The Journal of neuroscience : the official journal of the Society for Neuroscience
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There is increasing evidence that CD4(+) T-cell-dependent responses are associated with the maintenance of neuropathic pain. However, little is known about the precise mechanism(s) underlying the activation of CD4(+) T-cells. We herein show that inhibition of cathepsin S (CatS) activity, either through genetic deletion or via a pharmacological inhibitor, Z-Phe-Leu-COCHO (Z-FL), significantly attenuated the maintenance of tactile allodynia, splenic hypertrophy, increased number of splenic CD4(+) T-cells and the final cleavage step of the MHC class II-associated invariant chain following peripheral nerve injury. ⋯ Moreover, CatS deficiency, Z-FL treatment, or splenectomy significantly attenuated the proliferation of microglia 14 d after peripheral nerve injury. These results show a peripheral pivotal role of CatS in the development of neuropathic pain through the antigen-specific activation of CD4(+) T-cells. After activation, CD4(+) T-cells infiltrate into the dorsal spinal cord and secrete IFN-γ to reactivate microglia, which contribute to the transition of acute pain to a chronic pain state.
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Hippocampal high-frequency oscillations (HFOs) are prominent in physiological and pathological conditions. During physiological ripples (100-200 Hz), few pyramidal cells fire together coordinated by rhythmic inhibitory potentials. In the epileptic hippocampus, fast ripples (>200 Hz) reflect population spikes (PSs) from clusters of bursting cells, but HFOs in the ripple and the fast ripple range are vastly intermixed. ⋯ We found a major effect of extracellular Ca(2+) in modulating intrinsic excitability and disynaptic inhibition, two critical factors shaping network dynamics. Moreover, locally modulating the extracellular Ca(2+) concentration in an in vivo environment had a similar effect on disynaptic inhibition, pyramidal cell excitability, and ripple dynamics. Therefore, the HFO frequency band reflects a range of firing dynamics of hippocampal networks.
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Human C-tactile (CT) afferents respond vigorously to gentle skin stroking and have gained attention for their importance in social touch. Pharmacogenetic activation of the mouse CT equivalent has positively reinforcing, anxiolytic effects, suggesting a role in grooming and affiliative behavior. We recorded from single CT axons in human participants, using the technique of microneurography, and stimulated a unit's receptive field using a novel, computer-controlled moving probe, which stroked the skin of the forearm over five velocities (0.3, 1, 3, 10, and 30 cm s(-1)) at three temperatures (cool, 18 °C; neutral, 32 °C; warm, 42 °C). ⋯ Furthermore, the CT firing frequency correlated with hedonic ratings to the same mechano-thermal stimulus only at the neutral stimulus temperature, where the stimuli were felt as pleasant at higher firing rates. We conclude that CT afferents are tuned to respond to tactile stimuli with the specific characteristics of a gentle caress delivered at typical skin temperature. This provides a peripheral mechanism for signaling pleasant skin-to-skin contact in humans, which promotes interpersonal touch and affiliative behavior.
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3,4-Dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia (LID) is a debilitating side effect of long-term dopamine replacement therapy in Parkinson's Disease. At present, there are few therapeutic options for treatment of LID and mechanisms contributing to the development and maintenance of these drug-induced motor complications are not well understood. We have previously shown that pharmacological reduction of cholinergic tone attenuates the expression of LID in parkinsonian mice with established dyskinesia after chronic L-DOPA treatment. ⋯ We show that Cre recombinase-mediated DT-A ablation selectively eliminated ChIs when injected into striatum. The depletion of ChIs markedly attenuated LID without compromising the therapeutic efficacy of L-DOPA. These results provide evidence that ChIs play a key and selective role in LID and that strategies to reduce striatal cholinergic tone may represent a promising approach to decreasing L-DOPA-induced motor complications in Parkinson's disease.
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The basal forebrain (BF) plays an important role in the control of cortical activation and attention. Understanding the modulation of BF neuronal activity is a prerequisite to treat disorders of cortical activation involving BF dysfunction, such as Alzheimer's disease. Here we reveal the interaction between cholinergic neurons and cortically projecting BF GABAergic neurons using immunohistochemistry and whole-cell recordings in vitro. ⋯ Furthermore, optogenetic stimulation of cholinergic neurons/fibers caused a mecamylamine- and atropine-sensitive inward current in putative GABAergic neurons. Thus, cortically projecting, BF GABAergic/PV neurons are excited by neighboring BF and/or brainstem cholinergic neurons. Loss of cholinergic neurons in Alzheimer's disease may impair cortical activation, in part, through disfacilitation of BF cortically projecting GABAergic/PV neurons.