16 p., Spontaneous activity refers to the firing of action potentials by neurons in the absence of external stimulation. Initially considered an artifact or ?noise? in the nervous system, it is now recognized as a potential feature of neural function. Spontaneous activity has been observed in various brain areas, in experimental preparations from different animal species, and in live animals and humans using non-invasive imaging techniques. In this review, we specifically focus on the spontaneous activity of dorsal horn neurons of the spinal cord. We use a historical perspective to set the basis for a novel classification of the different patterns of spontaneous activity exhibited by dorsal horn neurons. Then we examine the origins of this activity and propose a model circuit to explain how the activity is generated and transmitted to the dorsal horn. Finally, we discuss possible roles of this activity during development and during signal processing under physiological conditions and pain states. By analyzing recent studies on the spontaneous activity of dorsal horn neurons, we aim to shed light on its significance in sensory processing. Understanding the different patterns of activity, the origins of this activity, and the potential roles it may play, will contribute to our knowledge of sensory mechanisms, including pain, to facilitate the modeling of spinal circuits and hopefully to explore novel strategies for pain treatment., Ministerio de Ciencia e Innovación, Unión Europea, FEDER

Spinal interneurons located in the dorsal horn induce primary afferent depolarization (PAD) controlling the excitability of the afferent?s terminals. Following inflammation, PAD may reach firing threshold contributing to maintain inflammation and pain. Our aim was to study the collective behavior of dorsal horn neurons, its relation to backfiring of primary afferents and the effects of a peripheral inflammation in this system. Experiments were performed on slices of spinal cord obtained from naïve adult mice or mice that had suffered an inflammatory pretreatment. Simultaneous recordings from groups of dorsal horn neurons and primary afferents were obtained and machine-learning methodology was used to analyze effective connectivity between them. Dorsal horn recordings showed grouping of spontaneous action potentials from different neurons in ?population bursts.? These occurred at irregular intervals and were formed by action potentials from all classes of neurons recorded. Compared to naïve, population bursts from treated animals concentrated more action potentials, had a faster onset and a slower decay. Population bursts were disrupted by perfusion of picrotoxin and held a strong temporal correlation with backfiring of afferents. Effective connectivity analysis allowed pinpointing specific neurons holding pre- or post-synaptic relation to the afferents. Many of these neurons had an irregular fast bursting pattern of spontaneous firing. We conclude that population bursts contain action potentials from neurons presynaptic to the afferents which are likely to control their excitability. Peripheral inflammation may enhance synchrony in these neurons, increasing the chance of triggering action potentials in primary afferents and contributing toward central sensitization., Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación, Universidad de Alcalá

Central terminals of primary afferents and dorsal horn neurons usually exhibit spontaneous activity, the two phenomena being interrelated. Spontaneous activity may constitute a system for adjusting the level of excitation of spinal circuits and the processing of somatosensory information. Superficial dorsal horn neurons fire action potentials in a coordinated form, giving rise to population events. These population events are altered by peripheral inflammation, suggesting their implication in central sensitisation. In this work, we aimed to define the role of primary afferents in the occurrence of this coordinated activity. Channelrhodopsin-2, archaerhodopsin-3 or the hM4Di-DREADD receptor were expressed in primary afferents by Cre-recombination under control of the advillin promoter. Dorsal roots and superficial dorsal horn neurons were simultaneously recorded using in vitro spinal cord slices from neonatal mice. Depolarisation of primary afferents by activation of channelrhodopsin-2 inhibited dorsal root activity and the coordinated firing of dorsal horn neurons. DREADD activation reduced the activity in the afferents and depressed coordinated activity in dorsal horn neurons. In contrast, hyperpolarisation of afferents by archaerhodopsin-3 augmented dorsal root responses and increased the coordinated activity of spinal neurons. The present results demonstrate a direct implication of primary afferents in the generation of coordinated spontaneous firing in superficial dorsal horn neurons., Agencia Estatal de Investigación

The dorsal horn of the spinal cord represents the first site in the central nervous system (CNS) where nociceptive signals are integrated. As a result, there has beenarapidgrowthinthenumberofstudiesinvestigating the ionic mechanisms regulating the excitability of dorsal horn neurons under normal and pathological conditions. We believe that it is time to look back and to critically examine what picture emerges from this wealth of studies. What are the actual types of neurons described in the literature based on electrophysiological criteria? Are these electrophysiologically-defined subpopulations strongly linked to specific morphological, functional, or molecular traits? Are these electrophysiological properties stable, or can they change during development or in response to peripheral injury? Here we provide an in-depth overview of both early and recent publications that explore the factors influencing dorsal horn neuronal excitability (including intrinsic membrane properties and synaptic transmission), how these factors vary across distinct subtypes of dorsal horn neurons, and how such factors are altered by peripheral nerve or tissue damage. The metaresearch presented below leads to the conclusion that the dorsal horn is comprised of highly heterogeneous subpopulations in which the observed electrophysiological properties of a given neuron often fail to easily predict other properties such as biochemical phenotype or morphology. This highlights the need for future studies which can more fully interrogate the properties of dorsal horn neurons in a multi-modal manner., Agencia Estatal de Investigación