The Experts below are selected from a list of 96 Experts worldwide ranked by ideXlab platform
Henrik Bringmann - One of the best experts on this subject based on the ideXlab platform.
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a wake Active locomotion circuit depolarizes a sleep Active Neuron to switch on sleep
PLOS Biology, 2020Co-Authors: Michal Turek, Judith Besseling, Henrik Bringmann, Elisabeth Maluck, Inka Busack, Florentin Masurat, Karl Emanuel BuschAbstract:Sleep-Active Neurons depolarize during sleep to suppress wakefulness circuits. Wake-Active wake-promoting Neurons in turn shut down sleep-Active Neurons, thus forming a bipartite flip-flop switch. However, how sleep is switched on is unclear because it is not known how wakefulness is translated into sleep-Active Neuron depolarization when the system is set to sleep. Using optogenetics in Caenorhabditis elegans, we solved the presynaptic circuit for depolarization of the sleep-Active RIS Neuron during developmentally regulated sleep, also known as lethargus. Surprisingly, we found that RIS activation requires Neurons that have known roles in wakefulness and locomotion behavior. The RIM interNeurons-which are Active during and can induce reverse locomotion-play a complex role and can act as inhibitors of RIS when they are strongly depolarized and as activators of RIS when they are modestly depolarized. The PVC command interNeurons, which are known to promote forward locomotion during wakefulness, act as major activators of RIS. The properties of these locomotion Neurons are modulated during lethargus. The RIMs become less excitable. The PVCs become resistant to inhibition and have an increased capacity to activate RIS. Separate activation of neither the PVCs nor the RIMs appears to be sufficient for sleep induction; instead, our data suggest that they act in concert to activate RIS. Forward and reverse circuit activity is normally mutually exclusive. Our data suggest that RIS may be activated at the transition between forward and reverse locomotion states, perhaps when both forward (PVC) and reverse (including RIM) circuit activity overlap. While RIS is not strongly activated outside of lethargus, altered activity of the locomotion interNeurons during lethargus favors strong RIS activation and thus sleep. The control of sleep-Active Neurons by locomotion circuits suggests that sleep control may have evolved from locomotion control. The flip-flop sleep switch in C. elegans thus requires an additional component, wake-Active sleep-promoting Neurons that translate wakefulness into the depolarization of a sleep-Active Neuron when the worm is sleepy. Wake-Active sleep-promoting circuits may also be required for sleep state switching in other animals, including in mammals.
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a wake Active locomotion circuit depolarizes a sleep Active Neuron to switch on sleep
bioRxiv, 2019Co-Authors: Michal Turek, Judith Besseling, Henrik Bringmann, Elisabeth Maluck, Inka Busack, Florentin Masurat, Karl Emanuel BuschAbstract:Abstract Sleep-Active Neurons depolarize during sleep to suppress wakefulness circuits. Wake-Active wake-promoting Neurons in turn shut down sleep-Active Neurons, thus forming a bipartite flip-flop switch. However, how sleep is switched on is unclear because it is not known how wakefulness is translated into sleep-Active Neuron depolarization when the system is set to sleep. Using optogenetics in C. elegans, we solved the presynaptic circuit for depolarization of the sleep-Active RIS Neuron during developmentally-regulated sleep, also known as lethargus. Surprisingly, we found that RIS activation requires Neurons that have known roles in wakefulness and locomotion behavior. The RIM interNeurons, which are Active during and can induce reverse locomotion, play a complex role and can act as inhibitors of RIS when they are strongly depolarized and as activators of RIS when they are modestly depolarized. The PVC command interNeurons, which are known to promote forward locomotion during wakefulness, act as major activators of RIS. The properties of these locomotion Neurons are modulated during lethargus. The RIMs become less excitable. The PVCs become resistant to inhibition and have an increased capacity to activate RIS. Separate activation of neither the PVCs nor the RIMs appears to be sufficient for sleep induction; instead, our data suggests that they act in concert to activate RIS. Forward and reverse circuit activity is normally mutually exclusive. Our data suggest that RIS may be activated at the transition between forward and reverse locomotion states, perhaps when both reverse (including RIM) and forward (PVC) circuit activity overlaps. While RIS is not strongly activated outside of lethargus, altered activity of the locomotion interNeurons during lethargus favors strong RIS activation and thus sleep. The control of sleep-Active Neurons by locomotion circuits suggests that sleep may have evolved from locomotion quiescence. The flip-flop sleep switch in C. elegans thus requires an additional component, wake-Active sleep-promoting Neurons that translate wakefulness into the depolarization of a sleep-Active Neuron when the worm is sleepy. Wake-Active sleep-promoting circuits may also be required for sleep state switching in other animals including in mammals.
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automated detection and manipulation of sleep in c elegans reveals depolarization of a sleep Active Neuron during mechanical stimulation induced sleep deprivation
Scientific Reports, 2018Co-Authors: Jan Spies, Henrik BringmannAbstract:Across species, sleep is characterized by a complex architecture. Sleep deprivation is a classic method to study the consequences of sleep loss, which include alterations in the activity of sleep circuits and detrimental consequences on well being. Automating the observation and manipulation of sleep is advantageous to study its regulation and functions. Caenorhabditis elegans shows sleep behavior similar to other animals that have a nervous system. However, a method for real-time automatic sleep detection that allows sleep-specific manipulations has not been established for this model animal. Also, our understanding of how sleep deprivation affects sleep Neurons in this system is incomplete. Here we describe a system for real-time automatic sleep detection of C. elegans grown in microfluidic devices based on a frame-subtraction algorithm using a dynamic threshold. As proof of principle for this setup, we used automated mechanical stimulation to perturb sleep behavior and followed the activity of the sleep-Active RIS Neuron. We show that our system can automatically detect sleep bouts and deprive worms of sleep. We found that mechanical stimulation generally leads to the activation of the sleep-Active RIS Neuron, and this stimulation-induced RIS depolarization is most prominent during sleep deprivation.
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sleep Active Neuron specification and sleep induction require flp 11 neuropeptides to systemically induce sleep
eLife, 2016Co-Authors: Michal Turek, Judith Besseling, Janphilipp Spies, Sabine Konig, Henrik BringmannAbstract:Sleep is an essential behavioral state. It is induced by conserved sleep-Active Neurons that express GABA. However, little is known about how sleep Neuron function is determined and how sleep Neurons change physiology and behavior systemically. Here, we investigated sleep in Caenorhabditis elegans, which is induced by the single sleep-Active Neuron RIS. We found that the transcription factor LIM-6, which specifies GABAergic function, in parallel determines sleep Neuron function through the expression of APTF-1, which specifies the expression of FLP-11 neuropeptides. Surprisingly FLP-11, and not GABA, is the major component that determines the sleep-promoting function of RIS. FLP-11 is constantly expressed in RIS. At sleep onset RIS depolarizes and releases FLP-11 to induce a systemic sleep state.
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an ap2 transcription factor is required for a sleep Active Neuron to induce sleep like quiescence in c elegans
Current Biology, 2013Co-Authors: Michal Turek, Ines Lewandrowski, Henrik BringmannAbstract:Summary Background Sleep is an essential behavior that is found in all animals that have a nervous system. Neural activity is thought to control sleep, but little is known about the identity and the function of neural circuits underlying sleep. Lethargus is a developmentally regulated period of behavioral quiescence in C. elegans larvae that has sleep-like properties. Results We studied sleep-like behavior in C. elegans larvae and found that it requires a highly conserved AP2 transcription factor, aptf-1 , which was expressed strongly in only five interNeurons in the head. Expression of aptf-1 in one of these Neurons, the GABAergic Neuron RIS, was required for quiescence. RIS was strongly and acutely activated at the transition from wake-like to sleep-like behavior. Optogenetic activation of aptf-1 -expressing Neurons ectopically induced acute behavioral quiescence in an aptf-1 -dependent manner. RIS ablation caused a dramatic reduction of quiescence. RIS-dependent quiescence, however, does not require GABA but requires neuropeptide signaling. Conclusions We conclude that RIS acts as a sleep-Active, sleep-promoting Neuron that requires aptf-1 to induce sleep-like behavior through neuropeptide signaling. Sleep-promoting GABAergic-peptidergic Neurons have also been identified in vertebrate brains, suggesting that common circuit principles exist between sleep in vertebrates and sleep-like behavior in invertebrates.
Mark Zorbas - One of the best experts on this subject based on the ideXlab platform.
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Morphologic, Stereologic, and Morphometric Evaluation of the Nervous System in Young Cynomolgus Monkeys (Macaca fascicularis) Following Maternal Administration of Tanezumab, a Monoclonal Antibody to Nerve Growth Factor
2016Co-Authors: Mark Butt, Thomas Cummings, Satoru Oneda, Mark Evans, Christopher J. Bowman, David Shelton, Mark ZorbasAbstract:Tanezumab, an antibody to nerve growth factor, was administered to pregnant cynomolgus monkeys at 0, 0.5, 4, and 30 mg/kg weekly, beginning gestation day (GD) 20 through parturition (GD165). Maternal tanezumab administration appeared to increase stillbirths and infant mortality, but no consistent pattern of gross and/or microscopic change was detected to explain the mortality. Offspring exposed in utero were evaluated at 12 months of age using light microscopy (all tissues), stereology (basal forebrain cholinergic and dorsal root ganglia Neurons), and morphometry (sural nerve). Light microscopy revealed decreased number of Neurons in sympathetic ganglia (superior mesenteric, cervicothoracic, and ganglia in the thoracic sympathetic trunk). Stereologic assessment indicated an overall decrease in dorsal root ganglion (thoracic) volume and number of Neurons in animals exposed to tanezumab 4 mg/kg (n9) and 30 mg/kg (n1). At all tanezumab doses, the sural nerve was small due to decreases in myelinated and unmyelinated axons. Existing axons/ myelin sheaths appeared normal when viewed with light and transmission electron microscopy. There was no indication of tanezumab-related, Active Neuron/nerve fiber degeneration/necrosis in any tissue, indicating decreased sensory/ sympathetic Neurons and axonal changes were due to hypoplasia or atrophy. These changes in the sensory and sympathetic portions of the peripheral nervous system suggest some degree of developmental neurotoxicity, although what effect, if any, the changes had on normal function and survival was not apparent. Overall, these changes wer
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morphologic stereologic and morphometric evaluation of the nervous system in young cynomolgus monkeys macaca fascicularis following maternal administration of tanezumab a monoclonal antibody to nerve growth factor
Toxicological Sciences, 2014Co-Authors: Mark Butt, Thomas Cummings, Satoru Oneda, David L Shelton, Mark Evans, Christopher N. Bowman, Mark ZorbasAbstract:Tanezumab, an antibody to nerve growth factor, was administered to pregnant cynomolgus monkeys at 0, 0.5, 4, and 30 mg/kg weekly, beginning gestation day (GD) 20 through parturition (� GD165). Maternal tanezumab administration appeared to increase stillbirths and infant mortality, but no consistent pattern of gross and/or microscopic change was detected to explain the mortality. Offspring exposed in utero were evaluated at 12 months of age using light microscopy (all tissues), stereology (basal forebrain cholinergic and dorsal root ganglia Neurons), and morphometry (sural nerve). Light microscopy revealed decreased number of Neurons in sympathetic ganglia (superior mesenteric, cervicothoracic, and ganglia in the thoracic sympathetic trunk). Stereologic assessment indicated an overall decrease in dorsal root ganglion (thoracic) volume and number of Neurons in animals exposed to tanezumab 4 mg/kg (n ¼ 9) and 30 mg/kg (n ¼ 1). At all tanezumab doses, the sural nerve was small due to decreases in myelinated and unmyelinated axons. Existing axons/ myelin sheaths appeared normal when viewed with light and transmission electron microscopy. There was no indication of tanezumab-related, Active Neuron/nerve fiber degeneration/necrosis in any tissue, indicating decreased sensory/ sympathetic Neurons and axonal changes were due to hypoplasia or atrophy. These changes in the sensory and sympathetic portions of the peripheral nervous system suggest some degree of developmental neurotoxicity, although what effect, if any, the changes had on normal function and survival was not apparent. Overall, these changes were consistent with published data from rodent studies.
Elisabeth Maluck - One of the best experts on this subject based on the ideXlab platform.
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a wake Active locomotion circuit depolarizes a sleep Active Neuron to switch on sleep
PLOS Biology, 2020Co-Authors: Michal Turek, Judith Besseling, Henrik Bringmann, Elisabeth Maluck, Inka Busack, Florentin Masurat, Karl Emanuel BuschAbstract:Sleep-Active Neurons depolarize during sleep to suppress wakefulness circuits. Wake-Active wake-promoting Neurons in turn shut down sleep-Active Neurons, thus forming a bipartite flip-flop switch. However, how sleep is switched on is unclear because it is not known how wakefulness is translated into sleep-Active Neuron depolarization when the system is set to sleep. Using optogenetics in Caenorhabditis elegans, we solved the presynaptic circuit for depolarization of the sleep-Active RIS Neuron during developmentally regulated sleep, also known as lethargus. Surprisingly, we found that RIS activation requires Neurons that have known roles in wakefulness and locomotion behavior. The RIM interNeurons-which are Active during and can induce reverse locomotion-play a complex role and can act as inhibitors of RIS when they are strongly depolarized and as activators of RIS when they are modestly depolarized. The PVC command interNeurons, which are known to promote forward locomotion during wakefulness, act as major activators of RIS. The properties of these locomotion Neurons are modulated during lethargus. The RIMs become less excitable. The PVCs become resistant to inhibition and have an increased capacity to activate RIS. Separate activation of neither the PVCs nor the RIMs appears to be sufficient for sleep induction; instead, our data suggest that they act in concert to activate RIS. Forward and reverse circuit activity is normally mutually exclusive. Our data suggest that RIS may be activated at the transition between forward and reverse locomotion states, perhaps when both forward (PVC) and reverse (including RIM) circuit activity overlap. While RIS is not strongly activated outside of lethargus, altered activity of the locomotion interNeurons during lethargus favors strong RIS activation and thus sleep. The control of sleep-Active Neurons by locomotion circuits suggests that sleep control may have evolved from locomotion control. The flip-flop sleep switch in C. elegans thus requires an additional component, wake-Active sleep-promoting Neurons that translate wakefulness into the depolarization of a sleep-Active Neuron when the worm is sleepy. Wake-Active sleep-promoting circuits may also be required for sleep state switching in other animals, including in mammals.
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a wake Active locomotion circuit depolarizes a sleep Active Neuron to switch on sleep
bioRxiv, 2019Co-Authors: Michal Turek, Judith Besseling, Henrik Bringmann, Elisabeth Maluck, Inka Busack, Florentin Masurat, Karl Emanuel BuschAbstract:Abstract Sleep-Active Neurons depolarize during sleep to suppress wakefulness circuits. Wake-Active wake-promoting Neurons in turn shut down sleep-Active Neurons, thus forming a bipartite flip-flop switch. However, how sleep is switched on is unclear because it is not known how wakefulness is translated into sleep-Active Neuron depolarization when the system is set to sleep. Using optogenetics in C. elegans, we solved the presynaptic circuit for depolarization of the sleep-Active RIS Neuron during developmentally-regulated sleep, also known as lethargus. Surprisingly, we found that RIS activation requires Neurons that have known roles in wakefulness and locomotion behavior. The RIM interNeurons, which are Active during and can induce reverse locomotion, play a complex role and can act as inhibitors of RIS when they are strongly depolarized and as activators of RIS when they are modestly depolarized. The PVC command interNeurons, which are known to promote forward locomotion during wakefulness, act as major activators of RIS. The properties of these locomotion Neurons are modulated during lethargus. The RIMs become less excitable. The PVCs become resistant to inhibition and have an increased capacity to activate RIS. Separate activation of neither the PVCs nor the RIMs appears to be sufficient for sleep induction; instead, our data suggests that they act in concert to activate RIS. Forward and reverse circuit activity is normally mutually exclusive. Our data suggest that RIS may be activated at the transition between forward and reverse locomotion states, perhaps when both reverse (including RIM) and forward (PVC) circuit activity overlaps. While RIS is not strongly activated outside of lethargus, altered activity of the locomotion interNeurons during lethargus favors strong RIS activation and thus sleep. The control of sleep-Active Neurons by locomotion circuits suggests that sleep may have evolved from locomotion quiescence. The flip-flop sleep switch in C. elegans thus requires an additional component, wake-Active sleep-promoting Neurons that translate wakefulness into the depolarization of a sleep-Active Neuron when the worm is sleepy. Wake-Active sleep-promoting circuits may also be required for sleep state switching in other animals including in mammals.
Michal Turek - One of the best experts on this subject based on the ideXlab platform.
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a wake Active locomotion circuit depolarizes a sleep Active Neuron to switch on sleep
PLOS Biology, 2020Co-Authors: Michal Turek, Judith Besseling, Henrik Bringmann, Elisabeth Maluck, Inka Busack, Florentin Masurat, Karl Emanuel BuschAbstract:Sleep-Active Neurons depolarize during sleep to suppress wakefulness circuits. Wake-Active wake-promoting Neurons in turn shut down sleep-Active Neurons, thus forming a bipartite flip-flop switch. However, how sleep is switched on is unclear because it is not known how wakefulness is translated into sleep-Active Neuron depolarization when the system is set to sleep. Using optogenetics in Caenorhabditis elegans, we solved the presynaptic circuit for depolarization of the sleep-Active RIS Neuron during developmentally regulated sleep, also known as lethargus. Surprisingly, we found that RIS activation requires Neurons that have known roles in wakefulness and locomotion behavior. The RIM interNeurons-which are Active during and can induce reverse locomotion-play a complex role and can act as inhibitors of RIS when they are strongly depolarized and as activators of RIS when they are modestly depolarized. The PVC command interNeurons, which are known to promote forward locomotion during wakefulness, act as major activators of RIS. The properties of these locomotion Neurons are modulated during lethargus. The RIMs become less excitable. The PVCs become resistant to inhibition and have an increased capacity to activate RIS. Separate activation of neither the PVCs nor the RIMs appears to be sufficient for sleep induction; instead, our data suggest that they act in concert to activate RIS. Forward and reverse circuit activity is normally mutually exclusive. Our data suggest that RIS may be activated at the transition between forward and reverse locomotion states, perhaps when both forward (PVC) and reverse (including RIM) circuit activity overlap. While RIS is not strongly activated outside of lethargus, altered activity of the locomotion interNeurons during lethargus favors strong RIS activation and thus sleep. The control of sleep-Active Neurons by locomotion circuits suggests that sleep control may have evolved from locomotion control. The flip-flop sleep switch in C. elegans thus requires an additional component, wake-Active sleep-promoting Neurons that translate wakefulness into the depolarization of a sleep-Active Neuron when the worm is sleepy. Wake-Active sleep-promoting circuits may also be required for sleep state switching in other animals, including in mammals.
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a wake Active locomotion circuit depolarizes a sleep Active Neuron to switch on sleep
bioRxiv, 2019Co-Authors: Michal Turek, Judith Besseling, Henrik Bringmann, Elisabeth Maluck, Inka Busack, Florentin Masurat, Karl Emanuel BuschAbstract:Abstract Sleep-Active Neurons depolarize during sleep to suppress wakefulness circuits. Wake-Active wake-promoting Neurons in turn shut down sleep-Active Neurons, thus forming a bipartite flip-flop switch. However, how sleep is switched on is unclear because it is not known how wakefulness is translated into sleep-Active Neuron depolarization when the system is set to sleep. Using optogenetics in C. elegans, we solved the presynaptic circuit for depolarization of the sleep-Active RIS Neuron during developmentally-regulated sleep, also known as lethargus. Surprisingly, we found that RIS activation requires Neurons that have known roles in wakefulness and locomotion behavior. The RIM interNeurons, which are Active during and can induce reverse locomotion, play a complex role and can act as inhibitors of RIS when they are strongly depolarized and as activators of RIS when they are modestly depolarized. The PVC command interNeurons, which are known to promote forward locomotion during wakefulness, act as major activators of RIS. The properties of these locomotion Neurons are modulated during lethargus. The RIMs become less excitable. The PVCs become resistant to inhibition and have an increased capacity to activate RIS. Separate activation of neither the PVCs nor the RIMs appears to be sufficient for sleep induction; instead, our data suggests that they act in concert to activate RIS. Forward and reverse circuit activity is normally mutually exclusive. Our data suggest that RIS may be activated at the transition between forward and reverse locomotion states, perhaps when both reverse (including RIM) and forward (PVC) circuit activity overlaps. While RIS is not strongly activated outside of lethargus, altered activity of the locomotion interNeurons during lethargus favors strong RIS activation and thus sleep. The control of sleep-Active Neurons by locomotion circuits suggests that sleep may have evolved from locomotion quiescence. The flip-flop sleep switch in C. elegans thus requires an additional component, wake-Active sleep-promoting Neurons that translate wakefulness into the depolarization of a sleep-Active Neuron when the worm is sleepy. Wake-Active sleep-promoting circuits may also be required for sleep state switching in other animals including in mammals.
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sleep Active Neuron specification and sleep induction require flp 11 neuropeptides to systemically induce sleep
eLife, 2016Co-Authors: Michal Turek, Judith Besseling, Janphilipp Spies, Sabine Konig, Henrik BringmannAbstract:Sleep is an essential behavioral state. It is induced by conserved sleep-Active Neurons that express GABA. However, little is known about how sleep Neuron function is determined and how sleep Neurons change physiology and behavior systemically. Here, we investigated sleep in Caenorhabditis elegans, which is induced by the single sleep-Active Neuron RIS. We found that the transcription factor LIM-6, which specifies GABAergic function, in parallel determines sleep Neuron function through the expression of APTF-1, which specifies the expression of FLP-11 neuropeptides. Surprisingly FLP-11, and not GABA, is the major component that determines the sleep-promoting function of RIS. FLP-11 is constantly expressed in RIS. At sleep onset RIS depolarizes and releases FLP-11 to induce a systemic sleep state.
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an ap2 transcription factor is required for a sleep Active Neuron to induce sleep like quiescence in c elegans
Current Biology, 2013Co-Authors: Michal Turek, Ines Lewandrowski, Henrik BringmannAbstract:Summary Background Sleep is an essential behavior that is found in all animals that have a nervous system. Neural activity is thought to control sleep, but little is known about the identity and the function of neural circuits underlying sleep. Lethargus is a developmentally regulated period of behavioral quiescence in C. elegans larvae that has sleep-like properties. Results We studied sleep-like behavior in C. elegans larvae and found that it requires a highly conserved AP2 transcription factor, aptf-1 , which was expressed strongly in only five interNeurons in the head. Expression of aptf-1 in one of these Neurons, the GABAergic Neuron RIS, was required for quiescence. RIS was strongly and acutely activated at the transition from wake-like to sleep-like behavior. Optogenetic activation of aptf-1 -expressing Neurons ectopically induced acute behavioral quiescence in an aptf-1 -dependent manner. RIS ablation caused a dramatic reduction of quiescence. RIS-dependent quiescence, however, does not require GABA but requires neuropeptide signaling. Conclusions We conclude that RIS acts as a sleep-Active, sleep-promoting Neuron that requires aptf-1 to induce sleep-like behavior through neuropeptide signaling. Sleep-promoting GABAergic-peptidergic Neurons have also been identified in vertebrate brains, suggesting that common circuit principles exist between sleep in vertebrates and sleep-like behavior in invertebrates.
Mark Butt - One of the best experts on this subject based on the ideXlab platform.
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Morphologic, Stereologic, and Morphometric Evaluation of the Nervous System in Young Cynomolgus Monkeys (Macaca fascicularis) Following Maternal Administration of Tanezumab, a Monoclonal Antibody to Nerve Growth Factor
2016Co-Authors: Mark Butt, Thomas Cummings, Satoru Oneda, Mark Evans, Christopher J. Bowman, David Shelton, Mark ZorbasAbstract:Tanezumab, an antibody to nerve growth factor, was administered to pregnant cynomolgus monkeys at 0, 0.5, 4, and 30 mg/kg weekly, beginning gestation day (GD) 20 through parturition (GD165). Maternal tanezumab administration appeared to increase stillbirths and infant mortality, but no consistent pattern of gross and/or microscopic change was detected to explain the mortality. Offspring exposed in utero were evaluated at 12 months of age using light microscopy (all tissues), stereology (basal forebrain cholinergic and dorsal root ganglia Neurons), and morphometry (sural nerve). Light microscopy revealed decreased number of Neurons in sympathetic ganglia (superior mesenteric, cervicothoracic, and ganglia in the thoracic sympathetic trunk). Stereologic assessment indicated an overall decrease in dorsal root ganglion (thoracic) volume and number of Neurons in animals exposed to tanezumab 4 mg/kg (n9) and 30 mg/kg (n1). At all tanezumab doses, the sural nerve was small due to decreases in myelinated and unmyelinated axons. Existing axons/ myelin sheaths appeared normal when viewed with light and transmission electron microscopy. There was no indication of tanezumab-related, Active Neuron/nerve fiber degeneration/necrosis in any tissue, indicating decreased sensory/ sympathetic Neurons and axonal changes were due to hypoplasia or atrophy. These changes in the sensory and sympathetic portions of the peripheral nervous system suggest some degree of developmental neurotoxicity, although what effect, if any, the changes had on normal function and survival was not apparent. Overall, these changes wer
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morphologic stereologic and morphometric evaluation of the nervous system in young cynomolgus monkeys macaca fascicularis following maternal administration of tanezumab a monoclonal antibody to nerve growth factor
Toxicological Sciences, 2014Co-Authors: Mark Butt, Thomas Cummings, Satoru Oneda, David L Shelton, Mark Evans, Christopher N. Bowman, Mark ZorbasAbstract:Tanezumab, an antibody to nerve growth factor, was administered to pregnant cynomolgus monkeys at 0, 0.5, 4, and 30 mg/kg weekly, beginning gestation day (GD) 20 through parturition (� GD165). Maternal tanezumab administration appeared to increase stillbirths and infant mortality, but no consistent pattern of gross and/or microscopic change was detected to explain the mortality. Offspring exposed in utero were evaluated at 12 months of age using light microscopy (all tissues), stereology (basal forebrain cholinergic and dorsal root ganglia Neurons), and morphometry (sural nerve). Light microscopy revealed decreased number of Neurons in sympathetic ganglia (superior mesenteric, cervicothoracic, and ganglia in the thoracic sympathetic trunk). Stereologic assessment indicated an overall decrease in dorsal root ganglion (thoracic) volume and number of Neurons in animals exposed to tanezumab 4 mg/kg (n ¼ 9) and 30 mg/kg (n ¼ 1). At all tanezumab doses, the sural nerve was small due to decreases in myelinated and unmyelinated axons. Existing axons/ myelin sheaths appeared normal when viewed with light and transmission electron microscopy. There was no indication of tanezumab-related, Active Neuron/nerve fiber degeneration/necrosis in any tissue, indicating decreased sensory/ sympathetic Neurons and axonal changes were due to hypoplasia or atrophy. These changes in the sensory and sympathetic portions of the peripheral nervous system suggest some degree of developmental neurotoxicity, although what effect, if any, the changes had on normal function and survival was not apparent. Overall, these changes were consistent with published data from rodent studies.
