In spite of Stein and Glasier's justifiable conclusion that initial optimism concerning the immediate clinical applicability of neural transplantation was premature, there exists much experimental evidence to support the potential for incorporating this procedure into a therapeutic arsenal in the future. To realize this potential will require continued evolution of our knowledge at multiple levels of the clinical and basic neurosciences.

To demonstrate that a fallacy is committed, Block needs to convince us of two things: first, that the concept of phenomenal consciousness is distinct from that of access consciousness, and second, that it picks out a different property from that of access consciousness. I raise doubt about both of these claims, suggesting that the concept of a phenomenal property is the concept of a property to which we have a special sort of access.

The cyclic GMP-gated channel responds to changes in free intracellular cGMP, and as a result, it plays a central role in the phototransduction process in rod and cone photoreceptor cells. Recent biochemical, immunochemical, and molecular biology studies indicate that this channel consists of a complex of two distinct subunits and one or more associated proteins. Primary structural analysis indicates that the a and (3 subunits contain a cGMP-binding domain, an even number of membrane-spanning segments, a voltage sensor motif and a pore region. The latter two features are found in voltage-gated channels and suggest that these two classes of channels have evolved from the same ancestral channel protein. A working model for the membrane topography of the channel subunits is proposed based on immunogold labeling studies and sequence analysis. Recent studies also indicate that calmodulin binds to the 240 kDa protein of the channel complex and modulates the sensitivity of the channel for cGMP in a Ca2+-dependent manner. The molecular properties of the channel complex and the possible role of Ca2+-calmodulin modulation of the channel during photoactivation and photorecovery are discussed in relation to the current mechanism of phototransduction in photoreceptor cells

A theory of representation is incomplete if it states “representations are X” where X can be symbols, cell assemblies, functional states, or the flock of birds from Theaetetus, without explaining the nature of the link between the universe of Xs and the world. Amit's thesis, equating representations with reverberations in Hebbian cell assemblies, will only be considered a solution to the problem of representation when it is complemented by a theory of how a reverberation in the brain can be a representation of anything.

Diseases causing inherited retinal degeneration in humans, such as retinitis pigmentosa and macular dystrophy, are genetically heterogeneous and clinically diverse. More than 40 genes causing retinal degeneration have been mapped to specific chromosomal sites; of these, at least 10 have been cloned and characterized. Mutations in two proteins, rhodopsin and peripherin/RDS, account for approximately 35% of all cases of autosomal dominant retinitis pigmentosa and a lesser fraction of other retinal conditions. This target article reviews the genes and mutations causing retinal degeneration and proposes mechanisms whereby specific mutations lead to particular clinical consequences, that is, the relationship between genotype and phenotype. Retinitis pigmentosa and macular dystrophy are genetically heterogeneous diseases that cause retinal degeneration in humans and often result in severe visual impairment or blindness. Although many of the genes causing these diseases have not been identified, three photoreceptor-specific proteins have been implicated: rhodopsin, peripherin/RDS, and the P-subunit of rod phosphodiesterase. Mutations in the genes for these three proteins can cause either dominant retinitis pigmentosa, recessive retinitis pigmentosa, dominant congenital stationary night blindness, or dominant macular degeneration. Why this multiplicity of clinical phenotypes? Our target article summarizes the genetic and biochemical background to this question and proposes a number of possible explanations. Discussion focuses mainly on 73 distinct disease-causing mutations of rhodopsin. We feel that rhodopsin and other photoreceptor proteins can serve as model systems for unraveling the connection between genotype and phenotype, not only for inherited retinal diseases but for other degenerative disorders as well.

In contrast to the views put forth by Stein & Glasier, we support the use of inbred strains of rodents in studies of the immunobiology of neural transplants. Inbred strains demonstrate homology of the major histocompatibility complex (MHC). Virtually all experimental work in transplantation immunology is performed using inbred strains, yet very few published studies of immune rejection in intracerebral grafts have used inbred animals.

Recurrent excitation is experimentally well documented in cortical populations. It provides for intracortical excitatory biases that linearize negative feedback interactions and induce macroscopic state transitions during perception. The concept of the local neighborhood should be expanded to spatial patterns as the basis for perception, in which large areas of cortex are bound into cooperative behavior with near-silent columns as important as active columns revealed by unit recording.

The differences Block attempts to capture with his putative distinction between P-consciousness and A-consciousness are more directly and perspicuously handled in terms of differences in richness of content and degree of influence. Block's critiques, based on his misbegotten distinction, evaporate on closer inspection.

Three experiments on neural grafting with adult rat hosts are described. Working memory impairments were produced by lesioning the hippocampus or severing its connections with the septum by ablating the fimbria-fornix. The results suggest that the survival and growth of a neural graft, whether an autograft or a xenograft, is not a necessary condition for functional recovery on a task tapping working memory.

Propositions as to the nature of consciousness, based on disorders of perception that result from brain damage, and taking insufficient account of the numerous ways in which normal subjects may deviate from that “usual” sequence of events (input → subjective awareness → output) risk increasing rather than diminishing any existing confusion about the function of consciousness.

Evidence suggests that the Ca2+/calmodulin-sensitive adenylyl cyclase may play a key role in neural plasticity and learning in Aplysia, Drosophila, and mammals. This dually-regulated enzyme has been proposed as a possible site of stimulus convergence during associative learning. This commentary discusses the evidence that is required to demonstrate that a protein in a second messenger cascade actually functions as a molecular site of associative integration. It also addresses the issue of how a dually-regulated protein could contribute to the temporal pairing requirements of classical conditioning: that relationship between stimuli display both temporal contiguity and predictability.

This commentary questions the target articles inferences from a limited set of empirical data to support this model and conceptual scheme. Especially questionable is the attribution of internal representation properties to an assembly of cells in a discrete cortical module firing at a discrete attractor frequency. Alternative inferences are drawn from cortical cooling and cell-firing data that point to the internal representation as a broad and specific cortical network defined by cortico-cortical connectivity. Active memory, it is proposed, consists in the sustained activation of the component neuron populations of the network.

The concept of structure, operation, and functionality, as they may be understood by clinicians or researchers using neural transplantation techniques, are briefly defined. Following Stein & Glasier, we emphasize that the question of whether an intracerebral graft is really functional should be addressed not only in terms of what such a graft does in a given brain structure, but also in terms of what it does at the level of the organism.

The structure of rhodopsin is a subject of intense interest. Solving the structure by traditional methods has proved exceedingly challenging. It may therefore be useful to confront the problem by a combination of alternate techniques. These include FTIR (Fourier transform infrared spectroscopy) and AFM (atomic force microscopy) on the intact protein. Furthermore, additional insights may be gained through structural investigations of discrete rhodopsin domains.

The concept of an attractor in a mathematical dynamical system is reviewed. Emphasis is placed on the distinction between a cell assembly, the corresponding attractor, and the attractor dynamics. The biological significance of these entities is discussed, especially the question of whether the representation of the stimulus requires the full attractor dynamics, or merely the cell assembly as a set of reverberating neurons. Comparison is made to Freeman's study of dynamic patterns in olfaction.

Although not the main point of his target article, Block defends the view that perception and awareness of perception could be functions of different brain systems. I will argue that the available data do not support this view, and that Block's defense of the view rests on problematic eonstruals of the “executive system” and of the components of information-processing models.

Should we distinguish between access and phenomenal consciousness? Block says yes and that various pathologies of consciousness support and clarify the distinction. The commentary charge that the distinction is neither supported nor clarified by the clinical data. It recommends an alternative reading of the data and urges Block to clarify the distinction.

The candidate gene approach has identified many causes of photoreceptor rod cell death in retinitis pigmentosa. Some mutations lead to increased cyclicGMP concentrations in rods. Rod photoreceptors are also particularly susceptible to some mutations in housekeeping genes. Although many more cases of macular degeneration than retinitis pigmentosa occur each year, there is much less known about both genetic and sporadic forms of this disease.

Further tests of Amit's model are indicated. One strategy is to use the apparent coding sparseness of the model to make predictions about coding sparseness in Miyashita's network. A second approach is to use memory overload to induce false positive responses in modules and biological systems. In closing, the importance of temporal coding and timing requirements in developing biologically plausible attractor networks is mentioned.

Gene therapy approaches have great promise in the treatment of neurodegenerative disorders and malignant brain tumors. Neuwelt et al. review available viral-mediated gene therapy methods and their blood-brain-barrier (BBB) disruption delivery technique, briefly mentioning nonviral mediated gene therapy methods. This commentary discussed the BBB disruption delivery technique, viral and nonviral mediated gene therapy approaches to Parkinson's disease, and the potential use of antisense oligo to suppress malignant brain tumors.