RESEARCH INTERESTS
Research in the Mentis laboratory aims to uncover the molecular, cellular and neural circuits mechanisms involved in spinal motor control, and how neuronal dysfunction leads to deficits observed in neurodegenerative diseases. We are interested in unraveling the mechanisms responsible for the complex rhythmogenic behavior involved in locomotor behavior. We utilize functional and morphological assays in cellular and vertebrate animal models. Perturbations of normal function in neural circuits, leading to a state of dysfunction and often neuronal degeneration, are studied in the two motor neuron diseases, Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS). |
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Developmental organization of motor neuronal circuitry
Spinal motor neurons serve as mediators of motor output from the central to the peripheral nervous system. In the context of locomotion, their activity is governed by a network of spinal neurons, known as the central pattern generator, which is responsible for the coordinated and patterned motor output.
Locomotion and the spinal network that generates the required patterns of muscle activity is an appealing system for studying how the nervous system produces complex behavior. In our laboratory, we have taken a developmental approach to the study of locomotion in the neonatal mouse – a system that offers several major experimental advantages: first, the isolated neonatal mouse spinal cord can generate locomotor-like activity in vitro, in response to stimulation of the brainstem, sensory fibers, as well as by application of pharmacological agents; and second, it is a genetically tractable system in which the identity and manipulation of spinal neurons via a set of molecular markers are employed to study their role in the formation and function of spinal locomotor circuitry.
Traditionally, motor neurons are thought to be solely the mediators of motor output from the spinal cord. However, as we have reported recently, stimulation of motor neuron axons in neonates can also trigger locomotor activity. We have recently reported that ventral spinocerebellar tract (VSCT) neurons are major players in controlling locomotor behavior, both during postnatal development and in adulthood. Currently, we are studying the neuronal circuit mechanisms between VSCTs, motor neurons and other spinal interneurons in locomotor activity. Unraveling the functional organization of these spinal circuits is critical both to our understanding of normal motor function and impairments in neurodegenerative diseases affecting movement.
Spinal motor neurons serve as mediators of motor output from the central to the peripheral nervous system. In the context of locomotion, their activity is governed by a network of spinal neurons, known as the central pattern generator, which is responsible for the coordinated and patterned motor output.
Locomotion and the spinal network that generates the required patterns of muscle activity is an appealing system for studying how the nervous system produces complex behavior. In our laboratory, we have taken a developmental approach to the study of locomotion in the neonatal mouse – a system that offers several major experimental advantages: first, the isolated neonatal mouse spinal cord can generate locomotor-like activity in vitro, in response to stimulation of the brainstem, sensory fibers, as well as by application of pharmacological agents; and second, it is a genetically tractable system in which the identity and manipulation of spinal neurons via a set of molecular markers are employed to study their role in the formation and function of spinal locomotor circuitry.
Traditionally, motor neurons are thought to be solely the mediators of motor output from the spinal cord. However, as we have reported recently, stimulation of motor neuron axons in neonates can also trigger locomotor activity. We have recently reported that ventral spinocerebellar tract (VSCT) neurons are major players in controlling locomotor behavior, both during postnatal development and in adulthood. Currently, we are studying the neuronal circuit mechanisms between VSCTs, motor neurons and other spinal interneurons in locomotor activity. Unraveling the functional organization of these spinal circuits is critical both to our understanding of normal motor function and impairments in neurodegenerative diseases affecting movement.
Dysfunction of motor circuits leads to severe deficits in neurodegenerative disease of Spinal Muscular Atrophy (SMA)
Spinal muscular atrophy is an inherited motor neuron disease caused by deficiency of SMN protein due to a mutation of the Survival Motor Neuron 1 (SMN1) gene. SMA affects newborn infants and is the most common inherited disorder lethal to infants and newborns. SMA is characterized by degeneration of motor neurons in the spinal cord and skeletal muscle atrophy. Life expectancy in the most severe cases is only 1 to 2 years. While much is known about the genetic causes of the disease, less information is available on the physiological alterations that explain the severity of motor symptoms displayed by affected individuals. The long-term objective of our research is to better understand early physiological changes in SMA in the hope that this will serve as a basis for uncovering causally related mechanisms which may be used as novel therapeutic approaches.
In neurodegenerative diseases, abnormalities of synaptic connectivity are thought to account for early clinical deficits. Dysfunction of specific, vulnerable neuronal populations may precipitate secondary changes in neural circuits that could exacerbate neuronal dysfunction. However, in many disease models, the primary targets and the precise sequence of functional and cellular changes that initiate the disease process remain unclear. Advances in our understanding of the genetic basis of heritable, motor neuron diseases such as SMA have also made it possible to model these disorders in mice.
We are currently concentrating our efforts on mouse models of SMA that closely mimic severe forms of the disease in infants. Mutant SMN-deficient mice exhibit severe motor abnormalities at birth and die within two weeks. To date, the majority of SMA studies have focused on molecular aspects of motor neuron degeneration and on changes at the neuromuscular junction. Little is known however, about the pathophysiology of the disease as it relates to spinal cord circuitry and motor neuron activity. Our studies have shown that there are significant defects in the sensory-motor circuitry. The reduced synaptic responses in spinal motor neurons raises the possibility that dysfunction of neuronal partners to motor neurons may contribute to the progression of SMA, and so provide a novel cellular target for therapeutic development. To address this, we are currently studying the effects of the SMN deficiency in specific neuronal populations.
We have recently reported that microglia are responsible for removal of select synapses on vulnerable motor neurons in SMA and implicated the classical complement cascade, through activation of C1q. We are currently devoting a significant aspect in our efforts to better understand the molecular mechanisms for synaptic dysfunction and their elimination.
Spinal muscular atrophy is an inherited motor neuron disease caused by deficiency of SMN protein due to a mutation of the Survival Motor Neuron 1 (SMN1) gene. SMA affects newborn infants and is the most common inherited disorder lethal to infants and newborns. SMA is characterized by degeneration of motor neurons in the spinal cord and skeletal muscle atrophy. Life expectancy in the most severe cases is only 1 to 2 years. While much is known about the genetic causes of the disease, less information is available on the physiological alterations that explain the severity of motor symptoms displayed by affected individuals. The long-term objective of our research is to better understand early physiological changes in SMA in the hope that this will serve as a basis for uncovering causally related mechanisms which may be used as novel therapeutic approaches.
In neurodegenerative diseases, abnormalities of synaptic connectivity are thought to account for early clinical deficits. Dysfunction of specific, vulnerable neuronal populations may precipitate secondary changes in neural circuits that could exacerbate neuronal dysfunction. However, in many disease models, the primary targets and the precise sequence of functional and cellular changes that initiate the disease process remain unclear. Advances in our understanding of the genetic basis of heritable, motor neuron diseases such as SMA have also made it possible to model these disorders in mice.
We are currently concentrating our efforts on mouse models of SMA that closely mimic severe forms of the disease in infants. Mutant SMN-deficient mice exhibit severe motor abnormalities at birth and die within two weeks. To date, the majority of SMA studies have focused on molecular aspects of motor neuron degeneration and on changes at the neuromuscular junction. Little is known however, about the pathophysiology of the disease as it relates to spinal cord circuitry and motor neuron activity. Our studies have shown that there are significant defects in the sensory-motor circuitry. The reduced synaptic responses in spinal motor neurons raises the possibility that dysfunction of neuronal partners to motor neurons may contribute to the progression of SMA, and so provide a novel cellular target for therapeutic development. To address this, we are currently studying the effects of the SMN deficiency in specific neuronal populations.
We have recently reported that microglia are responsible for removal of select synapses on vulnerable motor neurons in SMA and implicated the classical complement cascade, through activation of C1q. We are currently devoting a significant aspect in our efforts to better understand the molecular mechanisms for synaptic dysfunction and their elimination.