ABSTRACT
Substantia nigra dopamine neurons have been implicated in the initiation and invigoration of movement, presumably through their modulation of striatal projection neuron (SPN) activity. However, the impact of native dopaminergic transmission on SPN excitability has not been directly demonstrated. Using perforated patch-clamp recording, we found that optogenetic stimulation of nigrostriatal dopamine axons rapidly and persistently elevated the excitability of D1 receptor-expressing SPNs (D1-SPNs). The evoked firing of D1-SPNs increased within hundreds of milliseconds of stimulation and remained elevated for ≥ 10 min. Consistent with the negative modulation of depolarization- and Ca2+-activated K+ currents, dopaminergic transmission accelerated subthreshold depolarization in response to current injection, reduced the latency to fire, and transiently diminished action potential afterhyperpolarization. Persistent modulation was protein kinase A dependent and associated with a reduction in action potential threshold. Together, these data demonstrate that dopaminergic transmission potently increases D1-SPN excitability with a time course that could support subsecond and sustained behavioral control.
Subject(s)
Dopamine/physiology , Neostriatum/physiology , Neurons/physiology , Neurotransmitter Agents/physiology , Receptors, Dopamine D1/physiology , Synaptic Transmission/physiology , Animals , Electrophysiological Phenomena , Female , Male , Mice , Neostriatum/cytology , Neostriatum/metabolism , Optogenetics , Patch-Clamp TechniquesABSTRACT
Basophils are evolutionarily conserved in vertebrates, despite their small numbers and short life span, suggesting that they have beneficial roles in maintaining health. However, these roles are not fully defined. Here we demonstrate that basophil-deficient mice exhibit reduced bacterial clearance and increased morbidity and mortality in the cecal ligation and puncture (CLP) model of sepsis. Among the several proinflammatory mediators that we measured, tumor necrosis factor (TNF) was the only cytokine that was significantly reduced in basophil-deficient mice after CLP. In accordance with that observation, we found that mice with genetic ablation of Tnf in basophils exhibited reduced systemic concentrations of TNF during endotoxemia. Moreover, after CLP, mice whose basophils could not produce TNF, exhibited reduced neutrophil and macrophage TNF production and effector functions, reduced bacterial clearance, and increased mortality. Taken together, our results show that basophils can enhance the innate immune response to bacterial infection and help prevent sepsis.
