Critical period
In imprinting and developmental biology, a critical period is a maturational stage in the lifespan of an organism during which the nervous system is especially sensitive to certain environmental stimuli. If, for some reason, the organism does not receive the appropriate stimulus during this "critical period" to learn a given skill or trait, it may be difficult, ultimately less successful, or even impossible, to develop certain associated functions later in life. Functions that are indispensable to an organism's survival, such as vision, are particularly likely to develop during critical periods. "Critical period" also relates to the ability to acquire one's first language. Researchers found that people who passed the "critical period" without having developed communication skills would not acquire their first language fluently.
Some researchers differentiate between 'strong critical periods' and 'weak critical periods' —defining 'weak critical periods' / 'sensitive periods' as more extended periods, after which learning is still possible. Other researchers consider these the same phenomenon.
For example, the critical period for the development of a human child's binocular vision is thought to be between three and eight months, with sensitivity to damage extending up to at least three years of age. Further critical periods have been identified for the development of hearing and the vestibular system.
Strong versus weak critical periods
Examples of strong critical periods include monocular deprivation, filial imprinting, monaural occlusion, and Prefrontal Synthesis acquisition. These traits cannot be acquired after the end of the critical period.Examples of weak critical periods include phoneme tuning, grammar processing, articulation control, vocabulary acquisition, music training, auditory processing, sport training, and many other traits that can be significantly improved by training at any age.
Critical period mechanisms
Critical period opening
Critical periods of plasticity occur in the prenatal brain and continue throughout childhood until adolescence and are very limited during adulthood. Two major factors influence the opening of critical periods: cellular events and sensory experience. Both need to coincide for the critical period to open properly. At the cellular level, critical periods are characterized by maturation of the inhibitory circuits. More precisely, factors such as brain-derived neurotrophic factor and orthodenticle homeobox 2 contribute to the maturation of a major class of inhibitory neurons: parvalbumin-positive interneurons. Prior to the onset of the critical period, modulation of this circuit is hampered by early factors such as polysialic acid. PSA acts, in part, by preventing Otx2 interaction with PV cells. Soon after the opening of the critical period, PSA levels decrease, allowing PV cell maturation by activating inhibitory GABAa receptors that facilitate inhibitory circuit remodeling. Artificially removing PSA, or experimentally manipulating inhibitory transmission can result in early opening of the critical period. While the timing of these molecular events seems to be partially explained by clock genes, experience is crucial as sensory deprivation experiments have been shown to interfere with the proper timing of critical periods.Activity-dependent competition
guides the idea of activity-dependent competition: if two neurons both have the potential to make a connection with a cell, the neuron that fires more will make the connection.Ocular dominance
This phenomenon of activity-dependent competition is especially seen in the formation of ocular dominance columns within the visual system. Early in development, most of the visual cortex is binocular, meaning it receives roughly equal input from both eyes. Normally, as development progresses, the visual cortex will segregate into monocular columns that receive input from only one eye. However, if one eye is patched, or otherwise prevented from receiving sensory input, the visual cortex will shift to favor representation of the uncovered eye. This demonstrates activity-dependent competition and Hebbian theory because inputs from the uncovered eye make and retain more connections than the patched eye.Axon growth
is another key part of plasticity and activity-dependent competition. Axon growth and branching has been shown to be inhibited when the neuron's electrical activity is suppressed below the level of an active neighbor. This shows that axonal growth dynamics are not independent but rather depend on the local circuits within which they are active.Microglia
inherently play a role in synaptic pruning during adolescence. As resident immune cells of the central nervous system, microglia's main role is phagocytosis and engulfment. Studies have found that during critical periods in the visual cortex, neural synapses become the target of microglial phagocytosis. Neurons who received less frequent input from retinal ganglion cells during early postnatal periods were more prone to be engulfed and pruned by microglia, as per monocular deprivation experiments. Similar results were found when manipulating G-coupled purinergic receptors on microglial processes. Blocking these receptors or performing a knockout experiment significantly lowered microglial interactions and synaptic pruning during the early visual cortex critical period. More recently, the expression of the complement component 4 gene has been found to significantly contribute to abnormally high levels of microglial synaptic pruning during early stages of development in the neurons and microglia of schizophrenics, suggesting a genomic connection between the immune system and critical periods.Spine motility
Dendritic spine motility is the altering of the dendritic morphology of a neuron, specifically the appearing and disappearing of the small protrusions known as spines. In early postnatal development, spine motility has been found to be at very high levels. Due to its most pronounced occurrence during postnatal days 11 through 15, spine motility is thought to have a role in neurogenesis. Motility levels significantly decrease before the start of the visual cortex critical period and monocular deprivation experiments show that motility levels steadily decrease until the critical period is over, hinting that motility might not be explicitly involved in this process. However, binocular deprivation before eye-opening resulted in a significant up-regulation of spine motility until the peak of the critical period, resulting in controversial findings regarding the role of dendritic spine motility.Excitatory-inhibitory balance
Another critical component of neuronal plasticity is the balance of excitatory and inhibitory inputs. Early in development, GABA, the major inhibitory neurotransmitter in the adult brain, exhibits an excitatory effect on its target neurons. However, due to changes in internal chloride levels due to the up-regulation of potassium chloride pumps, GABA then switches to inhibitory synaptic transmission. The maturation of the GABAergic inhibitory system helps to trigger the onset of critical periods. Strengthened GABAergic systems can induce an early critical period, while weaker GABAergic inputs can delay or even prevent plasticity. Inhibition also guides plasticity once the critical period has begun. For example, lateral inhibition is especially important in guiding columnar formation in the visual cortex. Hebbian theory provides insight on the importance of inhibition within neural networks: without inhibition, there would be more synchronous firing and therefore more connections, but with inhibition, fewer excitatory signals get through, allowing only the more salient connections to mature.Critical period closure
Perineuronal nets
Critical period closure has been shown to be modulated by the maturation of inhibitory circuits, mediated by the formation of perineuronal nets around inhibitory neurons. Perineuronal nets are structures in the extracellular matrix formed by chondroitin sulfate proteoglycans, hyaluronan, and link proteins. These structures envelop the soma of inhibitory neurons in the central nervous system, appearing with age to stabilize mature circuits. PNN development coincides with the closure of critical periods, and both PNN formation and critical period timing is delayed in dark-rearing. For example, PNN digestion by ABC chondroitinase in rats leads to a shift in ocular dominance upon monocular deprivation, which is normally restricted to its critical period much earlier in development.Additionally, PNNs are negatively charged, which is theorized to create a cation-rich environment around cells, potentially leading to an increased firing rate of inhibitory neurons, thereby allowing for increased inhibition after the formation of PNNs and helping to close the critical period. The role of PNNs in critical period closure is further supported by the finding that fast-spiking parvalbulmin-positive interneurons are often surrounded by PNNs.
Perineuronal nets have also been found to contain chemorepulsive factors, such as semaphorin3A, which restrict axon growth necessary for plasticity during critical periods. In all, these data suggest a role for PNNs in the maturation of CNS inhibition, the prevention of plastic axonal growth, and subsequently, critical period closure.
Myelin
Another mechanism that closes the critical period is myelination. Myelin sheaths are formed by oligodendrocytes in the CNS that wrap around segments of axons to increase their firing speed. Myelin is formed in the early stages of development and progresses in waves, with brain areas of later phylogenetic development having later myelination. The maturation of myelination in intracortical layers coincides with critical period closure in mice, which has led to further research on the role of myelination on critical period duration.Myelin is known to bind many different axonal growth inhibitors that prevent plasticity seen in critical periods. The Nogo receptor is expressed in myelin and binds to the axonal growth inhibitors Nogo and Myelin-associated glycoprotein , preventing axon growth in mature, myelinated neurons. Instead of affecting the timing of the critical period, mutations of the Nogo receptor prolong the critical period temporarily. A mutation of the Nogo receptor in mice was found to extend the critical period for monocular dominance from around 20–32 days to 45 or 120 days, suggesting a likely role of the myelin Nogo receptor in critical period closure.
Additionally, the effects of myelination are temporally limited, since myelination itself may have its own critical period and timing. Research has shown that social isolation of mice leads to reduced myelin thickness and poor working memory, but only during a juvenile critical period. In primates, isolation is correlated with abnormal changes in white matter potentially due to decreased myelination.
In all, myelin and its associated receptors bind several important axonal growth inhibitors which help close the critical period. The timing of this myelination, however, is dependent on the brain region and external factors such as the social environment.