Spinal Interneurons: Plasticity after Spinal Cord Injury

Front Cover
Spinal Interneurons
Spinal Interneurons: Plasticity after Spinal Cord Injury
Copyright
Contents
List of contributors
Preface
I - Spinal interneurons – motor and sensory neuronal networks
	1 - The neuronal cell types of the spinal cord
		Introduction
		History of research on spinal cord neurons
		Classification systems for spinal cord interneuron cell types
			Anatomy
			Morphology
			Connectivity
			Electrophysiology
			Neurochemistry
			Molecular markers
			Embryonic lineage
			Multiomics profiling
			Perspective
		The dorsal horn neurons of the spinal cord
			Superficial dorsal neurons
				Laminae I–II
				Laminae II–III
			Deep dorsal neurons
				Laminae III–IV
				Laminae V–VI
			Perspective
		The ventral horn neurons of the spinal cord
			V0 lineage
			V1 lineage
			V2 lineage
			Motor neuron lineage
			V3 lineage
			Dorsally derived ventral neurons
				Perspective
		Future directions for understanding spinal cord neuron types
			Broader views on anatomy
			Context-dependent function of spinal cord cell types
			Dynamic perspectives on cell types and cell states
		Abbreviations
		Acknowledgments
		References
	2 - Identified interneurons contributing to locomotion in mammals
		Introduction
		Organization of spinal locomotor interneurons
		Spinal interneurons with locomotor functions
		Transcription factor code to identify interneuron populations
			V0 interneurons
			V1 interneurons
			V2 interneurons
				V2a interneurons
				V2b interneurons
			V3 interneurons
			Dorsally derived interneuron populations
				dI3 interneurons
				dI6 interneurons
			Other populations
				Hb9 interneurons
				Shox2 interneurons
			Limitations of transcription factor code
		Interneurons in a locomotor framework
			There are flexor and extensor burst generators on each side of the cord
			V1 and V2b interneurons provide mutual inhibition of the half centers
			V1 and V2b interneurons are partly functionally redundant but have distinct positions in the circuit
			Two commissural pathways involving V0 interneurons secure left-right alternation
			V3 interneurons may synchronize left and right sides
		Plasticity of interneurons following spinal cord injury
			V2a interneurons
			V3 interneurons
			dI3 interneurons
			Shox2 interneurons
			Inhibitory interneurons modulating locomotion
		Future perspectives
		Abbreviations
		Acknowledgments
		References
	3 - Decoding touch: peripheral and spinal processing
		Introduction
		Part I: detecting touch
		What do cutaneous sensory neurons look like?
		The incredible heterogeneity of somatosensory neurons
		A quick sense of touch: Aβ fibers
			Shape and texture: Aβ SAI-LTMRs
			Stretch sensors: Aβ SAII-LTMRs
			Vibration sensors: Aβ RA-LTMRs
			Skin stroking: Aβ Field-LTMRs
			Ultrafast pain: Aβ-HTMRs
			Fast pain and light touch: Aδ fibers
			Touch directionality: Aδ-LTMRs
			Fast localization of pain: Aδ-nociceptors
			The tiny ones that can hurt or comfort: C-fibers
			The caress neurons: C-LTMRs
			Burning pain: peptidergic C-nociceptors
			Mechanical pain and itch: nonpeptidergic C-nociceptors
		Touch encoding by skin sensory neurons: an integrative view
			Layer 1: unique electrophysiological properties
			Layer 2: unique end organ associations
			Layer 3: unique spatial distribution patterns
			Layer 4: unique peripheral processing
			Putting it all together
		Part II: processing touch information in the spinal cord
		Touching the spinal cord: LTMR inputs to the dorsal horn
		The middlemen: neurons of the dorsal horn
		Interneurons: more than a relay station
		Projection neurons: sending a message to the brain
		The spinal circuits of touch
		Interneurons involved in touch perception
		Projection neurons involved in touch perception
		LTMR circuits, what do they do?
		Touch influences the way we move and recover from spinal cord injury
		Cutaneous input modulates motor output
		Interneurons involved in touch-motor circuits
		Touch and motor recovery
		Future challenges and direction in unraveling spinal LTMR circuits
		Abbreviations
		Acknowledgments
		References
	4 - Spinal interneurons and pain: identity and functional organization of dorsal horn neurons in acute and persiste ...
		Introduction
		Molecular organization of the dorsal horn
		Lamina I
		Lamina II
		Laminae III–IV
		Acute pain signaling
		Spinal projection neurons in acute pain
		Lamina I projection neurons
		Laminae III–V projection neuron
		Spinal interneurons
		Laminae I–II interneurons
		Laminae III–V interneurons
		Spinal mechanisms of chronic pain
		Superficial SDH interneuron subpopulations and chronic pain
		Lamina II interneurons and chronic pain
		Somatostatin lineage interneurons
		Dynorphin interneurons
		Protein kinase C gamma interneurons
		Calretinin interneurons
		Laminae III–IV interneurons and chronic pain
		Neuropeptide Y interneurons
		Parvalbumin interneurons
		Transient VGLUT3 interneurons
		Cholecystokinin interneurons
		Early receptor tyrosine kinase interneurons
		Conclusions
		Abbreviations
		References
	5 - Cholinergic spinal interneurons
		Introduction
			Cholinergic dorsal horn interneurons
			Central canal cluster cells within lamina X
			Partition cells in the intermediate gray matter
		Conclusions
		List of abbreviations
		References
	6 - Spinal interneurons, motor synergies, and modularity
		Introduction
		The comparative neuroethology and evolutionary perspective on synergy
			The evolutionary history of interneuron systems—comparative evolution
			Natural selection pressures and the comparative perspective
			Selection and constraints that might favor conserved and highly “anticipatory” organization of many parts of spinal circuitry
		Neuromechanics perspectives on motor synergies
			Motor primitives and synergies in relation to spinal interneuron systems
				Mechanism 1: temporal burst elements as primitives
				Mechanism 2: time-varying synergy elements
				Mechanism 3: spatial synergy elements
				Mechanism 4: unitary bursts of a spatial motor synergy
				Mechanism 5: primitives in self-organized pattern formation
				Mechanism 6: primitives in flexible combinations of rhythm and pattern element mechanisms
			Neurophysiological support of unitary interneuron circuits tied to motor synergies
			Stimulation results supporting motor synergies
			Afferent manipulation effects on unitary motor synergies
			Identifying interneuron projections with spike triggered averaging
			Trunk and higher level spinal interactions with motor synergies
			Developmental issues—interneuronal infrastructure and functional stability over the lifespan
		Neuroengineering with spinal interneuron systems
			Neuroengineering methods
				Intraspinal microstimulation
				Epidural stimulation
				Optogenetics
			Plasticity induced by neuroengineered interventions and rehabilitation efforts—motor synergy stability
				Crafted and contingent stimulation strategies for plasticity and motor synergies
			Cross-talk and integration of motor synergy and autonomic pathways?
		Discussion and conclusions
		Abbreviations
		Acknowledgments
		References
II - Spinal interneurons – a role in injury and disease
	7 - Propriospinal neurons as relay pathways from brain to spinal cord
		Introduction
		Direct and indirect pathways from the brain to spinal cord motor neurons
			Direct pathways between the motor cortex and spinal motor neurons for hand dexterity
			Indirect pathways between the motor cortex and spinal motor neurons enable hand dexterity: corticospinal propriospinal pathways
		Spinal interneurons propagate locomotor commands from supraspinal locomotor regions
			PNs reconnect supraspinal neurons and spinal motor neurons
			PNs reconstitute local spinal circuits to bypass lesions after SCI
		Dormant relay pathways after SCI: formation of maladaptive plasticity in injured spinal cord
			Peri-lesion hyperinhibition after SCI silences relay circuits
			Maladaptive sensorimotor circuits below the injury
		Therapeutic strategies for SCI: utilizing spinal interneurons
			Correction of maladaptive SpIN activity in the brain–spinal relay circuit to promote locomotion recovery
		Concluding remarks
		Abbreviations
		References
	8 - Changes in motor outputs after spinal cord injury
		Introduction
			Muscle spasms following spinal cord injury
			Descending neuromodulation of spinal sensorimotor circuits
		Mechanisms of motor outputs following injury
			Changes in motor neuron excitability
				The role of motor neuron PICs in generating muscle spasms
			Unregulated sensory inputs after injury
				Loss of descending serotonergic neuromodulation
				Broadening of sensory receptive fields
				Bursting deep dorsal horn interneurons
			Changes in genetically identified spinal interneurons after injury
				dI3 interneurons
				dI6 interneurons
				V0 interneurons
				V1 and V2b interneurons
				V2a interneurons
				V3 interneurons
			Excitation–inhibition balance in spinal interneurons
				Increased premotor excitatory drive
				Decreased activity/efficacy of inhibitory synaptic drive
		Concluding remarks
		Abbreviations
		References
	9 - Spinal interneurons and breathing
		Introduction
		Spinal interneurons integrated into respiratory networks
		Spinal respiratory networks
		Phrenic motor circuit
			Electrophysiological characterization
			Anatomical characterization
			SpIN neurotransmitter phenotypes
		Intercostal motor circuitry
			Electrophysiological characterization
			Anatomical characterization
			Molecular characterization
		Abdominal motor circuitry
		SpINs and their role in neuroplasticity
		Respiratory SpINs following spinal cord injury
		Respiratory SpINs and degenerative disease
		Future perspectives
		List of abbreviations
		References
	10 - Spinal interneuronal control of the lower urinary tract
		Introduction
		Spinal interneurons and micturition
		Distribution of spinal interneurons involved in micturition reflex circuitry
			Bladder
			Urethra
			External urethral sphincter
			Overlap of interneuronal distribution
		Role of spinal interneurons in micturition function
		Plasticity of spinal interneurons following SCI
		Targeting interneurons for LUT therapeutics
		Concluding remarks
		Abbreviations
		Conflicts of interest
		Acknowledgments
		References
	11 - Spinal interneurons and autonomic dysreflexia after injury
		Introduction—characteristics of spinal cord interneurons
		Properties of interneurons related to autonomic function
		Role of interneurons in autonomic dysfunction after spinal cord injury
			Thermoregulatory and bowel/bladder dysfunction
			Cardiovascular dysfunction
		Autonomic interneuronal plasticity in relation to autonomic dysreflexia after spinal cord injury
		Conclusion
		Abbreviations
		References
	12 - Human spinal networks: motor control, autonomic regulation, and somatic-visceral neuromodulation
		Introduction
		The discovery of complex human spinal cord circuitry
			Early observations of complex motor patterns
			Immature human locomotor activity
			Neuromodulation of human spinal circuitry
		The role of sensory processing in control of human locomotion
			Locomotor (recovery) training
			Plantar pressure stimulation
			Vibration
		Neuromodulation for motor control
			Two approaches for spinal cord epidural stimulation for walking
			Voluntary movement with epidural stimulation
			Spinal cord epidural stimulation and task specific stand training reveals human spinal circuitry learning
			Transcutaneous spinal neuromodulation
			Multi-modal neuromodulation to control posture and locomotion
			Neuromodulation of autonomic function
			Mechanisms of human spinal networks and neuromodulation
		Translation to therapeutics and future directions
		Abbreviations
		References
	13 - Spinal interneurons post-injury: emergence of a different perspective on spinal cord injury
		Introduction
		Role of spinal networks in coordinating movements
			What are the consequences of redundancies of neural networks?
			Importance and robustness of sensory information in controlling movement
		Progress in spinal stimulation facilitating recovery of locomotor function
		Mechanisms of recovery of locomotor function
			Spinal stimulation increases the excitability of spinal interneurons and enhances sensory input to facilitate reorganization
		Dynamics of spinal networks
			Voluntary control becoming independent of original long descending axons after a “complete” spinal injury
			Is sensory-driven recovery of locomotion assignable to specific sensory receptor types?
			Is central pattern generation a contributing factor to the recovery of organ systems following paralysis?
		References
	14 - A “Unified Theory” of spinal interneurons and activity-based rehabilitation after spinal cord injury
		Introduction
			Supporting evidence from the cat model
			Supporting evidence from the bipedal rat model
			Supporting evidence from the contused rat model
			Some clinical evidence: the chronically injured spinal cord can respond to load-related afferent input
			Whence cometh the weakness?
			In summary: the Unified Theory
		Abbreviations
		Acknowledgments
		References
	15 - Spinal interneurons and cell transplantation
		Introduction
		Neural transplantation: lessons learned from preclinical models
			Spinal cord injury: clinical challenges and pathophysiology
			History of neural tissue transplantation in preclinical studies
			Emergence of fetal tissue transplantation in spinal cord injury models
			Transplantation of multipotent and lineage-restricted progenitors
			Transplantation of enriched or restricted populations of spinal cord progenitors
			Characterization of transplanted interneuron phenotypes
		Differentiation and transplantation of human spinal cord neurons
			Recapitulating spinal cord development through directed differentiation
			Molecular strategies for directed differentiation in vitro
			Generation of specific interneuron subtypes from human PSCs
			Evidence for the importance of regional identity in functional recovery
		Conclusion: the future of clinical transplantation approaches for SCI
		Abbreviations
		References
	16 - Spinal interneurons and cellular engineering
		Introduction
		Delivery of genetic material
		Genomic integration methods
		Conditional gene expression
		Neuromodulation through optogenetic, sonogenetic, or chemogenetic means
			Optogenetics
			Sonogenetics
			Chemogenetics
				Chemogenetic gene expression modulation
				Chemogenetic functional modulation
		Conclusion
		Abbreviations
		References
Index
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	D
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	H
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	T
	U
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	W
	Z
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