Age Related Microgravity Effects and Critical Periods

4.4.1 Critical Period

One interesting feature of sensory, neuronal, and motor systems is the existence of critical periods during their development. The concept of critical period during development goes back to studies performed by Nobel prizes



Figure 5-22. Left: Tail suspension technique used to unload the gravity load on the hind limb of the animals during various phases of their development. Right: Postnatal development of hind limb movements during swimming in neonate rats following tail suspension (S) during postnatal days P2 to P7 or P8 to PI 3. Swimming abilities defined by the stroke duration of the hind limb was slightly impaired after periods of suspension between postnatal days P2 to P7, while suspension between postnatal days P8 to P13 caused a dramatic impairment of swimming. When tested on Pll, they were unable to swim. This demonstrates a sensitive period in the development of motor patterns in the rat. Adapted from Walton (1998).

laureates Huber and Wiesel (1982) on the visual system in kitten. Deprivation is the preferred scientific method to study the existence and duration of critical periods. Consequently, every long-lasting change in the environment may have its specific critical period.

In general, three criteria have to be fulfilled to define a development period as "critical":

a. The developing system must be susceptible to a specific environmental modification;

b. The extent of modification must be related to age, and in particular to a well-defined period of development;

c. The modification must persist for long periods of postnatal life or even permanently.

In space studies, the first two criteria were observed. However, long-duration effects of irreversibity were rarely noted.

4.4.2 Development of Organs

Exposure to gravity deprivation using microgravity or weight unloading techniques gave evidence for the existence of age-related susceptibilities for morphological as well as for physiological and behavioral development. During the 16-day Neurolab mission, the development of various organs in flown neonate rats was strongly modified in the group launched at postnatal day P7. However, the modifications were smaller or absent in pups launched at postnatal day P14. In particular, after the flight, lung, heart, kidney, and adrenal glands of the P7 group were larger than ground controls. Thymus, spleen mesentery, and pancreas were smaller, and the aortic nerve had less unmyelinated fibers. In contrast, in the flight rats from the P14 group, only the kidney was heavier and the ovary lighter than in the ground controls (Miyake et al 2004). These observations clearly identified the second week of life as sensitive to gravity deprivation for morphological organ development.

4.4.3 Cell Cultures

Age-related effects of microgravity exposure became also obvious in cell cultures. Flown isolated embryonic mouse pretarsal mesenchym differentiated to cartilage as in the ground controls. The extent of this differentiation, however, depended on the state at launch. If pre-metatarsals had initiated chondrogenesis and morphometric patterning prior to launch, then cartilage rod size increased and rod shape was maintained. By contrast, older pre-metatarsal tissue, which had already terminally differentiated to hypertrophied cartilage, maintained rod structure and cartilage phenotype during the spaceflight (Klement and Spooner 1994).

Another example for age-related susceptibilities of cell cultures came from the development of neuron and myoblast synapses, as revealed by the

ACh receptor patches (Figure 5-06). Clinostat rotation on Earth inhibited the formation of nerve-associated ACh receptor patches if nerve contact took place during or shortly before onset of microgravity simulation, but not if this contact took place long before microgravity stimulation (Gruener and Hoeger 1990).

4.4.4 Motor and Sensory Systems

An age-related susceptibility to actual and simulated microgravity has been extensively described for motor and sensory systems. These studies mainly included observations in rats, amphibians, and fish.

In rats, motor development concerning the ability of swimming revealed a high susceptibility to weight unloading if tail suspension was performed between P8 and PI3 (Figure 5-22). Tail suspension during other periods was either ineffective or only slightly impaired swimming (Walton 1998).

The existence of a critical period for the development of the rVOR in zebrafish Danio rerio was unequivocally shown. The study by Moorman and collaborators (1999, 2002) is, so far, the only study for which the duration of the critical period was clearly determined. Zebrafish embryos were placed in a bioreactor developed by NASA at different periods of embryonic development. The bioreactor rotation started either at 3, 24, 30, 36, 48, or 72 hours after fertilization. The animals were then tested for their rVOR at 96 hours after fertilization. In other animals, rotation was started immediately after fertilization and measurements were done at different ages (24, 36, 48, 60, 66, 72, or 96 hours) after fertilization. Modifications of the rVOR were classified as normal, weakly depressed of short persistence, or depressed during a period of 5 days. Based on this classification, it was found that the critical period for rVOR lasted from 30 to 66 hours after fertilization.

As mentioned above, an age-related sensitivity of the rVOR with respect to microgravity also exists in fish Oreochromis mossambicus and in tadpoles Xenopus laevis (see Figures 5-15 and 5-16, respectively). In both species, the age at which the rVOR appeared for the first time revealed to be critical concerning the effects of microgravity (Sebastian et al. 1996, Sebastian and Horn 2002, Horn 2004).

Age-related susceptibilities also exist for exposure to hypergravity. For example, the rVOR of Xenopus laevis was not modified after a 12-day exposure to hypergravity starting about 12 hours after egg fertilization, but its further development in 1-g conditions was blocked. Older stages including the hind limb bud stage exposed to 3 g for 10 days revealed a significant decrease in the rVOR gain after return to normal gravity. In these groups, however, development continued normally after return to 1-g conditions, and normalization took place after several weeks depending on the stage at the onset of hypergravity (Horn and Sebastian 1996). Another example of a stage-related susceptibility to hypergravity is the development of the size of specific inhibitory GABAergic neurons (the common inhibitors CI1, CI2 and CI3) within the thoracic ganglia of house crickets Acheta domesticus after a 16-day exposure to 3-g centrifugation (Horn et al. 2001).

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