Effects of a protein synthesis inhibitor on the hormonally mediated regression and death of motoneurons in the tobacco hornworm,Manduca sexta

The larval–pupal transformation of Manduca sexta is accompanied by the loss of the abdominal prolegs. The proleg muscles degenerate, the dendritic arbors of proleg motoneurons regress, and a subset of the proleg motoneurons dies. The regression and death of proleg motoneurons are triggered by the prepupal peak of ecdysteroids in the hemolymph. To investigate the possible involvement of protein synthesis in these events, we gave insects repeated injections of the protein synthesis inhibitor, cycloheximide (CHX), during the prepupal peak. Examination of insects 3–5 days following CHX treatment showed that CHX inhibited the death of proleg motoneurons and the production of pupal cuticle in a dose-dependent fashion. When insects were allowed to survive for 10 days after the final CHX injection, motoneuron death and pupal cuticle production sometimes occurred belatedly, apparently in response to the ecdysteroid rise that normally triggers adult development. CHX treatments that inhibited motoneuron death were less effective in inhibiting dendritic regression in the same neurons. In another set of experiments, abdomens were isolated from the ecdysteroid-secreting glands prior to the prepupal peak, and infused with 20-hydroxyecdysone (20-HE). Single injections of CHX delivered just prior to the start of the 20-HE infusion inhibited motoneuron death and pupal cuticle production, but in the range of doses tested, did not prevent dendritic regression. Our findings suggest that protein synthesis is a required step in the steroid-mediated death of proleg motoneurons, and that dendritic regression is less susceptible to inhibition by CHX than is motoneuron death. © 1993 John Wiley & Sons, Inc.     

A rectifying electrotonic synapse in the central nervous system of a vertebrate

The adductor muscles of the pectoral fins of the hatchetfish Gasteropelecus are innervated by bilateral pools of about 40 motoneurons which lie primarily in the first spinal segment. A pair of giant fibers on each side of the medulla send processes ventroposteriorly to the motoneuron pools. Electrophysiological evidence indicates that giant fibers are presynaptic to ipsilateral motoneurons, but not to contralateral ones. Transmission across the giant fiber, motoneuron synapse is electrically mediated as is indicated by direct measurement of electrotonic spread in either direction across the synapse, and by the extremely short latency of the giant fiber postsynaptic potentials (PSP's) in the motoneuron. The coupling resistance across the synapse was calculated from measurements of input and transfer resistance. The coupling resistance rectifies in such a way as to facilitate spread of depolarization from giant fiber to motoneuron, and to oppose transmission in the opposite direction. As a consequence of rectification, the giant fiber PSP in a motoneuron is augmented by hyperpolarization of the motoneuron. The coupling resistance calculated on the basis of this effect is in good agreement with calculations from input and transfer resistance data. Rectification at the electrotonic synapses may permit the motoneurons to act in small swimming movements as well as to fire synchronously in an extremely fast escape reflex mediated by Mauthner and giant fibers.     

Nerve-muscle interactions regulate motor terminal growth and myoblast distribution during muscle development

Interactions between motoneurons and muscles influence many aspects of neuromuscular development in all animals. These interactions can be readily investigated during adult muscle development in holometabolous insects. In this study, the development of the dorsolongitudinal flight muscle (DLM) and its innervation is investigated in the moth, Manduca sexta, to address the specificity of neuromuscular interactions. The DLM develops from an anlage containing both regressed larval template fibers and imaginal myoblasts. In the adult, each fiber bundle (DLM1-5) is innervated by a single motoneuron (MN1-MN5), with the dorsal-most fiber bundle (DLM5) innervated by a mesothoracic motoneuron (MN5). The DLM failed to develop following complete denervation because myoblasts failed to accumulate in the DLM anlage. After lesioning MN1-4, MN5 retained its specificity for the DLM5 region of the anlage and failed to rescue DLM1-4. Thus specific innervation of the DLM fiber bundles does not depend on interactions among motoneurons. Myoblast accumulation, but not myonuclear proliferation, increased around the MN5 terminals, producing a hypertrophied adult DLM5. Therefore, motoneurons compete for uncommitted myoblasts. MN5 terminals subsequently grew more rapidly over the hypertrophied DLM5 anlage, indicating that motoneuron terminal expansion is regulated by the size of the target muscle anlage.     

Dendritic Targeting in the Leg Neuropil of Drosophila: The Role of Midline Signalling Molecules in Generating a Myotopic Map

Neural maps are emergent, highly ordered structures that are essential for organizing and presenting synaptic information. Within the embryonic nervous system of Drosophila motoneuron dendrites are organized topographically as a myotopic map that reflects their pattern of innervation in the muscle field. Here we reveal that this fundamental organizational principle exists in adult Drosophila, where the dendrites of leg motoneurons also generate a myotopic map. A single postembryonic neuroblast sequentially generates different leg motoneuron subtypes, starting with those innervating proximal targets and medial neuropil regions and producing progeny that innervate distal muscle targets and lateral neuropil later in the lineage. Thus the cellular distinctions in peripheral targets and central dendritic domains, which make up the myotopic map, are linked to the birth-order of these motoneurons. Our developmental analysis of dendrite growth reveals that this myotopic map is generated by targeting. We demonstrate that the medio-lateral positioning of motoneuron dendrites in the leg neuropil is controlled by the midline signalling systems Slit-Robo and Netrin-Fra. These results reveal that dendritic targeting plays a major role in the formation of myotopic maps and suggests that the coordinate spatial control of both pre- and postsynaptic elements by global neuropilar signals may be an important mechanism for establishing the specificity of synaptic connections.     

Comparison of identified leg motoneuron structure and function between larval and adult Manduca sexta

Persistent leg motoneurons of the moth Manduca sexta were investigated in larval and adult animals to compare their dendritic structures, intrinsic electrical properties and pattern of target innervation. The study focused on two identified motoneurons of the prothoracic leg. Despite the complete remodeling of leg muscles, the motoneurons innervated pretarsal flexor muscles in both larval and adult legs. Similarly, although the central dendrites regress and regrow, the branching pattern was similar with the exception of a prominent midline branch that was not present in the adult stage. The intrinsic electrical properties of the motoneurons differed between larval and adult stages. Larval motoneurons had significantly higher membrane input resistances and more depolarized resting membrane potentials than did motoneurons in pharate adults or adults. In all stages, one motoneuron had a low maximal firing frequency, whereas the second motoneuron, which innervated the other half of the muscle, had a high maximum firing frequency. Although the two motoneurons continued to innervate the same halves of the target muscle, their relative effects on muscular contraction were reversed during metamorphosis along with concomitant changes in intrinsic properties. Pretarsal flexor motoneurons in pharate adults (just prior to emergence) displayed properties similar to those in emerged adults. Accepted: 8 January 2000     

Postembryonic development of centrally generated flight motor patterns in the hawkmoth, Manduca sexta

This study analyses the maturation of centrally generated flight motor patterns during metamorphosis of Manduca sexta. Bath application of the octopamine agonist chlordimeform to the isolated central nervous system of adult moths reliably induces fictive flight patterns in wing depressor and elevator motoneurons. Pattern maturation is investigated by chlordimeform application at different developmental stages. Chlordimeform also induces motor patterns in larval ganglia, which differ from fictive flight, indicating that in larvae and adults, octopamine affects different networks. First changes in motoneuron activity occur at the pupal stage P10. Rhythmic motor output is induced in depressor, but not in elevator motoneurons at P12. Adult-like fictive flight activity in motoneurons is observed at P16 and increases in speed and precision until emergence 2 days later. Pharmacological block of chloride channels with picrotoxin also induces fictive flight in adults, suggesting that the pattern-generating network can be activated by the removal of inhibition, and that proper network function does not rely on GABA_A receptors. Our results suggest that the flight pattern-generating network becomes gradually established between P12 and P16, and is further refined until adulthood. These findings are discussed in the context of known physiological and structural CNS development during Manduca metamorphosis.     

Differential effects of octopamine and tyramine on the central pattern generator for <Emphasis Type="Italic">Manduca</Emphasis> flight

The biogenic amine, octopamine, modulates a variety of aspects of insect motor behavior, including direct action on the flight central pattern generator. A number of recent studies demonstrate that tyramine, the biological precursor of octopamine, also affects invertebrate locomotor behaviors, including insect flight. However, it is not clear whether the central pattern generating networks are directly affected by both amines, octopamine and tyramine. In this study, we tested whether tyramine affected the central pattern generator for flight in the moth, Manduca sexta. Fictive flight was induced in an isolated ventral nerve cord preparation by bath application of the octopamine agonist, chlordimeform, to test potential effects of tyramine on the flight central pattern generator by pharmacological manipulations. The results demonstrate that octopamine but not tyramine is sufficient to induce fictive flight in the isolated ventral nerve cord. During chlordimeform induced fictive flight, bath application of tyramine selectively increases synaptic drive to depressor motoneurons, increases the number of depressor spikes during each cycle and decreases the depressor phase. Conversely, blocking tyramine receptors selectively reduces depressor motoneuron activity, but does not affect cycle by cycle elevator motoneuron spiking. Therefore, octopamine and tyramine exert distinct effects on the flight central pattern generating network.     

Segment-specific retention of a larval neuromuscular system and its role in a new, rhythmic, pupal motor pattern in Manduca sexta

At pupation in Manduca sexta, accessory planta retractor muscles and their motoneurons degenerate in segment-specific patterns. Accessory planta retractor muscles in abdominal segments 2 and 3 survive in reduced form through the pupal stage and degenerate after adult emergence. Electromyographic and electrophysiological recordings show that these accessory planta retractor muscles participate in a new, rhythmic `pupal motor pattern' in which all four muscles contract synchronously at ∼4 s intervals for extended bouts. Accessory planta retractor muscle contractions are driven by synaptic activation of accessory planta retractor motoneurons and are often accompanied by rhythmic activity in intersegmental muscles and spiracular closer muscles. The pupal motor pattern is influenced by descending neural input although isolated abdominal ganglia can produce a pupal motor pattern-like rhythm. The robust pupal motor pattern first seen after pupal ecdysis weakens during the second half of pupal life. Anemometric recordings indicate that the intersegmental muscle and spiracular closer muscle component of the pupal motor pattern produces ventilation. Accessory planta retractor muscle contractions lift the flexible abdominal floor, to which the developing wings and legs adhere tightly. We hypothesize that, by a bellows-like action, the accessory planta retractor muscle contractions circulate hemolymph in the appendages. Morphometric analysis shows that dendritic regression is similar in accessory planta retractor motoneurons with different pupal fates, and that accessory planta retractor motoneurons begin to participate in the pupal motor pattern while their dendrites are regressed. Accepted: 29 March 1998     

Neuroprotective Effects on the Morphology of Somatic Motoneurons Following the Death of Neighboring Motoneurons: A Role for Microglia?

Partial depletion of spinal motoneuron populations induces dendritic atrophy in neighboring motoneurons, and treatment with testosterone protects motoneurons from induced dendritic atrophy. We explored a potential mechanism for this induced atrophy and protection by testosterone, examining the microglial response to partial depletion of motoneurons. Motoneurons innervating the vastus medialis muscles of adult male rats were killed by intramuscular injection of cholera toxin‐conjugated saporin; some saporin‐injected rats were treated with testosterone. Microglia were later visualized via immunohistochemical staining, classified as monitoring or activated, and counted stereologically. Partial motoneuron depletion increased the number of activated microglia in the quadriceps motor pool, and this increase was attenuated with testosterone treatment. The attenuation in microglial response could reflect an effect of testosterone on suppressing microglia activation, potentially sparing motoneuron dendrites. Alternatively, testosterone could be neuroprotective, sparing motoneuron dendrites, secondarily resulting in reduced microglial activation. To discriminate between these hypotheses, following partial motoneuron depletion, rats were treated with minocycline to inhibit microglial activation. Motoneurons innervating the ipsilateral vastus lateralis muscle were later labeled with cholera toxin‐conjugated horseradish peroxidase, and dendritic arbors were reconstructed. Reduction of microglial activation by minocycline did not prevent induced dendritic atrophy following partial motoneuron depletion. Further, reduction of microglial activation by minocycline treatment resulted in dendritic atrophy in intact animals. Together, these findings indicate that the neuroprotective effect of testosterone on dendrites following motoneuron death is not due to inhibiting microglial activation, and that microglial activity contributes to the normal maintenance of dendritic arbors.     

The back and forth of dendritic plasticity

Synapses are located throughout the often-elaborate dendritic tree of central neurons. Hebbian models of plasticity require temporal association between synaptic input and neuronal output to produce long-term potentiation of excitatory transmission. Recent studies have highlighted how active dendritic spiking mechanisms control this association. Here, we review new work showing that associative synaptic plasticity can be generated without neuronal output and that the interplay between neuronal architecture and the active electrical properties of the dendritic tree regulates synaptic plasticity.     

Metamorphic-like changes in the nervous system of the nematode Caenorhabditis elegans

During postembryonic development of the nematode Caenorhabditis elegans, one class of embryonic motoneurons, the DD cells, respecifies its pattern of synaptic connections. At the same time, a closely related set of postembryonic motoneurons, the VD cells, complete differentiation and assume a pattern of connections equivalent to the original pattern of the DD cells. These types of changes are reminiscent of changes observed in the nervous systems of animals as they undergo metamorphosis. The DD and VD neurons arise through different lineage mechanisms and in the adult, receive different synaptic inputs and make different outputs. The embryonic DD motoneurons are clonally related to one another; whereas the postembryonic VD motoneurons are produced by a repeated sublineage in which each stem cell generates four or five cell types in addition to the VD cells. In spite of these differences, it has been possible to identify only one gene by mutation that effects one of the two motoneuronal classes. Mutations in the gene unc-55 (unc meaning uncoordinated) cause the VD cells to become essentially identical to the DD cells; thus the unc-55 gene product appears necessary and sufficient to transform homeotically the pattern of synaptic connections of an entire class of motoneuron.     

Opiate-Induced Suppression of Rat Hypoglossal Motoneuron Activity and Its Reversal by Ampakine Therapy

Background

Hypoglossal (XII) motoneurons innervate tongue muscles and are vital for maintaining upper-airway patency during inspiration. Depression of XII nerve activity by opioid analgesics is a significant clinical problem, but underlying mechanisms are poorly understood. Currently there are no suitable pharmacological approaches to counter opiate-induced suppression of XII nerve activity while maintaining analgesia. Ampakines accentuate α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor responses. The AMPA family of glutamate receptors mediate excitatory transmission to XII motoneurons. Therefore the objectives were to determine whether the depressant actions of μ-opioid receptor activation on inspiratory activity includes a direct inhibitory action at the inspiratory premotoneuron to XII motoneuron synapse, and to identify underlying mechanism(s). We then examined whether ampakines counteract opioid-induced depression of XII motoneuron activity.

Methodology/Principal Findings

A medullary slice preparation from neonatal rat that produces inspiratory-related output in vitro was used. Measurements of inspiratory burst amplitude and frequency were made from XII nerve roots. Whole-cell patch recordings from XII motoneurons were used to measure membrane currents and synaptic events. Application of the μ-opioid receptor agonist, DAMGO, to the XII nucleus depressed the output of inspiratory XII motoneurons via presynaptic inhibition of excitatory glutamatergic transmission. Ampakines (CX614 and CX717) alleviated DAMGO-induced depression of XII MN activity through postsynaptic actions on XII motoneurons.

Conclusions/Significance

The inspiratory-depressant actions of opioid analgesics include presynaptic inhibition of XII motoneuron output. Ampakines counteract μ-opioid receptor-mediated depression of XII motoneuron inspiratory activity. These results suggest that ampakines may be beneficial in countering opiate-induced suppression of XII motoneuron activity and resultant impairment of airway patency.     

Neuroprotective effect of testosterone treatment on motoneuron recruitment following the death of nearby motoneurons

Motoneuron loss is a significant medical problem, capable of causing severe movement disorders or even death. We have previously shown that motoneuron death induces marked dendritic atrophy in surviving nearby motoneurons. Additionally, in quadriceps motoneurons, this atrophy is accompanied by decreases in motor nerve activity. However, treatment with testosterone partially attenuates changes in both the morphology and activation of quadriceps motoneurons. Testosterone has an even larger neuroprotective effect on the morphology of motoneurons of the spinal nucleus of the bulbocavernosus (SNB), in which testosterone treatment can completely prevent dendritic atrophy. The present experiment was performed to determine whether the greater neuroprotective effect of testosterone on SNB motoneuron morphology was accompanied by a greater neuroprotective effect on motor activation. Right side SNB motoneurons were killed by intramuscular injection of cholera toxin‐conjugated saporin in adult male Sprague‐Dawley rats. Animals were either given Silastic testosterone implants or left untreated. Four weeks later, left side SNB motor activation was assessed with peripheral nerve recording. The death of right side SNB motoneurons resulted in several changes in the electrophysiological response properties of surviving left side SNB motoneurons, including decreased background activity, increased response latency, increased activity duration, and decreased motoneuron recruitment. Treatment with exogenous testosterone attenuated the increase in activity duration and completely prevented the decrease in motoneuron recruitment. These data provide a functional correlate to the known protective effects of testosterone treatment on the morphology of these motoneurons, and further support a role for testosterone as a therapeutic agent in the injured nervous system. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2009     

The role of delayed excitation in the co-ordination of some metathoracic flight motoneurons of a locust

Summary Intracellular recordings have been made from the somata of two metathoracic flight motoneurons, one innervating an elevator muscle of the hindwing, the tergosternal muscle 113 and the other a depressor, the first basalar muscle 127. The locust,Ghortoicetes terminifera was mounted ventral side uppermost with the thorax restrained and opened for access to the thoracic ganglia. Patterns of electrical activity recorded from the thoracic muscles were similar to those shown by a locust during flight when tethered in a more normal posture. In flight the left and right 113 motoneurons each receive a single impulse together at every stroke of the wing, with the 127 muscles active in approximate antiphase. A spike in a 113 motoneuron causes a delayed wave of excitation simultaneously upon itself and its contralateral partner (Fig. 2). The epsp's which form these waves summate and may cause a spike which follows the original one with a delay equal to the wingbeat period. The delayed excitation of the contralateral motoneuron is of larger amplitude than the ipsilateral one so that spikes in either motoneuron must activate separate but symmetrical pathways. A single spike may cause multiple waves in either motoneuron, each separated by intervals equal to the wingbeat period (Fig. 3). In the pathway must be neurons capable of reverberation.A spike in a 113 motoneuron causes a delayed excitation of the ipsilateral 127 motoneuron so that its membrane potential is lowered antiphasically to that of 113 (Fig. 17). A spike in a 127 motoneuron has no effect on the 113 motoneurons. In flight these pathways causing delayed excitation may co-ordinate the motoneurons.The left and right 113 motoneurons receive common synaptic inputs from at least two sources (Fig. 8). These occur as bursts of epsp's at intervals approximately equal to or multiples of the wingbeat period and in the absence of flight. Epsp's of sufficient amplitude cause a spike in the motoneuron which is in the correct phase in the flight pattern relative to any other active motoneurons (Fig. 9). During sustained flight epsp's contribute to the wave of depolarization that the motoneuron undergoes at each wingbeat (Fig. 11). In the absence of the epsp's the motoneuron does not oscillate on its own. At the end of flight bursts of epsp's may continue at the flight frequency long after all activity in the muscles has ceased.Beit Memorial Research Fellow.     

Phrenic motoneuron morphology during rapid diaphragm muscle growth.

In the adult rat, there is a general correspondence between the sizes of motoneurons, motor units, and muscle fibers that has particular functional importance in motor control. During early postnatal development, after the establishment of singular innervation, there is rapid growth of diaphragm muscle (Dia(m)) fibers. In the present study, the association between Dia(m) fiber growth and changes in phrenic motoneuron size (both somal and dendritic) was evaluated from postnatal day 21 (D21) to adulthood. Phrenic motoneurons were retrogradely labeled with fluorescent tetramethylrhodamine dextran (3,000 MW), and motoneuron somal volumes and surface areas were measured using three-dimensional confocal microscopy. In separate animals, phrenic motoneurons retrogradely labeled with choleratoxin B-fragment were visualized using immunocytochemistry, and dendritic arborization was analyzed by camera lucida. Between D21 and adulthood, Dia(m) fiber cross-sectional area increased by approximately 164% overall, with the growth of type II fibers being disproportionate to that of type I fibers. There was also substantial growth of phrenic motoneurons ( approximately 360% increase in total surface area), during this same period, that was primarily attributable to an expansion of dendritic surface area. Comparison of the distribution of phrenic motoneuron surface areas between D21 and adults suggests the establishment of a bimodal distribution that may have functional significance for motor unit recruitment in the adult rat.     

Impact of motor activity and antennal mechanosensory input on the intensity of proctolin-like immunoreactivity in antennal motoneurons of crickets (Gryllus bimaculatus)

The change of the intensity of proctolin immunolabeling of 2 of 17 proctolinergic antennal motoneurons [one adductor (Ad3), and one depressor (D5)] was quantitatively studied in crickets in relation to flight and antennal deafferentation. During flight, the maintained forward position of the antennae is supported by high frequency tonic firing of Ad3 but probably all motoneurons are activated. In animals sacrificed immediately after the last of five consecutive flight periods the intensity of proctolin-like immunolabeling showed a significant decrease in the Ad3 soma in comparison to the Ad3 of non-flyers. The identical result was observed in the D5 soma. In animals sacrificed 40 h after flight, no difference in the intensity of proctolin immunolabeling between the Ad3 soma of flyers and non-flyers was evident. Thus, at high motoneuron activity, the production of proctolin may not be able to keep pace with its transport from the soma. Deletion of all proprioceptors of one antenna which respond to horizontal movements only led to a significant decrease of the intensity of proctolin immunolabeling in the Ad3 soma on the operated side, but not in the soma of D5. This indicates that selected afferent input has an impact on proctolin expression in distinct motoneuron pools. Accepted: 7 February 1997     

Effects of evoked and spontaneous motoneuronal firing on synapse competition and elimination in skeletal muscle

Synapse elimination is a general feature of the development of neural connections, including the connections of motoneurons to skeletal muscle fibers. Our work addressed two questions: (1) how the action potentials generated in the set of motoneurons innervating an individual muscle (i.e., in a motor pool) are correlated in time during development in vivo; (2) what influence different firing patterns exert on the processes of polyneuronal innervation and synapse elimination which characterize the establishment of muscle innervation. We recorded the spontaneous electromyographic activity of the tibialis anterior and soleus muscles of late embryonic and neonatal rats, identifying the firing of at least two single motor unit signals in each record. We found that a striking switch occurs a few days after birth from a highly synchronous type of firing to an asynchronous one, the first thus characterizing embryonic while the second one adult motoneurons. We also investigated the effects of an evoked synchronous type of discharge on neuromuscular synapse formation, measuring polyneuronal innervation and synapse elimination. This was done in an adult in vivo model of de novo synapse formation, while a chronic TTX nerve conduction block, placed centrally with respect to the stimulating electrodes, eliminated the natural activity of motoneurons. We found that the imposed synchronous activity greatly inhibits synapse elimination, causing polyneuronal innervation to persist. We conclude that the early synchronous firing, favors the establishment of polyneuronal innervation while the subsequent switch to an asynchronous one promotes synapse elimination.     

Neuroprotective effects of testosterone metabolites and dependency on receptor action on the morphology of somatic motoneurons following the death of neighboring motoneurons

Partial depletion of spinal motoneuron populations induces dendritic atrophy in neighboring motoneurons, and treatment with testosterone is neuroprotective, attenuating induced dendritic atrophy. In this study we examined whether the protective effects of testosterone could be mediated via its androgenic or estrogenic metabolites. Furthermore, to assess whether these neuroprotective effects were mediated through steroid hormone receptors, we used receptor antagonists to attempt to prevent the neuroprotective effects of hormones after partial motoneuron depletion. Motoneurons innervating the vastus medialis muscles of adult male rats were selectively killed by intramuscular injection of cholera toxin‐conjugated saporin. Simultaneously, some saporin‐injected rats were treated with either dihydrotestosterone or estradiol, alone or in combination with their respective receptor antagonists, or left untreated. Four weeks later, motoneurons innervating the ipsilateral vastus lateralis muscle were labeled with cholera toxin‐conjugated horseradish peroxidase, and dendritic arbors were reconstructed in three dimensions. Compared with intact normal animals, partial motoneuron depletion resulted in decreased dendritic length in remaining quadriceps motoneurons. Dendritic atrophy was attenuated with both dihydrotestosterone and estradiol treatment to a degree similar to that seen with testosterone, and attenuation of atrophy was prevented by receptor blockade. Together, these findings suggest that neuroprotective effects on motoneurons can be mediated by either androgenic or estrogenic hormones and require action via steroid hormone receptors, further supporting a role for hormones as neurotherapeutic agents in the injured nervous system. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 691–707, 2017     

Androgenic, but not estrogenic, protection of motoneurons from somal and dendritic atrophy induced by the death of neighboring motoneurons

Motoneuron loss is a significant medical problem, capable of causing severe movement disorders or even death. We have been investigating the effects of motoneuron loss on surviving motoneurons in a lumbar motor nucleus, the spinal nucleus of the bulbocavernosus (SNB). SNB motoneurons undergo marked dendritic and somal atrophy following the experimentally induced death of other nearby SNB motoneurons. However, treatment with testosterone at the time of lesioning attenuates this atrophy. Because testosterone can be metabolized into the estrogen estradiol (as well as other physiologically active steroid hormones), it was unknown whether the protective effect of testosterone was an androgen effect, an estrogen effect, or both. In the present experiment, we used a retrogradely transported neurotoxin to kill the majority of SNB motoneurons on one side of the spinal cord only in adult male rats. Some animals were also treated with either testosterone, the androgen dihydrotestosterone (which cannot be converted into estradiol), or the estrogen estradiol. As seen previously, partial motoneuron loss led to reductions in soma area and in dendritic length and extent in surviving motoneurons. Testosterone and dihydrotestosterone attenuated these reductions, but estradiol had no protective effect. These results indicate that the neuroprotective effect of testosterone on the morphology of SNB motoneurons following partial motoneuron depletion is an androgen effect rather than an estrogen effect.