The effects of exercise training on heart, brain and behavior, in the isoproterenol-induced cardiac infarct model in middle-aged female rats

Women with cardiovascular disease may be more susceptible to concomitant mental health problems, such as depression and cognitive decline. Exercise training has beneficial effects on the cardiovascular system as well as on mental functions. Aim of the present study was to study the effects of exercise training on heart, brain and behavior in the isoproterenol (ISO) model in middle-aged female rats. Twelve months old female Wistar rats were submitted to ISO injections (70 mg/kg s.c., on two consecutive days) or received saline. One week later, rats were assigned to either exercise training (treadmill running) or control handling for five weeks. During the last 7 days, tests were performed regarding depressive-like behavior and cognitive function. Then, rats were sacrificed and heart and brains were dissected for (immuno)histochemistry. ISO-induced cardiac effects were eminent from cardiac fibrosis and declined cardiac function. Exercise training reversed cardiac damage and partly restored ISO-induced cardiac dysfunction. However, ISO treatment could not be associated with neuroinflammation, nor impaired hippocampal neurogenesis or neuronal function. Accordingly, no cognitive impairment or depressive-like behavior were observed. Actually, hippocampal microglia hyper-ramification was observed after ISO. Exercise left neuroinflammation and behavior merely unaltered, and even reduced neuronal function. Our data indicated that the cardiac damage after ISO in middle-aged female rats, and the subsequent beneficial effects of five weeks exercise training on the heart, were not reflected in changes in the brain nor in altered behavior

Sex dimorphism in isoproterenol-induced cardiac damage associated neuroinflammation and behavior in old rats

Acute cardiac damage can be induced by isoproterenol injections in animals. The associated inflammatory response could be reflected in the brain as neuroinflammation, with potential consequences for brain function and behavior. Although cardiac responses are reported age and sex-related, for neuroinflammation and brain function this is virtually unknown. Therefore, cardiac damage and its consequences for neuroinflammation, brain function and behavior were compared in aged male and female rats. Wistar rats of 24 months of age were treated with isoproterenol (ISO, twice s.c.) or saline. Four weeks after injections, exploratory behavior and short-term memory were tested. Then, rats were sacrificed. Hearts were collected to measure cardiac damage. Brain tissue was collected to obtain measures of neuroinflammation and brain function. In male-, but not in female rats, ISO induced significant cardiac damage. Accordingly, mortality was higher in males than in females. Baseline hippocampal microglia activity was lower in females, while ISO induced neuroinflammation in both sexes, Hippocampal brain-derived neurotrophic factor expression appeared lower in females, without effects of ISO. In the open field test, ISO-treated males, but not females, displayed anxiety-like behavior. No effects of ISO were observed on short-term memory in either sex. In conclusion, sex dimorphism in effects of ISO was observed for cardiac damage and open field behavior. However, these effects could not be related to differences in hippocampal neuroinflammation or neuronal function

Vaccination prevented short-term memory loss, but deteriorated long-term spatial memory in Alzheimer's disease mice, independent of amyloid-β pathology

Background: Soluble oligomeric amyloid-β (Aβ), rather than Aβ plaques, seems to be the culprit in Alzheimer's disease (AD). Accordingly, a new concept vaccine of small cyclic peptide conjugates, selectively targeting oligomeric Aβ, has been developed.Objective: Study the therapeutic potential of this new vaccine in a mouse model for AD.Methods: J20 mice, overexpressing human amyloid precursor protein, were validated for an AD-like phenotype. Then, J20 mice were vaccinated at 2, 3, and 4 months of age and AD phenotype was evaluated at 6, 9, and 12 months of age; or at 9, 10, and 11 months with evaluation at 12 months. Effects on Aβ pathology were studied by plaque load (immunohistochemistry; 6E10) and antibody titers against Aβ (ELISA). AD behavioral phenotype was evaluated by performance in a battery of cognitive tests.Results: J20 mice displayed age-related Aβ plaque development and an AD-like behavioral phenotype. A consistent antibody response to the cyclic peptides was, however, not extended to Aβ, leaving plaque load unaffected. Nevertheless, immunization at young ages prevented working- and short-term spatial memory loss, but deteriorated long-term spatial learning and memory, at 12 months of age. Immunization at later ages did not affect any measured parameter.Conclusion: J20 mice provide a relevant model for AD to study potential anti-Aβ treatment. Early vaccination prevented short-term memory loss at later ages, but deteriorated long-term spatial memory, however without affecting Aβ pathology. Later vaccination had no effects, but optimal timing may require further investigation.</p

Effects of exercise training on behavior and brain function after high dose isoproterenol-induced cardiac damage

Acute sympathetic stress can result in cardiac fibrosis, but may also lead to mental dysfunction. Exercise training after isoproterenol (ISO)-induced acute sympathetic stress was investigated regarding cardiac damage, neuroinflammation, brain function and behavior. Male Wistar rats (12 months) received ISO or saline. One week later, treadmill running or control handling (sedentary) started. After 4 weeks, cognitive- and exploratory behavior were evaluated, and heart and brain tissues were analyzed regarding cardiac damage, hippocampal neuroinflammation and neuronal function. ISO did not affect cognitive performance nor hippocampal function. However, ISO reduced anxiety, coinciding with locally reduced microglia (processes) size in the hippocampus. Exercise in ISO rats reversed anxiety, did not affect microglia morphology, but increased brain function. Thus, exercise after ISO did not affect cardiac damage, cognition or hippocampal neuroinflammation, but normalized anxiety. Increased localized BDNF expression may indicate improved brain function

Chronic whole body vibration ameliorates hippocampal neuroinflammation, anxiety-like behavior, memory functions and motor performance in aged male rats dose dependently

Whole body vibration (WBV) is a form of passive exercise by the stimulation of mechanical vibration platform. WBV has been extensively investigated through clinical studies with main focus on the musculoskeletal system. However, pre-clinical data in the context of behavior, memory and motor functions with aged rodents are limited. The aim of this experiment was to investigate the dose dependent effects of a five weeks long WBV intervention with an aged animal model including anxiety-related behavior, memory and motor functions, as well as markers of (neuro)inflammation. Male Wistar rats (18 months) underwent 5 or 20 min daily vibration exposure or pseudo-treatment (i.e.: being subjected to the same environmental stimuli for 5 or 20 min, but without exposure to vibrations) 5 times per week. After 5 weeks treatment, cognitive functions, anxiety-like behavior and motor performance were evaluated. Finally, brain tissue was collected for immunohistological purposes to evaluate hippocampal (neuro)inflammation. Animals with 20 min daily session of WBV showed a decrease in their anxiety-like behavior and improvement in their spatial memory. Muscle strength in the grip hanging test was only significantly improved by 5 min daily WBV treatments, whereas motor coordination in the balance beam test was not significantly altered. Microglia activation showed a significant decrease in the CA1 and Dentate gyrus subregions by both dose of WBV. In contrast, these effects were less pronounced in the CA3 and Hilus subregions, where only 5 min dose showed a significant effect on microglia activation. Our results indicate, that WBV seems to be a comparable strategy on age-related anxiety, cognitive and motor decline, as well as alleviating age-related (neuro)inflammation

Enteral enriched nutrition to prevent cognitive dysfunction after surgery:A study in rats

BACKGROUND: Inflammation plays an important role in postoperative cognitive dysfunction (POCD), particularly in elderly patients. Enteral enriched nutrition was shown to inhibit the response on inflammatory stimuli. Aim of the present study was to explore the therapeutic potential of enteral enriched nutrition in our rat model for POCD. The anticipated mechanism of action was examined in young rats, while responses in the target group of elderly patients were evaluated in old rats. METHODS: Male 3 and 23 months old Wistar rats received a bolus of enteral fat/protein-enriched nutrition 2 ​h and 30 ​min before surgery. The inflammatory response was evaluated by systemic inflammation markers and brain microglia activity. Additionally, in old rats, the role of the gut-brain axis was studied by microbiome analyses of faecal samples. Days 9–14 after surgery, rats were subjected to cognitive testing. Day 16, rats were sacrificed and brains were collected for immunohistochemistry. RESULTS: In young rats, enriched nutrition improved long-term spatial learning and memory in the Morris Water Maze, reduced plasma IL1-β and VEGF levels, but left microglia activity and neurogenesis unaffected. In contrast, in old rats, enriched nutrition improved short-term memory in the novel object- and novel location recognition tests, but impaired development of long-term memory in the Morris Water Maze. Systemic inflammation was not affected, but microglia activity seemed even increased. Gut integrity and microbiome were not affected. CONCLUSION: Enteral enriched nutrition before surgery in young rats indeed reduced systemic inflammation and improved cognitive performance after surgery, whereas old rats showed a mixed favorable/unfavorable cognitive response, without effect on systemic inflammation. Anti-inflammatory effects of enriched nutrition were not reflected in decreased microglia activity. Neither was an important role for the gut-brain axis observed. Since the relatively straight forward effects of enriched nutrition in young rats could not be shown in old rats, as indicated by a mixed beneficial/detrimental cognitive outcome in the latter, caution is advised by translating effects seen in younger patients to older ones

Whole body vibration improves spatial memory, anxiety-like behavior, and motor performance in aged male and female rats

Aging is a progressive process leading to functional decline in many domains. Recent studies have shown that physical exercise (PE) has a positive influence on the progression of age-related functional decline, including motor and brain functions. Whole body vibration (WBV) is a form of passive stimulation by mechanical vibration platforms, which offers an alternative for PE interventions, especially for aged individuals. WBV has been demonstrated to mimic the beneficial effects of PE on the musculoskeletal system, as well on the central nervous system. However, preclinical data with aged rodents are very limited. Hence, the purpose of this experiment was to investigate the effects of a 5-week WBV intervention with an aged animal model on memory functions, anxiety-related behavior, and motor performance. The 18-month old male (N = 14) and female (N = 14) Wistar rats were divided into two groups, namely, vibration and pseudo-vibration. Animals underwent a 5-week WBV intervention protocol with low intensity (frequency of 30 Hz and amplitude of 50–200 μm) stimulation. After 5 weeks, the following cognitive and motor tests were administered: open-field, novel and spatial object recognition, grip-hanging, and balance-beam. WBV-treated rats showed a decrease in their anxiety level in the open field test compared with those in the pseudo-treated controls. In addition, WBV-treated male animals showed significantly increased rearing in the open-field test compared to their pseudo controls. Spatial memory was significantly improved by WBV treatment, whereas WBV had no effect on object memory. Regarding motor performance, both grip strength and motor coordination were improved by WBV treatment. Our results indicate that WBV seems to have comparable beneficial effects on age-related emotional, cognitive, and motor decline as what has been reported for active PE. No striking differences were found between the sexes. As such, these findings further support the idea that WBV could be considered as a useful alternative for PE in case active PE cannot be performed due to physical or mental issues

Brain changes due to hypoxia during light anaesthesia can be prevented by deepening anaesthesia:a study in rats

In anaesthetic practice the risk of cerebral ischemic/hypoxic damage is thought to be attenuated by deep anaesthesia. The rationale is that deeper anaesthesia reduces cerebral oxygen demand more than light anaesthesia, thereby increasing the tolerance to ischemia or hypoxia. However, evidence to support this is scarce. We thus investigated the influence of light versus deep anaesthesia on the responses of rat brains to a period of hypoxia. In the first experiment we exposed adult male Wistar rats to deep or light propofol anaesthesia and then performed [18F]- Fludeoxyglucose (FDG) Positron Emission Tomography (PET) scans to verify the extent of cerebral metabolic suppression. In subsequent experiments, rats were subjected to light/deep propofol anaesthesia and then exposed to a period of hypoxia or ongoing normoxia (n = 9-11 per group). A further 5 rats, not exposed to anaesthesia or hypoxia, served as controls. Four days later a Novel Object Recognition (NOR) test was performed to assess mood and cognition. After another 4 days, the animals were sacrificed for later immunohistochemical analyses of neurogenesis/neuroplasticity (Doublecortin; DCX), Brain Derived Neurotrophic Factor (BDNF) expression and neuroinflammation (Ionized calcium-binding adaptor protein-1; Iba-1) in hippocampal and piriform cortex slices. The hippocampi of rats subjected to hypoxia during light anaesthesia showed lower DCX positivity, and therefore lower neurogenesis, but higher BDNF levels and microglia hyper-ramification. Exploration was reduced, but no significant effect on NOR was observed. In the piriform cortex, higher DCX positivity was observed, associated with neuroplasticity. All these effects were attenuated by deep anaesthesia. Deepening anaesthesia attenuated the brain changes associated with hypoxia. Hypoxia during light anaesthesia had a prolonged effect on the brain, but no impairment in cognitive function was observed. Although reduced hippocampal neurogenesis may be considered unfavourable, higher BDNF expression, associated with microglia hyper-ramification may suggest activation of repair mechanisms. Increased neuroplasticity observed in the piriform cortex supports this, and might reflect a prolonged state of alertness rather than damage

Whole body vibration improves attention and motor performance in mice depending on the duration of the whole-body vibration session

BACKGROUND: Whole body vibration (WBV) is a form of physical stimulation via mechanical vibrations transmitted to a subject. It is assumed that WBV induces sensory stimulation in cortical brain regions through the activation of skin and muscle receptors responding to the vibration. The effects of WBV on muscle strength are well described. However, little is known about the impact of WBV on the brain. Recently, it was shown in humans that WBV improves attention in an acute WBV protocol. Preclinical research is needed to unravel the underlying brain mechanism. As a first step, we examined whether chronic WBV improves attention in mice.MATERIAL AND METHODS: A custom made vibrating platform for mice with low intensity vibrations was used. Male CD1 mice (3 months of age) received five weeks WBV (30 Hz; 1.9 G), five days a week with sessions of five (n=12) or 30 (n=10) minutes. Control mice (pseudo-WBV; n=12 and 10 for the five and 30 minute sessions, respectively) were treated in a similar way, but did not receive the actual vibration. Object recognition tasks were used as an attention test (novel and spatial object recognition - the primary outcome measure). A Balance beam was used for motor performance, serving as a secondary outcome measure.RESULTS: WBV sessions of five (but not WBV sessions of 30 minutes) improved balance beam performance (mice gained 28% in time needed to cross the beam) and novel object recognition (mice paid significantly more attention to the novel object) as compared to pseudo WBV, but no change was found for spatial object performance (mice did not notice the relocation). Although 30 minutes WBV sessions were not beneficial, it did not impair either attention or motor performance.CONCLUSION: These results show that brief sessions of WBV improve, next to motor performance, attention for object recognition, but not spatial cues of the objects. The selective improvement of attention in mice opens the avenue to unravel the underlying brain mechanisms.</p

Lipocalin 2 as a link between ageing, risk factor conditions and age-related brain diseases

Chronic (neuro)inflammation plays an important role in many age-related central nervous system (CNS) diseases, including Alzheimer's disease, Parkinson's disease and vascular dementia. Inflammation also characterizes many conditions that form a risk factor for these CNS disorders, such as physical inactivity, obesity and cardiovascular disease. Lipocalin 2 (Lcn2) is an inflammatory protein shown to be involved in different age-related CNS diseases, as well as risk factor conditions thereof. Lcn2 expression is increased in the periphery and the brain in different age-related CNS diseases and also their risk factor conditions. Experimental studies indicate that Lcn2 contributes to various neuropathophysiological processes of age-related CNS diseases, including exacerbated neuroinflammation, cell death and iron dysregulation, which may negatively impact cognitive function. We hypothesize that increased Lcn2 levels as a result of age-related risk factor conditions may sensitize the brain and increase the risk to develop age-related CNS diseases. In this review we first provide a comprehensive overview of the known functions of Lcn2, and its effects in the CNS. Subsequently, this review explores Lcn2 as a potential (neuro)inflammatory link between different risk factor conditions and the development of age-related CNS disorders. Altogether, evidence convincingly indicates Lcn2 as a key constituent in ageing and age-related brain diseases