The Journal of neuroscience : the official journal of the Society for Neuroscience
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The trophic factor neuregulin 1 (Nrg1) and its receptor ErbB4 are schizophrenia candidate genes. NRG1-ErbB4 signaling was thought to regulate spine formation and function in a cell-autonomous manner. Yet, recent studies indicate that ErbB4 expression is largely restricted to GABAergic interneurons and is very low or absent in pyramidal cells. ⋯ However, spine density and excitatory synapse number were reduced in PV-ErbB4(-/-) mice where ErbB4 was selectively ablated in parvalbumin-positive GABAergic interneurons. Concurrently, basal glutamate transmission was impaired in PV-ErbB4(-/-) mice, but not in mice where ErbB4 was deleted or overexpressed in pyramidal neurons. Our results demonstrate a role of ErbB4 in PV-positive interneurons for spine formation in excitatory neurons.
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Motivated behaviors are often characterized by a high degree of behavioral activation, and work output and organisms frequently make effort-related decisions based upon cost/benefit analyses. Moreover, people with major depression and other disorders often show effort-related motivational symptoms such as anergia, psychomotor retardation, and fatigue. It has been suggested that tasks measuring effort-related choice behavior could be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT) inhibitor tetrabenazine. ⋯ A behaviorally active dose of tetrabenazine decreased extracellular DA in nucleus accumbens and increased expression of DARPP-32 in accumbens medium spiny neurons in a pattern indicative of reduced transmission at both D1 and D2 DA receptors. These experiments demonstrate that tetrabenazine, which is used in animal models to produce depression-like effects, can alter effort-related choice behavior. These studies have implications for the development of animal models of the motivational symptoms of depression and related disorders.
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Epidural electrical stimulation (EES) of lumbosacral segments can restore a range of movements after spinal cord injury. However, the mechanisms and neural structures through which EES facilitates movement execution remain unclear. Here, we designed a computational model and performed in vivo experiments to investigate the type of fibers, neurons, and circuits recruited in response to EES. ⋯ The model also predicted the capacity of spatially distinct EES to modulate side-specific limb movements and, to a lesser extent, extension versus flexion. These predictions were confirmed during standing and walking enabled by EES in spinal rats. These combined results provide a mechanistic framework for the design of spinal neuroprosthetic systems to improve standing and walking after neurological disorders.
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Pain is the most common symptom of bone cancer. TGF-β, a major bone-derived growth factor, is largely released by osteoclast bone resorption during the progression of bone cancer and contributes to proliferation, angiogenesis, immunosuppression, invasion, and metastasis. Here, we further show that TGF-β1 is critical for bone cancer-induced pain sensitization. ⋯ Extracellular application of TGF-β1 significantly potentiated TRPV1 currents and increased [Ca(2+)]i in DRG neurons. Pharmacological studies revealed that the TGF-β1 sensitization of TRPV1 and the induction of thermal hyperalgesia required the TGF-βR-mediated Smad-independent PKCε and TGF-β activating kinase 1-p38 pathways. These findings suggest that TGF-β1 signaling contributes to bone cancer pain via the upregulation and sensitization of TRPV1 in primary sensory neurons and that therapeutic targeting of TGF-β1 may ameliorate the bone cancer pain in advanced cancer.
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Artificial grammars (AG) are designed to emulate aspects of the structure of language, and AG learning (AGL) paradigms can be used to study the extent of nonhuman animals' structure-learning capabilities. However, different AG structures have been used with nonhuman animals and are difficult to compare across studies and species. We developed a simple quantitative parameter space, which we used to summarize previous nonhuman animal AGL results. ⋯ A novel eye-tracking approach confirmed this result in the macaques and demonstrated evidence for more complex AGL. This study provides evidence for a previously unknown level of AGL complexity in Old World monkeys that seems less evident in New World monkeys, which are more distant evolutionary relatives to humans. The findings allow for the development of both marmosets and macaques as neurobiological model systems to study different aspects of AGL at the neuronal level.