A dominant form of inherited retinal degeneration caused by a non-photoreceptor cell-specific mutation

We have isolated a dominant mutation, night blindness a (nba), that causes a slow retinal degeneration in zebrafish. Heterozygous nba fish have normal vision through 2–3 months of age but subsequently become night blind. By 9.5 months of age, visual sensitivity of affected fish may be decreased more than two log units, or 100-fold, as measured behaviorally. Electroretinographic (ERG) thresholds of mutant fish are also raised significantly, and the ERG b-wave shows a delayed implicit time. These defects are due primarily to a late-onset photoreceptor cell degeneration involving initially the rods but eventually the cones as well. Homozygous nba fish display an early-onset neuronal degeneration throughout the retina and elsewhere in the central nervous system. As a result, animals develop with small eyes and die by 4–5 days postfertilization (pf). These latter data indicate that the mutation affecting nba fish is not in a photoreceptor cell-specific gene.

Cerebral cortical hyperactivation in response to mental stress in patients with coronary artery disease

The central nervous system (CNS) effects of mental stress in patients with coronary artery disease (CAD) are unexplored. The present study used positron emission tomography (PET) to measure brain correlates of mental stress induced by an arithmetic serial subtraction task in CAD and healthy subjects. Mental stress resulted in hyperactivation in CAD patients compared with healthy subjects in several brain areas including the left parietal cortex [angular gyrus/parallel sulcus (area 39)], left anterior cingulate (area 32), right visual association cortex (area 18), left fusiform gyrus, and cerebellum. These same regions were activated within the CAD patient group during mental stress versus control conditions. In the group of healthy subjects, activation was significant only in the left inferior frontal gyrus during mental stress compared with counting control. Decreases in blood flow also were produced by mental stress in CAD versus healthy subjects in right thalamus (lateral dorsal, lateral posterior), right superior frontal gyrus (areas 32, 24, and 10), and right middle temporal gyrus (area 21) (in the region of the auditory association cortex). Of particular interest, a subgroup of CAD patients that developed painless myocardial ischemia during mental stress had hyperactivation in the left hippocampus and inferior parietal lobule (area 40), left middle (area 10) and superior frontal gyrus (area 8), temporal pole, and visual association cortex (area 18), and a concomitant decrease in activation observed in the anterior cingulate bilaterally, right middle and superior frontal gyri, and right visual association cortex (area 18) compared with CAD patients without myocardial ischemia. These findings demonstrate an exaggerated cerebral cortical response and exaggerated asymmetry to mental stress in individuals with CAD.

Traces of learning in the auditory localization pathway

One of the fascinating properties of the central nervous system is its ability to learn: the ability to alter its functional properties adaptively as a consequence of the interactions of an animal with the environment. The auditory localization pathway provides an opportunity to observe such adaptive changes and to study the cellular mechanisms that underlie them. The midbrain localization pathway creates a multimodal map of space that represents the nervous system's associations of auditory cues with locations in visual space. Various manipulations of auditory or visual experience, especially during early life, that change the relationship between auditory cues and locations in space lead to adaptive changes in auditory localization behavior and to corresponding changes in the functional and anatomical properties of this pathway. Traces of this early learning persist into adulthood, enabling adults to reacquire patterns of connectivity that were learned initially during the juvenile period.

Reconstitution of the hippocampal mossy fiber and associational-commissural pathways in a novel dissociated cell culture system.

Synapses of the hippocampal mossy fiber pathway exhibit several characteristic features, including a unique form of long-term potentiation that does not require activation of the N-methyl-D-aspartate receptor by glutamate, a complex postsynaptic architecture, and sprouting in response to seizures. However, these connections have proven difficult to study in hippocampal slices because of their relative paucity (<0.4%) compared to commissural-collateral synapses. To overcome this problem, we have developed a novel dissociated cell culture system in which we have enriched mossy fiber synapses by increasing the ratio of granule-to-pyramidal cells. As in vivo, mossy fiber connections are composed of large dynorphin A-positive varicosities contacting complex spines (but without a restricted localization). The elementary synaptic connections are glutamatergic, inhibited by dynorphin A, and exhibit N-methyl-D-aspartate-independent long-term potentiation. Thus, the simplicity and experimental accessibility of this enriched in vitro mossy fiber pathway provides a new perspective for studying nonassociative plasticity in the mammalian central nervous system.

Identification of a Drosophila G protein alpha subunit (dGq alpha-3) expressed in chemosensory cells and central neurons.

We have identified another Drosophila GTP-binding protein (G protein) alpha subunit, dGq alpha-3. Transcripts encoding dGq alpha-3 are derived from alternative splicing of the dGq alpha locus previously shown to encode two visual-system-specific transcripts [Lee, Y.-J., Dobbs, M.B., Verardi, M.L. & Hyde, D.R. (1990) Neuron 5, 889-898]. Immunolocalization studies using dGq alpha-3 isoform-specific antibodies and LacZ fusion genes show that dGq alpha-3 is expressed in chemosensory cells of the olfactory and taste structures, including a subset of olfactory and gustatory neurons, and in cells of the central nervous system, including neurons in the lamina ganglionaris. These data are consistent with a variety of roles for dGq alpha-3, including mediating a subset of olfactory and gustatory responses in Drosophila, and supports the idea that some chemosensory responses use G protein-coupled receptors and the second messenger inositol 1,4,5-trisphosphate.

Blockade of action potential activity alters initial arborization of thalamic axons within cortical layer 4.

In the formation of connections during the development of the nervous system, it is generally accepted that there is an early phase not requiring neural activity and a later activity-dependent phase. The initial processes of axonal pathfinding and target selection are not thought to require neural activity, whereas the later fine-tuning of connections into their final adult patterns does. We report an apparent exception to this rule in which action potential activity seems to be required very early in development for thalamic axons to form appropriate patterns of terminal arborizations with their ultimate target neurons in layer 4 of the cerebral cortex. Blockade of sodium action potentials during the 2-week fetal period when visual thalamic axons initially grow into the primary visual cortex in cats prevents the normally occurring branching of lateral geniculate nucleus axons within layer 4. This observation implies a role for action-potential activity in cerebral cortical development far earlier than previously suspected, weeks before eye-opening and the onset of the well-known process of activity-dependent reorganization of axonal terminal arbors that leads to the formation of ocular dominance columns.

Visual motion perception.

The primate visual motion system performs numerous functions essential for survival in a dynamic visual world. Prominent among these functions is the ability to recover and represent the trajectories of objects in a form that facilitates behavioral responses to those movements. The first step toward this goal, which consists of detecting the displacement of retinal image features, has been studied for many years in both psychophysical and neurobiological experiments. Evidence indicates that achievement of this step is computationally straightforward and occurs at the earliest cortical stage. The second step involves the selective integration of retinal motion signals according to the object of origin. Realization of this step is computationally demanding, as the solution is formally underconstrained. It must rely--by definition--upon utilization of retinal cues that are indicative of the spatial relationships within and between objects in the visual scene. Psychophysical experiments have documented this dependence and suggested mechanisms by which it may be achieved. Neurophysiological experiments have provided evidence for a neural substrate that may underlie this selective motion signal integration. Together they paint a coherent portrait of the means by which retinal image motion gives rise to our perceptual experience of moving objects.