Development and plasticity of the primary visual cortex

Abstract

Hubel and Wiesel began the modern study of development and plasticity of primary visual cortex (V1), discovering response properties of cortical neurons that distinguished them from their inputs and that were arranged in a functional architecture. Their findings revealed an early innate period of development and a later critical period of dramatic experience-dependent plasticity. Recent studies have used rodents to benefit from biochemistry and genetics. The roles of spontaneous neural activity and molecular signaling in innate, experience-independent development have been clarified, as have the later roles of visual experience. Plasticity produced by monocular visual deprivation (MD) has been dissected into stages governed by distinct signaling mechanisms, some of whose molecular players are known. Many crucial questions remain, but new tools for perturbing cortical cells and measuring plasticity at the level of changes in connections among identified neurons now exist. The future for the study of V1 to illuminate cortical development and plasticity is bright.

Figure 1. Functional Architecture of V1 in Cat and Mouse

Both cats and mice contain neurons in V1 that must receive and transform precise inputs from the LGNd. V1 in the adult cat (left) consists of neurons highly selective for specific orientations (denoted by the angle of lines) and dominated to varying degrees by the contralateral (red) or ipsilateral (green) eye, with many cells driven by both eyes (yellow). Both orientation and ocular dominance properties are organized into columns. Preferred orientation columns span all cortical layers, while ODCs are most pronounced in layer 4, where many cells are driven monocularly. Mouse V1 (right) does not have columnar organization of orientation or ocular dominance. However, neurons are still highly orientation selective and display a range of ocular dominance but with a bias toward the contralateral eye.

Figure 2. Timeline of the Development of Mouse V1

Retinotopic maps form well before eye opening. Orientation-selective and contralateral-eye-driven neurons are present at eye opening. During the subsequent days, neurons become more visually responsive and selective for orientation and respond increasingly well to ipsilateral-eye inputs. At the start of the critical period, individual neurons have mismatched eye-specific preferred orientations. During the critical period this binocular mismatch of orientations is reduced until the end of the critical period when responses reach adult levels.

Figure 3. Topographic Azimuth Maps in V1 Depend on EphrinA Signaling and Spontaneous Retinal Activity

(A) A diagram illustrating spatially restricted stimuli used to assay cortical azimuth maps. The color of each pixel on the cortical maps is determined by the relative response magnitude evoked by the bars along the three positions, with color component according to the diagram. (B) Wild-type mice with normal azimuth maps. (C) Combination knockouts that disrupt the majority of EphrinA signaling and early-stage spontaneous retinal activity demonstrate severely disrupted azimuth maps. (D–I) Neurons in LGNd were retrogradely labeled by injections of CTB-Alexa 488 (green) and CTB-Alexa 568 (red) 500 µm apart in V1 along the lateromedial axis (D). Note the separation between the green and red cells in (E) wild-type, and their complete lateromedial overlap in (F) combination knockouts. Dotted lines mark the border of LGNd. (G) Neurons in LGNd were also retrogradely labeled by injections in V1 along the elevation axis. Note the lack of overlap in (H) wild-type and (I) combination knockouts. Adapted from Cang et al. (2008).

Figure 4. Emergence of Binocular Inputs and the Matching of Preferred Orientations in Mice

Just after eye opening, individual neurons are selective for specific orientations. The majority of neurons at this point are largely dominated by contralateral-eye (red) inputs. During the next week, before the onset of the critical period, ipsilateral eye (green) inputs strengthen. At this developmental stage, the preferred orientations of individual cortical cells are mismatched through the two eyes. By the end of the critical period, preferred orientations are matched more precisely between the two eyes. Monocular deprivation of visual experience during the critical period permanently blocks the binocular matching of orientation preference. Collectively, normal visual experience during the critical period serves to match eye-specific inputs to individual cortical cells (from Wang et al., 2010). BV = binocular vision. MD = monocular deprivation.

Figure 5. Stages of Critical Period ODP in Mice

ODP induced by MD during the critical period in mice is characterized by three temporally and mechanistically distinct stages: (1) a Hebbian-dependent dramatic loss of response to the deprived eye (red) after 2–3 days of MD, (2) a Hebbian and homeostatic-dependent increase in open-eye (green) response together with a slight increase in deprived-eye response after 5 days of MD, and (3) a neurotrophic signaling-dependent return of responses to baseline levels after reopening the deprived eye and restoring binocular vision.

Figure 6. Possible Mechanisms for the Loss of Deprived-Eye Responses during the First Stage of Critical Period ODP

(A) The reduction of deprived-eye responses after 3 days of MD results solely from the selective anatomical pruning of deprived-eye connections, shown here as the disappearance of spines labeled in red. (B) The depression of deprived-eye responses results solely from the reduction in synaptic efficacy of deprived-eye connections by LTD-like mechanisms that last for days, shown here as the progressive removal of ionotropic receptors from spines labeled in red. (C) LTD causes the rapid removal of ionotropic receptors and then triggers slower mechanisms that prune the deprived-eye connections that had been rendered ineffective by the removal of receptors. (D) Pruning and LTD are independently triggered and act in parallel to reduce responses to the deprived eye. In all cases (A–D), nondeprived-eye connections are unchanged, shown here as spines labeled in green. Longitudinal imaging of structure coupled with temporally defined perturbations that selectively disrupt changes in synaptic efficacy or anatomy would resolve the primary mechanism involved in the first stage of ODP. For example, selectively blocking anatomical changes could inhibit (A or C), partially inhibit (D), or have no effect (B) on ODP.

Figure 7. Hypothesized Model for Structural and Functional Plasticity in V1

ODP induced by MD in cats and mice has little to no effect on eye-specific projections to the LGNd, but has dramatic effects on cortical function and structure. Diagrams in (A)–(C) depict changes occurring in visual centers in one hemisphere of the brain. Each circle represents a population of neurons. The color and intensity within each circle indicates the response level to the contralateral (red) or ipsilateral (green) eye with binocular responses shown as a mixture of red and green (yellow). Arrows represent information flow between centers of the visual pathway. The size of the arrowhead is proportional to the level of activity. The thickness of the arrow is proportional to the number of connections. Asterisks (*) indicate hypothesized changes that have not yet been experimentally measured. (A) In critical period cats, changes in cortical responses and connections occur faster in upper cortical layers than in cortical layer 4. Moreover, changes in deprived-eye responses and anatomy precede those of the nondeprived eye. Just 1 day of MD results in a reduction of deprived-eye responses and connections in upper cortical layers, but no change in layer 4. After 3 days of MD, deprived-eye responses are now reduced in layer 4 without accompanying structural changes. In addition, there is an increase in nondeprived-eye responses and connections in upper cortical layers, but not layer 4. MD for 6 days produces no further changes in upper cortical layers. However, in layer 4, deprived-eye connections are lost and now accompany the earlier reduction in deprived-eye responses. Additionally, nondeprived-eye responses in layer 4 get stronger, but without accompanying structural changes. Prolonged MD (3 weeks) results in further reduction of deprived-eye responses and connections in upper cortical layers. Nondeprived-eye responses are further increased in upper cortical layers and nondeprived-eye connections are increased in all cortical layers. Alternatively, reopening the deprived eye after brief MD for just 2 days restores responses to baseline levels in all cortical layers and restores connections in upper cortical layers, but is not sufficient to restore layer 4 connections. (B) In critical period mice, changes induced by MD occur slower than in critical period cats, but follow a similar progression. After 3 days of MD, deprived-eye responses and connections are reduced in upper cortical layers. In addition, deprived-eye responses are reduced in layer 4, although to a lesser extent and with little or no structural change. After 6 days of MD, there is an increase in nondeprived-eye responses and connections in upper cortical layers. Deprived-eye connections are also lost in layer 4 and now accompany the earlier reduction in deprived-eye responses. Non-deprived-eye responses in layer 4 also get stronger, but without accompanying structural changes. Prolonged MD (4 weeks), results in further reduction of deprived-eye responses and connections in upper cortical layers. Non-deprived-eye responses are further increased in upper cortical layers and connections are increased in all cortical layers. Alternatively, reopening the deprived eye after brief MD for just 2 days restores responses to baseline levels in all cortical layers and restores connections in upper cortical layers, but is not sufficient to restore layer 4 connections. (C) In adult mice, MD induces qualitatively and quantitatively different changes compared to critical period mice. After 3 days of MD, there are no changes in eye-specific responses or connections. After 7 days of MD, there is an increase in nondeprived-eye responses and connections in upper cortical layers. Nondeprived-eye responses also get stronger in layer 4, but without accompanying structural changes. There are no changes in deprived-eye responses or connections across all layers throughout this period of MD. After reopening the deprived eye, nondeprived-eye responses and connections are restored to baseline levels in all cortical layers. MD = monocular deprivation. BV = binocular vision.