-2-[2-(4-[(11)C]methoxyphenyl)-6,8-dichloroimidazol[1,2-a]pyridine-3-yl]acetamide ([(11)C]CB184) to image the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia in neuroinflammatory conditions. METHODS: In vitro selectivity of CB184 was characterized. The radiation absorbed dose by [(11)C]CB184 in humans was calculated from murine distribution data. Acute toxicity of CB184 hydrochloride in rats at a dose of 5.81 mg/kg body weight, which is >10,000-fold higher than the clinical equivalent dose of [(11)C]CB184, was evaluated. Acute toxicity of [(11)C]CB184 injection of a 400-fold dose to administer a postulated dose of 740 MBq [(11)C]CB184 was also evaluated after the decay-out of (11)C. The mutagenicity of CB184 was studied with a reverse mutation test (Ames test). The pharmacological effect of CB184 injection in mice was studied with an open field test. The first PET imaging of TSPO with [(11)C]CB184 in a normal human volunteer was performed. RESULTS: A suitable preparation method for [(11)C]CB184 injection was established. CB184 showed low activity in a 28-standard receptor binding profile. The radiation absorbed dose by [(11)C]CB184 in humans was sufficiently low for clinical use, and no acute toxicity of CB184 or [(11)C]CB184 injection was found. No mutagenicity or apparent effect on locomotor activity or anxiety status was observed for CB184. We safely performed brain imaging with PET following administration of [(11)C]CB184 in a normal human volunteer. A 90-min dynamic scan showed rapid initial uptake of radioactivity in the brain followed by prompt clearance. [(11)C]CB184 was homogeneously distributed in the gray matter. The total distribution volume of [(11)C]CB184 was highest in the thalamus followed by the cerebellar cortex and elsewhere. Although regional differences were small, the observed [(11)C]CB184 binding pattern was consistent with the TSPO distribution in normal human brain. Peripherally, [(11)C]CB184 was metabolized in humans: 30 % of the radioactivity in plasma was detected as the unchanged form after 60 min. CONCLUSIONS: [(11)C]CB184 is suitable for imaging TSPO in human brain and provides an acceptable radiation dose. Pharmacological safety was noted at the dose required for PET imaging.

Data on the optimization of behavioral tasks for senescence-accelerated mouse prone 8 (SAMP8).

This data article contains the supporting information for the research article entitled "Early onset of behavioral alterations in senescence-accelerated mouse prone 8 (SAMP8)" [1]. Senescence-accelerated mouse prone 8 (SAMP8), which originally developed from AKR/J mice, shows learning and memory impairments at the age of 8-12 months. However, little information is still available on phenotypical characteristics of younger SAMP8. To fully understand the phenotype of younger SAMP8, we optimized two behavioral tasks for SAMP8. In the object recognition task, 4-month-old SAMP8 made significantly more contacts with the familiar objects compared to age-matched SAMR1, however, distance traveled for both strains of mice were comparable. In the fear conditioning task, conventionally-used CS-US combination failed to induce robust conditioned fear in both strains of mice.

Early onset of behavioral alterations in senescence-accelerated mouse prone 8 (SAMP8).

Senescence-accelerated mouse (SAM) is inbred lines of mice originally developed from AKR/J mice. Among the six SAM prone (SAMP) substrains, 8- to 12-month-old SAMP8 have long been used as a model of age-related cognitive impairments. However, little is still known for younger SAMP8 mice. Here, we examined the phenotypical characteristics of 4-month-old SAMP8 using a battery of behavioral tests. Four-month-old SAMP8 mice failed to recognize spatially displaced object in an object recognition task and performed poorly in the probe test of the Morris water maze task compared to SAMR1, suggesting that SAMP8 have impaired spatial memory. In addition, young SAMP8 exhibited enhanced anxiety-like behavior in an open field test and showed depression-like behavior in the forced-swim test. Their circadian rhythm was also disrupted. These abnormal behaviors of young SAMP8 are similar to behavioral alterations also observed in aged mice. In summary, age-related behavioral alterations occur in SAMP8 as young as 4 months old.

Cilostazol improves hippocampus-dependent long-term memory in mice.

RATIONALE: Phosphodiesterases (PDEs) play an important role in the regulation of intracellular signaling mediated by cyclic adenosine monophosphate (cAMP). Recently, several PDE inhibitors were assessed for their possible cognitive enhancing properties. However, little is known about the effect of PDE3 inhibitors on memory function. OBJECTIVES: We examined how the PDE3 inhibitor cilostazol affects C57BL/6 J mice as they perform various behavioral tasks. After behavioral assessment, brains of the mice were analyzed immunohistochemically to quantify the phosphorylation of cAMP-responsive element binding protein (CREB), a downstream component of the cAMP pathway. RESULTS: Oral administration of cilostazol significantly enhanced recollection of the exact platform location in the Morris water maze probe test. Cilostazol also improved context-dependent long-term fear memory, without affecting short-term memory. No apparent effect was observed in cue-dependent fear memory. The results suggest that cilostazol selectively improves hippocampus-dependent long-term memory in these tasks. Cilostazol also significantly increased the number of phosphorylated-CREB-positive cells in hippocampal dentate gyrus. CONCLUSIONS: These results suggest that cilostazol may exert its beneficial effects on learning and memory by enhancing the cAMP system in hippocampus, where it increases intracellular cAMP activity.

Human ultrasonic hearing is induced by a direct ultrasonic stimulation of the cochlea.

Ultrasound can be perceived by bone-conduction. The cochlear basal turn is involved in processing bone-conducted ultrasound (BCU) information. Previous studies have suggested that ultrasonic perception is induced by ultrasound itself. In contrast, it has also been suggested that a lower frequency sound is generated in non-linear process during the transmission pathway to the cochlea to induce an auditory sensations. To address this issue, we assessed cisplatin-induced changes in BCU sensitivity at 27, 30 and 33kHz in 20 participants (40 ears) who were scheduled to undergo cisplatin chemoradiation therapy. Following the treatment, 62.5% ears were diagnosed with hearing loss according to the criteria of the American Speech-Language-Hearing Association. As expected, significant increases in sensitivity threshold were observed for air-conducted sounds ranging from 8 to 14kHz. In contrast, the BCU threshold significantly decreased after the treatment. Considering that both air-conducted high-frequency sound and BCU are perceived in the cochlear basal turn, these findings indicate that ultrasonic perception is independent of hearing a lower frequency sound generated in non-linear process. In addition, our findings support the hypothesis that ultrasound itself induces ultrasonic perception in the cochlea. The observed cisplatin-induced increase in BCU sensitivity may be explained by hypersensitivity associated with outer hair cells' disorder.