Neuroscience
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The striatum is thought to be an essential region for integrating diverse information in the brain. Rapid inhibitory gating (IG) of sensory input is most likely an early factor necessary for appropriate integration to be completed. Gating is currently evaluated in clinical settings and is dramatically altered in a variety of psychiatric illnesses. ⋯ Gating was strengthened (Tamp/Camp ratios approaching 0) following acute stress (saline injection) at both the single unit and LFP level due to the reduction in the response to the second tone. Alterations in sensory responding reflected by changes in the neural response to the initial tone were primarily observed following long-term internal state deviation (food deprivation) and during general locomotion. Overall, our results support local IG by single neurons in striatum but also suggest that rapid inhibition is not the dominant activation profile observed in other brain regions.
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We previously demonstrated that peripherally located N-methyl-D-aspartic acid (NMDA) receptors contribute to acute muscle nociception and the development of chronic muscular hyperalgesia. In the present study, we investigated the potential role of peripheral group I metabotropic glutamate receptors (mGluRs 1/5) in the development of muscular hypersensitivity to mechanical stimulation, and attempted to elucidate intracellular signaling mechanisms associated with the mGluR activation in male Sprague-Dawley rats. First, our Western blot analyses revealed that mGluR 5 protein, but not mGluR 1 protein, is reliably detected in trigeminal ganglia and the masseter nerve. ⋯ Moreover, the DHPG-induced mechanical hypersensitivity was significantly blocked by inhibiting either the alpha or epsilon isoform of protein kinase C (PKC). Collectively, these data provide evidence that peripherally located mGluR 5 may play an important role in the development of masseter hypersensitivity, and that PKC activation is required for the modulatory effect of peripheral mGluR 5 in the craniofacial muscle tissue. Thus, selective targeting of peripheral mGluR 5 and PKCalpha, as well as PKCepsilon, might serve as an effective therapeutic strategy in the management of chronic muscle pain conditions, such as temporomandibular disorders.
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Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme that contributes to both neuronal death and survival under stress conditions. PARP-1 is the most abundant of several PARP family members, accounting for more than 85% of nuclear PARP activity, and is present in all nucleated cells of multicellular animals. ⋯ PARP-1 activation is thereby a key mediator of neuronal death during excitotoxicity, ischemia, and oxidative stress, and PARP-1 gene deletion or pharmacological inhibition can markedly improve neuronal survival in these settings. PARP-1 activation has also been identified in Alzheimer's disease and in experimental allergic encephalitis, but the role of PARP-1 in these disorders remains to be established.
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Oligodendrocytes are crucial to the function of the mammalian brain: they increase the action potential conduction speed for a given axon diameter and thus facilitate the rapid flow of information between different brain areas. The proliferation and differentiation of developing oligodendrocytes, and their myelination of axons, are partly controlled by neurotransmitters. ⋯ Mutations in oligodendrocyte neurotransmitter receptors or their interacting proteins may cause defects in CNS function. Here we review the roles of neurotransmitter receptors in the normal function, and malfunction in pathological conditions, of oligodendrocytes.
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Patients with the genetic disease xeroderma pigmentosum (XP) lack the capacity to carry out a specific type of DNA repair process called nucleotide excision repair (NER). The NER pathway plays a critical role in the repair of DNA damage resulting from ultraviolet (UV) radiation. A subset of XP patients develops a profound neurodegenerative condition known as XP neurological disease. ⋯ In this manuscript, I consider the evidence that a particular class of oxidative DNA lesions, the 8,5'-cyclopurine-2'-deoxynucleosides, fulfills many of the criteria expected of neurodegenerative DNA lesions in XP. Specifically, these lesions are chemically stable, endogenous DNA lesions that are repaired by the NER pathway but not by any other known process, and strongly block transcription by RNA polymerase II in cells from XP patients. A similar set of criteria might be used to evaluate other candidate DNA lesions responsible for neurological diseases resulting from defects in other DNA repair mechanisms as well.