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In JoVE (1)
Other Publications (11)
- The Journal of Comparative Neurology
- Proceedings of the National Academy of Sciences of the United States of America
- General and Comparative Endocrinology
- The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
- Hormones and Behavior
- The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
- Neurorehabilitation and Neural Repair
- The Journal of Comparative Neurology
- Development, Growth & Differentiation
- The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
- The Journal of Physiology
Articles by Christopher K. Thompson in JoVE
JoVE Clinical and Translational Medicine
Methods to Quantify Pharmacologically Induced Alterations in Motor Function in Human Incomplete SCI
1Sensory Motor Performance Program, Rehabilitation Institute of Chicago, 2Department of Kinesiology and Nutrition, University of Illinois at Chicago, 3Department of Physical Therapy, University of Illinois at Chicago
This video demonstrates modulation of reflex activity, volitional strength and ambulation through clinical and quantitative assessments in individuals with motor incomplete SCI as a result of acute oral administration of a serotonin reuptake inhibitor (SSRI).
Other articles by Christopher K. Thompson on PubMed
Seasonal Change in Neuron Size and Spacing but Not Neuronal Recruitment in a Basal Ganglia Nucleus in the Avian Song Control System
Neural plasticity in the song control system of seasonally breeding songbirds accompanies seasonal changes in singing behavior. The volume of Area X, a song control nucleus that forms a portion of the avian basal ganglia, is 75% larger in the spring than it is in the fall. The neuronal basis of the seasonal plasticity in Area X is largely unknown, however. We examined neuronal attributes of Area X in wild adult male song sparrows (Melospiza melodia) captured during the spring and the fall after being implanted for 30 days with osmotic pumps containing [3H]thymidine. We measured the volume of Area X from thionin-stained sections, and neuronal density and number, and average area of the soma from sections labeled with an antibody against Hu, a neuron-specific protein. We sampled two neuron classes: "small" neurons that were most likely striatal-like spiny neurons and "large" neurons, which most likely included pallidal-like projection neurons. We also analyzed seasonal patterns of neuronal recruitment to Area X. The average area of the soma and neuronal spacing for both neuronal classes were greater in breeding birds. There was no difference in total neuron number for both neuronal classes between seasons. The average area of the soma and density and number of newly recruited neurons did not vary across seasons. These results demonstrate that seasonal plasticity in Area X includes changes in neuron size and neuronal density, but not changes in the rate at which new neurons are recruited.
Rapid Seasonal-like Regression of the Adult Avian Song Control System
We analyzed how rapidly avian song control nuclei regress after testosterone (T) withdrawal. Regression of neuronal attributes resulting from T withdrawal has been observed in several animal models. The time course over which regression occurs is not known, however. To address this issue, we castrated adult male white-crowned sparrows and rapidly shifted them to short-day photoperiods after being held under breeding conditions (long-day photoperiod and systemic T exposure) for 3 weeks. We found that the volume of one song nucleus, HVC, regressed 22% within 12 h after T withdrawal. Changes in HVC neuron density after T withdrawal were dynamic; density increased at 12 h and then decreased by 4 days. HVC neuron number was reduced by 26% by 4 days. The volumes of Area X and the robust nucleus of the arcopallium (RA) were significantly regressed by 7 and 20 days, respectively. RA somatic area and neuronal spacing were significantly reduced by 2 days. The rapidity of HVC regression is unprecedented among vertebrate models of hormone-sensitive neural circuits. These results reveal that the rapid regression of the song control system provides a model for the important role sex steroid hormones play in mediating adult neural plasticity and in neuroprotection.
Seasonal-like Growth and Regression of the Avian Song Control System: Neural and Behavioral Plasticity in Adult Male Gambel's White-crowned Sparrows
Birdsong is regulated by a series of discrete brain nuclei known as the song control system. In seasonally-breeding male songbirds, seasonal changes in steroid sex hormones regulate the structure and electrophysiology of song control system neurons, resulting in dramatic changes in singing behavior. Male songbirds can be brought into the laboratory, where circulating levels of steroid hormone and photoperiod can be abruptly manipulated, providing controlled conditions under which rapid "seasonal-like" changes in behavior and morphology can be carefully studied. In this mini-review, we discuss the steroidal and cellular mechanisms underlying seasonal-like growth and regression of the song control system in adult male Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii), and its impact on song behavior. Specifically, we discuss recent advances concerning: (1) the role of androgen and estrogen receptors in inducing seasonal-like growth of the song control system; (2) how photoperiod modulates the time course of testosterone-induced growth of the song control system; (3) how bilateral intracerebral infusion of androgen and estrogen receptor antagonists near the song control nucleus HVC prevents seasonal-like increases in song stereotypy but not song rate; and (4) the steroidal and cellular mechanisms that mediate rapid regression of the song control system. Throughout this mini-review we compare data collected from white-crowned sparrows to that from other songbird species. We conclude by outlining avenues of future research.
Caspase Inhibitor Infusion Protects an Avian Song Control Circuit from Seasonal-like Neurodegeneration
Sex steroids such as androgens and estrogens have trophic effects on the brain and can ameliorate neurodegeneration, and the withdrawal of circulating steroids induces neurodegeneration in several hormone-sensitive brain areas. Very little is known about the underlying molecular mechanisms that mediate neuronal regression caused by hormone-withdrawal, however. Here we show that reduction of programmed cell death by local infusion of caspase inhibitors rescues a telencephalic nucleus in the adult avian song control system from neurodegeneration that is induced by hormone withdrawal. This treatment also has trans-synaptic effects that provide some protection of an efferent target region. We found that unilateral infusion of caspase inhibitors in vivo in adult white-crowned sparrows rescued neurons within the hormone-sensitive song nucleus HVC (used as a proper name) from programmed cell death for as long as seven days after withdrawal of testosterone and a shift to short-day photoperiod and that the activation of caspase-3 was reduced by 59% on average in the ipsilateral HVC compared with the unmanipulated contralateral HVC. Caspase inhibitor infusion near HVC was sufficient to preserve neuron size ipsilaterally in a downstream nucleus, the robust nucleus of the arcopallium. This is the first report that sustained local application of caspase inhibitors can protect a telencephalic brain area from neurodegeneration in vivo and that a degenerating neural circuit rescued with caspase inhibitors produces sufficient trophic support to protect attributes of a downstream target that would otherwise degenerate. These results strengthen the case for the possible therapeutic use of caspase inhibitors under certain neurodegenerative conditions.
Time Course of Changes in Gambel's White-crowned Sparrow Song Behavior Following Transitions in Breeding Condition
Seasonal changes in behavior and in its underlying neural substrate are common across animal taxa. These changes are often triggered by steroid sex hormones. Song in seasonally breeding songbirds provides an excellent example of this phenomenon. In these species, dramatic seasonal changes mediated by testosterone and its metabolites occur in adult song behavior and in the neural circuitry controlling song. While song rate can quickly change in response to seasonal breeding cues, it is unknown how quickly other aspects of song change, particularly the stereotypy of song phonology and syntax. In this study we determined whether and how quickly song rate, phonology, and syntax change in response to breeding and non-breeding physiological cues. We asked these questions using Gambel's white-crowned sparrows (Zonotrichia leucophrys gambelii), a closed-ended learner with well-characterized changes in the neural circuitry controlling song behavior. We exposed ten photosensitive sparrows to long-day photoperiod and implanted them with subcutaneous testosterone pellets (day 0) to simulate breeding conditions. We continuously recorded song and found that song rate increased quickly, reaching maximum around day 6. The stereotypy of song phonology changed more slowly, reaching maximum by day 10 or later. Song syntax changed minimally after day 6, the earliest time point examined. After 21 days, we transitioned five birds from breeding to non-breeding condition. Song rate declined precipitously. These results suggest that while song rate changes quickly, song phonology changes more slowly, generally following or in parallel with previously investigated changes in the neural substrate.
Neurogenesis in an Adult Avian Song Nucleus is Reduced by Decreasing Caspase-mediated Apoptosis
Neuron death and replacement are fundamental components of brain plasticity. Much remains unknown, however, about the mechanistic interaction between neuron death and neurogenesis in adult vertebrates. In seasonally breeding adult male white-crowned sparrows, the song system nucleus HVC loses approximately 26% of its neurons via caspase-dependent apoptosis within 4 d after a transition to nonbreeding physiological conditions. To determine whether neuronal death is necessary for the recruitment of new neurons, we infused caspase inhibitors into HVC in vivo and suppressed neurodegeneration for at least 20 d after the transition to nonbreeding conditions. The blockade of HVC neuron death reduced the number and density of new neurons recruited to the ipsilateral HVC by 48 and 29%, respectively, compared with contralateral HVC. Our results are the first to show that reducing neuronal death in the adult brain decreases the recruitment of new neurons.
Repeated Maximal Volitional Effort Contractions in Human Spinal Cord Injury: Initial Torque Increases and Reduced Fatigue
Substantial data indicate greater muscle fatigue in individuals with spinal cord injury (SCI) compared with healthy control subjects when tested by using electrical stimulation protocols. Few studies have investigated the extent of volitional fatigue in motor incomplete SCI.
Neuroprotective Effects of Testosterone in a Naturally Occurring Model of Neurodegeneration in the Adult Avian Song Control System
Seasonal regression of the avian song control system, a series of discrete brain nuclei that regulate song learning and production, serves as a useful model for investigating the neuroprotective effects of steroids. In seasonally breeding male songbirds, the song control system regresses rapidly when males are transferred from breeding to nonbreeding physiological conditions. One nucleus in particular, the HVC, regresses in volume by 22% within days of castration and transfer to a nonbreeding photoperiod. This regression is mediated primarily by a 30% decrease in neuron number, a result of a caspase-dependent process of programmed cell death. Here we examine whether testosterone (T) can act locally in the brain to prevent seasonal-like neurodegeneration in HVC. We began to infuse T intracerebrally near HVC on one side of the brain in breeding-condition male white-crowned sparrows 2 days prior to T withdrawal and shifting them to short-day photoperiods. The birds were killed 3 or 7 days later. Local T infusion significantly protected ipsilateral HVC from volume regression and neuron loss. In addition, T infusion significantly reduced the number, density, and number/1,000 neurons of activated caspase-3 cells and cells positive for cleaved PARP, both markers for programmed cell death, in the ipsilateral HVC. T infusion near HVC also prevented regression of ipsilateral efferent targets of HVC neurons, including the volumes of robust nucleus of the arcopallium (RA) and Area X and the soma area and density of RA neurons. Thus T can act locally in the brain to have a neuroprotective effect and act transsynaptically to prevent regression of efferent nuclei.
Cell Death and the Song Control System: a Model for How Sex Steroid Hormones Regulate Naturally-occurring Neurodegeneration
The production, learning, and perception of song in songbirds are regulated by a series of discrete brain nuclei known as the song control system. In most songbird species, the song control system is sexually dimorphic, and these dimorphisms become more robust after birds have hatched. In seasonally breeding songbirds, the song control system grows and regresses depending upon breeding context. The development and seasonal plasticity of the song control system are dependent upon neurodegenerative processes, which can be ameliorated, at least in part, by circulating sex steroid hormones. I will describe two areas of song control system research that have provided important information about how hormonal control of cell death contributes to the shaping of behaviorally-relevant brain circuits. First, sexual dimorphism in the zebra finch song control system is robust and emerges partially due to substantial regression of female song control system nuclei during development. Second, in seasonally-breeding songbirds, the song control system regresses as birds transition from breeding to non-breeding conditions. In a controlled laboratory setting where hormones can be acutely withdrawn, these brain areas regress in only a matter of hours to days. Taken together, these results demonstrate that the study of cell death in the song control system provides an excellent opportunity for understanding how changes in circulating levels of sex steroids affect the degeneration of hormone-sensitive brain circuits.
Extra Forces Evoked During Electrical Stimulation of the Muscle or Its Nerve Are Generated and Modulated by a Length-dependent Intrinsic Property of Muscle in Humans and Cats
Extra forces or torques are defined as forces or torques that are larger than would be expected from the input or stimuli, which can be mediated by properties intrinsic to motoneurons and/or to the muscle. The purpose of this study was to determine whether extra forces/torques evoked during electrical stimulation of the muscle or its nerve with variable frequency stimulation are modulated by muscle length/joint angle. A secondary aim was to determine whether extra forces/torques are generated by an intrinsic neuronal or muscle property. Experiments were conducted in 14 able-bodied human subjects and in eight adult decerebrate cats. Torque and force were measured in human and cat experiments, respectively. Extra forces/torques were evoked by stimulating muscles with surface electrodes (human experiments) or by stimulating the nerve with cuff electrodes (cat experiments). In humans and cats, extra forces/torques were larger at short muscle lengths, indicating that a similar regulatory mechanism is involved. In decerebrate cats, extra forces and length-dependent modulation were unaffected by intrathecal methoxamine injections, despite evidence of increased spinal excitability, and by transecting the sciatic nerve proximal to the nerve stimulations. Anesthetic nerve block experiments in two human subjects also failed to abolish extra torques and the length-dependent modulation. Therefore, these data indicate that extra forces/torques evoked during electrical stimulation of the muscle or nerve are muscle length-dependent and primarily mediated by an intrinsic muscle property.
Central Excitability Contributes to Supramaximal Volitional Contractions in Human Incomplete Spinal Cord Injury
Despite greater muscle fatigue in individuals with spinal cord injury (SCI) when compared to neurologically intact subjects using neuromuscular electrical stimulation (NMES)protocols, few studies have investigated the extent of volitional fatigue in motor incomplete SCI. Using an established protocol of 20 repeated, intermittent, maximal volitional effort (MVE) contractions, we previously demonstrated that subjects with incomplete SCI unexpectedly demonstrated a 15% increase in peak knee extensor torques within the first five MVEs with minimal evidence of fatigue after 20 contraction. In the present study, we investigated potential segmental mechanisms underlying this supramaximal torque generation. Changes in twitch properties and maximum compound muscle action potentials (M-waves) were assessed prior to and following one, three and five MVEs, revealing a significant 17% increase only in maximum twitch torques after a single MVE. Despite this post-activation potentiation of the muscle, use of conventional NMES protocols to elicit repeated muscular contractions resulted in a significant decrease in evoked torque generation, suggesting limited the muscular contributions to the observed phenomenon. To evaluate potential central mechanisms underlying the augmented torques, non-linear responses to wide-pulse width (1 ms), low-intensity, variable-frequency (25–100 Hz) NMES were also tested prior to and following repeated MVEs.When variable-frequency NMES was applied following the repeated MVEs, augmented and prolonged torques were observed and accompanied by sustained quadriceps electromyographic activity often lasting > 2s after stimulus termination. Such data suggest a potential contribution of elevated spinal excitability to the reserve in volitional force generation in incomplete SCI.
