Patients with sleeping sickness, caused by the parasite Trypanosoma brucei , have disruptions in both sleep timing and sleep architecture. However, the underlying cause of these sleep disturbances is not well understood. Here, we assessed the sleep architecture of male mice infected with T. brucei and found that infected mice had drastically altered sleep patterns. Interestingly, T. brucei -infected mice also had a reduced homeostatic sleep response to sleep deprivation, a response modulated by the adenosine system. We found that infected mice had a reduced electrophysiological response to an adenosine receptor antagonist and increased adenosine receptor gene expression. Although the mechanism by which T. brucei infection causes these changes remains to be determined, our findings suggest that the symptoms of sleeping sickness may be because of alterations in homeostatic adenosine signaling. SIGNIFICANCE STATEMENT Sleeping sickness is a fatal disease that disrupts the circadian clock, causes disordered te...

Kevin C. Hoy, Misty M. Strain, Joel D. Turtle, Kuan H. Lee, J. Russell Huie, et al. (see pages [9186–9209][1]) Animals quickly adapt motor behaviors in response to sensory feedback. For example, when leg extension causes pain, animals keep the leg flexed. This has been demonstrated in rats: if

Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS. Cuprizone (CZ), a copper chelator, is widely used to study demyelination and remyelination in the CNS, in the context of MS. However, the mechanisms underlying oligodendrocyte (OL) cell loss and demyelination are not known. As copper-containing enzymes play important roles in iron homeostasis and controlling oxidative stress, we examined whether chelating copper leads to disruption of molecules involved in iron homeostasis that can trigger iron-mediated OL loss. We show that giving mice (male) CZ in the diet induces rapid loss of OL in the corpus callosum by 2 d, accompanied by expression of several markers for ferroptosis, a relatively newly described form of iron-mediated cell death. In ferroptosis, iron-mediated free radicals trigger lipid peroxidation under conditions of glutathione insufficiency, and a reduced capacity to repair lipid damage. This was further confirmed using a small-molecule inhibitor of ferroptosis that prevents C...

Aralar/AGC1/Slc25a12, the mitochondrial aspartate-glutamate carrier expressed in neurons, is the regulatory component of the NADH malate-aspartate shuttle. AGC1 deficiency is a neuropediatric rare disease characterized by hypomyelination, hypotonia, developmental arrest, and epilepsy. We have investigated whether β-hydroxybutyrate (βOHB), the main ketone body (KB) produced in ketogenic diet (KD), is neuroprotective in aralar -knock-out (KO) neurons and mice. We report that βOHB efficiently recovers aralar -KO neurons from deficits in basal-stimulated and glutamate-stimulated respiration, effects requiring βOHB entry into the neuron, and protects from glutamate excitotoxicity. Aralar -deficient mice were fed a KD to investigate its therapeutic potential early in development, but this approach was unfeasible. Therefore, aralar -KO pups were treated without distinction of gender with daily intraperitoneal injections of βOHB during 5 d. This treatment resulted in a recovery of striatal markers of the dopaminer...

Events that overlap with previous experience may trigger reactivation of existing memories. However, such reactivation may have different representational consequences within the hippocampal circuit. Computational theories of hippocampal function suggest that dentate gyrus and CA2,3 (DG/CA2,3) are biased to differentiate highly similar memories, whereas CA1 may integrate related events by representing them with overlapping neural codes. Here, we tested whether the formation of differentiated or integrated representations in hippocampal subfields depends on the strength of memory reactivation during learning. Human participants of both sexes learned associations (AB pairs, either face-shape or scene-shape), and then underwent fMRI scanning while they encoded overlapping associations (BC shape-object pairs). Both before and after learning, participants were also scanned while viewing indirectly related elements of the overlapping memories (A and C images) in isolation. We used multivariate pattern analyses t...

Membrane remodeling by inflammatory mediators influences the function of sensory ion channels. The capsaicin- and heat-activated TRPV1 channel contributes to neurogenic inflammation and pain hypersensitivity, in part due to its potentiation downstream of phospholipase C-coupled receptors that regulate phosphoinositide lipid content. Here, we determined the effect of phosphoinositide lipids on TRPV1 function by combining genetic dissection, diet supplementation, behavioral, biochemical, and functional analyses in Caenorhabditis elegans . As capsaicin elicits hot and pain sensation in mammals, transgenic TRPV1 worms exhibit an aversive response to capsaicin. TRPV1 worms with low levels of phosphoinositide lipids display an enhanced response to capsaicin, whereas phosphoinositide lipid supplementation reduces TRPV1-mediated responses. A worm carrying a TRPV1 construct lacking the distal C-terminal domain features an enhanced response to capsaicin, independent of the phosphoinositide lipid content. Our results...

Animal locomotion requires changing direction, from forward to backward. Here, we tested the hypothesis that sensorimotor circuits within the spinal cord generate backward locomotion and adjust it to task demands. We collected kinematic and electromyography data during forward and backward locomotion at different treadmill speeds before and after complete spinal transection in six adult cats (3 males and 3 females). After spinal transection, 5/6 cats performed backward locomotion, which required tonic somatosensory input in the form of perineal stimulation. One spinal cat performed forward locomotion but not backward locomotion while two others stepped backward but not forward. Spatiotemporal adjustments to increasing speed were similar in intact and spinal cats during backward locomotion and strategies were similar to forward locomotion, with shorter cycle and stance durations and longer stride lengths. Patterns of muscle activations, including muscle synergies, were similar for forward and backward locom...

Chronic pain, encompassing conditions, such as low back pain, arthritis, persistent post-surgical pain, fibromyalgia, and neuropathic pain disorders, is highly prevalent but remains poorly treated. The vast majority of therapeutics are directed solely at neurons, despite the fact that signaling between immune cells, glia, and neurons is now recognized as indispensable for the initiation and maintenance of chronic pain. This review highlights recent advances in understanding fundamental neuroimmune signaling mechanisms and novel therapeutic targets in rodent models of chronic pain. We further discuss new technological developments to study, diagnose, and quantify neuroimmune contributions to chronic pain in patient populations.