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Dendritic atrophy following partial motoneuron depletion: Time course of recovery and protection with androgens and estrogens.
Coons KD, Munoz F, Osborne MC, Sengelaub DR (2009) Dendritic atrophy following partial motoneuron depletion: Time course of recovery and protection with androgens and estrogens. Neuroscience 2009 Abstracts 743.2/R17. Society for Neuroscience, Chicago, IL.
Summary: We have previously demonstrated that partial depletion of motoneurons innervating the quadriceps muscles induces dendritic atrophy and loss of function in remaining motoneurons. Furthermore, treatment with testosterone is neuroprotective, and dendritic atrophy and loss of function following partial motoneuron depletion are attenuated in a dose-dependent fashion, and in both male and female rats. In the present study, we assessed dendritic atrophy after partial motoneuron depletion at a variety of time points to determine its time course and pattern with and without testosterone treatment. We also examined the potential neuroprotective effects of the androgenic and estrogenic metabolites of testosterone. Motoneurons innervating the vastus medialis muscle were selectively killed by intramuscular injection of cholera toxin-conjugated saporin. Simultaneously, saporin-injected males were given implants containing either testosterone (45mm), dihydrotestosterone (30mm), estradiol (10%, 10mm), or left untreated. At 2, 4, 6, or 10 weeks after partial motoneuron depletion, motoneurons innervating the ipsilateral vastus lateralis muscle were labeled with cholera toxin-conjugated HRP, and dendritic arbors were reconstructed in 3 dimensions. Animals treated with dihydrotestosterone or estradiol were assessed only at 4 weeks post depletion. Dendritic arbors were also assessed in a group of untreated normal males. Quadriceps motoneuron dendrites underwent a rapid atrophy and protracted recovery following partial motoneuron depletion. Dendritic atrophy in remaining quadriceps motoneurons was apparent at 2 weeks after motoneuron depletion, with a decrease of over 50% in dendritic length, and this atrophy remained through 6 weeks post-depletion; dendritic length recovered by 10 weeks post-depletion. Treatment with testosterone attenuated induced dendritic atrophy at all time points, and recovery to normal lengths was present at 6 weeks post-depletion. Treatment with dihydrotestosterone or estradiol was as effective as testosterone in attenuating dendritic atrophy in remaining quadriceps motoneurons. These results suggest that treatment with testosterone is neuroprotective, both attenuating induced dendritic atrophy and accelerating recovery. Furthermore, this effect can be achieved with both androgenic and estrogenic metabolites, further supporting a role for hormones as neurotherapeutic agents in the injured nervous system.
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Poster: Expression of cell fate determinants and plastic changes after neurotoxic lesion of adult mice spinal cord by cholera toxin-B saporin.
Gulino R, Gulisano M (2009) Poster: Expression of cell fate determinants and plastic changes after neurotoxic lesion of adult mice spinal cord by cholera toxin-B saporin. Neuroscience 2009 Abstracts 563.15/DD51. Society for Neuroscience, Chicago, IL.
Summary: Recent studies have attempted to achieve recovery after spinal cord (SC) injury or disease by either increase neurogenesis or stimulate neuroplasticity. Sonic hedgehog (Shh) Notch-1 and Numb are involved in the regulation of stem cell function. Additionally, Notch-1 has a role as modulator of synaptic plasticity. Little is known about the role of these proteins in the adult SC after selective removal of motoneurons. We injected Cholera toxin-B saporin into the gastrocnemius muscle to induce a selective depletion of motoneurons within lumbar mice SC and analysed the expression levels of Shh, Notch-1, Numb, Choline acetyltransferase (ChAT) and Synapsin-I proteins. The functional outcome of the lesion was monitored by grid walk test and rotarod. The neurotoxin lesion determined a motoneuron depletion and a decrease of ChAT and Synapsin-I protein levels in the lumbar SC. ChAT and Synapsin-I appeared correlated each other and with the motor performance, suggesting that the recovery of locomotion could depend from synaptic plasticity. Moreover, we observed a number of proliferating cells within the depleted SC, which were identified as active astrocytes. Shh and Notch-1 appeared reduced in the lesioned tissue and correlated with ChAT and Synapsin-I levels, suggesting a role in modulating synaptic plasticity. Numb expression was also reduced after lesion and appeared correlated with motor performance Therefore, given the role of these proteins in adult neurogenesis, we presume their involvement also in the observed glial reaction. The in vivo manipulation of Shh, Notch-1 and Numb signalling after lesion could be a way to reduce glial reaction and improve functional recovery.
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Neuroprotective effect of testosterone treatment on motoneuron recruitment following the death of nearby motoneurons.
Fargo KN, Foster AM, Sengelaub DR (2009) Neuroprotective effect of testosterone treatment on motoneuron recruitment following the death of nearby motoneurons. Dev Neurobiol 69:825-835. doi: 10.1002/dneu.20743
Summary: Previous work has demonstrated that testosterone treatment can prevent dendritic atrophy due to death of nearby motoneurons. This experiment examined whether this protection extends to motor activation. Rats received a 1 µg injection of CTB-SAP (Cat. #IT-14) into each of the right bulbocavernosus and levator ani muscles. Animals treated with testosterone preserved more of the activity duration than untreated animals, as well as no decrease in motoneuron recruitment.
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Targeted ablation of cardiac sympathetic neurons reduces resting, reflex and exercise-induced sympathetic activation in conscious rats.
Lujan HL, Palani G, Chen Y, Peduzzi JD, Dicarlo SE (2009) Targeted ablation of cardiac sympathetic neurons reduces resting, reflex and exercise-induced sympathetic activation in conscious rats. Am J Physiol Heart Circ Physiol 296:H1305-H1311. doi: 10.1152/ajpheart.00095.2009
Summary: This work examines the capability of CTB-SAP (Cat. #IT-14) to eliminate cardiac sympathetic neurons. The right and left stellate ganglia of rats were each injected with 10 µg of CTB-SAP. Lesioned animals displayed physiolo-gical differences from controls, as well as specific reduction of numbers of neurons in the stellate ganglion and spinal cord.
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Neuroprotective effects of testosterone on the morphology and function of somatic motoneurons following the death of neighboring motoneurons.
Little CM, Coons KD, Sengelaub DR (2009) Neuroprotective effects of testosterone on the morphology and function of somatic motoneurons following the death of neighboring motoneurons. J Comp Neurol 512:359-372. doi: 10.1002/cne.21885
Summary: Atrophy of androgen-sensitive motoneurons due to proximity to damaged motoneurons can be attenuated by testosterone. This work examined whether typical motoneurons respond in the same way. Rats received 5-ng injections of CTB-SAP (Cat. #IT-14) that eliminated motoneurons innervating the vastus medialis muscle. Partial motoneuron depletion resulted in atrophy of the remaining quadriceps motoneurons; this was attenuated by the administration of testosterone.
Related Products: CTB-SAP (Cat. #IT-14)
Protection from dendritic atrophy with testosterone following partial motoneuron depletion: Timing and duration of treatment, functional correlates in motor activation
Coons KD, Sengelaub DR (2008) Protection from dendritic atrophy with testosterone following partial motoneuron depletion: Timing and duration of treatment, functional correlates in motor activation. Neuroscience 2008 Abstracts 556.23/CC10. Society for Neuroscience, Washington, DC.
Summary: We have previously demonstrated that partial depletion of motoneurons innervating the quadriceps muscles induces dendritic atrophy in remaining motoneurons; this atrophy can be attenuated in a dose-dependent fashion, and in both male and female rats, with testosterone (T) treatment. In the present study, we examined (1) how the timing and duration of T treatment affect its ability to attenuate induced atrophy in remaining quadriceps motoneurons, and (2) the effects of induced atrophy and T treatment on subsequent motor function in male rats. Motoneurons innervating the vastus medialis muscles were selectively killed by intramuscular injection of cholera toxin-conjugated saporin. Rats were then treated with supplemental T at different times post-saporin injection (immediately, or at 2 or 3 weeks), or for different durations (1, 2, 3, or 4 weeks) or left untreated. All T treatments consisted of subcutaneous implants designed to produce plasma titers in the normal physiological range. Following treatment, the morphology of motoneurons innervating the ipsilateral vastus lateralis muscles was examined using retrograde labeling with cholera toxin-conjugated HRP. In a separate set of rats, quadriceps motoneuron activation was assessed using peripheral nerve recording. Motoneuron morphology and motor activation were also assessed in a group of untreated normal males. Partial motoneuron depletion resulted in dendritic atrophy in remaining quadriceps motoneurons. Treatment with T attenuated this atrophy, but in a time-sensitive manner. Four weeks of T treatment (delivered immediately post-saporin), or two weeks of T treatment (after a delay of two weeks post-saporin) were both effective in attenuating induced dendritic atrophy. However, dendritic atrophy in animals with immediate T treatment of shorter durations or longer delays in the start of treatment was comparable to that of animals who received no supplemental T. Consistent with the morphological changes, partial motoneuron depletion in otherwise untreated males resulted in deficits in motor activation: activation of quadriceps motoneurons required greater stimulus intensities and resulted in decreased amplitudes of motor nerve activity. Importantly, just as observed for dendritic morphology, these changes were attenuated by treatment with supplemental T. These results demonstrate that the neuroprotective effect of T on motoneuron morphology is more dependent on the timing of treatment than on its duration, and also provide a functional correlate of the morphological effects of that treatment, further supporting a role for T as a neurotherapeutic agent in the injured nervous system.
Related Products: CTB-SAP (Cat. #IT-14)
Sonic hedgehog expression and glial reaction after neurotoxic lesion of adult mice spinal cord by Cholera Toxin-B Saporin
Gulino R, Gulisano M (2008) Sonic hedgehog expression and glial reaction after neurotoxic lesion of adult mice spinal cord by Cholera Toxin-B Saporin. Neuroscience 2008 Abstracts 124.14/B14. Society for Neuroscience, Washington, DC.
Summary: The spinal cord (SC) has ever been considered non-neurogenic because no neurons seem to be generated in the intact SC and only very few recent articles have reported spontaneous generation of new neurons after lesion. Conversely, many studies have demonstrated the occurrence of glial reaction after either mechanical or selective neurotoxic lesion. Sonic hedgehog (Shh) is a member of hedgehog family of secreted glycoproteins, which stimulate cell proliferation as well as neuron and oligodendrocyte differentiation during either development and adulthood. Few data are available about its role in the adult SC after injury. In this study, we used Cholera toxin-B saporin (CTB-sap), a retrogradely transported, ribosome-inactivating toxin, to induce a mild neurotoxic depletion of motoneurons within lumbar SC and to subsequently study the expression levels of Shh and the possible cell proliferation and differentiation within the depleted SC of young adult mice. After an injection of CTB-sap into the gastrocnemius muscle, we found a 30% depletion of lumbar SC motoneurons, and a comparable decrease of ChAT expression levels in the lumbar SC, one week after lesion. Moreover, we found a significant down-regulation of Shh expression, which significantly correlate with ChAT decrease. Both proteins recovered to near normal levels of expression at one month after lesion. The expression of ChAT also correlate with the performance of mice on a grid walk test. So, the observed spontaneous recovery of locomotion was associated with the spontaneous recovery of ChAT and Shh expression. Moreover, we observed a cell proliferation within the depleted SC parenchyma, which was associated with a visible increase of GFAP-positive astrocytes in the same area. Colocalization studies showed that the majority of these proliferating cells are active astrocytes. We hypothesized that Shh expression could have a role in both SC plasticity and the observed glial reaction after neurotoxic lesion. The restoration of normal levels of Shh during the first days after lesion could be a way to partially inhibit glial reaction and to improve functional recovery.
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Selective impairment of the cerebellar C1 module involved in rat hind limb control reduces step-dependent modulation of cutaneous reflexes.
Pijpers A, Winkelman BH, Bronsing R, Ruigrok TJ (2008) Selective impairment of the cerebellar C1 module involved in rat hind limb control reduces step-dependent modulation of cutaneous reflexes. J Neurosci 28:2179-2189. doi: 10.1523/JNEUROSCI.4668-07.2008
Summary: The cerebellar cortex is arranged in a series of modules. Elucidation of module-specific function has been difficult because of the closely arranged structure of these modules. Here the authors lesioned the C1/C3 hindlimb module of the rat with CTB-SAP (Cat. #IT-14). Rats received 75-125 ng injections of CTB-SAP into the C1 zone of the copula pyramidis or the paramedian lobule of the right cerebellar hemisphere. C1-injected animals displayed marked diminishment of cutaneously induced reflexes with no significant impact on walking or stepping pattern.
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Protection from dendritic atrophy with testosterone following partial motoneuron depletion: dose-dependence in males and efficacy in females
Coons KD, Wilson RE, Sengelaub DR (2007) Protection from dendritic atrophy with testosterone following partial motoneuron depletion: dose-dependence in males and efficacy in females. Neuroscience 2007 Abstracts 56.11/S5. Society for Neuroscience, San Diego, CA.
Summary: Partial depletion of motoneurons from the highly androgen-sensitive spinal nucleus of the bulbocavernosus (SNB), or the more typical somatic motoneuron population innervating the quadriceps muscles, induces dendritic atrophy in remaining motoneurons. Treatment with testosterone (T) is neuroprotective, and dendritic atrophy following partial motoneuron depletion is attenuated in both populations. In the present study, we examined the dose-dependency of T effects in male rats, as well as its potential efficacy in females. Motoneurons innervating the bulbocavernosus/levator ani (BC/LA) or vastus medialis muscles were selectively killed by intramuscular injection of cholera toxin-conjugated saporin. Simultaneously, saporin-injected rats were given T implants designed to produce plasma titers ranging from 0.75 to 5.0 ng/ml or left untreated. Four weeks later, motoneurons innervating the contralateral BC or the ipsilateral vastus lateralis muscles were labeled with cholera toxin-conjugated HRP, and dendritic arbors were reconstructed in 3 dimensions. Partial motoneuron depletion resulted in dendritic atrophy in remaining SNB and quadriceps motoneurons (40% and 36% of normal length, respectively). T treatment attenuated this atrophy in a dose-dependent manner, with maximum effectiveness at 2.0-2.5 ng/ml (the normal adult physiological level). This dosage of T resulted in SNB dendritic lengths that did not differ from those of intact control males. In contrast, although dendritic atrophy in quadriceps motoneurons was attenuated by the same dosage of T, resultant dendritic lengths were 60% of normal length, and did not improve further with higher levels of T. Neuroprotective effects of T treatment were also assessed in quadriceps motoneurons in female rats (adult female rats lack the SNB neuromuscular system). As described above, motoneurons innervating the vastus medialis muscles were selectively killed by saporin injection, and females were given T implants (resulting in plasma levels of 2.0-2.5 ng/ml) or left untreated. Four weeks later, motoneurons innervating the ipsilateral vastus lateralis muscles were labeled with cholera toxin-conjugated HRP, and dendritic arbors were reconstructed. As in males, partial motoneuron depletion in females resulted in dendritic atrophy (52% of normal length) in remaining quadriceps motoneurons, and this atrophy was attenuated (70% of normal length) with T treatment. Together, these findings suggest that the neuroprotective effects of T on dendrites are achieved with dosages within the normal physiological range, and furthermore can be observed in motoneurons of both male and female rats.
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Dendritic atrophy following partial motoneuron depletion: time course of recovery and protection with testosterone
Ferguson AS, Sengelaub DR (2007) Dendritic atrophy following partial motoneuron depletion: time course of recovery and protection with testosterone. Neuroscience 2007 Abstracts 56.24/S18. Society for Neuroscience, San Diego, CA.
Summary: In male rats, motoneurons of the spinal nucleus of the bulbocavernosus (SNB) project to the bulbocavernosus and levator ani (BC/LA) muscles, and both the motoneurons and their target muscles are highly androgen-sensitive. We have previously demonstrated that partial depletion of motoneurons from the SNB induces dendritic atrophy in remaining motoneurons, and that treatment with testosterone (T) is neuroprotective against this atrophy. In the present study, we assessed dendritic atrophy after partial motoneuron depletion in SNB motoneurons at a variety of time points, to determine its time course and pattern with and without T treatment. Motoneurons innervating the BC/LA muscles in gonadally intact males were selectively killed by intramuscular injection of cholera toxin-conjugated saporin. Simultaneously, saporin-injected males were given T implants (45mm) or left untreated. At 2, 4, 6, or 10 weeks after motoneuron depletion, motoneurons innervating the contralateral BC were labeled with cholera toxin-conjugated HRP, and dendritic arbors were reconstructed in 3 dimensions. As previously reported, partial motoneuron depletion resulted in dendritic atrophy in remaining SNB motoneurons. While motoneuron depletion occurs within 7 days after saporin injection, dendritic atrophy in remaining SNB motoneurons progresses linearly over several weeks, with a decrease of 32% present at 2 weeks after motoneuron depletion, and a decrease to 66% at 4 weeks. Evidence of recovery in dendritic lengths was observed at 6 weeks post depletion (only 43% decreased), and by 10 weeks SNB dendritic lengths had returned to those of normal, intact males. Treatment with T altered the pattern of dendritic atrophy. While initial dendritic atrophy was similar to that of untreated saporin-injected males (29% decreased at 2 weeks post motoneuron depletion), T treatment attenuated dendritic atrophy. Four weeks after motoneuron depletion, SNB dendritic lengths had not declined further in T-treated males (32% decreased), and were now 102% longer than those of untreated, saporin-injected males. These findings suggest that SNB dendrites undergo a protracted atrophy and subsequent recovery following partial motoneuron depletion, and that the neuroprotective effects of T attenuate the magnitude of the induced atrophy.
Related Products: CTB-SAP (Cat. #IT-14)