An abnormal retinogeniculate projection in Siamese cats

All information about the visual world is conveyed to the brain by a single type of neurons at the back of the eye called retinal ganglion cells (RGCs). Understanding how RGC axons locate and wire up with their targets is therefore critical to understanding visual development. In recent years, several important technological and conceptual advances have been made in this area, and yet, many fundamental questions remain unanswered. Indeed, while much is now known about how RGC axons pathfind at the optic chiasm and form retinotopic maps within their targets, how RGCs select their overall targets in the first place is poorly understood. Moreover, the signals that direct mammalian RGC axons to their appropriate layer within those targets remain unknown. The recent advent of genetic tools to selectively label and manipulate defined groups of RGCs is starting to provide a way to resolve these and other important questions about RGC wiring specificity. This field is therefore positioned to reveal new principles of visual circuit development that no doubt will extend to other regions of the CNS.

This article develops the Synchronous Matching Adaptive Resonance Theory (SMART) neural model to explain how the brain may coordinate multiple levels of thalamocortical and corticocortical processing to rapidly learn, and stably remember, important information about a changing world. The model clarifies how bottom-up and top-down processes work together to realize this goal, notably how processes of learning, expectation, attention, resonance, and synchrony are coordinated. The model hereby clarifies, for the first time, how the following levels of brain organization coexist to realize cognitive processing properties that regulate fast learning and stable memory of brain representations: single-cell properties, such as spiking dynamics, spike-timing-dependent plasticity (STDP), and acetylcholine modulation; detailed laminar thalamic and cortical circuit designs and their interactions; aggregate cell recordings, such as current source densities and local field potentials; and single-cell and large-scale inter-areal oscillations in the gamma and beta frequency domains. In particular, the model predicts how laminar circuits of multiple cortical areas interact with primary and higher-order specific thalamic nuclei and nonspecific thalamic nuclei to carry out attentive visual learning and information processing. The model simulates how synchronization of neuronal spiking occurs within and across brain regions, and triggers STDP. Matches between bottom-up adaptively filtered input patterns and learned top-down expectations cause gamma oscillations that support attention, resonance, learning, and consciousness. Mismatches inhibit learning while causing beta oscillations during reset and hypothesis testing operations that are initiated in the deeper cortical layers. The generality of learned recognition codes is controlled by a vigilance process mediated by acetylcholine.

Tyrosinase (TYR) is a multifunctional copper-containing glycoenzyme (∼80 kDa), which plays a key role in the rate-limiting steps of the melanin biosynthetic pathway. This membrane-bound protein, possibly evolved by the fusion of two different copper-binding proteins, is mainly expressed in epidermal, ocular and follicular melanocytes. In the melanocytes, TYR functions as an integrated unit with other TYR-related proteins (TYRP1, TYRP2), lysosome-associated membrane protein 1 (LAMP1) and melanocyte-stimulating hormone receptors; thus forming a melanogenic complex. Mutations in the TYR gene (TYR, 11q14-21, MIM 606933) cause oculocutaneous albinism type 1 (OCA1, MIM 203100), a developmental disorder having an autosomal recessive mode of inheritance. In addition, TYR can act as a modifier locus for primary congenital glaucoma (PCG) and it also contributes significantly in the eye developmental process. Expression of TYR during neuroblast division helps in later pathfinding by retinal ganglion cells from retina to the dorsal lateral geniculate nucleus. However, mutation screening of TYR is complicated by the presence of a pseudogene–TYR like segment (TYRL, 11p11.2, MIM 191270), sharing ∼98% sequence identity with the 3′ region of TYR. Thus, in absence of a full-proof strategy, any nucleotide variants identified in the 3′ region of TYR could actually be present in TYRL. Interestingly, despite extensive search, the second TYR mutation in 15% of the OCA1 cases remains unidentified. Several possible locations of these “uncharacterized mutations” (UCMs) have been speculated so far. Based on the structure of TYR gene, its sequence context and some experimental evidences, we propose two additional possibilities, which on further investigations might shed light on the molecular basis of UCMs in TYR of OCA1 patients; (i) partial deletion of the exons 4 and 5 region of TYR that is homologous with TYRL and (ii) variations in the polymorphic GA complex repeat located between distal and proximal elements of the human TYR promoter that can modulate the expression of the gene leading to disease pathogenesis.

The pattern of inputs from the two eyes to the lateral geniculate nucleus (LGN) is a distinguishing feature of mammalian species. Eye-specific connections to the LGN form through a process involving the segregation of right versus left eye ganglion cell axons, from an initially overlapping state. Recent experiments have shown that this process requires both spontaneous retinal activity and axon guidance cues. The specific role of eye-specific segregation in visual processing is unknown, but manipulations that alter the pattern or degree of segregation may provide new insights. Since the degree of eye-specific segregation in the LGN generally correlates with the degree of binocular vision, we consider how the evolution of frontally placed eyes and eye-specific connections in the LGN may relate to one another in terms of visual function and developmental mechanisms.

The representation of the visual field in early visual areas is retinotopic. The point-to-point relationship on the retina is therefore maintained on the convoluted cortical surface. Functional magnetic resonance imaging (fMRI) has been able to demonstrate the retinotopic representation of the visual field in occipital cortex of normal subjects. Furthermore, visual areas that are retinotopic can be identified on computationally flattened cortical maps on the basis of positions of the vertical and horizontal meridians. Here, we investigate abnormal retinotopic representations in human visual cortex with fMRI. We present three case studies in which patients with visual disorders are investigated. We have tested a subject who only possesses operating rod photoreceptors. We find in this case that the cortex undergoes a remapping whereby regions that would normally represent central field locations now map more peripheral positions in the visual field. In a human albino we also find abnormal visual cortical activity. Monocular stimulation of each hemifield resulted in activations in the hemisphere contralateral to the stimulated eye. This is consistent with abnormal decussation at the optic chiasm in albinism. Finally, we report a case where a lesion to white matter has resulted in a lack of measurable activity in occipital cortex. The activity was absent for a small region of the visual field, which was found to correspond to the subject's field defect. The cases selected have been chosen to demonstrate the power of fMRI in identifying abnormalities in the cortical representations of the visual field in patients with visual dysfunction. Furthermore, the experiments are able to show how the cortex is capable of modifying the visual field representation in response to abnormal input.