Neuron
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The precise regulation of cerebral blood flow is critical for normal brain function, and its disruption underlies many neuropathologies. The extent to which smooth muscle-covered arterioles or pericyte-covered capillaries control vasomotion during neurovascular coupling remains controversial. We found that capillary pericytes in mice and humans do not express smooth muscle actin and are morphologically and functionally distinct from adjacent precapillary smooth muscle cells (SMCs). ⋯ Optogenetic, whisker stimulation, or cortical spreading depolarization caused microvascular diameter or flow changes in SMC but not pericyte-covered microvessels. During early stages of brain ischemia, transient SMC but not pericyte constrictions were a major cause of hypoperfusion leading to thrombosis and distal microvascular occlusions. Thus, capillary pericytes are not contractile, and regulation of cerebral blood flow in physiological and pathological conditions is mediated by arteriolar SMCs.
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Human genetic studies have revealed an association between GTP cyclohydrolase 1 polymorphisms, which decrease tetrahydrobiopterin (BH4) levels, and reduced pain in patients. We now show that excessive BH4 is produced in mice by both axotomized sensory neurons and macrophages infiltrating damaged nerves and inflamed tissue. ⋯ Using a structure-based design, we developed a potent SPR inhibitor and show that it reduces pain hypersensitivity effectively with a concomitant decrease in BH4 levels in target tissues, acting both on sensory neurons and macrophages, with no development of tolerance or adverse effects. Finally, we demonstrate that sepiapterin accumulation is a sensitive biomarker for SPR inhibition in vivo.
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Hippocampal theta rhythm arises from a combination of recently described intrinsic theta oscillators and inputs from multiple brain areas. Interneurons expressing the markers parvalbumin (PV) and somatostatin (SOM) are leading candidates to participate in intrinsic rhythm generation and principal cell (PC) coordination in distal CA1 and subiculum. We tested their involvement by optogenetically activating and silencing PV or SOM interneurons in an intact hippocampus preparation that preserves intrinsic connections and oscillates spontaneously at theta frequencies. ⋯ However, SOM interneurons were able to strongly modulate temporoammonic inputs. In contrast, activation of PV interneurons powerfully controlled PC network and rhythm generation optimally at 8 Hz, while continuously silencing them disrupted theta. Our results thus demonstrate a pivotal role of PV but not SOM interneurons for PC synchronization and the emergence of intrinsic hippocampal theta.
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The classical view of somatosensory processing holds that proprioceptive and cutaneous inputs are conveyed to cortex through segregated channels, initially synapsing in modality-specific areas 3a (proprioception) and 3b (cutaneous) of primary somatosensory cortex (SI). These areas relay their signals to areas 1 and 2 where multimodal convergence first emerges. However, proprioceptive and cutaneous maps have traditionally been characterized using unreliable stimulation tools. ⋯ Single-unit recordings in SI revealed that most neurons responded to cutaneous and proprioceptive stimuli, including cells in areas 3a and 3b. Multimodal responses were characterized by linear and nonlinear effects that emerged during early (∼20 ms) and latter (> 100 ms) stages of stimulus processing, respectively. These data are incompatible with the modality specificity model in SI, and provide evidence for distinct mechanisms of multimodal processing in the somatosensory system.
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In this issue of Neuron, Santello and Nevian (2015) report HCN channel plasticity and increased temporal summation in layer 5 ACC neurons following nerve injury. They are able to restore HCN channel function and reduce behavioral hypersensitivity with selective serotonin receptor targeting.