Background: Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory, and demyelinating disease of the central nervous system (CNS). Several cytokines are thought to be involved in the regulation of MS pathogenesis. We recently identified interleukin (IL)-9 as a cytokine reducing inflammation and protecting from neurodegeneration in relapsing–remitting MS patients. However, the expression of IL-9 in CNS, and the mechanisms underlying the effect of IL-9 on CNS infiltrating immune cells have never been investigated.Methods: To address this question, we first analyzed the expression levels of IL-9 in post-mortem cerebrospinal fluid of MS patients and the in situ expression of IL-9 in post-mortem MS brain samples by immunohistochemistry. A complementary investigation focused on identifying which immune cells express IL-9 receptor (IL-9R) by flow cytometry, western blot, and immunohistochemistry. Finally, we explored the effect of IL-9 on IL-9-responsive cells, analyzing the induced signaling pathways and functional properties.Results: We found that macrophages, microglia, and CD4 T lymphocytes were the cells expressing the highest levels of IL-9 in the MS brain. Of the immune cells circulating in the blood, monocytes/macrophages were the most responsive to IL-9. We validated the expression of IL-9R by macrophages/microglia in post-mortem brain sections of MS patients. IL-9 induced activation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 and reduced the expression of activation markers, such as CD45, CD14, CD68, and CD11b in inflammatory macrophages stimulated in vitro with lipopolysaccharide and interferon (IFN)-γ. Similarly, in situ the number of activated CD68⁺macrophages was significantly reduced in areas with high levels of IL-9. Moreover, in the same conditions, IL-9 increased the secretion of the anti-inflammatory cytokine, transforming growth factor (TGF)-β.Conclusions: These results reveal a new cytokine expressed in the CNS, with a role in the context of MS. We have demonstrated that IL-9 and its receptor are both expressed in CNS. Moreover, we found that IL-9 decreases the activation state and promotes the anti-inflammatory properties of human macrophages. This mechanism may contribute to the beneficial effects of IL-9 that are observed in MS, and may be therapeutically potentiated by modulating IL-9 expression in MS.

Information is transmitted between brain regions through the release of neurotransmitters from long-range projecting axons. Understanding how the activity of such long-range connections contributes to behavior requires efficient methods for reversibly manipulating their function. Chemogenetic and optogenetic tools, acting through endogenous G-protein-coupled receptor pathways, can be used to modulate synaptic transmission, but existing tools are limited in sensitivity, spatiotemporal precision or spectral multiplexing capabilities. Here we systematically evaluated multiple bistable opsins for optogenetic applications and found that the Platynereis dumerilii ciliary opsin (PdCO) is an efficient, versatile, light-activated bistable G-protein-coupled receptor that can suppress synaptic transmission in mammalian neurons with high temporal precision in vivo. PdCO has useful biophysical properties that enable spectral multiplexing with other optogenetic actuators and reporters. We demonstrate that PdCO can be used to conduct reversible loss-of-function experiments in long-range projections of behaving animals, thereby enabling detailed synapse-specific functional circuit mapping.

Tactile perception is obtained by coordinated motor-sensory processes. We studied the processes underlying the perception of object location in freely moving rats. We trained rats to identify the relative location of two vertical poles placed in front of them and measured at high resolution the motor and sensory variables (19 and 2 variables, respectively) associated with this whiskers-based perceptual process. We found that the rats developed stereotypic head and whisker movements to solve this task, in a manner that can be described by several distinct behavioral phases. During two of these phases, the rats' whiskers coded object position by first temporal and then angular coding schemes. We then introduced wind (in two opposite directions) and remeasured their perceptual performance and motor-sensory variables. Our rats continued to perceive object location in a consistent manner under wind perturbations while maintaining all behavioral phases and relatively constant sensory coding. Constant sensory coding was achieved by keeping one group of motor variables (the “controlled variables”) constant, despite the perturbing wind, at the cost of strongly modulating another group of motor variables (the “modulated variables”). The controlled variables included coding-relevant variables, such as head azimuth and whisker velocity. These results indicate that consistent perception of location in the rat is obtained actively, via a selective control of perception-relevant motor variables.

Sensory information is coded in space and in time. The organization of neuronal activity in space maintains straightforward relationships with the spatial organization of the perceived environment. In contrast, the temporal organization of neuronal activity is not trivially related to external features due to sensor motion. Still, the temporal organization shares similar principles across sensory modalities. Likewise, thalamocortical circuits exhibit common features across senses. Focusing on touch, vision, and audition, we review their shared coding principles and suggest that thalamocortical systems include circuits that allow analogous recoding mechanisms in all three senses. These thalamocortical circuits constitute oscillations-based phase-locked loops, that translate temporally-coded sensory information to rate-coded cortical signals, signals that can integrate information across sensory and motor modalities. The loop also allows predictive locking to the onset of future modulations of the sensory signal. The paper thus suggests a theoretical framework in which a common thalamocortical mechanism implements temporal demodulation across senses.

Rats' whisking motion and objects' palpation produce tactile signals sensed by mechanoreceptors at the vibrissal follicles. Rats adjust their whisking patterns to target information type, flow, and resolution, adapting to their behavioral needs and the changing environment. This coordination requires control over the activity of the mystacial pad's intrinsic and extrinsic muscles. Studies have relied on muscle recording and stimulation techniques to describe the roles of individual muscles. However, these methods lack the resolution to isolate the mystacial pad's small and compactly arranged muscles. Thus, we propose functional anatomy as a complementary approach for studying the individual and coordinated effects of the mystacial pad muscles on vibrissae movements. Our functional analysis addresses the kinematic measurements of whisking motion patterns recorded in freely exploring rats. Combined with anatomical descriptions of muscles and fascia elements of the mystacial pad in situ, we found: (1) the contributions of individual mystacial pad muscles to the different whisking motion patterns; (2) active touch by microvibrissae, and its underlying mechanism; and (3) dynamic position changes of the vibrissae pivot point, as determined by the movements of the corium and subcapsular fibrous mat. Finally, we hypothesize that each of the rat mystacial pad muscles is specialized for a particular function in a way that matches the architecture of the fascial structures. Consistent with biotensegrity principles, the muscles and fascia form a network of structural support and continuous tension that determine the arrangement and motion of the embedded individual follicles.