Testosterone fails to save androgen-sensitive rat motoneurons following early target removal

doi:10.1016/0165-3806(92)90196-4

Developmental Brain Research

Volume 70, Issue 2, 18 November 1992, Pages 181-189

https://doi.org/10.1016/0165-3806(92)90196-4 Get rights and content

Abstract

Axotomy during development can result in the death of up to 100% of the affected motoneurons. However, axotomy-induced death can be ]ignificantly reduced by administration of androgens in young rats. Motoneuron death in the spinal nucleus of the bulbocavernosus (SNB) has previously been shown to be regulated by androgens during development. The present experiment examined the effects of androgen treatment on the survival of SNB motoneurons after target removal and concomitant axotomy early in development. On the day of birth, two target muscles of SNB motoneurons of male and female rats were bilaterally extirpated. Target removal resulted in a dramatic loss of SNB motoneurons within 48 h of surgery, with an ultimate loss of virtually all motoneurons projecting to the extirpated muscles by postnatal day 10. Treatment with testosterone failed to save SNB motoneurons from target removal-induced death. Pups treated with testosterone after target removal did not differ in the pattern or timing of motoneuron loss from untreated pups at any age examined. Counts of degenerating cells in the SNB reflected the extensive motoneuron loss and also did not differ with testosterone treatment. These results indicate that testosterone cannot save the androgen-sensitive SNB motoneurons from death after target removal and concomitant axotomy early in development. The failure of testosterone treatment to rescue SNB motoneurons in the absence of the SNB target musculature further suggests that during normal development, both androgens and target muscles are necessary for SNB motoneuron survival.

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Given that the effects of conditional ARKO in myocytes is similar between developmental and adult myocyte ARKO (Rana et al., 2016), we infer that the reduction in LA size reflects an activational effect, rather than an organizational effect. Nonetheless, we remain confident that the site of action of androgen in the organization of a masculine SNB system is in the vicinity of the target muscles, as extirpation or local flutamide treatment of target muscles prevents masculinization of SNB motoneurons in rats (Kurz et al., 1992; Fishman and Breedlove, 1992). Selective genetic manipulations have also been used to study activational androgenic influence on the SNB system.
Testicular androgens are the major endocrine factor promoting masculine phenotypes in vertebrates, but androgen signaling is complex and operates via multiple signaling pathways and sites of action. Recently, selective androgen receptor mutants have been engineered to study androgenic mechanisms of sexual differentiation of the nervous system and behavior. The focus of these studies has been to evaluate androgenic mechanisms within the nervous system by manipulating androgen receptor conditionally in neural tissues. Here we review both the effects of neural loss of AR function as well as the effects of neural overexpression of AR in relation to global AR mutants. Although some studies have conformed to our expectations, others have proved challenging to assumptions underlying the dominant hypotheses. Notably, these studies have called into question both the primacy of direct, neural mechanisms and also the linearity of the relationship between androgenic dose and sexual differentiation of brain and behavior.
Androgen regulation of axon growth and neurite extension in motoneurons
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Androgens act on the CNS to affect motor function through interaction with a widespread distribution of intracellular androgen receptors (AR). This review highlights our work on androgens and process outgrowth in motoneurons, both in vitro and in vivo. The actions of androgens on motoneurons involve the generation of novel neuronal interactions that are mediated by the induction of androgen-dependent neurite or axonal outgrowth. Here, we summarize the experimental evidence for the androgenic regulation of the extension and regeneration of motoneuron neurites in vitro using cultured immortalized motoneurons, and axons in vivo using the hamster facial nerve crush paradigm. We place particular emphasis on the relevance of these effects to SBMA and peripheral nerve injuries.
Cell death and sexual differentiation of the nervous system
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Sex differences in nuclear volume or neuron number often are attributed to the hormonal control of cell death. In the spinal nucleus of the bulbocavernosus, the central portion of the medial preoptic nucleus, and the principal nucleus of the bed nucleus of the stria terminalis testicular hormones decrease cell death during perinatal life, resulting in a male advantage in neuron number in adulthood. Conversely, males have more dying cells during development and fewer neurons in adulthood than do females in the anteroventral periventricular nucleus of the hypothalamus. This review discusses several limitations and unresolved issues in the literature on sexually dimorphic cell death, and identifies molecular mechanisms by which gonadal steroids may control cell survival. In particular, evidence is presented for the hormonal regulation of neurotrophic factors and involvement of Bcl-2 family proteins in the determination of sex differences in neuron number.
Cell death of spinal interneurones
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Circulating hormones may also modulate cell survival, although in some instances, such as the androgen-dependent perineal motoneurones in the lower lumbar spinal cord, their action appears to be mediated indirectly through maintenance of the target muscles rather than directly on the motoneurones (Kurz et al., 1992).
The occurrence of neuronal death during development is well documented for some neuronal populations, such as motoneurones and dorsal root ganglion cells, whose connecting pathways are clearly defined. Cell survival is thought to be regulated largely by target and input connections, a process that serves to match the size of synaptically linked neuronal populations. Far less is known about interneurones. It is assumed that most interneurone populations are excluded from this process because their connections are more diffuse. Recent studies on the rat spinal cord have indicated that interneurone death does occur, both naturally during development and induced following peripheral nerve injury. Here the evidence for spinal interneurone death is reviewed and the factors influencing it are discussed. There are many functional types of interneurones in the spinal cord that may differ in vulnerability to cell death, but it is concluded that for most spinal interneurones the traditional view of target regulation is unlikely. Instead it is proposed that developmental interneurone death in the spinal cord forms part of a plastic response to altered sensory activation rather than a size-matching exercise. There is also emerging evidence that interneurone death may play a more direct role in some neurodegenerative diseases than hitherto considered.
Anabolic-androgenic steroid induced alterations in choline acetyltransferase messenger RNA levels of spinal cord motoneurons in the male rat
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The effect of chronic supraphysiological doses of anabolic-androgenic steroids, such as those illegally used by recreational, amateur and professional athletes to increase muscle mass and strength, on motoneurons has not been established. The choline acetyltransferase activity levels of perineal muscles in the male rat are modulated by plasma testosterone levels. These muscles are innervated by the sexually dimorphic motoneurons of the spinal nucleus of the bulbocavernosus. Since the primary source of choline acetyltransferase in muscle is motoneuronal, testosterone may modulate perineal muscle choline acetyltransferase activity by regulating choline acetyltransferase messenger RNA levels in motoneurons. The purpose of this study was to determine if choline acetyltransferase messenger RNA levels in cervical and lumbar spinal motoneurons are affected by chronic (four weeks) changes of plasma testosterone levels in the adult male rat. Using in situ hybridization, choline acetyltransferase messenger RNA levels were analysed in four motor columns: the spinal nucleus of the bulbocavernosus, the retrodorsal lateral nucleus of the lumbar spinal cord, and the lumbar lateral motor columns of the cervical and lumbar spinal cords. Chronic exposure to supraphysiological levels of testosterone (five- to ten-times physiologic levels) significantly increased choline acetyltransferase messenger RNA in all four motor columns. Subsequent to castration, choline acetyltransferase messenger RNA levels decreased in motoneurons of the spinal nucleus of the bulbocavernosus and the retrodorsal lateral nucleus. This observation suggests that the decrease in choline acetyltransferase activity levels of muscles innervated by spinal nucleus of the bulbocavernosus motoneurons may be due to changes in choline acetyltransferase protein levels. Indeed, testosterone replacement therapy of castrated males prevented the decline of choline acetyltransferase messenger RNA levels in motoneurons.
The results of this study demonstrate that anabolic-androgenic steroids can affect the levels of specific messenger RNAs in motoneuron populations throughout the spinal cord suggesting that motoneuronal characteristics are modulated by circulating anabolic-androgenic steroid levels regardless of the purported “androgen sensitivity” of the specific neuromuscular system.
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Sex steroids are known to play a crucial role in reproductive neuroendocrine functions in adulthood. A number of neurons in the neuroendocrine brain contain sex steroid receptors, and are thought to be a key element of functional neural circuits that are regulated by sex steroids. Motoneurons in the spinal nucleus of the bulbocavernosus in adult male rodents are one of the androgen-sensitive neural substrates. In the spinal nucleus of the bulbocavernosus, castration of adult male rats results in a significant decrease in the somatic size and dendritic length of the motoneurons, and in the number and size of chemical and electrical (gap junction) synapses onto these motoneurons. Androgen treatment of castrates reverses these changes. Furthermore, androgen has been reported to be involved in regulation of androgen receptor expression and gene expression of structural proteins such as β-actin, β-tubulin and gap junction channels in these motoneurons. The findings suggest that androgen induces morphological and molecular changes in the motoneurons that reflect their neural functions, and may provide evidence for the mechanisms of hormonally induced neuronal plasticity in the motoneurons in adulthood.

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Research reportTestosterone fails to save androgen-sensitive rat motoneurons following early target removal

Abstract

Dev. Brain Res.

Brain Res.

Exp. Neurol.

Neurosci. Res.

Dev. Brain Res.

Exp. Neurol.

Exp. Neurol.

Exp. Neurol.

Immediate postnatal rise in whole body androgen content in male rats: correlation with increased testicular content and reduced body clearance of testosterone

Biol. Reprod.

Hormone accumulation in a sexually dimorphic motor nucleus of the rat spinal cord

Science

Sexually dimorphic motor nucleus in rat spinal cord: Response to adult hormone manipulation, absence in androgen-insensitive rats

Brain Res.

Hormonal control of a developing neuromuscular system: I. Complete demasculinization of the male rat spinal nucleus of the bulbocavernosus using the anti-androgen flutamide

J. Neurosci.

Hormonal control of a developing neuromuscular system: II. Sensitive periods for the androgen-induced masculinization of the rat spinal nucleus of the bulbocavernosus

J. Neurosci.

Sex differences in the pattern of steroid accumulation of motoneurons of the rat lumbar spinal cord

J. Comp. Neurol.

Involution and hormone-induced persistence of the muscle sphincter (levator) ani in female rats

J. anat.

Androgen treatment does not prevent the death of sexually dimorphic rat spinal motoneurons following early target removal

Soc. Neurosci. Abstr.

The dependence of motoneurons on their target muscle during postnatal development of the mouse

J. Neurosci.

Androgen and estrogen binding in rat skeletal and perineal muscles

Can. J. Biochem.

Androgen blockade of bulbocavernosus muscle inhibits testosterone-dependent masculinization of spinal motoneurons in newborn female rats

Soc. Neurosci. Abstr.

Neonatal androgen maintains sexually dimorphic muscles in the absence of innervation

Muscle Nerve

Evidence for androgen receptors in sexually dimorphic perineal muscles of neonatal male rats

J. Neurobiol.

Seasonal variation in mammalian striated muscle mass and motoneuron morphology

J. Neurobiol.

Hormonal control of neuron number in sexually dimorphic spinal nuclei of the rat: IV. Masculinization of the spinal nucleus of the bulbocavernosus the testosterone metabolites

J. Neurobiol.

Androgen regulation of dendritic growth and retraction in the development of a sexually dimorphic spinal nucleus

J. Neurosci.

The Anatomy of the Rat

Cell death in the development of the lateral motor column of the chick embryo

J. Comp. Neurol.

Penile mechanisms and the role of the striated penile muscles in penile reflexes

Physiol. Behav.

Ontogeny of steroid accumulation in spinal lumbar motoneurons of the rat: implications for androgen's site of action during synapse elimination

J. Comp. Neurol.

The role of gonadal hormones in neuromuscular synapse elimination in rats: I. Androgen delays the loss of multiple innervation in the levator ani muscle

J. Neurosci.

The role of gonadal hormones in neuromuscular synapse elimination in rats: II. Multiple innervation persists in the adult levator ani after juvenile androgen treatment

J. Neurosci.

Research report
Testosterone fails to save androgen-sensitive rat motoneurons following early target removal