Experience-independent development of the hamster circadian visual system

Experience-dependent functional plasticity is a hallmark of the primary visual system, but it is not known if analogous mechanisms govern development of the circadian visual system. Here we investigated molecular, anatomical, and behavioral consequences of complete monocular light deprivation during extended intervals of postnatal development in Syrian hamsters. Hamsters were raised in constant darkness and opaque contact lenses were applied shortly after eye opening and prior to the introduction of a light-dark cycle. In adulthood, previously-occluded eyes were challenged with visual stimuli. Whereas image-formation and motion-detection were markedly impaired by monocular occlusion, neither entrainment to a light-dark cycle, nor phase-resetting responses to shifts in the light-dark cycle were affected by prior monocular deprivation. Cholera toxin-b subunit fluorescent tract-tracing revealed that in monocularly-deprived hamsters the density of fibers projecting from the retina to the suprachiasmatic nucleus (SCN) was comparable regardless of whether such fibers originated from occluded or exposed eyes. In addition, long-term monocular deprivation did not attenuate light-induced c-Fos expression in the SCN. Thus, in contrast to the thalamocortical projections of the primary visual system, retinohypothalamic projections terminating in the SCN develop into normal adult patterns and mediate circadian responses to light largely independent of light experience during development. The data identify a categorical difference in the requirement for light input during postnatal development between circadian and non-circadian visual systems.     

The role of nAChR-mediated spontaneous retinal activity in visual system development

In the developing vertebrate retina, nAChR synapses are among the first to appear. This early cholinergic circuitry plays a key role in generating "retinal waves," spontaneously generated waves of action potentials that sweep across the ganglion cell layer. These retinal waves exist for a short period of time during development when several circuits within the visual system are being established. Here I review the cholinergic circuitry of the developing retina and the role these early circuits play in the development of the retina itself and of retinal projections to the lateral geniculate nucleus of the thalamus.     

Effect of Monocular Deprivation on Uptake and Binding of [3H]Glutamate in the Visual System of Rat Brain

Abstract: [³H]Glutamate uptake and binding studies were performed in the visual cortices, lateral geniculate nuclei (LGN), and superior colliculi of 3-month-old rats with one eyelid surgically closed from postnatal day 10 (monocular deprivation). Uptake and binding were highest in the lateral geniculate nucleus followed by the visual cortex (69% and 15%, respectively compared to LGN values) and the superior colliculus (32% and 59% of LGN values). Monocular deprivation did not affect [³H]glutamate uptake in any of the visual regions examined. However, a 46% decrease in [³H]glutamate binding in the lateral geniculate nucleus ipsilateral to the sutured eye was detected. Binding levels in other regions were not affected.     

Development of GABAA receptors in the central visual structures of rat brain. Effect of visual pattern deprivation

The postnatal development of high-affinity 3H-muscimol binding to GABAA receptors was studied in the lateral geniculate nucleus, superior colliculus, frontal and visual cortex of the rat brain. In the lateral geniculate nucleus 3H-muscimol binding rises from day 10 through day 37 reaching the highest value during the entire development followed by a slight decrease until adulthood. In the superior colliculus 3H-muscimol binding increased continuously from day 10 through day 37, and then decreased until day 50 reaching the adult value. In the visual and frontal cortex, binding reached the highest levels on days 14 and 25, respectively, persisted until day 37 followed by a slight decrease until adulthood. The ontogeny of 3H-muscimol binding sites in the visual regions does not essentially differ from that in other brain regions, suggesting that the appearance of 3H-muscimol binding sites in the visual system is not correlated with the functional maturation of the visual system. Unilateral eyelid closure from day 11 until day 25 did not affect the development of GABAA receptors in any of the central visual regions examined, indicating the lack of environmentally controlled mechanism.     

Apoptosis in the dorsal lateral geniculate nucleus after monocular deprivation involves glutamate signaling, NO production, and PARP activation

In mammals, visual experience during early postnatal life is critical for normal development of the visual system. Here we report that monocular deprivation for 2, 7, and 14 consecutive days causes p53 accumulation, cell death, and progressive loss of neurones in the dorsal lateral geniculate nucleus (dLGN) of newborn rats and these are prevented by NMDA and non-NMDA glutamate receptor antagonists, and by L-NAME, an inhibitor of nitric oxide synthesis. Monocular deprivation also increases dLGN levels of citrulline, the coproduct of nitric oxide synthesis, and this, as well as cell death and neuronal loss, is abolished by antagonists of glutamate receptors and by L-NAME. Finally, poly-(ADP-ribose) polymerase (PARP) knock-out mice appear to be protected from monocular deprivation-induced cell death. In conclusion, during early postnatal development of the rat visual system monocular deprivation causes excitotoxic, nitric oxide-mediated, cell death in the dLGN that appears to be apoptotic and also requires activation of PARP.     

Propagating waves in visual cortex: a large-scale model of turtle visual cortex

This article describes a large-scale model of turtle visual cortex that simulates the propagating waves of activity seen in real turtle cortex. The cortex model contains 744 multicompartment models of pyramidal cells, stellate cells, and horizontal cells. Input is provided by an array of 201 geniculate neurons modeled as single compartments with spike-generating mechanisms and axons modeled as delay lines. Diffuse retinal flashes or presentation of spots of light to the retina are simulated by activating groups of geniculate neurons. The model is limited in that it does not have a retina to provide realistic input to the geniculate, and the cortex and does not incorporate all of the biophysical details of real cortical neurons. However, the model does reproduce the fundamental features of planar propagating waves. Activation of geniculate neurons produces a wave of activity that originates at the rostrolateral pole of the cortex at the point where a high density of geniculate afferents enter the cortex. Waves propagate across the cortex with velocities of 4 m/ms to 70 m/ms and occasionally reflect from the caudolateral border of the cortex.     

Sleep enhances plasticity in the developing visual cortex

During a critical period of brain development, occluding the vision of one eye causes a rapid remodeling of the visual cortex and its inputs. Sleep has been linked to other processes thought to depend on synaptic remodeling, but a role for sleep in this form of cortical plasticity has not been demonstrated. We found that sleep enhanced the effects of a preceding period of monocular deprivation on visual cortical responses, but wakefulness in complete darkness did not do so. The enhancement of plasticity by sleep was at least as great as that produced by an equal amount of additional deprivation. These findings demonstrate that sleep and sleep loss modify experience-dependent cortical plasticity in vivo. They suggest that sleep in early life may play a crucial role in brain development.     

A role of the basal ganglia in the occurrence of visual hallucinations (a hypothetical mechanism)

A hypothetical mechanism of the basal ganglia involvement in visual hallucinations is proposed. According to this mechanism, hallucination is the result of modulation of the efficacy of corticostriatal synaptic inputs and changes in spiny cell activity due to the rise of striatal dopamine concentration (or due to other reasons). These changes cause an inhibition of neurons in the substantia nigra pars reticulata and subsequent disinhibition of neurons in the superior colliculus and pedunculopontine nucleus (including its cholinergic cells). In the absence of afferentation from the retina this disinhibition leads to activation of neurons in the lateral geniculate nucleus, pulvinar and other thalamic nuclei projecting to the primary and highest visual cortical areas, prefrontal cortex, and also back to the striatum. Hallucinations as conscious visual patterns are the result of selection of signals circulating in several interconnected loops each of which includes one of above mentioned neocortical areas, one of thalamic nuclei, limbic and one of visual areas of the basal ganglia, superior colliculus and/or pedunculopontine nucleus. According to our model, cannabinoids, opioids and ketamine may lead to hallucinations due to their promotional role in the LTD of cortical inputs to GABAergic spiny cells of striatal striosomes projecting to dopaminergic neurons, disinhibition of the lasts, and increase in striatal dopamine concentration.     

Recovery of the vertical vestibulo-ocular reflex gain in rabbits submitted to bilateral and unilateral visual deprivation from birth

Rabbits were raised in complete darkness from birth to the age of 3 months. At this age, the animals were submitted to dynamic vestibular stimulation consisting of lateral sinusoidal oscillations of different frequencies and fixed amplitude. The vertical VOR, elicited in complete darkness, was then recorded. While the phase of the response was perfectly adequate to ensure head movements compensation, the gain values recorded were clearly reduced with respect to the values obtained in a normally raised control group of the same age. After exposure to light, the visually deprived animals showed a complete recovery of normal VOR gain values in a relatively short period of time. Another group of animals was submitted to monocular prolongation of light deprivation during the fourth month of life. After 2 weeks these rabbits displayed a clear unbalance of the VOR between the two eyes: the eye in which vision was allowed showed a complete recovery of VOR gain values, while the gain of the occluded eye remained unchanged. The present results confirm that visual experience in early life is necessary for a correct development of the VOR. If visual deprivation is limited to the first few months of life, the impairment of the reflex characteristics is completely reversible. Finally, data on monocular deprivation suggest that, in the rabbit, the neural structures which preside to the development of the vertical VOR compensatory properties are lateralized.     

Protein synthesis in the visual cortex is needed for ocular dominance plasticity

Experience-dependent remodelling of neural connections progresses through stages, and early phases eventually give way to later long-lasting ones. The transition from early to late stages, often associated with structural changes, depends on protein synthesis. Suppression of cortical but not geniculate protein synthesis blocks ocular dominance plasticity at its earliest stage, suggesting that structural changes occur rapidly in the visual cortex following monocular deprivation.     

Developmental regulation of spine and filopodial motility in primary visual cortex: reduced effects of activity and sensory deprivation

Dendritic protrusions are highly motile during postnatal development. Although spine morphological plasticity could be associated with synaptic plasticity, the function of rapid spine/filopodial motility is still unknown. To investigate the role of spine motility in the development of the visual cortex and its relation with critical periods, we used two-photon imaging of neurons from layers receiving visual input in developing mouse primary visual cortex and compared motility between control and visually deprived animals. Spine and filopodia motility was prominent during early synaptogenesis (P11-P13) but greatly decreased after P15. This "switch" was coincident with a 2.5-fold increase in protrusion density and spine formation. Spine motility was not regulated during the critical period for monocular deprivation (P19-P34). Moreover, delaying the critical period by dark rearing did not delay the normal developmental decrease of spine motility, but caused a modest further reduction in motility at P28-P35. Dark rearing and enucleation also mildly reduced spine motility before eye opening and dark rearing reduced the proportion of filopodia. We conclude that (1) rapid spine motility is not related to critical period plasticity, but is likely to play a role in early synaptogenesis, and (2) neuronal activity stimulates spine motility during synaptogenesis and promotes the appearance of dendritic filopodia.     

NMDA-receptor blockade enhances cell apoptosis in the developing retina of the postnatal rat

During visual system development, programmed cell death occurs in order to facilitate the establishment of correct connections and synapses. During this period, glutamate plays a very important role as an excitatory neurotransmitter. With a view to evaluating if NMDA glutamate receptors participate in the regulation of apoptosis which occurs during the development of the rat retina, we subcutaneously injected the NMDA receptor antagonist MK-801 into rats at different stages of early postnatal development (P2 to P9). Ensuing cell death in the retina and superior colliculus was analyzed by using the Feulgen method. MK-801 administration had no effect on the survival of photoreceptor cells. In contrast, the presence of this antagonist induced a significant increase in the number of apoptotic cells in the neuroblastic layer (P7 and P8) and ganglion cell layer (P6-P8), as well as in the superior colliculus which receives afferent contacts from retinal ganglion cells during P7-P9. We conclude that during development, specific types of cells in the mammalian retina are critically dependent for their survival on glutamate stimulation through NMDA receptors. These findings thus throw fresh light on the mechanisms of development of the rat visual system by identifying NMDA glutamate receptors as participants in the regulation of apoptotic processes which occur during the initial stages of development.     

Formation of slow background activity in different parts of the visual analyzer following section of half the tectum mesencephali

Significant changes in the formation of electrical activity rhythms have been revealed in the lateral geniculate body, superior colliculus and visual cortex during section of one half of midbrain operculum in cats anesthetized with nembutal. It was determined that all changes in slow activity generation in the lateral geniculate body, superior colliculus are reflected in changes in the formation of electrical activity of the visual cortex. It is suggested that lateral geniculate body and superior colliculus may be involved in the generation of some electrical activity rhythms of the visual cortex.     

Effect of visual deprivation on evoked potentials in the visual cortex and superior colliculus in rabbits

Evoked potentials arising in the visual cortex and superior colliculus to stimulation of the collateral eye by single, paired, and repetitive flashes were recorded in rabbits reared in darkness or in normal illumination. The absence of significant change in the latent period and amplitudes of the first two components of the collicular responses and of the recovery cycle and response to repetitive stimulation in the light-deprived animals suggest that photic stimulation does not affect the normal functional development of the rabbit retinotectal system. However, functional deafferentation in the early postnatal period gives rise to serious disturbances of visual cortical function, as reflected in a marked decrease in amplitude of the primary response, lengthening of the recovery cycle, and narrowing of the range of rhythm-binding frequencies of flashes. These disturbances were reversible. The period of maximal sensitivity of the rabbit retinocortical system to visual deprivation begins at the end of the first month of postnatal life. The possible mechanisms lying at the basis of these functional disturbances in light-deprived animals are discussed.     

Neural mechanisms of recovery following early visual deprivation

Natural patterned early visual input is essential for the normal development of the central visual pathways and the visual capacities they sustain. Without visual input, the functional development of the visual system stalls not far from the state at birth, and if input is distorted or biased the visual system develops in an abnormal fashion resulting in specific visual deficits. Monocular deprivation, an extreme form of biased exposure, results in large anatomical and physiological changes in terms of territory innervated by the two eyes in primary visual cortex (V1) and to a loss of vision in the deprived eye reminiscent of that in human deprivation amblyopia. We review work that points to a special role for binocular visual input in the development of V1 and vision. Our unique approach has been to provide animals with mixed visual input each day, which consists of episodes of normal and biased (monocular) exposures. Short periods of concordant binocular input, if continuous, can offset much longer episodes of monocular deprivation to allow normal development of V1 and prevent amblyopia. Studies of animal models of patching therapy for amblyopia reveal that the benefits are both heightened and prolonged by daily episodes of binocular exposure.     

Role of the basal ganglia in the occurrence of paradoxical sleep dreams (hypothetical mechanism)

A hypothetical mechanism of the basal ganglia involvement in the occurrence of paradoxical sleep dreams and rapid eye movements is proposed. According to this mechanism, paradoxical sleep is provided by facilitation of activation of cholinergic neurons in the pedunculopontine nucleus as a result of suppression of their inhibition from the output basal ganglia nuclei. This disinhibition is promoted by activation of dopaminergic cells by pedunculopontine neurons, subsequent rise in dopamine concentration in the input basal ganglia structure. striatum, and modulation of the efficacy of cortico-striatal inputs. In the absence of signals from retina, a disinhibition of neurons in the pedunculopontine nucleus and superior colliculus allows them to excite neurons in the lateral geniculate body and other thalamic nuclei projecting to the primary and higher visual cortical areas, prefrontal cortex and back into the striatum. Dreams as visual images and "motor hallucinations" are the result of an increase in activity of definitely selected groups of thalamic and neocortical neurons. This selection is caused by modifiable action of dopamine on long-term changes in the efficacy of synaptic transmission during circulation of signals in closed interconnected loops, each of which includes one of the visual cortical areas (motor cortex), one of the thalamic nuclei, limbic and one of the visual areas (motor area) of the basal ganglia. pedunculopontine nucleus, and superior colliculus. Simultaneous modification and modulation of synapses in diverse units of neuronal loops is provided by PGO waves. Disinhibition of superioir colliculus neurons and their excitation by pedunculopontine nucleus lead to an appearance of rapid eye movements during paradoxical sleep.     

A model of the early stages of the human visual system: Functional and topological transformations performed in the peripheral visual field

A model of the early stages of the visual system is presented, with particular reference to the region of the visual field outside the fovea and to the class of retinal and lateral geniculate nucleus cells which are most active in the processing of pattern information (X-cells). The main neuroanatomical and neurophysiological properties taken into account are: the linear increase of the receptive fields diameter with eccentricity, the constancy of the overlap factor and the topological transformation operated upon the retinal image by the retino-cortical connection. The type of filtering taking place between the retina and the visual cortex is analyzed and some simulations are presented. It is shown that such a filtering is of a band-pass space variant type, with center frequencies that decrease from the center (i.e. the fovea) toward the periphery of the visual field. This processing is form invariant under linear scaling of the input. Moreover, considering the properties of the retino-cortical connection, it is shown that the cortical images undergo simple shifts whenever the retinal images are scaled or rotated.     

Age-dependent ocular dominance plasticity in adult mice

Background

Short monocular deprivation (4 days) induces a shift in the ocular dominance of binocular neurons in the juvenile mouse visual cortex but is ineffective in adults. Recently, it has been shown that an ocular dominance shift can still be elicited in young adults (around 90 days of age) by longer periods of deprivation (7 days). Whether the same is true also for fully mature animals is not yet known.

Methodology/Principal Findings

We therefore studied the effects of different periods of monocular deprivation (4, 7, 14 days) on ocular dominance in C57Bl/6 mice of different ages (25 days, 90–100 days, 109–158 days, 208–230 days) using optical imaging of intrinsic signals. In addition, we used a virtual optomotor system to monitor visual acuity of the open eye in the same animals during deprivation. We observed that ocular dominance plasticity after 7 days of monocular deprivation was pronounced in young adult mice (90–100 days) but significantly weaker already in the next age group (109–158 days). In animals older than 208 days, ocular dominance plasticity was absent even after 14 days of monocular deprivation. Visual acuity of the open eye increased in all age groups, but this interocular plasticity also declined with age, although to a much lesser degree than the optically detected ocular dominance shift.

Conclusions/Significance

These data indicate that there is an age-dependence of both ocular dominance plasticity and the enhancement of vision after monocular deprivation in mice: ocular dominance plasticity in binocular visual cortex is most pronounced in young animals, reduced but present in adolescence and absent in fully mature animals older than 110 days of age. Mice are thus not basically different in ocular dominance plasticity from cats and monkeys which is an absolutely essential prerequisite for their use as valid model systems of human visual disorders.     

Visual deprivation alters development of synaptic function in inner retina after eye opening.

Visual deprivation impedes refinement of neuronal function in higher visual centers of mammals. It is often assumed that visual deprivation has minimal effect, if any, on neuronal function in retina. Here we report that dark rearing reduces the light-evoked responsiveness of inner retinal neurons in young mice. We also find that 1 to 2 weeks after eye opening, there is a surge (>4-fold) in the frequency of spontaneous excitatory and inhibitory synaptic events in ganglion cells. Dark rearing reversibly suppresses this surge, but recovery takes >6 days. Frequency changes are not accompanied by amplitude changes, indicating that synaptic reorganization is likely to be presynaptic. These findings indicate there is a degree of activity-dependent plasticity in the mammalian retina that has not been previously described.     

The corticofugal pathways of the visual system

Cortical neurons belonging to the same topological ensemble send axons to thalamic and mesencephalic structures and also to contra and ipsilateral cortical areas. The projections are called the corticofugal system. This review addresses the organization and the functions of the efferent cortical fibers within the visual network. For example, the cortico-geniculate fibers participate in shaping the structure of the concentric receptive fields of geniculate cells. Namely, the size of the surround area depends on descending impulses from the cortex. By contrast, cortico-mesencephalic fibers have a more global influence on visual responses. Following the interruption of cortical activity all responses to visual stimuli decline; although in rodents and lagomorphs cortical inactivation does not eliminate those visual responses that are sent to the superior colliculus or pretectum directly from the retina. In each hemisphere it has been demonstrated that contra-lateral cortico-cortical fibers participate in the continuity of the two visual hemi-fields, as the interruption of the callosal impulses results in a truncated field in which the contralateral part of the receptive field is missing., overlaps the vertical meridian is missing. Finally, ipsilateral cortico-cortical fibers allow a consolidation of visual properties of cortical cells. It must be added that there are considerable differences among species in the organization of cortico-cortical relationships. However, this survey seems to indicate that all corticofugal axons are excitatory.