Brain Aging Neuronal Plasticity Neurodegeneration What Do We Know Review
Nosotros practice not all grow older in the aforementioned fashion. Some individuals have a cognitive decline earlier and faster than others who are older in years but cerebrally younger. This is peculiarly piece of cake to verify in people who have maintained regular physical activity and healthy and cognitively stimulating lifestyle and even in the clinical field. There are patients with advanced neurodegeneration, such as Alzheimer's affliction (AD), that, despite this, have mild cognitive damage. What determines this interindividual difference? Certainly, information technology cannot be the result of only genetic factors. We are made in a certain manner and what nosotros do acts on our encephalon. In fact, our genetic ground can be modulated, modified, and inverse by our experiences such as education and life events; daily, by sleep schedules and habits; or also past dietary elements. And this tin be seen as true even if our experiences are indirectly driven by our genetic basis. In this newspaper, nosotros will review some current scientific research on how our experiences are able to modulate the structural organization of the brain and how a healthy lifestyle (regular physical activity, correct slumber hygiene, and healthy diet) appears to positively touch cognitive reserve.
1. Introduction
Numerous clinical and experimental studies demonstrated that many environmental factors may bear upon both the physiological functions of the fundamental nervous system (CNS) and its ability to counteract pathological changes. It has been demonstrated that experience shapes our neural circuits, making them more functional, keeping them "young." Experience is then the factor which induces our brain to exist more plastic. In other words, experience may increase neuroplasticity. The complex of molecular and cellular processes known as neuroplasticity represents the biological ground of the then called "cerebral reserves." The first to introduce the concept of "reserve" was Yaakov Stern who noticed a higher prevalence of Alzheimer's disease (Advert) in people with lower didactics. For Stern, the reserve is a mechanism, which may explain how, in the face of neurodegenerative changes that are similar in nature and extent, individuals vary considerably in the severity of cerebral crumbling and clinical dementia [one]. Clinical studies provide evidence that people with a high level of instruction accept a slower cerebral decline [2, three].
According to Stern, 2 types of cerebral reserves are recognized: brain reserve (BR) and cognitive reserve (CR). BR is based on the protective potential of anatomical features such equally encephalon size, neuronal density, and synaptic connectivity. This reserve is passive and is also defined as the corporeality of brain damage that can be sustained earlier reaching a threshold for clinical expression [1]. It besides explains differential susceptibility to functional impairment in the presence of pathology or neurological insult [4]. This concept arose by the observation that the prevalence of dementia is lower in individuals with larger brains [5–7]. In dissimilarity, CR posits the differences in cerebral processes as a function of lifetime intellectual activities and other environmental factors that explain the nonlinear relationship between the severity of patients' brain impairment and the correspondent clinical symptoms. The CR suggests that the brain actively copes with brain damage by using the preexisting cognitive processes or by enlisting compensatory mechanisms [1, 3]. Thus, CR represents a functional reserve because information technology is based on the efficiency of neural circuits [8]. CR is considered an "agile reserve" because the brain dynamically attempts to cope with brain damage past using preexisting cognitive processing networks or by enlisting compensatory networks [ane, 3]. It is important to emphasize that BR and CR are non mutually exclusive but are involved together, at unlike levels, in providing protection against brain impairment [9]. For this reason, it is possible to refer to the accumulated structural reserve (BR) and chapters for functional bounty (CR) using the new construct of "brain and cognitive reserve" (BCR) [ten]. In fact, whatsoever morphological change results in a modification of the functional properties of a circuit and vice versa, and whatsoever change in neuronal efficiency and functionality is based on morphological modifications. For example, factors associated with an increased CR, such equally cognitively stimulating experiences or a great deal of concrete activity, are associated with neurogenesis, increased levels of neurotrophic factors, and diminution of neuronal apoptosis [11]. Therefore, functional and anatomical factors collaborate in the construction of the cerebral reserves [12].
In clinical research, we can study the relation betwixt structural (BR) and functional (CR) changes past analyzing the grayness matter damage in AD patients (structural measure out) and then correlating it with a cognitive evaluation (functional mensurate) [13].
More straight measures of feel-due structural and functional changes are provided by experimental research on animal models. For example, BR measures are the changes at cellular and molecular levels [14], while direct CR measures are the performances in behavioral tasks, such as spatial tasks [8, 15]. The studies carried out by using enriched surroundings animal models enabled us to understand what kinds of experiences are necessary to trigger the phenomenon of brain plasticity and thus to increment cerebral reserves.
The purpose of the present work is to provide an up-to-date overview on the effects of the environmental factors on promoting neural plasticity in physiological and pathological conditions taking into business relationship both human being and brute studies.
2. Animal Studies
There is evidence showing that individuals with more than CR are those who have a high level of education, who maintain regular concrete activity, and who eat in a salubrious mode [xvi–19]. Despite such evidence, homo studies practice not allow us to determine whether one kind of feel determines the increase in cognitive reserve more than the other ones. Human research cannot separate the dissimilar variables that make upwardly feel because we cannot analyze them separately. The experimental research on animals may compensate for these shortcomings past forcing the stimulation of a specific experience or a combination of experiences, as occurs in enriched environment animal models. The animal models of environmental enrichment (EE) allow u.s. to obtain a straight, real, and tangible mensurate of which environmental factors are able to model neuronal circuits [viii].
EE represents an experimental model in which the fauna is exposed for a certain time period to a combination of experiences, such every bit an intense motor activity and sustained cerebral stimulation. This condition is ordinarily compared to the standard condition of regular laboratory housing [xx].
The majority of EE animal models concern rodents, but studies have also been carried out on nonhuman primates, birds, and fish [21].
At the get-go glance, it may seem strange that the EE in animals may be actually compared to cognitive, motor, social, and emotional experiences in humans. Although this correlation may seem incommunicable, exposure of animals to an enriched surroundings is actually similar to that which occurs in man lifestyle [8]. In fact, in humans, the development of reserves tin can exist influenced by several factors, such every bit educational level, physical activity, social integration, and emotional interest. In animal models, all these factors are provided by the environmental complexity and novelty the animals are exposed to. The repeated replacing of objects in the home cages creates a broad range of opportunities for enhanced cerebral stimulation, formation of efficient spatial maps, and heightened ability to detect novelty. Physical grooming is represented by foraging in large cages, exploration of new objects that are constantly introduced into the cages, and general motor activity related to the use of wheels. The social aspect that characterizes man relationships may be mimicked by rearing the animals in a group of conspecifics. In fact, if the animals are stimulated to live together in the same muzzle, a social bureaucracy emerges and a ascendant effigy arranges and controls the spaces of the cage and when to eat. Effigy i shows an example of the rearing in an enriched environs.
(a)
(b)
The first to introduce the experimental concept of enriched surroundings was Donald Hebb, although it was the famous American psychologist Marker Richard Rosenzweig who clarified the enriched environment every bit "a combination of circuitous inanimate and social stimulations" [22].
Thus, the implementation of a setting of EE is a quite complex process, in which motor activity, cerebral abilities, and social interaction should be taken into business relationship. Although recently information technology has been shown that as well concrete activity lonely is able to increase CR, most studies show that all these factors should be stimulated to increase brain plasticity [8].
An EE prototype is used with healthy animals to analyze neuroplastic functional and structural changes [23], with animals that present neurodegenerative lesions or transgenic mutations to analyze neuroprotective and therapeutic furnishings [10, 15, 24–27], and recently even with an beast model of psychiatric disorders, such as schizophrenia, to evaluate the ameliorative effects on behavioral symptoms [28–30].
In general, cognitive abilities in animals are evaluated by means of specific behavioral tasks such as Morris h2o maze (MWM) and radial arm maze (RAM) that analyze the different facets of spatial memory. In fact, the memory can be divided into at least 2 types, such as declarative and procedural. Declarative noesis refers to things that nosotros know that are accessible to conscious recollection ("knowing that"), while procedural material regards memories on how to practise something ("knowing how") and those that are seen every bit implicit and unconsciously learned [31]. The 2 types of memory have different and specific neural correlates. Declarative memory mainly involves the hippocampal structures, while procedural learning and memory rely more on the cerebellum and basal ganglia [32–34]. Majority results discussed in the next sessions come from MWM and RAM behavioral tasks.
ii.i. Functional and Structural Effects of EE
Many studies conducted on healthy animals show that rearing in an enriched surroundings has meaning functional and structural furnishings (Table 1, Figure 2).
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| EE refers to a circuitous stimulation of experiences. BDNF: brain-derived neurotrophic cistron; NGF: nerve growth cistron; ACTH: adrenocorticotropic hormone; Hard disk: huntington'southward disease; PD: parkinson'due south disease; AD: alzheimer'south disease; DA: dopamine. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
To evaluate the functional effects of EE on the performances in behavioral tasks, spatial tasks are analyzed. In particular, these tasks permit us to analyze the unlike facets of spatial cerebral function and so to evaluate the functioning of underlying neural circuits. For example, Leggio and coworkers compared the spatial performances in radial arm maze and in Morris water maze of healthy animals reared in an enriched environment for three months afterward the weaning with those of animals reared in standard weather condition [23]. In both spatial tasks, the animals reared in an enriched environment made fewer errors than the conspecifics reared in standard laboratory atmospheric condition and showed a precocious development of spatial cognitive mapping of the environs.
In EE structural effects, the changes at cellular level (such as neurogenesis, gliogenesis, angiogenesis, and synaptogenesis) and the alterations at molecular level (such equally changes in neurotransmitter and neurotrophin expression) are considered [15]. By studying synaptogenesis, Gelfo and coworkers evidenced as indices of improved neuronal circuitry the increased dendritic length and spine density shown past the frontal and parietal pyramidal neuron apical and basal arborizations of rats reared in EE [35]. Molecular effects that follow EE take been demonstrated by analyzing the neurotrophin levels in brain structures where neurotrophins are produced or transported. In item, multiple studies in rodent models showed that EE increases the expression of a brain-derived neurotrophic factor (BDNF) in the hippocampus that heavily supports the EE-induced improvement in learning and retentivity [36, 37]. Moreover, neurotrophin levels were found to be also increased in the cerebellum and other cerebral areas following EE [fourteen].
Functional and structural effects of EE are analyzed even from a transgenerational point of view. In particular, Caporali and coworkers [38] reared female rats in enriched weather and and then studied the motor behavior and the neurotrophin levels of their pups reared in standard weather. This written report demonstrates that positive maternal experiences were transgenerationally transmitted and influenced offspring phenotype at both behavioral and biochemical levels. In fact, the pups from enriched mothers caused circuitous motor behaviors before than the pups from mothers reared in standard atmospheric condition. Moreover, in the pups from enriched mothers, the cerebellar and striatal neurotrophin expression was significantly higher. Show presents that also paternal EE is able to transgenerationally alter affective behavioral and neuroendocrine phenotypes of the offspring [39–41]. These studies propose that the cerebral reserves could be even inherited.
2.ii. Neuroprotective Effects of EE
As nosotros mentioned, many studies showed that EE or even simply motor exercise induces neuroprotection against neurodegenerative diseases [xv, 24–26]. In a bright review on the EE models, Nithianantharajah and Hannan showed that motor exercise alone produces a positive consequence at behavioral, cellular, and molecular levels on some diseases that affect the cognitive-motor sphere, such as Huntington'due south disease (HD), Parkinson's disease (PD), and AD [15]. To give some examples, in Hard disk mouse models, it was demonstrated that bike-running exercise delays the onset of specific motor deficits [42–44] and diminished the damage in spatial retention and cognitive flexibility, also attenuating neuropathology [45]. Behavioral performance has been demonstrated to be improved by concrete training also in PD rodent models [46, 47], with neuroprotective furnishings on the regulation of neurochemical factors [48, 49]. Finally, in Ad, an intensive locomotor training increases the quality of performance in behavioral tasks concerning spatial learning and memory [50]. At cellular level, a decrease in beta-amyloid plaques occurs and, only in the instance of more complex stimulation, an increase in the levels of neurotrophic substances as synaptophysin was as well observed [51–53].
Examples coming from transgenic murine models, which provide the precious advantage to determine exactly when a structural alteration occurs, permit to evaluate when it is best to enrich the animals. For example, past means of transgenic Advert mice (Tg2576), Verret and coworkers showed that the EE effects are more than powerful if the animals are reared in an enriched environment before the germination of beta-amyloid plaques [54], that is, before their deleterious effects on brain office and retention processing become permanent.
Decreased levels of beta-amyloid plaque in response to EE have been highlighted also past Beauquis and coworkers who analyzed the astroglial changes in the hippocampus of transgenic animals [55]. In fact, growing prove shows that glial changes may precede neuronal alterations and behavioral impairment in the progression of Ad and that the modulation of these changes could be addressed every bit a potential therapeutic strategy [56–58]. In detail, Beauquis and coworkers evidenced that in enriched transgenic animals (APP mice), a decrement in levels of astrocytes was present, suggesting that glial alterations have an early onset in Advert pathogenesis and the exposure to an enriched surroundings is an appropriate strategy to contrary them.
Moreover, the confirmation that glial alterations play an important part in cognitive reserves comes from a recent report that investigated the functional and structural effects of intermittent EE (3 hours/twenty-four hour period for two months) on anile rats [58]. In fact, even at advanced ages, behavioral results showed that EE improved performances in a radial water maze job and structural information evidenced plastic changes in the hippocampal astrocytes suggesting that these neuroplastic alterations are involved in a coping machinery with age-related cognitive impairment.
Several authors wondered until which bespeak in life the enrichment has positive effects on cerebral function. Fuchs and coworkers assessed the impact of tardily housing condition (e.thousand., from the age of 18 months) on spatial learning and memory of anile rats (24 months) previously exposed or unexposed to EE during young adulthood (until eighteen months) [59]. The results showed that late EE was non required for spatial memory maintenance in anile rats previously housed in EE. In contrast, late EE mitigates spatial memory deficit in anile rats previously unexposed to EE. These outcomes propose that EE exposure up to middle age provides a reserve-like reward that supports an enduring preservation of spatial capabilities in old age [60, 61].
In improver to the transgenic animal models of EE, also the studies on lesioned animals contributed to highlighting the neuroprotective role of ecology stimulation. For example, it was establish that rats exposed to EE at weaning about 3 months earlier a cholinergic basal forebrain depletion (which mimics AD) recover some cerebral abilities such as spatial retentiveness and cognitive flexibility [62]. These improvements in the cognitive-motor domain were likewise accompanied past changes at the morphological level [26], demonstrating once once again the shut link between construction and part and, in this case, between CR and BR.
The chief neuroprotective effects of EE are shown in Tabular array ane.
3. Environmental Factors and Lifestyle in Man
Research on animal models provides an important insight into understanding the key role of environmental factors in promoting cerebral reserve. On the other paw, human studies showed that not but high-demand cerebral activities are able to improve cognitive skills and annul a physiological and pathological cognitive decline just even other environmental factors such as regular physical action and correct slumber hygiene tin substantially contribute to brain well-being.
three.1. Physical Activity (PA) and Neuroplasticity
In EE animal models, information technology has been shown that motor exercise has significant effects on neuroplasticity and counteracts a pathological cognitive decline [10, 15]. In humans, it seems necessary to distinguish betwixt physical activity (PA) and physical exercise (PE). In fact, PA is any movement of the body produced by skeletal muscles that results in free energy expenditure over the baseline levels, including all structured daily activities, such every bit housework and leisure activities. Conversely, PE is a structured and repetitive concrete activity, aimed at maintaining or improving one or more than components of physical fitness.
PA and PE are often related to health benefits in the prevention and in the treatment of many pathological conditions, such every bit metabolic diseases [63–65] also as diseases associated with compromised cognition and brain function [66]. Several studies exercise exist showing that the practice of regular and abiding PA reduces the risk of developing dementia [67].
PA increases blood flow, improves cerebrovascular health, and determines benefits of glucose and lipid metabolism carrying "food" to the brain. It has been showed that PA causes neural plasticity phenomena. For example, PA facilitates the release of neurotrophic factors like BDNF, stimulates neurogenesis phenomena, and determines structural changes such every bit the comeback of white thing integrity [68]. The brain changes are inevitably reflected in functional modifications. In this context, children with college levels of aerobic fitness showed greater brain volumes in grayness matter encephalon regions (structural changes) and the best performances in learning and memory tasks (functional changes) in comparing to sedentary children [69]. It is important to underlie that all the structural and functional changes are derived by an aerobic type of PA. Recently, it has been showed that only regular aerobic exercise is associated with larger size of the hippocampal regions [70]. Moreover, aerobic practice increases greyness and white matter volume in the prefrontal cortex [71] and increases the functioning of cardinal nodes in the executive control network [72, 73] (Figure 2).
three.ii. Slumber and Neuroplasticity
In the terminal decades, it has been shown that sleep is an essential characteristic of fauna and human brain plasticity, which involves both basic (due east.1000., [74]) and higher-lodge functions (e.g., [75]).
Sleep is an active, repetitive, and reversible behavior that is in the service of several unlike functions that occur all over the brain and the body [76, 77]: from repair and growth to learning or memory consolidation and up to restorative processes. This bones role of slumber is also indirectly substantiated by the fact that almost all the animal species, from fruit flies to the biggest mammals [78], share a behavioral state that tin be defined as "sleeplike." Thus, if sleep subserves all these aspects of fauna life, it would be seen as a crucial survival-directed drive, so that chronic or repeated sleep deprivation in rodents brings cellular and molecular changes in the encephalon [79] while in humans, it tin dramatically disrupt several high-order cognitive functions [75, eighty–83].
Different hypotheses take been suggested to securely explain the functions of sleep, and one of the well-accepted ideas is that slumber is linked to memory, learning, and neuroplasticity mechanisms [74] (Figure 2).
Several studies showed that slumber plays an important role in learning processes and retention consolidation [84, 85] although no directly relationships have been plant between different kinds of retentiveness and dissimilar sleep stages [86]. These studies clearly indicated that sleep deprivation tin can impair learning and different kinds of memory that can be divided into at least two types, such as declarative and procedural (every bit discussed to a higher place). Thanks to this distinction, a dual-process hypothesis has been proposed [87]: the effect of a sleep state on retention processes would exist task-dependent, with the procedural memory gaining from REM (rapid eye motion) slumber and declarative memory from NREM (nonrapid eye motility) sleep [88].
Only other data [89] have been interpreted as in line with the alternative indicate of view, that is, the hypothesis of a sequential processing of memories during slumber stages [90, 91] suggesting that memory formation would be prompted by NREM sleep (and particularly past its slow-moving ridge content, namely, stages 3 and 4) and then consolidated by REM sleep, indicating that for an efficient consolidation of both knowledge (declarative) and skills (procedural), the worst enemy is sleep loss or, at least, slumber fragmentation.
The nature of the link between slumber and synaptic plasticity is not fully understood: several different processes of synaptic reorganization would occur during slumber period, but their functional role needs to be antiseptic. In a very recent review [74], it has been discussed that consecration of plastic changes during wake can produce coherent and topographically specific local changes in EEG slow action in the subsequent slumber and that during sleep, synaptic plasticity would be restored.
Independently by the actual nature of the link between sleep and neuroplasticity, now, information technology is well known and accepted that a good quality of sleep allows an efficient and successful crumbling [92]. In fact, several recent studies have conspicuously indicated the relevance of sleep quantity and quality every bit a marking of general health, well-being, and adaptability in later life [93–95]. This literature can help in developing health programs devoted to the oldest aim of improving sleep hygiene in order to guarantee avoidance of disease, maintenance of high cognitive and physical function, and connected engagement with life.
4. Conclusions
Experimental enquiry strongly suggests that in guild to increment our cerebral reserves, nosotros have to follow a lifestyle that takes into business relationship many factors. Clinical studies provided show that individuals with more cerebral reserves are those who take a high level of education, who maintain regular physical activity, who swallow in a salubrious way, and then on. The EE animal models confirmed that the experience plays a primal role in increasing brain plasticity phenomena. Although nosotros are still far from identifying the bones ingredient responsible for increasing our brain plasticity and for counteracting neurodegenerative impairment, we can say with confidence that to deal with physiological and pathological situations, information technology is not only important to exist "genetically lucky" but too to maintain a lifestyle rich in experiences likewise including high levels of physical action and good slumber hygiene.
Ethical Approval
This article is based on the review of previous papers, and thus, it does not incorporate any studies with man participants or animals performed by any of the authors.
Conflicts of Involvement
The authors declare that they accept no conflict of interest.
Acknowledgment
The piece of work was supported by the University of Naples Parthenope "Ricerca locale" (Giuseppe Sorrentino and Laura Mandolesi) and "Ricerca Competitiva" (Laura Mandolesi).
Copyright
Copyright © 2017 Laura Mandolesi et al. This is an open admission article distributed under the Creative Eatables Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Source: https://www.hindawi.com/journals/np/2017/7219461/
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