The pioneering work of Hubel, Wiesel, and their colleagues showed that early experience is a critical prerequisite for the emergence of normal structure and function in the visual cortex. However, despite four decades of research, many questions about the cellular and molecular mechanisms that underlie the critical period have remained unanswered. Hubel, Wiesel, and their disciples studied cats and monkeys, in which manipulations of cells and molecules are difficult. Recently, many investigators have begun to address these issues in mice because they are more amenable to mechanistic analysis.
Reorganization Depends on a Change in the Balance of Excitatory and Inhibitory Inputs
When one eye is closed or patched, the cortex no longer receives input from that eye. If the loss of input is prolonged for a few days before the eye is reopened, the cortex cannot be activated by input from the formerly deprived eye. Nor can the cells of the cortex be activated by direct stimulation of the corresponding optic nerve.
What converts this early loss of functional input into a permanent alteration of functional capability? One idea is that thalamic axons carrying information from the deprived eye lose their ability to activate cortical neurons. A decrease in efficacy of the thalamocortical synapse may contribute to this effect, but this is not the whole story. In cats and monkeys each thalamic axon carries input from only one eye (Figure 56–2). Because loss of responsiveness to the deprived eye occurs only if the other eye remains active, one might imagine that the earliest changes would occur where inputs from the two eyes converge on binocular cells. Local circuits connect the targets of the monocular thalamic inputs in layer IV to the binocular neurons in layers II/III and V. The first physiological changes following closure of one eye occur in layers II/III and V, not in layer IV. This implies that the loss of cortical responsiveness to the deprived eye results from a circuit alteration rather than from a simple loss of input.
What changes in cell function account for these changes in circuitry? At least three have been proposed. First, excitatory synapses within the primary visual cortex may decrease in strength, perhaps by undergoing long-term depression (LTD) (see Chapter 66). In fact, direct recording from cortical neurons shows that LTD does occur soon after eye closure. Second, inhibitory synapses may become stronger, leading to a net decrease in the level of excitation of cortical neurons by inputs from the closed eye. Third, an increase in inhibition within the cortex may alter network properties in a more subtle way, such as tuning the circuit to favor LTD.
The involvement of inhibition has been demonstrated by studies in the binocular region of mouse visual cortex. In mice, as in cats and monkeys, closure of the contralateral eye during the critical period for ocular dominance markedly shifts the preference of binocular neurons to inputs from the ipsilateral eye (Figure 56–9). Closure before or after the time of this normal critical period, however, fails to alter the preference of the neurons. Physiological studies have shown that monocular deprivation potentiates inhibitory feedback onto the neurons that the deprived eye normally excites. Moreover, the critical period in which monocular deprivation elicits changes in preference can be advanced using a genetic method to enhance gamma-aminobutyric acid (GABA) signaling (Figure 56–10). Conversely, the period in which monocular deprivation enhances the preference for ipsilateral eye input can be delayed by delaying GABA signaling (Figure 56–10). Thus a balance of intracortical excitation and inhibition is required for reorganization during this critical period.
A critical period for ocular dominance plasticity is evident in mice.
(Adapted, with permission, from Hensch et al. 2005.)
A. The visual cortex in mice contains a small region that receives thalamic (LGN) inputs from both eyes. In this binocular region most neurons are responsive to contralateral eye input, fewer respond to binocular inputs, and very few respond to ipsilateral eye input only.
B. When the contralateral eye has been closed during the normal critical period and then reopened, inputs from that eye are underrepresented and many more neurons respond to binocular or ipsilateral eye input. Eye closure before or after the time of the normal critical period does not elicit the same shift in responsiveness.
The timing of the critical period for ocular dominance plasticity in mice is sensitive to the level of GABAergic neurotransmission.
Altering the status of GABA (γ-aminobutyric acid) synthesis and signaling shifts the period in which monocular deprivation can change the response properties of neurons in the visual cortex. Enhancing GABA signaling, through administration of benzodiazepines, shifts the critical period for monocular deprivation to an earlier developmental time. In contrast, delaying GABA signaling, by reducing GABA synthesis genetically and then administering benzodiazepines at a later time, shifts the critical period for monocular deprivation to a later developmental time. (Adapted, with permission, from Hensch et al. 1998.)
What explains the change in responsiveness? After one eye is closed responsiveness to the open eye increases. This increase involves enhanced efficacy of synaptic transmission, a process resembling long-term potentiation (see Chapters 66 and 67). Inputs firing together with the majority of their neighbors become stronger, whereas inputs that are improperly matched to the majority pattern become weaker. This mechanism of reorganization conforms to Hebb's theory.
Postsynaptic Structures Are Rearranged During the Critical Period
What are the structural correlates of the physiological changes that result in altered responsiveness of the visual cortex to input from the closed and open eyes? Particular attention has been paid to dendritic spines as potential sites of plasticity.
Spines are small protrusions from the dendrites of many cortical neurons on which excitatory synapses form. They are dynamic structures, and their appearance and loss are thought to reflect the formation and elimination of synapses. Spine motility is especially marked during early postnatal development, and increases in spine dynamics and number have been associated with changes in behavior.
Striking alterations in the motility and number of dendritic spines on neurons in the mouse visual cortex are observed following closure of one eye. Two days after eye closure in young mice the motility and turnover of dendritic spines on neurons in the visual cortex increases, suggesting that synaptic connections are beginning to rearrange (Figure 56–11). A few days later the number of spines begins to change—the number of spines on the apical dendrites of pyramidal neurons initially decreases but after longer periods of deprivation increases again.
The motility of dendritic spines in the mouse visual cortex changes after one eye is closed.
The dendrites of pyramidal neurons in the visual cortex have many spines, the density of which remains comparatively constant under normal conditions. Closure of one eye (contralateral in this example) during the critical period for binocular development enhances the motility of dendritic spines and over time results in an increase in the proportion of spines that receive synaptic input from the open eye. Similar changes in spine motility are not observed if the eye is closed after the critical period. (Reproduced, with permission, from Oray et al. 2004.)
These alterations in spine motility and number can be correlated with three known features of the critical period. First, rather than occurring in layer IV, the changes occur primarily in superficial and deep layers of the cortex, where binocular cells lie. Second, they occur only in the portion of the visual cortex that normally receives binocular input. Third, they fail to occur following eye closure in adult mice (Figure 56–11).
Together these results support a model that links spine dynamics with critical period plasticity. According to this model, spine motility increases before physiological changes in responsiveness can be recorded. This condition may result from the imbalance of inputs to binocular neurons from the open and closed eyes, and it may reflect the first stages in synaptic rearrangement. In turn, the loss of spines, and presumably of synapses, corresponds in time and space to the loss of input from the closed eye and may provide a structural basis for the permanence of this loss. The later growth of new spines occurs as or after responsiveness to the open eye increases, and may underlie the adaptive rearrangement that permits the cortex to make the best use of the input available to it.
Thalamic Inputs Are Also Remodeled
How are local changes in spines related to the large-scale structural changes in ocular dominance columns shown in Figure 56–4? When developing axons from the lateral geniculate nucleus first reach the cortex, the terminal endings of several neurons overlap extensively. Each fiber extends a few branches over an area of the visual cortex that spans several future ocular dominance columns. As the cortex matures, axons retract some branches, expand others, and even form new branches (Figure 56–12A).
The branching of thalamocortical fibers in the visual cortex of kittens changes after the closure of an eye.
(Adapted, with permission, from Antonini and Stryker 1993.)
A. During normal postnatal development the axons of lateral geniculate nucleus cells branch widely in the visual cortex. The branching eventually becomes confined to a small region.
B. After one eye is closed the terminal arbors of neurons in the pathway from that eye are dramatically smaller compared to those of the open eye.
With time each geniculate neuron becomes connected almost exclusively to a group of neighboring cortical neurons within a single column. The arbors become segregated into columns through the pruning or retraction of certain axons and the sprouting of others. This dual process of axon retraction and sprouting occurs widely throughout the nervous system during development.
What happens after one eye is closed? Axons from a closed eye are at a disadvantage and a greater than normal proportion retract. At the same time, axons from the open eye sprout new terminals at sites vacated by fibers that would otherwise convey input from the closed eye (Figure 56-12B). If an animal is deprived of the use of one eye early during the critical period of axonal segregation, the normal processes of axon retraction and outgrowth are perturbed. In contrast, if an animal is deprived of the use of one eye only after the ocular dominance columns are almost fully segregated, axons conveying input from the open eye actually sprout collaterals in regions of the cortex that they had vacated earlier (see Figure 56–6).
Initially it was believed that rearrangements of thalamocortical axons in monocularly deprived animals caused the changes in cortical responsiveness to the open and closed eyes. We now know, through electrophysiological recording and assays of spine dynamics described above, that physiological changes and synaptic alterations precede these large-scale axonal rearrangements. So rather than causing the physiological changes, axonal remodeling may contribute to making these changes enduring and irreversible. The question then becomes: How do alterations in synaptic structure and function within the cortex lead to alterations in the input?
One idea is that activity regulates the secretion of neurotrophic factors by cortical neurons. Such factors may then regulate survival of some neurons at the expense of others (see Chapter 53) or promote the expansion of some axonal arbors at the expense of others. One such factor, brain-derived neurotrophic factor (BDNF), is indeed synthesized and secreted by cortical neurons. Administering excess BDNF, or interfering with its receptor trkB, modifies the formation of ocular dominance columns. Nevertheless, interpreting the actions of these trophic factors is not straightforward. BDNF and trkB signaling affect the cortex in many ways, including enhancing the growth of thalamocortical axons. BDNF can also speed the maturation of inhibitory circuits, which, as noted above, can influence plasticity. It remains unclear whether BDNF is a specific catalyst of the competition that preferentially promotes expansion of some arbors.
Synaptic Stabilization Contributes to Closing the Critical Period
A hallmark of critical periods is that the time interval in which experience affects the development of neural circuits is limited. What determines the timing of this remarkable biological response? To answer this question we must ask what opens the critical period and what closes it.
Opening of critical periods could result from maturation of systems required for plasticity. As we have mentioned, genetic studies indicate that maturation of inhibitory circuits in the visual cortex is required for initiation of the critical period for binocular development. Likewise, synapses that are modified by competitive interactions between the eyes, or by synchronous activity, may not undergo long-term potentiation or depression until they reach a sufficient level of maturity.
The factors that terminate the critical period have been studied in more detail. Since synapses and circuits are labile during critical periods, an obvious idea is that stabilizing factors bring this period of heightened plasticity to a close. The cellular and molecular landscape of the cortex changes in many ways as the brain matures, and several of these alterations may play roles. One parameter is the state of myelination of axons, which occurs around the time the critical period closes. Formation of myelin creates physical barriers to sprouting and axonal growth. Moreover, as discussed in detail in Chapter 57, myelin contains factors such as Nogo and myelin-associated glycoprotein that actively inhibit growth of axons. In mutant mice lacking Nogo or one of its receptors, NogoR, the critical period remains open into adulthood, suggesting that the appearance of these receptors normally contributes to closing the critical period (Figure 56–13).
The critical period for monocular deprivation is extended in mice lacking Nogo signaling.
The drawings show arborization patterns of thalamocortical axons carrying signals from contralateral and ipsilateral eyes to the binocular zone in visual cortex. Monocular deprivation during the critical period elicits a shift in ocular preference in neurons in the bi-nocular zone in both wild type mice and mice mutant for Nogo or the Nogo receptor. After the normal critical period (at 45 days) monocular deprivation continues to elicit a marked shift in axonal input and ocular preference in mice mutant for Nogo-A or the Nogo receptor but not in wild type mice. The plot shows that elimination of Nogo signaling prevents closure of the critical period. (Adapted, with permission, from McGee et al. 2005.)
Another possible agent of closure is the perineuronal net, a web of glycosaminoglycans that wraps certain classes of inhibitory neurons. These nets form around the time that the critical period closes. Infusion of the enzyme chondroitinase, which digests perineuronal nets, maintains plasticity. Thus critical periods may close once molecular barriers to synaptic growth and rearrangement come into play.
Why should there be an end to critical periods? Would it not be advantageous for the brain to maintain its ability to remodel into adulthood? Perhaps not—the ability of our brain to adapt to variations in sensory input, to gradual physical growth (eg, increases in the distance between the eyes affecting binocular correspondence), and to various congenital disorders is a valuable asset. At an extreme, if one eye is lost it is advantageous to devote all available cortical real estate to the remaining eye. Conversely, one would not want wholesale reorganization, possibly accompanied by loss of skills and memories, if vision through one eye were lost temporarily in adulthood due to disease or injury. So enhancing plasticity during a critical period may represent an adaptive compromise between flexibility and stability.