The neurobiology of circadian rhythms

Purpose of review There is growing awareness of the importance of circadian rhythmicity in various research fields. Exciting developments are ongoing in the field of circadian neurobiology linked to sleep, food intake, and memory. With the current knowledge of critical ‘clock genes’ (genes found to be involved in the generation of circadian rhythms) and novel techniques for imaging cyclic events in brain and peripheral tissue, this field of research is rapidly expanding. We reviewed only some of the highlights of the past year, and placed these findings into a mutual circadian perspective. Recent findings Recent findings on the organization of the circadian clock systems are addressed, ranging from the retina to the suprachiasmatic nucleus and peripheral organs. Novel developments in sleep, food intake, and memory research linked to circadian aspects are discussed. Summary The neurobiology of circadian rhythms is pivotal to the orchestration of the temporal organization of an individual’s physiology and behavior. Endogenous circadian timing systems underlie coupling and uncoupling mechanisms of many neuronal and physiological processes, the latter possibly inducing health risks to the organism. The integration of sleep, food intake and memory in a circadian setting has clear potential as a systems neurobiology line of research.

Morris Water Maze Learning in Two Rat Strains Increases the Expression of the Polysialylated Form of the Neural Cell Adhesion Molecule in the Dentate Gyrus But Has No Effect on Hippocampal Neurogenesis

In the current study, the authors investigated whether Morris water maze learning induces alterations in hippocampal neurogenesis or neural cell adhesion molecule (NCAM) polysialylation in the dentate gyrus. Two frequently used rat strains, Wistar and Sprague–Dawley, were trained in the spatial or the nonspatial version of the water maze. Both training paradigms did not have an effect on survival of newly formed cells that were labeled 7–9 days prior to the training or on progenitor proliferation in the subgranular zone. However, the granule cell layer of the spatially trained rats contained significantly more positive cells of the polysialylated form of the NCAM. These data demonstrate that Morris water maze learning causes plastic change in the dentate gyrus without affecting hippocampal neurogenesis.

Aging of the brain

An increasing number of persons live for nine or more decades and enjoy the benefits of a well-functioning brain until the end of their life. In that respect, the cognitive performance in later life and the quality maintenance of the brain are amazing biological phenomena. Since most nerve cells are generated during pregnancy and have to survive an active lifetime, the brain has to be endowed with a maintenance machinery of surprising long-term quality. During successful, that is, non-pathological, aging in most brain regions, there is very little or no evidence for a decrease in numbers of neurons. In some brain structures, a limited reduction of nerve cells may occur, but it is generally conceived that aging and aging-related cognitive impairments are not the result of massive cell loss but rather the result of synaptic changes, receptor dysfunction or signaling deficits, and metabolic decline. Besides, nerve cell loss during normal aging may be compensated by synaptogenesis, dendritic branching, or in certain brain structures like dentate gyrus by neurogenesis from progenitor stem cells. Yet most human individuals suffer from a mild but life-disturbing condition we call agingrelated memory impairment (AMI). In this chapter, some of the mechanisms will be shortly explored that are considered to be causal to non-pathological deterioration of cognitive faculties. In particular several cellular and molecular neuronal changes will be addressed that occur during aging, the consequences for interneuronal communication and membrane potential, the blood supply to the brain and cerebrovascular condition, and some observations on the protective neuroimmune system of the brain

Vibration detection:Its function and recent advances in medical applications

Vibrations are all around us. We can detect vibrations with sensitive skin mechanoreceptors, but our conscious awareness of the presence of vibrations is often limited. Nevertheless, vibrations play a role in our everyday life. Here, we briefly describe the function of vibration detection and how it can be used for medical applications by way of whole body vibration. Strong vibrations can be harmful, but milder vibrations can be beneficial, although to what extent and how large the clinical relevance is are still controversial. Whole body vibration can be applied via a vibrating platform, used in both animal and human research. Recent findings make clear that the mode of action is twofold: next to the rather well-known exercise (muscle) component, it also has a sensory (skin) component. Notably, the sensory (skin) component stimulating the brain has potential for several purposes including improvements in brain-related disorders. Combining these two components by selecting the optimal settings in whole body vibration has clear potential for medical applications. To realize this, the field needs more standardized and personalized protocols. It should tackle what could be considered the "Big Five" variables of whole body vibration designs: vibration amplitude, vibration frequency, method of application, session duration/frequency, and total intervention duration. Unraveling the underlying mechanisms by translational research can help to determine the optimal settings. Many systematic reviews on whole body vibration end with the conclusion that the findings are promising yet inconclusive. This is mainly because of the large variation in the "Big Five" settings between studies and incomplete reporting of methodological details hindering reproducibility. We are of the opinion that when (part of) these optimal settings are being realized, a much better estimate can be given about the true potential of whole body vibration as a medical application

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

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

Gut-microbiome composition in response to phenylketonuria depends on dietary phenylalanine in BTBR Pah^enu2 mice

Phenylketonuria (PKU) is a metabolic disorder caused by a hepatic enzyme deficiency causing high blood and brain levels of the amino acid Phenylalanine (Phe), leading to severe cognitive and psychological deficits that can be prevented, but not completely, by dietary treatment. The behavioral outcome of PKU could be affected by the gut-microbiome-brain axis, as diet is one of the major drivers of the gut microbiome composition. Gut-microbiome alterations have been reported in treated patients with PKU, although the question remains whether this is due to PKU, the dietary treatment, or their interaction. We, therefore, examined the effects of dietary Phe restriction on gut-microbiome composition and relationships with behavioral outcome in mice. Male and female BTBR Pah(enu2) mice received either a control diet (normal protein, “high” Phe), liberalized Phe-restricted (33% natural protein restriction), or severe Phe-restricted (75% natural protein restriction) diet with protein substitutes for 10 weeks (n = 14 per group). Their behavioral performance was examined in an open field test, novel and spatial object location tests, and a balance beam. Fecal samples were collected and sequenced for the bacterial 16S ribosomal RNA (rRNA) region. Results indicated that PKU on a high Phe diet reduced Shannon diversity significantly and altered the microbiome composition compared with wild-type animals. Phe-restriction prevented this loss in Shannon diversity but changed community composition even more than the high-Phe diet, depending on the severity of the restriction. Moreover, on a taxonomic level, we observed the highest number of differentially abundant genera in animals that received 75% Phe-restriction. Based on correlation analyses with differentially abundant taxa, the families Entereococacceae, Erysipelotrichaceae, Porphyromonadaceae, and the genus Alloprevotella showed interesting relationships with either plasma Phe levels and/or object memory. According to our results, these bacterial taxa could be good candidates to start examining the microbial metabolic potential and probiotic properties in the context of PKU. We conclude that PKU leads to an altered gut microbiome composition in mice, which is least severe on a liberalized Phe-restricted diet. This may suggest that the current Phe-restricted diet for PKU patients could be optimized by taking dietary effects on the microbiome into account