Journal of Cytology & Tissue Biology Category: Clinical Type: Review Article
Structural, Metabolic Efficiency and Functional Monitoring of the Cerebellum and Basal Ganglia during Aging
- Entesar Ali Saber1, Randa Ahmed Ibrahim2, Soha A Abdel Wahab1, Seham Abd El-Raouf Abd El-Aleem3*
- 1 Department Of Histology And Cell Biology, Deraya University, Minia University, New Minia, Egypt
- 2 Department Of Histology And Cell Biology, Minia University, Minia, Egypt
- 3 Department Of Histology And Cell Biology, Minia University, New Minia, Egypt
*Corresponding Author:
Seham Abd El-Raouf Abd El-AleemDepartment Of Histology And Cell Biology, Minia University, New Minia, Egypt
Tel:+20 1002997270,
Email:sehamns@yahoo.com
Received Date: Dec 08, 2017 Accepted Date: Mar 12, 2018 Published Date: Mar 27, 2018
Abstract
Our understanding of the mechanisms responsible for decline of the human mental capabilities which accompany aging became one of the major concerns of the modern gerontology. The cerebellum is a vital organ playing a fundamental role in the postural control, equilibrium and motor coordination. Additionally, it is involved in cognitive functions such as forgetfulness, decreased ability to maintain focus and decreased problem-solving capability. Owing to its architectural and cellular simplicity, the cerebellum provides an excellent model for the study of the age-related changes at the cellular level. Moreover, the basal ganglia has received much attention over the last decades mainly because of their clinical relevance. It is now generally accepted that the basal ganglia are involved in a variety of non-motor functions, including those related to incentive and motivated behaviors. Our understanding of their cerebellum and the basal ganglia structure, organization, function and implication in diseases and age-related changes has increased equally. The most recent global analysis of the pathogenesis of aging process of the cerebellum and basal ganglia at the molecular level suggested that aging resulted in a gene expression profile indicative of an inflammatory response, oxidative stress, alteration in mitochondrial DNA, loss of homeostasis (dynamic equilibrium) in and out of the neuron and reduced neuro-tropic support in both brain regions. A strong association between the structural and functional abnormalities of the cerebellum and psychiatric disorders especially schizophrenia, depression, anorexia, anxiety, and autism was reported.
This review will discuss various aspects of these two inter-related structures, cerebellum and basal ganglia. Firstly, the structural and functional changes in them with aging. Secondarily, the factors affecting them causing age related disorders. Thirdly, the most common age-related disorders. Fourthly, the available diagnostic investigations and the prophylactic and therapeutic lines of treatments for age related disorders.
BACKGROUND
The last decade has witnessed' a significant turn in our understanding of the mechanisms responsible for decline of human mental capabilities which accompany aging. This became one of the major concerns of modern gerontology. However, it is admitted that the mechanisms of CNS aging remain far from being understood. Indeed, all aging humans will develop some degree of decline in cognitive capacity as time progresses [1].
Numerous theories of aging have been proposed [2]. The evolutionary theory of aging, oxidative damage theory and a non-adaptive programmed aging theory. Yet each of these by itself is inadequate to provide a global description of the causes of aging. For instance, the evolutionary theory, while successfully explaining how and why aging evolves, is uninformative about the specific mechanisms underlying aging. Likewise, while oxidative damage accumulation is a determinant of the rate of aging, it remains unclear (1) whether it is a primary cause of aging or a secondary event (2) why it occurs at such different rates in different species and (3) whether such differences reflect programmed or stochastic mechanisms. The theory of non-adaptive programmed aging proposes that underlying the traversal of adulthood in animals is the expression of a succession of age specific developmental genetic identities. Such a theory of programmed ageing can provide an explanatory link between the evolutionary and the oxidative damage theory. The capacity of such tripartite model to explain recent findings are explored, and some testable predictions which follow from it are set out [3].
Neurons are stable post-mitotic cells and hence apparently prone to develop age-related changes. The cerebellum is a vital organ that, besides playing a fundamental role in the postural control, equilibrium and motor coordination, is also involved in cognitive functions such as forgetfulness, decreased ability to maintain focus and decreased problem-solving capability. Owing to its architectural and cellular simplicity, the cerebellum provides an excellent model for the study of the age-related changes at the cellular level [4,5].
Additionally, the basal ganglia have received much attention during the last decades mainly because of their clinical relevance. It is now generally accepted that the basal ganglia are involved in a variety of non-motor functions, including those related to incentive and motivated behaviors. It is now clear that, in addition to afferents from the cerebral cortex, the Substantia Nigra Compacta (SNc) and thalamus, the basal ganglia receive many inputs from other sub-cortical structures, including the cerebellum, the locus coeruleus, the raphe nuclei, and the Pedunculo-Pontine Nucleus (PPN). The latter with its reciprocal connection with the stiatum, the GPi, and the SNr plays a key role in the control of posture and locomotion [6].
Our understanding of their structure, organization, function and implication in diseases and age-related changes has increased equally. Cognitive decline does not affect all individuals equally; clear associations exist between the rate and severity of cognitive decline and a variety of factors, including oxidative stress and free radical damage, chronic low-level inflammation, declining hormone levels, endothelial dysfunction, excess body weight, suboptimal nutrition, lifestyle, social network, other medical conditions, and various biomarkers. Fortunately, many of these factors are modifiable to a significant extent, and proactive lifestyle changes, cognitive training, and nutritional interventions have been shown to decrease the rate of intellectual decay and potentially reverse age-related cognitive decline [7]. Sierra & Kohanski reported that aging is the major risk factor for diseases such as macular degeneration, type 2 diabetes, atherosclerosis, cancer, pulmonary disease, Alzheimer’s Disease (AD), osteoporosis and arthritis [8].
THE CEREBELLUM ("LITTLE BRAIN")
The cerebellum is involved in the coordination of movement. The cerebellum is also partly responsible for motor learning, such as riding a bicycle. Unlike the cerebrum, this works entirely on a contralateral basis, the cerebellum works ipsilaterally. Some researchers suggested that the cerebellum is involved in the emotional domain; it acts as a mediator between the internal state and external environment for the unconscious and conscious levels of emotional process [4]. The cerebellum has been involved in a broad range of neuropsychological functions such as; Cognitive domains (i.e., attention), learning and memory, language and executive functioning [9]. Cavdar et al., provided a perspective on the role of the cerebellar cortex or nuclei upon their stimulation in eliciting or modifying a wide range of visceral responses (e.g. changes in blood pressure, heart rate, respiration, alteration in smooth muscle tone of the bladder & pupil and intestines) [10].
THE BASAL GANGLIA
The relationship between the cerebellum and basal ganglia

Structural changes of the cerebellum during aging
PATHOLOGICAL CHANGES IN THE CEREBELLAR CELLS PROMOTING AGE RELATED DISORDERS
Pathological changes in cerebellar Purkinje Cells (PCs) with age
Pathological changes in cerebellar cells in the granular cell layer in age related disorders
Pathological changes in cerebellar cells in the molecular cell layer in age related disorders
Pathological changes in cerebellar neuroglia cells in age related disorders
Remodelling of nerve cell connectivity in the aged cerebellum
Role of the mitochondria in the development of age related disorder
FACTORS THAT INFLUENCE AGING OF THE CEREBELLUM AND BASAL GANGLIA
Genomic approaches (gene influence)
Gender influence
Oxidative stress
Environmental factors
Loss of homeostasis
FACTORS AFFECTING HOMEOSTASIS IN AGE RELATED DISORDERS
Neurotransmitter (Nor Epinephrine (NE) & Acetylcholine (Ach) homeostasis
Level of the amino acid neurotransmitters produced by intrinsic neurons
Ca2+, K+ and Na+ homeostasis
Protein and lipid homeostasis
Neurotropic and growth factors homeostasis
Homeostasis across the Microvascular endothelia in aging
RESEARCH TECHNIQUES FOR DIAGNOSIS OF AGING PROCESS
Investigation of the molecular events associated with aging by lectin binding property for glycogen detection
High-Dimensional Single-Cell Mapping in CNS diseases
in situ hybridization
DNA microarray analysis
Fluorescent immune-histochemical (and immune-EM) techniques
Magnetic Resonance Imaging (MRI)
Morphometric techniques
A voxel-based morphometric analysis of age and sex-related changes in white matter volume in the normal aging brain
Diffusion tensor imaging of white matter
Stereological analysis
FUNCTIONAL ASSESSMENT OF THE AGING CEREBELLUM
Resting state functional connectivity
In vivo and ex vivo fluorescence microscopy
DISORDERS ASSOCIATE WITH AGING OF CEREBELLUM AND BASAL GANGLIA
Parkinson disease
Cerbello olivary degeneration of holmes
Schizophrenia
Autism spectrum disorders
Depression
Age-dependent decline in the food appetite (Anorexia)
PROPHYLACTIC AND THERAPEUTIC TREATMENTS OF AGE-RELATED DISORDER
Physical exercise
Diet
Drugs
Taurine administration: A single dose immediately before and after ozone exposure was found to block per oxidation effect (caused by ozone) in the striatum of old rats. So, this will lead to improvement short and long-term memory. The useful effects of taurine as an antioxidant have been attributed to its ability to stabilize biomembranes, to scavenge ROS, and to decrease the per oxidation of unsaturated membrane lipids [123]. In addition, taurine scavenges hypochlorous acid produced by the activation of granulocytes, forming taurine-chloramine, and thus may act as an indirect antioxidant [124].
Pentifylline and nicotinic acid: As an oral treatment of elderly human volunteers aged 52-70 years for two months with a combination of pentifylline (800 mg) and nicotinic acid (200 mg) improve the cerebral blood flow of the total brain, with a more pronounced improvement in the cerebellum and frontal cortex. These volunteers experienced an improvement in memory and general well-being [125]. Nicotinic acid (Niacin) is a water-soluble B-complex vitamin that induces a profound change in the plasma levels of various lipids and lipoproteins [126]. It could strongly increase the plasma concentration of high-density lipoprotein cholesterol. So, there is increasing evidence that nicotinic acid alone or in addition to LDL cholesterol-lowering drugs can reduce the progression of atherosclerosis and reduce the risk of cardiovascular events. Lukasova et al., and Zeman et al., stated that in addition, the identification of a nicotinic acid receptor expressed in adipocytes and immune cells helped to elucidate the mechanisms underlying the anti-atherosclerotic effect of the drug through direct and indirect effects on the vascular endothelium [127,128].
Melatonin: Melatonin hormone as antioxidant, along with its protective role could play a key role in aging and senescence. It is a regulator of the sleep/wake cycle and acts as an effective antioxidant and mitochondrial function protector. A reduction in the expression of melatonin receptors has been documented in the substantia nigra of Parkinson’s disease patients. The efficacy of melatonin for preventing neuronal cell death and for ameliorating PD symptoms has been demonstrated in animal models of PD employing neurotoxins. A small number of controlled trials indicate that melatonin is useful in treating disturbed sleep in PD [129].
Ayurveda herbal mixture: “Maharishi Amrit Kalash” (MAK): Electron microscopic observations of Vohra et al., revealed various degenerative changes in the mitochondria with age [130]. Treatment of the animals with the Ayurvedic herbal mixture "Maharishi Amrit Kalash" (MAK), 500 mg/kg body wt. daily for 2 months, significantly induced the activity of antioxidant enzymes, and reversed the pathological changes to a considerable extent. MAK increased the activity of GPx significantly only in the 32-month-old animals. This shows the specificity of the action of MAK.
Diethyl Hydroxylamine (DEHA): Sharma and Singh stated that rats fed a DEHA for 30, 60 and 90 days showed a significant reduction in lipid per oxidation levels and lipofuscin contents in the cerebellum, brain stem and spinal cord [131]. Moreover, DEHA is used as a free radical scavenger and antioxidants, metabolic rate and life expectancy increase in mice fed diethyl hydroxylamine DEHA [132].
Treatment with a cellular concentrate derived from an individual's own fat: Stem Genex online group reported that treatment with a cellular concentrate derived from an individual's own fat, known as the Stromal Vascular Fraction (SVF), has on the quality of life of people with PD [133]. They concluded that SVF contains components with "regenerative" properties, including stem cells that may can ameliorate specific disease conditions.
CONCLUSION
It could be concluded that aging of the brain leads to impairments in cognitive and motor skills, and is the major risk factor for several common neurological disorders such as depression, Parkinson disease, and Schizophrenia. As we have reviewed here normal cerebellar and basal ganglia aging is associated with subtle pathological and functional alterations, in specific neuronal circuits, as opposed to large-scale neuronal loss, atrophy of cells and synapses, cytoskeleton abnormalities and reactive astrocytes and microglia. The most recent global analysis of basal ganglia and cerebellar aging at the molecular level suggested that aging resulted in a gene expression profile indicative of an inflammatory response, oxidative stress and reduced neurotrophic support in both brain regions. The cerebellar cortex is a frequently used model in neuroscience research in general and particularly for the study of age changes in the CNS neurons including deep cerebellar nuclei and neurons of the basal ganglia [134,135]. Recent studies suggest that the cerebellum is an excellent model for the study of the age-related changes at the cellular level [136,137]. Recent studies provide a clue to void the unwanted age-related disorders, first caloric restriction which retards the aging process as it selectively attenuates the age associated induction of genes encoding inflammatory and stress response. Next physical exercise, nutritional supplementation with diets high in antioxidant capacity and intake of herbal mixture can prevent and/or reverse age-related degenerative changes.
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Citation: Saber EA, Ibrahim RA, Abdelwahab SA, Abd El-Aleem SA (2018) Structural, Metabolic Efficiency and Functional Monitoring of the Cerebellum and Basal Ganglia during Aging. J Cytol Tissue Biol 5: 017.
Copyright: © 2018 Entesar Ali Saber, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
