The Journal of neuroscience : the official journal of the Society for Neuroscience
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Homeostatic synaptic plasticity (HSP) has been implicated in the development of hyperexcitability and epileptic seizures following traumatic brain injury (TBI). Our in vivo experimental studies in cats revealed that the severity of TBI-mediated epileptogenesis depends on the age of the animal. To characterize mechanisms of these differences, we studied the properties of the TBI-induced epileptogenesis in a biophysically realistic cortical network model with dynamic ion concentrations. ⋯ Specific mechanisms of TBI-related epileptogenesis and how these mechanisms are affected by age remain to be understood. We test a hypothesis that the failure of homeostatic synaptic regulation, a slow negative feedback mechanism that maintains neural activity within a physiological range through activity-dependent modulation of synaptic strength, in older animals may augment TBI-induced epileptogenesis. Our results provide new insight into understanding this debilitating disorder and may lead to novel avenues for the development of effective treatments of TBI-induced epilepsy.
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Neuronal activity in medial prefrontal cortex (mPFC) is critical for the formation of trace fear memory, yet the cellular mechanisms underlying these memories remain unclear. One possibility involves the modulation of intrinsic excitability within mPFC neurons that project to the basolateral complex of amygdala (BLA). The current study used a combination of retrograde labeling and in vitro whole-cell patch-clamp recordings to examine the effect of trace fear conditioning on the intrinsic excitability of layer 5 mPFC-BLA projection neurons in adult rats. ⋯ This study involves a novel combination of electrophysiological recordings from fluorescently labeled mPFC-to-amygdala projection neurons in rats with acquisition and extinction of trace fear conditioning to determine how specific neurons change during behavior. This is the first study to demonstrate that trace fear conditioning significantly alters the intrinsic excitability of mPFC-to-amygdala projection neurons in a subregion- and cell-type-specific manner, which is also transient and reversed by extinction. These data are of broad interest to the neuroscientific community, and the results will inspire additional studies investigating the cellular mechanisms underlying circuit-specific changes within the brain as a result of associative learning and memory.
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Peripheral neuropathy is dose limiting in paclitaxel cancer chemotherapy and can result in both acute pain during treatment and chronic persistent pain in cancer survivors. The hypothesis tested was that paclitaxel produces these adverse effects at least in part by sensitizing transient receptor potential vanilloid subtype 1 (TRPV1) through Toll-like receptor 4 (TLR4) signaling. The data show that paclitaxel-induced behavioral hypersensitivity is prevented and reversed by spinal administration of a TRPV1 antagonist. ⋯ A direct functional interaction between TLR4 and TRPV1 is shown in rat and human dorsal root ganglion neurons, TLR4/TRPV1-coexpressing HEK293 cells, and in both rat and mouse spinal cord slices. Moreover, this is the first study to show that this interaction plays an important role in the generation of behavioral hypersensitivity in paclitaxel-related neuropathy. The key translational implications are that TLR4 and TRPV1 antagonists may be useful in the prevention and treatment of chemotherapy-induced peripheral neuropathy in humans.
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Neuropathic pain is a debilitating condition for which the development of effective treatments has been limited by an incomplete understanding of its molecular basis. The cationic current Ih mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels plays an important role in pain by facilitating ectopic firing and hyperexcitability in DRG neurons, however little is known regarding the role of Ih in supraspinal pain pathways. The medial prefrontal cortex (mPFC), which is reported to be involved in the affective aspects of pain, exhibits high HCN channel expression. ⋯ It is therefore imperative that we advance our understanding of the involvement of supraspinal pain pathways. Our electrophysiological and behavioral results support an important role for hyperpolarization-activated cyclic nucleotide-gated channels and the cAMP/protein kinase A signaling axis in promoting hyperexcitability and persistent firing in pyramidal neurons of the mPFC in neuropathic animals. These findings offer novel insights, with potential therapeutic implications, into pathophysiological mechanisms underlying the abnormal contribution of layer II/III prefrontal pyramidal neurons to chronic pain states.
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Docosahexaenoic acid (DHA) is an ω-3 polyunsaturated fatty acid that is essential in brain development and has structural and signaling roles. Acute DHA administration is neuroprotective and promotes functional recovery in animal models of adult spinal cord injury (SCI). However, the mechanisms underlying this recovery have not been fully characterized. Here we investigated the effects of an acute intravenous bolus of DHA delivered after SCI and characterized DHA-induced neuroplasticity within the adult injured spinal cord. We found robust sprouting of uninjured corticospinal and serotonergic fibers in a rat cervical hemisection SCI model. A mouse pyramidotomy model was used to confirm that this robust sprouting was not species or injury model specific. Furthermore, we demonstrated that corticospinal fibers sprouting to the denervated side of the cord following pyramidotomy contact V2a interneurons. We also demonstrated increased serotonin fibers and synaptophysin in direct contact with motor neurons. DHA also increased synaptophysin in rat cortical cell cultures. A reduction in phosphatase and tensin homolog (PTEN) has been shown to be involved in axonal regeneration and synaptic plasticity. We showed that DHA significantly upregulates miR-21 and downregulates PTEN in corticospinal neurons. Downregulation of PTEN and upregulation of phosphorylated AKT by DHA were also seen in primary cortical neuron cultures and were accompanied by increased neurite outgrowth. In summary, acute DHA induces anatomical and synaptic plasticity in adult injured spinal cord. This study shows that DHA has therapeutic potential in cervical SCI and provides evidence that DHA could exert its beneficial effects in SCI via enhancement of neuroplasticity. ⋯ In this study, we show that an acute intravenous injection of docosahexaenoic acid (DHA) 30 min after spinal cord injury induces neuroplasticity. We found robust sprouting of uninjured corticospinal and serotonergic fibers in a rat hemisection spinal cord injury model. A mouse pyramidotomy model was used to confirm that the robust sprouting involved V2a interneurons. We show that DHA significantly upregulates miR-21 and phosphorylated AKT, and downregulates phosphatase and tensin homolog (PTEN), which is involved in suppressing anatomical plasticity, in corticospinal neurons and in primary cortical neuron cultures. We conclude that acute DHA can induce anatomical and synaptic plasticity. This provides direct evidence that DHA could exert its beneficial effects in spinal cord injury via neuroplasticity enhancement.