Acute and Chronic Pain Processing in the Thalamocortical System of Humans and Animal Models.

Evaluation of the chronic effects of spinal cord injury (SCI) has long focused on sensorimotor deficits, neuropathic pain, bladder/bowel dysfunction, loss of sexual function, and emotional distress. Although not well appreciated clinically, SCI can cause cognitive impairment including deficits in learning and memory, executive function, attention, and processing speed; it also commonly leads to depression. Recent large-scale longitudinal population-based studies indicate that patients with isolated SCI (without concurrent brain injury) are at a high risk of dementia associated with substantial cognitive impairments. Yet, little basic research has addressed potential mechanisms for cognitive impairment and depression after injury. In addition to contributing to disability in their own right, these changes can adversely affect rehabilitation and recovery and reduce quality of life. Here, we review clinical and experimental work on the complex and varied responses in the brain following SCI. We also discuss potential mechanisms responsible for these less well-examined, important SCI consequences. In addition, we outline the existing and developing therapeutic options aimed at reducing SCI-induced brain neuroinflammation and post-injury cognitive and emotional impairments.

/pdf/dementia-depression-and-associated-brain-inflammatory-2xmrveych0.pdf

Dementia, Depression, and Associated Brain Inflammatory Mechanisms after Spinal Cord Injury

After paralyzing spinal cord injury the adult nervous system has little ability to 'heal' spinal connections, and it is assumed to be unable to develop extra-spinal recovery strategies to bypass the lesion. We challenge this assumption, showing that completely spinalized adult rats can recover unassisted hindlimb weight support and locomotion without explicit spinal transmission of motor commands through the lesion. This is achieved with combinations of pharmacological and physical therapies that maximize cortical reorganization, inducing an expansion of trunk motor cortex and forepaw sensory cortex into the deafferented hindlimb cortex, associated with sprouting of corticospinal axons. Lesioning the reorganized cortex reverses the recovery. Adult rats can thus develop a novel cortical sensorimotor circuit that bypasses the lesion, probably through biomechanical coupling, to partly recover unassisted hindlimb locomotion after complete spinal cord injury.

/pdf/cortex-dependent-recovery-of-unassisted-hindlimb-locomotion-3yq5fc3peo.pdf

Cortex-dependent recovery of unassisted hindlimb locomotion after complete spinal cord injury in adult rats.

Feasibility of imaging evoked activity throughout the rat brain using electrical impedance tomography.

The deterioration of neurons in Alzheimer's disease (AD) arises from genetic, immunologic, and cellular factors inside the cortex. The traditional consensus of the amyloid-beta (Aβ) paradigm as a singular cause of AD has been under revision, with the accumulation of exploding neurobiological evidence. Among the multifaceted casualties of AD, the involvement of glia gains significance for its dynamic contribution to neurons, either in a neuroprotective or neurotoxic fashion. Basically, microglia and astrocytes contribute to neuronal sustainability by releasing neuroprotective cytokines, maintaining an adequate amount of glutamate in the synapse, and pruning excessive synaptic terminals. Such beneficial effects divert to the other detrimental cascade in chronic neuroinflammatory conditions. In this change, there are new discoveries of specific cytokines, microRNAs, and complementary factors. Previously unknown mechanisms of ion channels such as Kv1.3, Kir2.1, and HCN are also elucidated in the activation of microglia. The activation of glia is responsible for the excitotoxicity through the overflow of glutamate transmitter via mGluRs expressed on the membrane, which can lead to synaptic malfunction and engulfment. The communication between microglia and astrocytes is mediated through exosomes as well as cytokines, where numerous pieces of genetic information are transferred in the form of microRNAs. The new findings tell us that the neuronal environment in the AD condition is a far more complicated and dynamically interacting space. The identification of each molecule in the milieu and cellular communication would contribute to a better understanding of AD in the neurobiological perspective, consequently suggesting a possible therapeutic clue.

https://www.mdpi.com/1422-0067/21/18/6676/pdf

Deleterious Alteration of Glia in the Brain of Alzheimer’s Disease

Increased responses in the somatosensory thalamus immediately after spinal cord injury.

Slow-wave activity homeostasis in the somatosensory cortex after spinal cord injury

Activation of microglia and astrocytes contributes to synaptic remodeling, tissue repair and neuronal survival following traumatic brain injury (TBI). However, the consequences of the interaction between both glial cell types in rewiring neuronal networks and repairing brain functions remains poorly understood. Here, we explored how microglia-induced astrocyte activation modified synapses and cerebrovascular integrity following TBI. Calcium imaging experiments from brain slices revealed increased number of active astrocytes responding with spontaneous Ca2+ events surrounding the injury at 1 d.a.i. These changes correlated with an increase in astrocytic GFAP-reactivity and microglia activation. Blocking microglia activation with the TLR4-blocker TAK242 reduced both the number of active and reactive astrocytes, suggesting a role for microglia in mediating astrocyte excitability. To determine the physiological consequences of microglia-induced astrocyte activation, we first quantified the number of synaptic puncta in TBI-mice treated with the TLR4-blocker. PSD-95/VGlut-1 staining showed that TAK-treatment reduced by half the synaptic loss observed in TBI-mice. Similar effects were also observed in the blood-brain barrier (BBB) integrity, in which blockage of microglia decreased Evans Blue extravasation, an indicative of preserved BBB. The acute effects of microglia inhibition on synapses and BBB were not observed in IP3R2-/- mice, indicating that the microglial effects depend on the subsequent astrocyte activation. In addition, acute TBI increases the release of the astrocytic-protein thrombospondin-1 (TSP-1) that seems to be necessary to modulate synaptic puncta in a sub-acute phase. Together, our data demonstrate that microglia-to-astrocyte communication plays a crucial role in the pathophysiology of TBI and that its inhibition prevents the synaptic loss and BBB damage accelerating the recovery/repair of damaged tissue. Overall, our data indicates that targeting the microglia-astrocyte crosstalk might represent a therapeutic potential in CNS injuries and disorders.

/pdf/microglia-to-astrocyte-communication-modulates-synaptic-and-31lork2i2f.pdf

Microglia-to-astrocyte communication modulates synaptic and cerebrovascular functions following traumatic brain injury

Astrocytes Adjust the Dynamic Range of Cortical Network Activity to Control Modality-Specific Sensory Information Processing

Myelin, critical for the correct function of the nervous system, is organized in different patterns that can include long non-myelinated axonal segments. How myelin patterning is regulated remains unexplained. The carbohydrate-binding protein galectin-4 (Gal-4) influences oligodendrocyte differentiation in vitro and is associated with non-myelinable axon segments (NMS) in cultured neurons. In consequence, Gal-4 has been proposed as a myelin patterning regulator, although no in vivo studies have corroborated this hypothesis. We used Gal-4-deficient mice (Lgals4-KO) to study the role of Gal-4 in cortical myelination in vivo. We show that cultured neurons of Lgals4-KO mice form NMS that are regulated as in control neurons. In addition, oligodendrocyte/myelin markers expression measured by biochemical and immunochemical means, and cortical myelin microstructure studied by in-depth image analysis appear unaltered in these animals. Consistently, myelin displays an essentially normal function assessed by in vivo electrophysiology and locomotion analyses. In conclusion, cortical myelin of Lgals4-KO mice does not show any significant defect in composition, organization or function, pointing to a negligible role of Gal-4 in myelination in vivo or, as discussed, to unknown mechanisms that compensate its absence.

/pdf/normal-cortical-myelination-in-galectin-4-deficient-mice-t5iqzvwl.pdf

E. Fernández-López

Papers

Increased responses in the somatosensory thalamus immediately after spinal cord injury.

Slow-wave activity homeostasis in the somatosensory cortex after spinal cord injury

Microglia-to-astrocyte communication modulates synaptic and cerebrovascular functions following traumatic brain injury

Astrocytes Adjust the Dynamic Range of Cortical Network Activity to Control Modality-Specific Sensory Information Processing

Normal Cortical Myelination in Galectin-4-Deficient Mice