Nineteenth century research on cell death

This paper reviews research on cell death in the 19th C. The first report of cell death was by Vogt in 1842, which was remarkably soon after the establishment of the cell theory by Schleiden and Schwann between 1838 and 1842. Initial studies on cell death, including that of Vogt, focused on its occurrence in metamorphosis (Vogt, 1842; Prévost and Lebert, 1844; Weismann, 1863–1866) or in blatant pathology (Virchow, 1858), but as histological techniques improved it was found to be involved in more subtle roles in numerous situations including endochondral ossification (Stieda, 1872), ovarian follicle atresia (Flemming, 1885), cell turnover (Nissen, 1886), the wholesale loss of a population of sensory neurons in fish (Beard, 1889), and the naturally occurring histogenetic death of myocytes (Felix, 1889) and neurons (Collin, 1906). The current categorization of cell death into about three main morphological types has 19th century roots in that apoptosis was well described by Flemming (1885), who called it chromatolysis, and various authors including Noetzel (1895) proposed a threefold classification. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”

Nineteenth century research on cell death

This paper reviews research on cell death in the 19th C. The first report of cell death was by Vogt in 1842, which was remarkably soon after the establishment of the cell theory by Schleiden and Schwann between 1838 and 1842. Initial studies on cell death, including that of Vogt, focused on its occurrence in metamorphosis (Vogt, 1842; Prévost and Lebert, 1844; Weismann, 1863–1866) or in blatant pathology (Virchow, 1858), but as histological techniques improved it was found to be involved in more subtle roles in numerous situations including endochondral ossification (Stieda, 1872), ovarian follicle atresia (Flemming, 1885), cell turnover (Nissen, 1886), the wholesale loss of a population of sensory neurons in fish (Beard, 1889), and the naturally occurring histogenetic death of myocytes (Felix, 1889) and neurons (Collin, 1906). The current categorization of cell death into about three main morphological types has 19th century roots in that apoptosis was well described by Flemming (1885), who called it chromatolysis, and various authors including Noetzel (1895) proposed a threefold classification. This article is part of a Special Issue entitled “Apoptosis: Four Decades Later”

Presynaptic initiation by action potentials of retrograde signals in developing neurons.

Until recently, the only means by which electrical activity was believed to initiate retrograde signals was via postsynaptic events: modulated synthesis or release of trophic factors. We have evidence in chick embryos for a presynaptic initiation of retrograde signals from the retina to the isthmo-optic nucleus, which is known to undergo 55% neuron death between embryonic days 12 and 17 and to become laminated during this period. Intraocular injections of saxitoxin just before embryonic day 14 reduce neuron death and prevent lamination in the isthmo-optic nucleus within as few as 6 hr. We show that these rapid effects are attributable to the direct action of saxitoxin on the isthmo-optic terminals. Alternative possibilities, such as an indirect effect via the target cells, are ruled out by control experiments. Normally, action potentials may lead to a chain of second messenger events in the axon terminal that is signaled retrogradely via the transport of a long-lived second messenger

Rapid onset of neuronal death induced by blockade of either axoplasmic transport or action potentials in afferent fibers during brain development.

We have investigated how neurons in the optic tecta of embryonic day 16 chick embryos depend for survival on their afferents from the retina. To distinguish between activity-mediated effects and other, "trophic," ones, we compared the effects on the tectal neurons of blocking intraocular axoplasmic transport (with colchicine) or action potentials (by means of TTX). Both interventions rapidly induced the appearance of dying (pyknotic) neurons in the tectum, with major increases in their number occurring within 13 hr post-colchicine and within 9 hr post-TTX. Following both drugs, the dying neurons were morphologically similar, and in both cases the cell death depended on protein synthesis. However, the effects of colchicine and of TTX could be dissociated, since the most superficial tectal neurons became pyknotic only in response to colchicine, and, with a sufficiently short survival time (9 hr), the deep cells of the stratum griseum centrale became pyknotic only in response to TTX. We hence argue that the survival of the tectal neurons depends on their ongoing maintenance by substances released from retinotectal axon terminals, the release being activity dependent in the case of the deep neurons but independent of activity in the case of the superficial ones

Postischemic treatment of neonatal cerebral ischemia should target autophagy.

OBJECTIVE: To evaluate the contributions of autophagic, necrotic, and apoptotic cell death mechanisms after neonatal cerebral ischemia and hence define the most appropriate neuroprotective approach for postischemic therapy. METHODS: Rats were exposed to transient focal cerebral ischemia on postnatal day 12. Some rats were treated by postischemic administration of pan-caspase or autophagy inhibitors. The ischemic brain tissue was studied histologically, biochemically, and ultrastructurally for autophagic, apoptotic, and necrotic markers. RESULTS: Lysosomal and autophagic activities were increased in neurons in the ischemic area from 6 to 24 hours postinjury, as shown by immunohistochemistry against lysosomal-associated membrane protein 1 and cathepsin D, by acid phosphatase histochemistry, by increased expression of autophagosome-specific LC3-II and by punctate LC3 staining. Electron microscopy confirmed the presence of large autolysosomes and putative autophagosomes in neurons. The increases in lysosomal activity and autophagosome formation together demonstrate increased autophagy, which occurred mainly in the border of the lesion, suggesting its involvement in delayed cell death. We also provide evidence for necrosis near the center of the lesion and apoptotic-like cell death in its border, but in nonautophagic cells. Postischemic intracerebroventricular injections of autophagy inhibitor 3-methyladenine strongly reduced the lesion volume (by 46%) even when given >4 hours after the beginning of the ischemia, whereas pan-caspase inhibitors, carbobenzoxy-valyl-alanyl-aspartyl(OMe)-fluoromethylketone and quinoline-val-asp(OMe)-Ch2-O-phenoxy, provided no protection. INTERPRETATION: The prominence of autophagic neuronal death in the ischemic penumbra and the neuroprotective efficacy of postischemic autophagy inhibition indicate that autophagy should be a primary target in the treatment of neonatal cerebral ischemia

A centrifugally controlled circuit in the avian retina and its possible role in visual attention switching.

The isthmo-optic nucleus (ION) is the main source of efferents to the retina in birds. Isthmo-optic neurons project in topographical order on amacrine cells in the ventral parts of the retina, and a subclass of these known as proprioretinal neurons project onto the dorsal retina. We propose that, through the intermediary of the amacrine target cells, activity in the isthmo-optic pathway excites ganglion cells locally in the ventral retina but inhibits those in dorsal regions. This circuit would thereby mediate centrifugally controlled switches in attention between the dorsal retina, involved in feeding, and the more ventral parts, involved in scanning for predators. This hypothesis accounts for a wide range of disparate data from behavior, comparative anatomy, endocrinology, hodology, and neurophysiology

Neuronal death in the development of the vertebrate central nervous system

Neuronal death occurs naturally in the development of the vertebrate central nervous system, deleting large numbers of neurons at the time when afferent and efferent connections are being formed. It is these that regulate it, by means of anterograde and retrograde survival signals that depend on trophic molecules and electrical activity. Possible roles include the regulation of neuronal numbers (numerical matching) and the elimination of axonal targeting errors

An unbiased correction factor for cell counts in histological sections.

It is common procedure to correct raw counts of cells (or nuclei or other such particles) in histological sections by multiplying them by a 'correction factor', to allow for sectioned particles being counted more than once. However, the derivation of the standard formulae assumes that the particles to be counted are of uniform size. Therefore, these formulae may be biased in practical situations. Here, a more general correction factor (C) not depending on this restrictive assumption is derived: C = sigma i = 1 m T/(T - h(i))/sigma i = 1 m (T - R - S + h(i))/(T - h(i)) where T is section thickness, h(i) is the height of particle i measured perpendicular to the section plane, R and S are the heights, assumed constant, of the upper and lower 'lost caps', and the summation is performed over m (about 20) particles sampled randomly from among those lying wholly within individual sections. It is proposed that h(i) be measured by a differential focusing method; the formula will then be valid for particles of variable shape as well as size

The genuineness of isthmo-optic neuronal death in chick embryos.

It has previously been estimated that about 60% of the neurons in the chick's isthmo-optic nucleus die during development, since its total number of neurons decreases by this percentage. Theoretically, however, the decrease need not have been due to cell death, but could have been caused by either of two alternative possibilities: neurons might have migrated out of the nucleus, or they might have shrunk and therefore been misidentified as glial cells at later developmental stages. These possibilities have been tested, using horseradish peroxidase and tritiated thymidine as tracers, and both have been disproved. Hence, the 60% neuronal death is genuine