What is neuroplasticity and how it works?

Highlights: 

• Neuroplasticity is an umbrella term uniting multiple mechanisms behind the brain changes during the life
• These changes are particularly regulated through glutamate, acetylcholine, dopamine, and epinephrine levels
• Neuroplasticity can be enhanced at any age through learning, brain training, interaction with an enriched environment, and cognitively loaded exercises

Introduction

The multiple mechanisms behind brain changes are united under the umbrella term neuroplasticity, which includes the brain’s ability to modify, adapt, and change its structure and function as a response to life experience. Though these processes are more pronounced in young children, this ability is also present in adults. The human brain can restore connections and create new ones, leading to better memory and cognitive skills. With sustained effort, even older adults can improve their cognitive state.

Dynamic brain

The term “neuroplasticity” was first used as early as 1948 by the “father of neuroscience” Santiago Ramón y Cajal, who described nonpathological changes in the structure of the adult brain (1). However, the first experimental research confirming that the human brain is indeed capable of life-long change started appearing only in the middle of the 20th century. In the 1970s, Eric Kandel established how the chemical signals changed the structure of connections between synapses and how these processes influenced the formation and consolidation of short-term and long-term memory (2). For this research, Kandel was awarded the Nobel Prize in Physiology and Medicine in 2000. 

Neuroplasticity encompasses not only morphological changes in brain areas but also changes in neuronal networks. This includes changes in neuronal connectivity, the generation of new neurons (neurogenesis) and also neurobiochemical changes. Scientists distinguish two main types of neuroplasticity (3):

• Structural neuroplasticity (or synaptic plasticity), which refers to changes in the strength of the connections between neurons. The term can include many processes, such as long-term changes in the number of neurotransmitter receptors, specialization of brain areas during development, and neurogenesis.

• Functional neuroplasticity, which refers to changes caused by learning and memorization.

Critical periods 

During childhood, the predominant type of neuroplasticity is structural, while in adult age our brain predominantly employs functional neuroplasticity mechanisms (4,5). The major changes connected with experiential learning occur early in life during limited periods (6), so-called critical periods (CP). After the CPs the brain stabilizes, which includes maturation of inhibitory networks and stabilization of interneurons – neurons connecting two brain regions. Though several types of interneurons remain stable with aging, a number of other types significantly decreases (7), subsequently influencing structural neuroplasticity. 

However, a growing body of evidence shows that CPs can be renewed later in life. For example, auditory CPs (or CPs critical for hearing development) typical for the early ages were observed in aging humans and rodents (7,8), suggesting that neuroplasticity can be regulated throughout the lifespan and peaking not only during developmental stages.

Neurogenesis

Another fascinating aspect of structural neuroplasticity is neurogenesis – the process of generating new neural cells. For many decades, it was thought that the neurons exist in a finite amount and slowly die with time. Still the topic of neurogenesis in adult humans remains controversial among researchers. It was shown that many adult organisms (including axolotl - a species of salamander (9), zebrafish (10), mice (11), and octopuses (12)) have a capacity for neurogenesis, but the results for adult humans were contradictory (13).

In the adult brain, neurogenesis supposedly occurs in two brain areas – the lateral subventricular zone (SVZ) and the subgranular zone (SGZ) in the dentate gyrus of the hippocampus (14). The hippocampus is known to be responsible for memory formation and consolidation, while the dentate gyrus is particularly connected with the formation of episodic memories. SGZ of the dentate gyrus is a particular region where granule cells (responsible for memory formation and learning) are produced from neural stem cells. SVZ is a brain region containing neural progenitor cells (cells, from which new neurons can be generated) located outside two large lateral ventricles.

The neurons formed in SVZ migrate majorly to the olfactory bulb, integrating into the olfactory neural circuitry (15). This type of neurogenesis is rudimentary in humans but is thought to contribute to the sense of smell (16). More attention and research efforts are pointed to neurogenesis in the SGZ, which is connected to memory and learning, as well as to protecting the brain from stress-induced attrition. Generated granule cells pass through several developmental stages characterized by specific protein markers (which can later be traced experimentally) before they can integrate into the hippocampal activity (17). After their integration, neurons can actively influence the functions of the hippocampus, including learning, memory, and motor performances. This type of neurogenesis helps to accommodate new experiences, increase resilience to stress and anxiety, and, presumably, prevent neurodegeneration (18).

As to levels of SGZ neurogenesis in human adults, some studies have shown an extremely low or non-existent number of novel neurons or progenitor neural cells and a rapid drop of neurogenesis levels with age (19,20). However, multiple studies observed the contrary – that neurogenesis is preserved in healthy human individuals up to 79 years of age (21,22). Moreno-Jimenez et al. observed not only persistent hippocampal neurogenesis in the healthy subjects but also its rapid decline in the patients with Alzheimer’s disease (23). And though the controversy persists, much of the existing data points towards the importance of neurogenesis (at a higher or lower rate) for the healthy functioning of the adult brain.

Molecular mechanisms behind neuroplasticity

As mentioned before, functional neuroplasticity is connected with memory and learning, and various neurotransmitters extensively regulate these processes. Probably the most important event for the occurrence of neural changes is NMDA (N-methyl D-aspartate) receptor activation (24). Its channel is blocked by a magnesium ion during normal activity, which dissociates after NMDA binding to glutamate. The opening of the NMDA receptor channel results in an increase in the intracellular level of calcium ions, which influences the AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors and thus modifies the strength of a given synapse. The level of intracellular calcium seems critical for the strengthening or weakening of synaptic connections. If the connections are strengthened, this process is called long-term potentiation, and if they are weakened, the opposite process is called long-term depression (25). These two processes present the key mechanisms of functional neuroplasticity.

Other neurotransmitters – such as dopamine, acetylcholine, and epinephrine – also influence the proper formation and strengthening of neural connections. Dopamine is a neurotransmitter regulating assertiveness, motivation, functioning of the immune and autonomic nervous system. Acetylcholine influences motor function, memory, motivation, and attention. Neuron activity is exerted by dopamine through the activation of D2-like receptors (family of dopamine receptors) and acetylcholine through nAChR (nicotinic acetylcholine) receptors (26,27). A disruption in dopamine or acetylcholine levels substantially influences learning and acquisition of motor skills (28,29). Age-related cognitive decline and attention deficit, as well as Parkinson’s disease (30) and various psychiatric disorders (31), were associated with a decrease in dopamine synthesis. Disruption of acetylcholine production in the brain was similarly observed in patients with Alzheimer’s disease (32). Alcohol and caffeine are known to deplete both dopamine and acetylcholine in the brain.

The important, albeit controversial, role is played by epinephrine and other stress hormones. Emotionally charged learning tasks cause the release of both epinephrine and corticosterone (cortisol in humans) are released during and immediately after stressful stimulation (33). The lack of these hormones impairs memory consolidation (34). However, stress hormone effects on memory consolidation show an inverted U-shaped dose-response effect as moderate doses of epinephrine or glucocorticoids enhance memory consolidation but lower or higher doses are less effective or may even impair memory consolidation (35,36). 

Ways to influence neuroplasticity

At the moment, multiple approaches to a healthy enhancement of neuroplasticity are known. First and foremost, an enriched (novel, attention-focusing, challenging) environment is crucial for promoting neuroplasticity, especially in adults (37,38). Such sort of enrichment can be reached in multiple ways, including simple ones like taking a new route every couple of days or using a non-dominant hand. Another effective strategy is learning a new subject (especially a complex one), such as a second language (39) or music (40,41), brain training (42), and sports (43). Developing neuroplasticity is also a necessary part of healthy aging, which helps sustain health and promote longevity by combating a decline in cognitive function (44).

Conclusions

 Neuroplasticity is the incredible ability of the human brain to develop during a whole lifetime. Many complex mechanisms are included in this process, but we were able to discuss only some of them in this article. However, the most important thing is that by employing learning, humans are able to live in a healthier and more fulfilled way and delay age-related cognitive decline. 

This article is the first part of the series. If you would like to know more about learning and its influence on neuroplasticity, please, read the article “Life-long learning keeps brain active”.

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