Neuroplasticity Automatic translate

Neuroplasticity is a fundamental property of the nervous system to alter its structure and functional organization in response to sensory experience, learning, or injury. This process is not limited to simply changing the efficiency of synaptic transmission but encompasses a wide range of modifications: from molecular rearrangements within individual neurons to large-scale reorganization of cortical maps. For a long time, neuroscience was dominated by the dogma of the static nature of the adult brain, but modern research confirms that plastic changes occur throughout ontogenesis, ensuring cognitive flexibility and the possibility of functional recovery.

Historical evolution of the concept

Concepts about the brain’s capacity for change have undergone a radical transformation over the past hundred years. In the early 20th century, Spanish neurohistologist Santiago Ramón y Cajal, who formulated the neural doctrine, postulated that neural pathways in the adult brain are fixed, finite, and immutable. According to this view, neurogenesis and large-scale reorganization were possible only in the embryonic and early postnatal periods. This paradigm hindered the development of rehabilitation medicine for decades, as it was believed that recovery from CNS damage was impossible.

A turning point came in the mid-20th century with the work of Donald Hebb. In 1949, he proposed a theoretical mechanism for synaptic plasticity, later dubbed "Hebb’s rule." The essence of the hypothesis was that if the axon of cell A is close enough to cell B to excite it and is constantly involved in its activation, then metabolic changes or growth processes occur in one or both cells that increase the effectiveness of stimulation. The phrase "neurons that fire together, wire together" became an axiom in neurophysiology.

In the 1960s and 1970s, David Hubel and Torsten Wiesel conducted a series of experiments on the visual cortex of kittens and monkeys, demonstrating the existence of critical periods of development. They showed that monocular deprivation (closing one eye) at an early age leads to an irreversible reduction in the ocular dominance columns responsible for the closed eye and an expansion of those for the open eye. This demonstrated the dependence of cortical structure formation on sensory input. Later, Michael Merzenich mapped the somatosensory cortex of monkeys and discovered that body maps can be reorganized even in adult animals when incoming signals change (for example, during finger amputation or training), definitively disproving the dogma of the immutability of the adult brain. Paul Bach-y-Rita, working on sensory substitution, demonstrated that the brain is capable of interpreting tactile signals from the back or tongue as visual information, paving the way for the creation of devices for the blind.

Molecular mechanisms of synaptic plasticity

At the microscopic level, neuroplasticity is based on changes in the efficiency of signal transmission between neurons — long-term potentiation (LTP) and long-term depression (LTD). These processes regulate the strength of synaptic connections, which is considered the physiological substrate of memory and learning.

LTP is a long-term enhancement of synaptic transmission that occurs after high-frequency stimulation. The mechanism of LTP induction in the hippocampus typically depends on the activation of NMDA receptors. At rest, these receptors are blocked by magnesium ions. During strong depolarization of the postsynaptic membrane (caused by AMPA receptors), the magnesium plug is knocked out, opening a channel for calcium ion entry. A sharp increase in intracellular calcium concentration activates calcium-calmodulin-dependent kinase II (CaMKII) and protein kinase C.

The early phase of LTP (lasting 1–3 hours) does not require the synthesis of new proteins and is mediated by the phosphorylation of existing AMPA receptors, which increases their conductance, as well as by the exocytosis of additional receptors from intracellular pools into the postsynaptic membrane. The late phase of LTP (lasting days to weeks) requires gene expression and protein synthesis. A signal is transmitted to the cell nucleus, where the transcription factor CREB (cAMP response element-binding protein) triggers the synthesis of proteins necessary for the growth of new synaptic contacts and stabilization of these changes.

LTD, on the other hand, is a process of weakening synaptic connections, which is necessary to remove irrelevant information and prevent network overexcitation. Low-frequency stimulation causes a moderate calcium influx, which activates protein phosphatases (e.g., calcineurin) rather than kinases. These enzymes dephosphorylate AMPA receptors and initiate their endocytosis (uptake into the cell), reducing synaptic sensitivity to glutamate. The balance between LTP and LTD ensures homeostasis of neural networks, preventing them from becoming epileptiformly active or completely silent.

Structural plasticity and remodeling

Functional changes are often accompanied by structural rearrangements. Structural plasticity involves physical changes in neuronal architecture: the growth and branching of dendrites, the formation of new dendritic spines, changes in the shape of synaptic contacts, and axonal sprouting.

Dendritic spines are tiny projections on dendrites that serve as the primary site of excitatory synapse formation. They are highly dynamic: they can appear, disappear, or change shape (from thin "filopodia" to stable "mushroom-shaped" spines) within minutes. The actin cytoskeleton within the spine plays a central role in this morphological flexibility. During learning, an increase in spine density is observed in the corresponding cortical areas. For example, in laboratory animals, when learning motor skills, new stable spines form in the motor cortex, which persist for a long time.

Axonal sprouting is observed as a compensatory mechanism following injury. If a primary nerve pathway is interrupted (for example, by stroke), surviving axons can produce lateral branches (collaterals) to innervate denervated areas. This process is regulated by a complex balance of growth factors (such as BDNF — brain-derived neurotrophic factor) and growth inhibitors (myelin proteins such as Nogo-A).

Neurogenesis in the adult brain

The possibility of new neurons forming in adults remained a subject of heated debate throughout the 20th century. Modern methods, including radiocarbon dating (assessing the incorporation of C-14 isotope, accumulated in the atmosphere during nuclear testing, into cellular DNA), have made it possible to obtain precise data.

In humans, neurogenesis has been reliably confirmed in the dentate gyrus of the hippocampus — a structure critical for the formation of episodic memory and spatial navigation. Research by Jonas Friesen’s group has shown that approximately 700 new neurons are formed daily in the adult hippocampus. This means that approximately 1.75% of the neuronal population in this region is renewed annually. New cells undergo proliferation, migration, and differentiation, integrating into existing neural networks. Young neurons exhibit increased excitability and plasticity, making them particularly important for pattern separation.

Unlike rodents, where active neurogenesis is also observed in the subventricular zone with cell migration to the olfactory bulb, in adult humans this pathway is virtually absent or does not lead to the formation of functional neurons in the olfactory bulb. This indicates species-specific differences in the mechanisms of plasticity. Factors that stimulate neurogenesis include aerobic exercise, an enriched environment, and learning, while chronic stress and aging suppress this process.

Critical and sensitive periods of development

Brain plasticity is not uniform throughout life. There are windows of time, called critical or sensitive periods, when neural networks are heightened in sensitivity to certain types of sensory experiences.

A classic example is the ocular dominance columns in the visual cortex (V1). At birth, the inputs from the left and right eyes in layer IV of the cortex overlap. During normal development, due to competitive interactions, they separate into distinct bands — columns — responding to each eye separately. If one eye is closed during the critical period (monocular deprivation), axons from the open eye invade the cortical territory of the closed eye. This leads to amblyopia — a decrease in vision in the deprived eye that cannot be corrected with glasses in adulthood, as the cortical representation is already improperly formed.

The mechanism that opens and closes critical periods is the maturation of inhibitory interneurons that secrete gamma-aminobutyric acid (GABA). Specifically, parvalbumin-positive interneurons form perineuronal nets — extracellular matrix structures that stabilize synapses and limit further plasticity, marking the end of the critical period. Pharmacological manipulation of the GABA system or destruction of perineuronal nets has been shown to artificially restore plasticity in adult animals, opening theoretical prospects for the treatment of amblyopia in adults.

Systemic reorganization and cortical maps

The brain has the capacity for large-scale topographic reorganization. The somatosensory and motor cortices are organized somatotopically: adjacent cortical areas control adjacent body parts (Penfield’s homunculus). This map is not rigid. When afferent input from a particular body part is lost (for example, during arm amputation), the corresponding cortical area does not die off, but is "captured" by input from neighboring body parts (for example, the face or stump).

This phenomenon underlies phantom sensations. When a person touches their face, activation of the "facial" cortex spreads to the adjacent, previously "hand" area, which is subjectively perceived as a touch on the missing hand. Similar processes occur during learning. In professional violinists, the representation of the fingers of the left hand in the somatosensory cortex is significantly greater than in people who do not practice music. This is an example of a functional adaptation that enables fine motor movements.

Maladaptive plasticity

Plasticity is not always positive. Maladaptive (pathological) plasticity is the cause of a number of neurological disorders. Phantom pain is considered the result of an error in cortical reorganization, when a misalignment between a motor command and the absence of a sensory response triggers a pain signal.

Another example is focal dystonia of musicians ("stage cramp"). Intense, stereotyped, and synchronous finger movements can lead to the fusion of their cortical representations. Instead of distinct, separate zones for each finger, a blurred map is formed, with neurons activated by the movement of any finger. This leads to a loss of individual control: attempting to bend one finger triggers the involuntary bending of the others. Treatment for such conditions often requires "retraining" the brain (sensorimotor retraining therapy) to restore differentiated maps.

Tinnitus (ringing in the ears) also has a central mechanism of origin. When hearing is lost at certain frequencies (for example, due to damage to the hair cells of the cochlea), neurons in the auditory cortex tuned to these frequencies lose the input signal. As a result of decreased lateral inhibition, they begin to exhibit spontaneous synchronous activity or respond to adjacent frequencies, which is perceived as a phantom sound.

The role of sleep in the regulation of plasticity

Sleep plays a critical role in memory consolidation and synaptic homeostasis. According to the synaptic homeostasis hypothesis (SHY), proposed by Giulio Tononi and Chiara Cirelli, during wakefulness, a widespread strengthening of synaptic weights (LTP) occurs as a result of learning and experience. This is energetically expensive and leads to synaptic saturation, reducing the signal-to-noise ratio.

During slow-wave sleep, global downscaling (a reduction in synaptic strength) occurs. Weak and insignificant connections formed during the day are eliminated, while strong connections are proportionally weakened but retain their relative structure. This process "reboots" the brain, restoring energy resources and freeing up space for new learning the following day. Molecular markers such as AMPA receptor phosphorylation confirm that after sleep, overall synaptic strength is reduced compared to before sleep.

Clinical application: rehabilitation and recovery

Understanding the mechanisms of neuroplasticity forms the basis of modern neurorehabilitation methods. One of the most evidence-based methods is CI (Constraint-Induced Movement Therapy), developed by Edward Taub for stroke patients.

After a stroke, patients often experience the phenomenon of "learned non-use." Initial paresis makes using the affected limb difficult and unsuccessful, leading to the formation of negative reinforcement. The patient compensates by using the healthy hand, which leads to a reduction in the cortical representation of the affected hand (secondary degeneration). CI therapy involves restricting movement of the healthy limb (for example, with a mitten) and intensively exercising the paretic hand for several hours daily. This forces the brain to utilize weakened neural pathways, stimulating cortical reorganization and expanding the control area of the affected limb.

Sensory substitution uses plasticity to compensate for lost senses. The TVSS (Tactile Vision Substitution System), developed by Paul Bach-y-Rita, converts video camera images into electrical impulses delivered to an array of electrodes on the tongue or back. After training, blind patients begin to perceive these tactile patterns as visual images in space (the cortex "visualizes" tactile signals), demonstrating the brain’s ability to repurpose sensory pathways.

Genetic and epigenetic regulation

The brain’s ability to change is not a universal constant for all people; it varies significantly depending on genetic profile. A key regulator here is the gene encoding brain-derived neurotrophic factor (BDNF). This protein is critical for neuronal survival, synapse growth, and the differentiation of new cells. The most studied variation of this gene is the single nucleotide polymorphism Val66Met, in which valine is replaced by methionine at position 66 of the amino acid sequence.

Carriers of the Met allele (approximately 20-30% of the Caucasian population) exhibit peculiarities in the intracellular transport of BDNF. They have reduced activity-dependent secretion of this protein, which may lead to a decrease in hippocampal volume and altered dynamics of cortical plasticity. Studies using transcranial magnetic stimulation show that the motor cortex of Met allele carriers is less responsive to artificially induced long-term potentiation (LTP) compared to Val allele carriers. However, this should not be interpreted as a definitive defect: reduced plasticity may provide greater stability of neural networks and resistance to memory loss, which, under certain conditions, confers an evolutionary advantage.

In addition to static genetics, plasticity is regulated by epigenetic mechanisms — chemical modifications of DNA and histones that do not alter the genetic code but influence gene activity. For long-term memory to be consolidated, chromatin (a complex of DNA and proteins) must be in an "open" state, accessible for reading. Histone acetylation weakens their binding to DNA, opening access to plasticity genes (such as Creb1 and Bdnf ). Histone deacetylases (HDACs), on the other hand, remove acetyl groups, compact chromatin, and "lock" genes, limiting plasticity. HDAC inhibitors have been shown to restore plasticity and cognitive function in experiments, even in neurodegenerative processes, returning the brain to a state of heightened susceptibility characteristic of youth.

Metaplasticity: homeostasis of synaptic change

If synapses could infinitely strengthen (LTP) with each activation, neural activity would quickly reach saturation, rendering the network unstable and epileptiform. Conversely, infinite weakening (LTD) would lead to complete network silencing. To prevent these extremes, a mechanism called metaplasticity — the "plasticity of plasticity" — exists. It is described by the Biknenstock-Cooper-Munro (BCM) theory, proposed in 1982.

BCM theory postulates the existence of a "sliding threshold" for synaptic modification. This threshold is not fixed, but depends on the activity history of the postsynaptic neuron. If a neuron was very active in the recent past, the threshold for LTP induction increases, and the likelihood of LTD increases. This makes it more difficult to further strengthen connections and facilitates their weakening, returning activity to normal. Conversely, if a neuron has been "silent" for a long time, the LTP threshold decreases, making synapses more sensitive to strengthening even with weak stimuli.

At the molecular level, this mechanism is realized through changes in the composition of NMDA receptors. During periods of low activity, the proportion of receptors containing the NR2B subunit increases in synapses. These receptors allow more calcium to pass through and remain open longer, facilitating the induction of LTP. This homeostatic mechanism explains why, after a period of sensory deprivation (for example, blindfolding), the visual cortex becomes hyperexcitable and plastic.

The influence of stress and physiology

Environmental factors and the body’s physiological state directly shape the architecture of neural networks. Chronic stress has a dichotomous effect on different brain structures. High levels of glucocorticoids (stress hormones) cause dendritic atrophy and spine loss in the hippocampus and premedial frontal cortex — areas responsible for memory and emotional control. This is the physiological basis for cognitive impairment in depression and anxiety disorders.

Meanwhile, in the amygdala — the center of fear and aggression — chronic stress causes the opposite effect: dendritic hypertrophy and the strengthening of synaptic connections. This leads to a vicious cycle: a strengthened amygdala sends out powerful alarm signals, while a weakened prefrontal cortex cannot effectively inhibit them.

Physical activity is a powerful positive modulator of neuroplasticity, but the mechanisms behind this effect are more complex than simply improving blood flow. Lactate (lactic acid), produced by muscles during intense exercise, plays a key role. Long considered a metabolic waste product, lactate can cross the blood-brain barrier and serve as a preferred energy source for neurons. Furthermore, lactate acts as a signaling molecule, stimulating Bdnf gene expression through activation of NMDA receptors and a subsequent cascade of reactions. Thus, muscle work directly translates into a molecular growth signal for hippocampal neurons.

Pharmacological and technological induction

In recent years, the field of targeted pharmacological stimulation of neuroplasticity has been rapidly developing. Of particular interest are psychoplastogens — a class of substances capable of inducing rapid structural changes in neurons. These include ketamine and classic psychedelics. Unlike traditional antidepressants (SSRIs), whose effects develop over weeks, psychoplastogens can induce the growth of dendritic spines in the prefrontal cortex within 24 hours of a single administration.

The mechanism of action of these substances is linked to the direct activation of the mTOR (mammalian target of rapamycin) signaling pathway, which triggers the synthesis of proteins necessary for the formation of new synapses. Ketamine, by blocking NMDA receptors on inhibitory interneurons, causes a surge in glutamate release, which paradoxically activates AMPA receptors and stimulates the release of BDNF. This opens up prospects for the treatment of treatment-resistant forms of depression, which is considered a consequence of a deficit in synaptic connections.

Non-invasive brain stimulation, such as transcranial direct current stimulation (tDCS), uses a weak direct current to alter cortical excitability. Anodal stimulation depolarizes neuronal membranes, increasing their firing rate and facilitating the induction of LTP (learning). Cathodal stimulation, on the other hand, hyperpolarizes membranes, promoting LTD and suppressing excessive activity. These methods allow for targeted modulation of plasticity in targeted areas, for example, to improve speech recovery after stroke.

Cognitive reserve and aging

With age, neuroplasticity declines, but the brain retains the ability to compensate. The concept of cognitive reserve, developed by Yakov Stern, explains why people with the same degree of brain damage (for example, Alzheimer’s disease) exhibit varying levels of cognitive impairment. Reserve is formed by two components: neural reserve (the efficiency and capacity of existing networks) and neural compensation (the ability to recruit alternative networks).

People with high cognitive reserves, accumulated through education, challenging professional activities, and bilingualism, are able to resist pathology longer. Their brains reorganize information processing pathways, using additional cortical areas to solve problems that, in younger people, are performed by more localized networks. For example, when performing memory tasks, older adults often engage both hemispheres (bilateralization), while younger people use only one. This is an example of functional plasticity, which acts as a protective mechanism against neurodegeneration.

Pathological plasticity in addictions

Neuroplasticity underlies the development of addictions. Drugs such as cocaine or opioids trigger a powerful release of dopamine in the nucleus accumbens, which initiates a cascade of plastic changes in the reward system. Chronic use leads to changes in the structure of dendritic spines and receptor density. Stable, "super-strong" synaptic connections are formed, encoding associations between substance use and context (place, people). These pathological memory traces are extremely persistent and can cause cravings (craving) even years after cessation of use, being activated by the return to a familiar environment. In this case, the therapeutic goal comes down to trying to "erase" or weaken these parasitic connections, inducing LTD in specific circuits.