The Journal of neuroscience : the official journal of the Society for Neuroscience
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We previously showed that intrathecal application of endomorphin 2 [EM2; the highly specific endogenous μ-opioid receptor (MOR) ligand] induces antinociception that varies with stage of the rat estrous cycle: minimal during diestrus and prominent during proestrus. Earlier studies, however, did not identify proestrus-activated signaling strategies that enable spinal EM2 antinociception. We now report that in female rats, increased spinal dynorphin release and κ-opioid receptor (KOR) signaling, as well as the emergence of glutamate-activated metabotropic glutamate receptor 1 (mGluR1) signaling, are critical to the transition from an EM2 nonresponsive state (during diestrus) to an analgesically responsive state (during proestrus). ⋯ We find that the magnitude of spinal endomorphin 2 (EM2) antinociception not only varies with stage of reproductive cycle, but is also differentially regulated during diestrus and proestrus. This finding highlights the need for sex-specific and cycle-specific approaches to pain management. Additionally, our finding that spinal EM2 antinociception in female rats is regulated by both the ebb and flow of spinal dynorphin/κ-opioid receptor signaling over the estrous cycle, as well as the nature of the endogenous mGluR1 activator, could encourage noncanonical pharmacological approaches to pain management, such as harnessing endogenous opioids for pain relief.
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This study aims to understand how functional connectivity (FC) between areas 3b and S2 alters following input deprivation and the neuronal basis of disrupted FC of resting-state fMRI signals. We combined submillimeter fMRI with microelectrode recordings to localize the deafferented digit regions in areas 3b and S2 by mapping tactile stimulus-evoked fMRI activations before and after cervical dorsal column lesion in each male monkey. An average afferent disruption of 97% significantly reduced fMRI, local field potential (LFP), and spike responses to stimuli in both areas. ⋯ These findings have important implications for fMRI studies aiming to probe FC alterations in pathological conditions involving deafferentation in humans. SIGNIFICANCE STATEMENT By directly comparing fMRI, local field potential, and spike signals in both tactile stimulation and resting states before and after severe disruption of dorsal column afferent, we demonstrated that reduction in fMRI responses to stimuli is accompanied by weakened resting-state fMRI functional connectivity (FC) in input-deprived and reorganized digit regions in area 3b of the S1 and S2. Concurrent reductions in local field potential and spike FC validated the use of resting-state fMRI signals for probing neural intrinsic FC alterations in pathological deafferented cortex, and indicated that disrupted FC between mesoscale functionally highly related regions may contribute to the behavioral impairments.
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The c-Jun-N-terminal kinase (JNK) signaling pathway regulates nervous system development, axon regeneration, and neuronal degeneration after acute injury or in chronic neurodegenerative disease. Dual leucine zipper kinase (DLK) is required for stress-induced JNK signaling in neurons, yet the factors that initiate DLK/JNK pathway activity remain poorly defined. In the present study, we identify the Ste20 kinases MAP4K4, misshapen-like kinase 1 (MINK1 or MAP4K6) and TNIK Traf2- and Nck-interacting kinase (TNIK or MAP4K7), as upstream regulators of DLK/JNK signaling in neurons. ⋯ The dual leucine zipper kinase (DLK)/c-Jun-N-terminal kinase (JNK) pathway represents a conserved regulator of neuronal injury signaling that drives both neurodegeneration and axon regeneration, yet little is known about the factors that initiate DLK activity. Here, we uncover a novel role for a subfamily of MAP4 kinases consisting of MAP4K4, Traf2- and Nck-interacting kinase (TNIK or MAP4K7), and misshapen-like kinase 1 (MINK1 or MAP4K6) in regulating DLK/JNK signaling in neurons. Inhibition of these MAP4Ks blocks stress-induced retrograde JNK signaling and protects from neurodegeneration, suggesting that these kinases may represent attractive therapeutic targets.
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In vivo optical imaging has emerged as a powerful tool with which to study cellular responses to injury and disease in the mammalian CNS. Important new insights have emerged regarding axonal degeneration and regeneration, glial responses and neuroinflammation, changes in the neurovascular unit, and, more recently, neural transplantations. Accompanying a 2017 SfN Mini-Symposium, here, we discuss selected recent advances in understanding the neuronal, glial, and other cellular responses to CNS injury and disease with in vivo imaging of the rodent brain or spinal cord. We anticipate that in vivo optical imaging will continue to be at the forefront of breakthrough discoveries of fundamental mechanisms and therapies for CNS injury and disease.
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Animals can readily learn that stimuli predict the absence of specific appetitive outcomes; however, the neural substrates underlying such outcome-specific conditioned inhibition remain largely unexplored. Here, using female and male rats as subjects, we examined the involvement of the lateral habenula (LHb) and of its inputs onto the rostromedial tegmental nucleus (RMTg) in inhibitory learning. In these experiments, we used backward conditioning and contingency reversal to establish outcome-specific conditioned inhibitors for two distinct appetitive outcomes. ⋯ Here we reveal that the lateral habenula is critical for negative predictors, but not positive predictors, to affect choice. Furthermore, these effects were found to require activation of lateral habenula inputs to the rostromedial tegmental nucleus. These results are consistent with the view that the lateral habenula establishes inhibitory relationships between stimuli and food outcomes and computes a negative prediction error in Pavlovian conditioning.