Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
Asst. Prof. Monika Liguz-Lęcznar works at the Laboratory of Neuroplasticity, Nencki Institute of Experimental Biology, Polish Academy of Sciences, where she researches plastic changes in aging rodent brains and post-injury plasticity in animal brains after ischemic strokes.
Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
Prof. Małgorzata Kossut heads the Department of Molecular and Cellular Neurobiology at the Nencki Institute of Experimental Biology, Polish Academy of Sciences, and the Department of Neurocognitive Science at the University of Social Sciences and Humanities (SWPS). She is a corresponding member of the Polish Academy of Sciences and the Polish Academy of Arts and Sciences.
The aging of the brain and the nervous system as a whole is a complicated process that includes structural changes, modifications in the brain’s metabolism, neuronal reactivity, and synaptic activity, as well as decreased neurogenesis and angiogenesis. This all results in progressive impairment of a person’s motor, sensory, and cognitive functions.
Strategies and obstacles
Despite the often-cited theory that cognitive deficits reveal themselves as late as after 60 years of age, there are numerous experimental studies indicating that, in fact, such deficits can be observed as early as in the fourth decade of life. Cognitive functions, including memory, recollection, working memory, attention processes, and spatial orientation deteriorate with age. The working memory can be compared to a buffer where new information can be stored for a short time. The capacity of this buffer decreases with age; consequently, elderly people struggle to multi-task, are more susceptible to distracting stimuli, and find it more difficult to focus on a given task. It should be noted, however, that significant individual differences in terms of cognitive performance can be observed in both animals and humans, and such variation is much more pronounced in older individuals. Interestingly, there is a link between brain activity pattern and success in performing specific tasks: people who struggle with specific tasks experience more extensive brain activation at the same time, with additional areas of the brain being activated. This probably indicates that the brain makes an additional effort to cope with such difficulties in task completion by developing a new, hopefully more effective strategy.
The energy-demanding 2%
For the brain to function properly, it needs a sufficient supply of oxygen and energy. Although the organ accounts for just approximately 2% of the human body’s weight, it consumes as much as 20% of the body’s energy. The main energy substrate for nerve cells is glucose. Positron emission tomography (PET) tests have shown that glucose metabolism in specific brain areas decreases with age. This phenomenon is accompanied by mitochondrial dysfunction, loss of structural integrity of brain tissue, as well as a reduced number of synapses and cognitive impairment. Cerebral blood flow also decreases with age; this phenomenon primarily affects the cerebral cortex. All of these factors lead to reduced energy metabolism and a lower level of activity, contributing to the decline in cognitive skills.
The anatomical changes occurring in the aging brain are not homogeneous and vary between its specific areas. The changes may affect the density of neurons, their number and morphology, including the number of synapses, dendritic tree complexity, and the number of dendritic spines, which are the main location of excitatory synapses.
The most pronounced change is the actual shrinkage of the brain as it ages. Loss of tissue mass and volume as well as reduction of the cortical thickness is correlated with increasing volume of the cerebral ventricles. The grey and white matter are known to age differently. Grey matter (bodies and processes of nerve cells) ages gradually; a 0.2% annual reduction in brain volume can be observed as early as at 35 years of age. For those over 60, this reduction is even more significant and can be more than 0.5% annually. White matter, in turn, consists of nerve fibers that connect various areas in the brain. More pronounced changes in its volume can be observed after 65 years of age; by the time one reaches 80, the length of myelinated nerve fibers shrinks by 45%.
Recent studies have shown that, in most areas, tissue volume loss is not associated with massive neuronal death, although some degree of nerve cell loss does naturally accompany the aging process. The prefrontal cortex is particularly vulnerable to this type of change, which is unfortunate as it is responsible for executive functions. Apart from neurons, these changes affect other cells too. The number of glial cells involved in the formation of the myelin sheath, especially oligodendrocytes, also decreases. Scientists researching the nervous system aging processes currently agree that it is not so much the loss of nerve cells but the reduced number of connections between them that is responsible for the age-related decline in cognitive function. Some decrease in the number of synaptic connections, of greater or lesser intensity, can be observed in virtually all brain structures. In the hippocampus, the structure involved in spatial memory and learning, a significant decrease in synaptic connections can be observed with an almost unchanged number of neurons. This is associated with a range of phenomena including shrinkage of apical dendrites and a reduction in the number of dendritic spines. These phenomena can be observed in both humans and animals in a number of brain areas.
The main aging-associated functional change affects neuronal activity. Electroence- phalography (EEG) tests have shown that levels of electrical activity when performing memory tasks decrease with age. Slower gamma oscillations in the prefrontal cortex are also observed in older animals. Disturbances in these oscillations may contribute to the impairment of a range of processes that are associated with attention, perception, and decision-making in behavioral tasks.
The functioning of the nervous system is also negatively affected by the aging-related disturbance in neuronal calcium homeostasis. This results in greater intracellular concentration of calcium, which in turn leads to nerve cell degeneration and death. Moreover, the production of free radicals increases and inflammatory reactions intensify, which further impedes proper neuronal activity. Additionally, expression of neurotrophic factors is also reduced, such as brain-derived neurotrophic factor (BDNF), which affects synaptic plasticity, neurogenesis, and neuronal survival.
Synapses under attack
Apart from changes in the number of synapses, the aging process of the nervous system also involves alterations in their ultrastructure, resulting in functional changes within the aging neuronal circuits. In the cortex of older animals, a reduced surface of presynaptic terminals is observed, with lower numbers of mitochondria and neurotransmitter-storing synaptic vesicles. Lower numbers of neurotransmitter receptors are also found. This mainly concerns the NMDA glutamate receptor, important in the processes of learning and memorization. Synaptic ultrastructure modification leads to dysregulation of neurotransmission; this applies to both excitatory and inhibitory transmission as well as neuromodulators. Our research on the sensory cortex of aging mice has shown that the balance between the two major cortical neurotransmitters (excitatory glutamate and inhibitory GABA gamma-aminobutyric acid) is disturbed as a result of aging. This balance plays a key role in the neuronal excitability regulation as well as their plasticity.
Plasticity, understood as the capacity to undergo structural and functional changes induced by external stimuli, is a key mechanism of a properly-functioning brain. It allows for flexible development and learning; it also enables the repair and restoration of specific functions following damage. The brain is characterized by plasticity throughout its whole life, although the period of nervous system development that occurs in the first few years of life is exceptional. Plasticity requires the strengthening or weakening of existing synapses. Alternatively, new synaptic connections can be established. Aging nervous systems, in view of the modified structure and functions of a range of elements, need to cope with a more challenging task. We have shown that various forms of plasticity are influenced by the aging process in varying degrees. Our team at the Nencki Institute is studying the mechanisms of plastic change occurring in the sensory cortex of mice, in the area responsible for processing tactile information received by the long sensory whiskers (vibrissae) situated on the faces of rodents.
It is widely recognized that older brains learn more slowly. We have succeeded in identifying one of the causes of this phenomenon. In our experiments, mice are taught that a stroking of the vibrissae represents a danger signal. As a result of such conditioning, the cortical representation of the stimulated vibrissae increases during the training. The occurrence of this plastic change requires increased neuronal inhibition based on gamma-aminobutyric acid, the most common inhibitory neurotransmitter found in the cerebral cortex. In older animals, however, such training does not induce increased inhibition. We also did not observe plastic changes in their sensory cortex, unless the training time was doubled. This means that the GABAergic system also shows signs of aging and becomes less efficient with age. Whenever a rapid response is needed and GABAergic neuronal activity increased, which is necessary to produce a plastic change, the aging nervous system is not able to respond in an appropriate manner.
Other, non-learning types of plastic change in the cortex are slightly less impaired. We have found that the compensatory plasticity of the cerebral cortex is not affected by age. This is something that occurs when a sensory information source is removed. For example, the amputation of a finger leads to the removal of its representation in the brain cortex; its place is taken by the cortical representation of adjacent fingers. The same thing happens when a mouse’s vibrissae are removed. The mechanisms of this type of plastic change are associated with reduced inhibitory interaction between the cortical representations of the tactile receptors and are not impaired in old mice.
Therefore, since various kinds of plastic changes involve different mechanisms remodeling the neuronal circuits in the cortex, old age affects them in differing ways and with different dynamics. The results obtained by our team suggest that, despite the adverse effect of older age, the mechanisms allowing the establishment of a plastic change following sensory training do still exist in the aging cortex, they just operate less efficiently. This is an optimistic piece of news as it suggests that, with a bit more effort, an aging brain can indeed be forced to change.
Help in reserve
What, therefore, should be done to help the aging nervous system to work more efficiently and effectively? Recent results suggest that building up a “cognitive reserve” may be of the greatest importance. The more neurons are connected to create functional circuits and the greater the efficiency of such circuits, the better our brain works, the greater its adaptability, and the longer it is able to resist unfavorable factors, including aging. Comparative studies have shown that better educated individuals enjoy an efficient mind for longer. It is currently widely recognized that the cognitive reserve may be actively boosted through increased mental effort and exercise. Neural functioning is improved with better cerebral circulation. Active individuals who engage in intellectual challenges therefore have a better chance of maintaining prolonged efficiency of mind.
Further reading:Staying Sharp: Memory and Aging. The Dana Foundation.
Riddle D. (Ed.). Brain Aging Models, Methods, and Mechanisms. Frontiers in Neuroscience. CRC Press: 2007.
Samson R.D., Barnes C.A. (2013). Impact of Brain Circuits on cognition. Eur. J. Neurosci 37(12), 1903-1915.
Mora F. (2013). Successful brain aging: plasticity, environmental enrichment, and lifestyle. Dialogues Clin Neurosci. 15(1), 45-52.
© Academia 3 (43) 2014