Spinal Interneurons: Plasticity after Spinal Cord Injury

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The spinal cord is comprised of four types of neurons: motor neurons, pre-ganglionic neurons, ascending projection neurons, and spinal interneurons. Interneurons are neurons that process information within local circuits, and have an incredible ability for neuroplasticity, whether due to persistent activity, neural injury, or in response to disease. Although, by definition, their axons are restricted to the same structure as the soma (in this case the spinal cord), spinal interneurons are capable of sprouting and rewiring entire neural circuits, and contribute to some restoration of disrupted neural communication after injury to the spinal cord (i.e., “bypassing” the lesion site).

Spinal Interneurons provides a focused overview of how scientists classify interneurons in general, the techniques used to identify subsets of interneurons, their roles in specific neural circuits, and the scientific evidence for their neuroplasticity. Understanding the capacity for neuroplasticity and identity of specific spinal interneurons that are optimal for recovery, may help determine cellular candidates for developing therapies.

Spinal Interneurons provides neuroscientists, clinicians, and trainees a reference book exclusively concentrating on spinal interneurons, the techniques and experiments employed to identify and study these cells as part of normal and compromised neural circuits, and highlights the therapeutic potential of these cells by presenting the relevant pre-clinical and clinical work to date. People in industry will also benefit from this book, which compiles the latest in therapeutic strategies for targeting spinal interneurons, what considerations there are for the development and use of treatments, and how such treatments can not only be translated to the clinic, but how existing treatments should be appropriately reverse-translated to the bench.

Author(s): Lyandysha Viktorovna Zholudeva, Michael Aron Lane
Publisher: Academic Press
Year: 2022

Language: English
Pages: 473
City: London

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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B
C
D
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F
G
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I
K
L
M
N
O
P
R
S
T
U
V
W
Z
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