Presynaptic Partners of Dorsal Raphe Serotonergic and GABAergic Neurons

Neuron (Impact Factor: 15.05). 08/2014; 83(3):645-662. DOI: 10.1016/j.neuron.2014.06.024
Source: PubMed


The serotonin system powerfully modulates physiology and behavior in health and disease, yet the circuit mechanisms underlying serotonin neuron activity are poorly understood. The major source of forebrain serotonergic innervation is from the dorsal raphe nucleus (DR), which contains both serotonin and GABA neurons. Using viral tracing combined with electrophysiology, we found that GABA and serotonin neurons in the DR receive excitatory, inhibitory, and peptidergic inputs from the same specific brain regions. Embedded in this overall similarity are important differences. Serotonin neurons are more likely to receive synaptic inputs from anterior neocortex while GABA neurons receive disproportionally higher input from the central amygdala. Local input mapping revealed extensive serotonin-serotonin as well as GABA-serotonin connectivity with a distinct spatial organization. Covariance analysis suggests heterogeneity of both serotonin and GABA neurons with respect to the inputs they receive. These analyses provide a foundation for further functional dissection of the serotonin system.

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    • "These findings are consistent with the hypothesis that 5-HT 7 receptors in the DRN are not localized on 5-HT cells, but rather on local GABAergic interneurons which modulate the activity of 5-HT projection neurons (Harsing, 2006). The 5-HT 7 receptor-dependent modulation of inhibitory influence on DRN projection neurons is has not yet been explored (Liu et al., 2000; Gocho et al., 2013; Weissbourd et al., 2014; Commons, 2015). Therefore, in the present study we aimed at determining how the 5-HT 7 receptor activation and blockade modulate the GABAergic synaptic input to electrophysiologically identified, broad action potentialexhibiting DRN neurons in a slice preparation. "
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    ABSTRACT: The 5-HT7 receptor is one of the several serotonin (5-HT) receptor subtypes that are expressed in the dorsal raphe nucleus (DRN). Some earlier findings suggested that 5-HT7 receptors in the DRN were localized on GABAergic interneurons modulating the activity of 5-HT projection neurons. The aim of the present study was to find out how the 5-HT7 receptor modulates the GABAergic synaptic input to putative 5-HT DRN neurons, and whether blockade of the 5-HT7 receptor would affect the release of 5-HT in the target structure. Male Wistar rats with microdialysis probes implanted in the prefrontal cortex (PFC) received injections of the 5-HT7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine hydrochloride (SB 269970), which induced an increase in the levels of 5-HT and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in the PFC. In another set of experiments whole-cell recordings from presumed projection neurons were carried out using DRN slices. SB 269970 application resulted in depolarization and in an increase in the firing frequency of the cells. In order to activate 5-HT7 receptors, 5-carboxamidotryptamine (5-CT) was applied in the presence of N-[2-[4-(2-methoxyphenyl)-1piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635). Hyperpolarization of cells and a decrease in the firing frequency were observed after activation of the 5-HT7 receptor. Blockade of 5-HT7 receptors caused a decrease in the mean frequency of spontaneous inhibitory postsynaptic currents (sIPSCs), while its activation induced an increase. The mechanism of these effects appears to involve tonically-active 5-HT7 receptors modulating firing and/or GABA release from inhibitory interneurons which regulate the activity of DRN serotonergic projection neurons.
    Frontiers in Cellular Neuroscience 09/2015; 9:324. DOI:10.3389/fncel.2015.00324 · 4.29 Impact Factor
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    • "Recent transsynaptic tracings reveal that DRN GABA neurons share a largely similar input pattern with 5-HT neurons (Dorocic et al. 2014; Weissbourd et al. 2014). However, neurons from the central amygdala and the bed nucleus of the stria terminalis preferentially innervate GABAergic neurons, suggesting that these brain areas exert a more powerful modulation of DRN functions through GABAergic interneurons (Weissbourd et al. 2014). A small fraction of DRN neurons (1000 in mice) in the rostral-dorsal part of the DRN expresses the dopamine markers tyrosine hydroxylase and dopamine transporter (DAT) (Flores et al. 2004). "
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    ABSTRACT: The dorsal raphe nucleus (DRN) represents one of the most sensitive reward sites in the brain. However, the exact relationship between DRN neuronal activity and reward signaling has been elusive. In this review, we will summarize anatomical, pharmacological, optogenetics, and electrophysiological studies on the functions and circuit mechanisms of DRN neurons in reward processing. The DRN is commonly associated with serotonin (5-hydroxytryptamine; 5-HT), but this nucleus also contains neurons of the neurotransmitter phenotypes of glutamate, GABA and dopamine. Pharmacological studies indicate that 5-HT might be involved in modulating reward- or punishment-related behaviors. Recent optogenetic stimulations demonstrate that transient activation of DRN neurons produces strong reinforcement signals that are carried out primarily by glutamate. Moreover, activation of DRN 5-HT neurons enhances reward waiting. Electrophysiological recordings reveal that the activity of DRN neurons exhibits diverse behavioral correlates in reward-related tasks. Studies so far thus demonstrate the strong power of DRN neurons in reward signaling and at the same time invite additional efforts to dissect the roles and mechanisms of different DRN neuron types in various processes of reward-related behaviors. © 2015 Luo et al.; Published by Cold Spring Harbor Laboratory Press.
    Learning & memory (Cold Spring Harbor, N.Y.) 09/2015; 22(9):452-60. DOI:10.1101/lm.037317.114 · 3.66 Impact Factor
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    • "rong et al . , 1983 ) , dopaminergic ( Björklund and Dunnett , 2007 ) and serotonergic neurons ( Fu et al . , 2010 ; Russo and Nestler , 2013 ) , have been analyzed using traditional methods ; however , these studies were limited primarily to local areas . Recently , the projection , location and distribution of specific subtypes of interneurons ( Weissbourd et al . , 2014 ) and of serotonergic neurons ( Pollak Dorocic et al . , 2014 ) have been characterized in the mouse brain with manually sectioning and imaging ."
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    ABSTRACT: There are some unsolvable fundamental questions, such as cell type classification, neural circuit tracing and neurovascular coupling, though great progresses are being made in neuroscience. Because of the structural features of neurons and neural circuits, the solution of these questions needs us to break through the current technology of neuroanatomy for acquiring the exactly fine morphology of neuron and vessels and tracing long-distant circuit at axonal resolution in the whole brain of mammals. Combined with fast-developing labeling techniques, efficient whole-brain optical imaging technology emerging at the right moment presents a huge potential in the structure and function research of specific-function neuron and neural circuit. In this review, we summarize brain-wide optical tomography techniques, review the progress on visible brain neuronal/vascular networks benefit from these novel techniques, and prospect the future technical development.
    Frontiers in Neuroanatomy 05/2015; 9. DOI:10.3389/fnana.2015.00070 · 3.54 Impact Factor
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