Ординатура / Офтальмология / Английские материалы / Eye, Retina, and Visual System of the Mouse_Chalupa, Williams_2008

blocking BDNF expression in the retina during this window of enhanced expression by means of antisense oligonucleotides counteracts the precocious development of retinal acuity in EE animals (figure 37.4C1 and C2; Landi et al., 2007b). EE, acting through BDNF, also has a strong effect on the developmental segregation of RGC dendrites into the ON and OFF sublaminae, crucial for the emergence of the ON and OFF pathways: in EE rats, RGC dendrite segregation is accelerated and the effects of DR on this process are prevented. Blocking retinal BDNF by means of antisense oligonucleotides blocks EE effects (Landi et al., 2007b).

Since visual development is strongly affected by manipulations occurring before eye opening and in the absence of visual input, provided that adequate levels of critical molecular factors are available to the developing circuitries, then, pushing the reasoning to the extreme, it should also be possible to manipulate the system during very early stages of maturation, in the prenatal life.

Maternal influence on offspring development occurs not only in the form of maternal care provided to pups during the first postnatal weeks but also in the form of supplying of nutrients, hormones, and respiratory gases to the fetus during pregnancy, through placental exchanges (for a review, see Anthony et al., 1995). The extent to which different environmental conditions experienced by the mother affect fetal development is still debated. Most experimental evidence is concerned with the deleterious effects of prenatal stress on fetal development, which include delayed somatic growth (Barlow et al., 1978, Benesova and Pavlik, 1989), delayed motor development (Gramsbergen and Mulder, 1998), and cognitive and behavioral abnormalities (Shiota and Kayamura, 1989; Schneider, 1992; Poltyrev et al., 1996; Lordi et al., 1997; Weinstock, 1997; Szuran et al., 2000; Kofman, 2002), which also occur in humans (Kofman, 2002; Mulder et al. 2002). Some of these effects on offspring development can be rescued by putting stressed mother and the pups into an EE just after delivery (Koo et al., 2003). Very little is known, on the other hand, regarding the possible beneficial effects on embryonic development that might be derived from maternal exposure to increased social and sensorimotor activities. Recent data show that the environment has a strong influence on the developing visual system during fetal life. Maternal EE extended for the entirety of the pregnancy results in a marked acceleration of retinal anatomical development in the rat embryos, with faster dynamics of programmed cell death in RGCs (Sale et al., 2007a). These effects are under the control of IGF-I: its levels, higher in EE pregnant rats and in their milk, are increased as well in the retina of embryos. Neutralization of IGF-I abolishes the action of maternal enrichment on retinal development, and chronic IGF-I injection given to non-EE dams mimics the effects of EE in the fetuses (Sale et al., 2007a).

Taken together, the results of various studies point to at least three distinct temporal phases during pup development that are controlled by the richness of the environment, through different mechanisms (figure 37.5 and color plate 30). In the first phase, maternal enrichment during pregnancy may affect the expression of factors such as IGF-I in the offspring, determining a faster development. An example is the increased IGF-I expression in the RGC layer, which results in an accelerated completion of the process of natural RGC death.

In the second phase, enhanced maternal care levels in EE rats trigger a precocious maturation of retinal acuity and visual cortical functions in the offspring, providing the developing subject with a robust tactile stimulation that could be responsible for the higher levels of IGF-I and BDNF in both the RGC layer and the visual cortex. Precocious expression of BDNF then leads to a precocious development of intracortical inhibition (Huang et al., 1999); in the retina, the precocious increase in BDNF in EE pups is necessary for the accelerated retinal development caused by EE (Landi et al., 2007b).

Finally, in the third phase, when pups begin to actively explore their surroundings, the complex sensorimotor stimulation provided by EE may directly influence their visual system development through IGF-I and possibly BDNF, and the maturation of perineural nets and intracortical inhibition, further accelerating the maturation of visual acuity, determining a faster closure of the critical period for OD plasticity, and preventing DR effects.

The changes documented for these three phases occur sequentially, but it is conceivable they are causally linked. In other words, each phase might act as a trigger for the successive ones. An example is the triggering effect of exposure to EE up to P10 on retinal acuity development (Landi et al., 2007b). It may also be possible that acceleration of developmental CRE-mediated gene expression in the visual cortex might be triggered by the early increase in BDNF expression, although a direct effect of pup exploratory activity is also likely, given the well-known effects of EE exposure on the CREB pathway and on other plasticity genes impinging on it (Molteni et al., 2002).

The effects of EE on visual cortical plasticity are not limited to the developmental period but seem to be present in the adult as well. Recent data show that exposing adult rats to EE strongly increases visual cortical plasticity to the point that it favors recovery from visual pathologies, such as amblyopia. Amblyopia is characterized by a loss of visual acuity in the eye deprived during the critical period. In all species tested so far, recovery from amblyopia is very limited in the adult because of the decline in visual cortical plasticity that occurs with critical period closure. EE control on adult visual cortical plasticity is achieved by modulating critical period determinants such as the intracortical inhibitory

I) Prenatal maternal influence (embryonic life)

Placental exchanges

Possible factors: IGF-I

Observed changes: increased IGF-I levels in the RGC layer Accelerated dynamics of natural RGCs’ death

Figure 37.5 Model of environmental enrichment effects on visual system development and plasticity. Shown is an interpretive framework for understanding the data on EE influence on the developing visual system. The effects elicited by EE on visual system development and plasticity are due not only to changes in the levels of sensory visual stimulation but also to very early factors activated even in the absence of vision. The available data support a model in which three distinct temporal phases during pup development are differently controlled by the richness of the environ-

system, extracellular matrix components, and BDNF (Sale et al., 2007b).

Conclusion

We began this chapter with the statement that each individual is the result of interactions between genes and the environment. Given the nature of the stimulation provided by EE, we think it unlikely that its effects are limited to visual system development. Rather, we think that EE effects on developmental visual cortical plasticity are indicative of the profound control exerted by the environment on sensory systems and more generally on brain development, a control that up to now has been underestimated.

Among the most surprising results are that environmental conditions start affecting neural circuit development during intrauterine life and that, even if restricted to short time windows in development, they set in motion, through specific factors, events that lead to changes in the maturational

ment: a prenatal phase in which the mother mediates the influence of the environment through placental exchanges with the fetus, an early postnatal phase in which higher levels of maternal care in EE stimulate the expression of experience-dependent factors in the visual system, and a third (and final) phase in which the autonomous interaction of the developing pup with the enriched environment further promotes the maturation of visual functions (see the text for details). See color plate 30.

time course of neural responses that take place weeks later (years later in human terms). This is strongly reminiscent of the longlasting effects of level of maternal care on stress responses in offspring. Maternal care levels appear to be one of the crucial mediators of EE effects on visual system development.

It is good to know that while we are cuddling our infants, in addition to building a love bond we may be contributing to their visual system development.

acknowledgment Work was supported by MIUR COFIN.

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The response properties of neurons in the visual cortex can be persistently modified following changes in the visual environment. Such modifications reflect changes in synaptic transmission that shape neuronal circuits and presumably store information. A leading model to study experiencedependent plasticity is the deprivation-induced ocular dominance (OD) shift observed early in postnatal development. Pioneering research by Hübel and Wiesel more than four decades ago demonstrated that if one eye was deprived of vision early in a kitten’s life, a dramatic shift in cell responsiveness occurred. The majority of neurons in the primary visual cortex no longer responded to stimuli presented to the deprived eye; these cells were driven by the open eye only (Wiesel and Hübel, 1963). However, in contrast to the profound effects observed in young animals, monocular deprivation (MD) in adult cats had virtually no effect (Hübel and Wiesel, 1970). Thus emerged the notion of a critical period for experience-dependent plasticity—a period of heightened brain plasticity during which experience could produce permanent, large-scale changes in neuronal circuits.

The significance of understanding the synaptic and molecular bases of OD plasticity cannot be overstated. First, although the depth of insight has increased sharply over the past decade with important discoveries about how synaptic transmission and plasticity are mediated in the cerebral cortex, we remain largely ignorant about the molecular basis of OD plasticity, despite more than 40 years of research. Second, the processes revealed by OD plasticity are likely to be the same as those that refine cortical circuitry in response to the qualities of sensory experience during development, and thus determine the capabilities of and limitations to visual performance in adults. Third, rapid OD plasticity is an example of cortical receptive field (RF) plasticity, the most common cellular correlate of memory in the brain. It is therefore likely that understanding the mechanisms of OD plasticity will yield insight into the molecular basis of learning and memory. Fourth, a detailed understanding of how synaptic connections are weakened by sensory deprivation may lead to strategies to reverse such changes, and possibly

overcome amblyopia. Finally, a detailed understanding of how synaptic connections are strengthened by experience is expected to lead to strategies to augment such changes and promote recovery of function after brain injury.

The phenomenon of OD plasticity has been studied in great detail in cats and primates. However, it may be a common feature among sighted mammals, as MD has been shown to alter the binocularity of visual cortical neurons in a number of diverse species (Dräger, 1978; Emerson et al., 1982; Issa et al., 1999; Maffei et al., 1992; Van Sluyters and Stewart, 1974). In many respects, mouse visual cortex is ideal for the mechanistic dissection of OD plasticity. First, mice display rapid and robust OD plasticity in response to MD. The kinetics and behavioral consequences of OD plasticity are very similar to those observed in other species, such as the cat. Second, the property of binocularity is established early in cortical processing by the convergence of thalamic inputs onto layer 4 neurons (there are no, or very few, neurons in mouse visual cortex that are activated exclusively by the ipsilateral eye), potentially simplifying analysis of the underlying synaptic changes. Third, mice are genetically homogeneous, easily obtained, and relatively inexpensive, enabling rapid progress using coordinated biochemical and electrophysiological studies in vitro and in vivo. Fourth, the absence of a columnar organization and other cortical anisotropy makes feasible extended duration recordings in awake animals. Fifth, genes can be delivered or deleted in mouse visual cortex by pronuclear injection, targeted insertion into embryonic stem cells, or viral infection. Finally, mice have emerged as valuable genetic models of human developmental disorders (e.g., fragile X syndrome), offering the opportunity to use the powerful paradigm of OD plasticity to understand how experience-dependent cortical development can go awry in genetic disorders and, hopefully, develop targeted treatments for these disorders.

It is worth drawing a distinction between OD plasticity, a phenomenon that appears to be expressed universally in sighted mammals, and OD column plasticity. OD columns, also discovered by Hübel and Wiesel, reflect the segregation

of lateral geniculate nucleus (LGN) axon terminals into regularly spaced bands or stripes in visual cortex. Although OD columns exist in some carnivores (e.g., cat and ferret) and some primates (e.g., macaque and human), they are not a feature of visual cortex in most mammals. In squirrel monkeys, for example, some individual animals express columns while others lack them or have them only in parts of primary visual cortex (Adams and Horton, 2003). Other species with excellent vision lack columns altogether (Van Hooser et al., 2005), leading some authors to refer to cortical columns as a “structure without a function” (Horton and Adams, 2005). Although the species traditionally used to study OD plasticity—the cat and macaque monkey—do have columns that can rearrange following MD, it is important to recognize that these species diverged very early in mammalian evolution (95 million years ago), 10 million years before the divergence of modern primates and rodents (Murphy et al., 2004). Columns and their modification by experience may arise from very different mechanisms in these divergent species. In any case, the key point is that the absence of columns in mice has no bearing on their value as a model to study the modification of binocular vision as a function of experience.

This chapter reviews recent progress made in the field of mouse visual cortical plasticity. In particular, the effects of changing an animal’s visual environment during the classically defined critical period and beyond are discussed in detail. Emphasis is on the use of an extended duration visually evoked potential (VEP) recording technique and its advantages for studying various forms of cortical plasticity, among them deprivation-induced depression, activitydependent potentiation, and stimulus-selective response potentiation.

Visually evoked potential recording technique

To gain the most from the numerous advantages of using the mouse visual cortex for mechanistic studies, it is necessary to understand the response changes that contribute to OD plasticity in mice. We chose a well-established technique of recording VEPs to monitor population neuronal activity. This technique has been pioneered and successfully used in rodents by Lamberto Maffei’s laboratory (Pizzorusso et al., 1997; Porciatti et al., 1999). VEPs are a form of local field potential (LFP) evoked by a visual stimulus. The magnitude of the cortical LFP reflects the extent and geometry of dendrites in the neocortex. The pyramidal cells with their apical dendrites running parallel to each other and perpendicular to the pial surface form an ideal open field arrangement and contribute maximally to the LFPs. Other cortical neurons that are oriented horizontally contribute to a much lesser degree to the sum of potentials (Logothetis, 2003). For many years, VEP recording has been a powerful tool in clinical

applications such as the estimation of refractive errors, visual acuity, binocular function, and the prognostic assessment of amblyopia (Sherman, 1979). The high correlation between VEPs and visual acuity testing makes VEP recordings a perfect tool for assessing the functional integrity of the visual system (Sokol, 1976).

Averaged over many stimulus presentations, the amplitude of the VEP waveform provides a quantitative measure of cortical input from the deprived versus nondeprived eye. By comparing VEP amplitudes across deprived and nondeprived eyes within a particular experimental group, it is possible to ascertain whether a change in OD is due to a decrease in the deprived-eye response (synaptic weakening) or an increase in the nondeprived-eye response (synaptic strengthening). In the field of visual cortical plasticity, most electrophysiological data have been derived from acute single-unit recordings that represent the ratio of deprivedeye to nondeprived-eye input. As a population signal, the VEP method avoids the problem of sampling bias due to a limited or skewed sample that is inherent in the single-unit approach. Furthermore, VEPs yield a more rapid assessment of OD than single-unit recordings and are potentially a high-throughput method to screen genetic mutants for visual cortical plasticity phenotypes. In addition, VEP recordings allow a comprehensive evaluation of visual system function. VEPs can be used both to obtain a measure of visual capabilities (spatial resolution, contrast threshold, response timing) that have a counterpart in behavioral capabilities (visual acuity, contrast sensitivity, reaction time) and to probe for information about cortical processing (retinotopy, laminar analysis). The ability to quickly screen numerous aspects of visual system function is critically important in the analysis of visual phenotypes in mutant mice. Finally, the VEP recording technique can be easily adapted to an extended duration recording situation in which the visual responses of a single animal can be followed over time, before and after visual deprivation.

We have developed an extended duration recording preparation in mice to better understand when and how OD is altered by MD. Figure 38.1A shows a mouse placed in a restraint apparatus designed in our laboratory. Perhaps the greatest advantage of the extended duration VEP recording technique is that visual activity can be monitored in the same experimental subjects over a prolonged period of time. There are additional benefits to this approach: (1) extended duration recordings can be made without the confounds of anesthesia, (2) the same animals can serve as their own controls, and (3) both absolute and relative changes in visual responsiveness can be measured.

Because chronic VEP recordings had not been attempted previously in mice, we first analyzed the laminar pattern of cortical activation in awake animals by performing current source density (CSD) analysis to better understand the

Figure 38.1 The extended duration VEP recording technique is a reliable method to assess OD plasticity in mice. A, Representation of VEP recording setup. A mouse previously implanted with recording electrodes in Oc1 is placed in a restraint apparatus in front of a computer monitor displaying visual stimuli. Mice are fully awake and alert during all recording sessions. B, Schematic diagram of the mouse visual system. Input from the stronger contralateral eye arrives via the LGN to the monocular and binocular zones of V1, whereas input from the weaker ipsilateral eye projects only to the small binocular zone. C, Current source density profile of VEPs for an adult mouse. Binocular VEP depth profile is shown in the left panel, with the corresponding cortical layers designated by arrowheads. Middle panel shows the CSD profile. Current sinks are nega-

tive-going and shaded black. The color image plot in the right panel is an interpolation of CSD traces. The earliest latency current sink is observed in layer 4, followed by longer latency sinks in layers 2/3 and 5. Cold and warm colors represent current sinks and sources, respectively. D, Typical VEP responses obtained during the three viewing conditions used in all experiments. Each trace is an average of 100 presentations of a reversing (1 Hz) sinusoidal grating. E, VEPs recorded from awake mice are stable over several days. Displayed in the left panel are the average VEP amplitude (n = 6 mice) in response to contralateral eye (blue bars) and ipsilateral eye (yellow bars) stimulation at baseline (day 0) and after 5 days of normal visual experience. Right panel shows the stability of contralateral/ ipsilateral ratios over days. See color plate 31.