The lens controls cell survival in the retina: Evidence from the blind cavefish Astyanax

The lens influences retinal growth and differentiation during vertebrate eye development but the mechanisms are not understood. The role of the lens in retinal growth and development was studied in the teleost Astyanax mexicanus, which has eyed surface-dwelling (surface fish) and blind cave-dwelling (cavefish) forms. A lens and laminated retina initially develop in cavefish embryos, but the lens dies by apoptosis. The cavefish retina is subsequently disorganized, apoptotic cells appear, the photoreceptor layer degenerates, and retinal growth is arrested. We show here by PCNA, BrdU, and TUNEL labeling that cell proliferation continues in the adult cavefish retina but the newly born cells are removed by apoptosis. Surface fish to cavefish lens transplantation, which restores retinal growth and rod cell differentiation, abolished apoptosis in the retina but not in the RPE. Surface fish lens deletion did not cause apoptosis in the surface fish retina or affect RPE differentiation. Neither lens transplantation in cavefish nor lens deletion in surface fish affected retinal cell proliferation. We conclude that the lens acts in concert with another optic component, possibly the RPE, to promote retinal cell survival. Accordingly, deficiency in both optic structures may lead to eye degeneration in cavefish.     

The Distribution of Primary Nitric Oxide Synthase- and Parvalbumin- Immunoreactive Afferents in the Dorsal Funiculus of the Lumbosacral Spinal Cord in a Dog

1. The aim of the present study was to examine the distribution of unmyelinated, small-diameter myelinated neuronal nitric oxide synthase immunoreactive (nNOS-IR) axons and large-diameter myelinated neuronal nitric oxide synthase and parvalbumin-immunoreactive (PV-IR) axons in the dorsal funiculus (DF) of sacral (S1–S3) and lumbar (L1–L7) segments of the dog. 2. nNOS and PV immunohistochemical methods were used to demonstrate the presence of nNOS-IR and PV-IR in the large-diameter myelinated, presumed to be proprioceptive, axons in the DF along the lumbosacral segments. 3. Fiber size and density of nNOS-IR and PV-IR axons were used to compartmentalize the DF into five compartments (CI–CV). The first compartment (CI) localized in the lateralmost part of the DF, containing both unmyelinated and small-diameter myelinated nNOS-IR axons, is homologous with the dorsolateral fasciculus, or Lissauer tract. The second compartment (CII) having similar fiber organization as CI is situated more medially in sacral segments. Rostrally, in lower lumbar segments, CII moves more medially, and at upper lumbar level, CII reaches the dorsomedial angle of the DF and fuses with axons of CIV. CIII is the largest in the DF and the only one containing large-diameter myelinated nNOS-IR and PV-IR axons. The largest nNOS-IR and PV-IR axons of CIII (8.0–9.2 μm in diameter), presumed to be stem Ia proprioceptive afferents, are located in the deep portion of the DF close to the dorsal and dorsomedial border of the dorsal horn. The CIV compartment varies in shape, appearing first as a small triangular area in S3 and S2 segments, homologous with the Philippe–Gombault triangle. Beginning at S1 level, CIV acquires a more elongated shape and is seen throughout the lumbar segments as a narrow band of fibers extending just below the dorsal median septum in approximately upper two-thirds of the DF. The CV is located in the basal part of the DF. In general, CV is poor in nNOS-IR fibers; among them solitary PV-IR fibers are seen. 4. The analysis of the control material and the degeneration of the large- and medium-caliber nNOS-IR fibers after unilateral L7 and S1 dorsal rhizotomy confirmed that large-caliber nNOS-IR and and PV-IR axons, presumed to be proprioceptive Ia axons, and their ascending and descending collaterals are present in large number in the DF of the lumbosacral intumescence. However, in the DF of the upper lumbar segments, the decrease in the number of nNOS-IR and PV-IR fibers is quite evident.     

Upregulation of thioredoxin system via Nrf2-antioxidant responsive element pathway in adaptive-retinal neuroprotection in vivo and in vitro

We tested the hypothesis that stress responses mediated by the Nrf2-antioxidant responsive element (ARE) pathway are involved in the initiation of retinal neuroprotection provided by bright-cyclic-light rearing. Albino rats born and raised in dim (5 lux) or bright (400 lux) cyclic light were exposed to damaging light (3000 lux, 6 h). After exposure, the outer nuclear layer thickness and area and the electroretinogram a- and b-wave amplitudes were significantly reduced in the dim-light-reared rats compared to the bright-light-reared rats, demonstrating a light adaptation neuroprotection phenomenon. In bright-cyclic-light-reared rats, the retinal levels of thioredoxin (Trx) (2.4-fold), Trx reductase (TrxR) (2.9-fold), and proteins modified by 4-hydroxynonenal (4-HNE) (1.5-fold) were upregulated by Western blot analyses, and the nuclear translocation of Nrf2 (2.2-fold) and the DNA binding activity of Nrf2, small Maf, and cJun to the ARE were increased as determined by electrophoretic mobility shift assays. In mouse photoreceptor-derived 661W cells, pretreatment with a sublethal dose of 4-HNE protected against H₂O₂-induced cell damage. Treatment with 4-HNE upregulated cellular Trx, TrxR, and heme oxygenase-1 (HO-1) levels in addition to DNA binding activity of Nrf2, small Maf, and cJun to the ARE. Downregulation of Nrf2 using RNA interference technology diminished 4-HNE-mediated upregulation of Trx and Trx reductase but did not affect the upregulation of HO-1 by 4-HNE. Cytoprotection by 4-HNE pretreatment against H₂O₂-induced cell damage was not observed in 661W cells with a silenced Nrf2 gene. The results suggest that upregulation of the Trx system by 4-HNE via the Nrf2–ARE pathway may be involved in the molecular mechanism of the retinal neuroprotection phenomenon.     

Facilitation between extensor carpi radialis and pronator teres in humans: A study using a post-stimulus time histogram method

Group I muscle afferents modulate the excitability of motor neurons through excitatory and inhibitory spinal reflexes. Spinal reflex relationships between various muscle pairs are well described in experimental animals but not in the human upper limb, which exhibits a fine control of movement. In the present study, spinal reflexes between the extensor carpi radialis (ECR) and pronator teres (PT) muscles were examined in healthy human subjects using a post-stimulus time histogram method. Electrical stimulation of low-threshold afferents of ECR nerves increased the motor neuron excitability in 31 of 76 PT motor units (MUs) in all eight subjects tested, while stimulation of low-threshold afferents of PT nerves increased the motor neuron excitability in 36 of 102 ECR MUs in all 10 subjects. The estimated central synaptic delay was almost equivalent to that of homonymous facilitation. Mechanical stimulation (MS) of ECR facilitated 16 of 30 PT MUs in all five subjects tested, while MS of PT facilitated 17 of 30 ECR MUs in all six subjects. These results suggest excitatory reflex (facilitation) between PT and ECR. Group I afferents should mediate the facilitation through a monosynaptic path.