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An inhibitory corticostriatal pathway
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Anatomical and physiological studies have led to the assumption that the dorsal striatum receives exclusively excitatory afferents from the cortex. Here we test the hypothesis that the dorsal striatum receives also GABAergic projections from the cortex. We addressed this fundamental question by taking advantage of optogenetics and directly examining the functional effects of cortical GABAergic inputs to spiny projection neurons (SPNs) of the mouse auditory and motor cortex. We found that the cortex, via corticostriatal somatostatin neurons (CS-SOM), has a direct inhibitory influence on the output of the striatum SPNs. Our results describe a corticostriatal long-range inhibitory circuit (CS-SOM inhibitory projections → striatal SPNs) underlying the control of spike timing/generation in SPNs and attributes a specific function to a genetically defined type of cortical interneuron in corticostriatal communication.https://doi.org/10.7554/eLife.15890.001
eLife digest
The striatum is located beneath the cerebral cortex, where it contributes to processes including learning and movement. The Spanish anatomist Ramon y Cajal, working in the early 20th century, was the first to observe individual neurons extending from the cortex to the striatum. Cajal published drawings of these neurons in his now celebrated anatomical papers, but knew little about their properties.
In the 1980s, advances in techniques for labeling individual cells made it possible to study these neurons in detail. The results suggested that the pathways are exclusively excitatory: that is, the cortical neurons always increase the activity of their partners in the striatum. However, this result made it difficult to explain why electrically stimulating the cortex can sometimes reduce or inhibit the activity of the striatum. To reconcile these facts, most people assumed that inhibition must occur when excitatory cortical neurons activate networks of inhibitory cells within the striatum itself.
Rock et al. now challenge this view by providing anatomical and physiological evidence for the existence of long-range inhibitory pathways from the cortex to the striatum in the mouse brain. These inhibitory neurons project from the auditory and motor regions of the cortex, and contain a substance called somatostatin. These neurons form connections with a specific type of striatal neuron called medium spiny neurons, which in turn project to other brain regions outside the striatum. The inhibitory cortical neurons can alter the activity of the medium spiny neurons, and can therefore directly control the output of the striatum.
The discovery that the striatum receives both excitatory and inhibitory inputs from cortex suggests that the timing and relative strength of these inputs can affect the activity of the striatum. Future experiments should examine whether this is a general mechanism by which sensory stimuli can influence the processes controlled by the striatum, such as movement.https://doi.org/10.7554/eLife.15890.002
It is very well established that cortical neurons regulate the activity of spiny projection neurons (SPNs) in the striatum through long-range glutamatergic/excitatory projections (Landry et al., 1984; Wilson, 1987; 2004; Graybiel et al., 1994; Lovinger and Tyler, 1996; Reiner et al., 2003; Kress et al., 2013), while inhibition is mediated by local feed-forward and feed-back circuits (for review [Tepper et al., 2008]). The feed-forward circuit is characterized by GABAergic striatal interneurons that receive excitatory inputs from the cortex and monosynaptically inhibit SPNs. The feed-back circuit is characterized by SPNs and their interconnections via local axon collaterals (Calabresi et al., 1991; Kawaguchi, 1993; Kita, 1993; 1996; Kawaguchi et al., 1995; Mallet et al., 2005; Planert et al., 2010; Ibanez-Sandoval et al., 2011). Because striatal neuronal activity has been shown to be involved in movement, learning, and goal-directed behavior (Graybiel, 1995; Schultz et al., 2003; Barnes et al., 2005; Kreitzer and Malenka, 2008), it is crucial to understand the cortical connectivity pattern and dynamics that shape the flow of information in the striatum.
Anatomical studies using retrograde tracers and immunohistochemistry have proposed that between 1–10% of the GABAergic 'interneurons' in rodents, cats, and monkeys also give rise to long-range corticocortical projections (McDonald and Burkhalter, 1993; Tomioka et al., 2005; Higo et al., 2007; Tomioka and Rockland, 2007; Higo et al., 2009). A growing body of evidence suggests that many of these projections arise from somatostatin-expressing neurons (Tomioka et al., 2005; Higo et al., 2007; Tomioka and Rockland, 2007; Higo et al., 2009; McDonald et al., 2012; Melzer et al., 2012). A previous study has demonstrated the presence of a corticostriatal GABAergic projection (Tomioka et al., 2015), but the cells of origin and physiological function of this GABAergic projection from the cortex to the dorsal striatum were not explored.
To test the hypothesis that the cortex has a direct inhibitory influence on the output neurons of the striatum, we measured the response of SPNs to optogenetic activation of corticostriatal somatostatin neuron (CS-SOM) axons. Our results describe a previously unknown corticostriatal direct inhibitory circuit (CS-SOM inhibitory projections → striatal SPNs) underlying the control of spike timing/generation in SPNs and attribute a specific function to a genetically defined type of cortical interneuron in corticostriatal communication. Overall this suggests that the timing and ratio of cortical excitatory and inhibitory inputs to the dorsal striatum, by shaping the activity pattern of SPNs, determines behavioral outcomes.
Anatomical and electrophysiological properties of corticostriatal somatostatin neurons
To visualize long-range GABAergic projections originating in the cortex and terminating in the dorsal striatum, we conditionally expressed GFP in somatostatin-expressing (SOM) interneurons by injecting AAV.GFP.Flex into the right auditory cortex (AC) of SOM-Cre-tdTomato transgenic mice (Figure 1a). GFP was colocalized with SOM/tdTomato-expressing neurons in the AC (Figure 1b left) and GFP-positive axons were visible in coronal sections of the right dorsal striatum in these mice (Figure 1b middle and right).
Next, to determine the layer of origin for the long-range corticostriatal SOM neurons (from this point forward referred to as CS-SOM neurons), we injected the AAV.GFP.Flex virus into the right dorsal striatum of SOM-Cre transgenic mice (Taniguchi et al., 2011) (Figure 1c). Using this virus, CS-SOM neurons were retrogradely labelled with GFP, and their somata were present primarily in layers 5 and 6 of the AC (Figure 1d, middle). This approach allowed us to visually identify and record from layer 5 and 6 CS-SOM neurons using whole-cell patch clamp. Confocal images of biocytin-filled CS-SOM neurons showed that they are similar to SOM interneurons in their morphology and send an axonal projection into the subcortical white matter (Figure 1d, right; Neurolucida-reconstructed CS-SOM neuron Figure 1e). We verified their identity based on the comparison with electrophysiological properties of SOM interneurons (Ma et al., 2006). These properties include a wide action potential and low rheobase (the smallest current step evoking an action potential) (Figure 1f, top; action potentials in CS-SOM neurons, shown in black, are wider than those from fast-spiking interneurons, example in red). The responses to current steps in CS-SOM neurons were typical for SOM interneurons (Figure 1f, bottom; notice the sag from a hyperpolarizing current step). Basic electrophysiological properties for CS-SOM neurons (n = 13) included (Figure 1g): resting membrane potential, −72.93 ± 1.16 mV; input resistance, 240 ± 26.98 MΩ; membrane time constant, 6.84 ± 0.71 ms; rheobase, 100 ± 15pA; action potential threshold, −41.35 ± 1.33 mV; action potential height, 54.18 ± 2.21 mV; action potential width, 0.49 ± 0.05 ms; F-I slope, 0.24 ± 0.03 Hz/pA step.
Although, in our experience, AAV1.Flex viral vectors (Atasoy et al., 2008) exhibited both anterograde and retrograde (Rothermel et al., 2013) transfection capabilities, when we injected this virus in the cortex we only observed anterograde labeling of CS-SOM neurons (i.e. no SOM somata transfected in the dorsal striatum; see Figure 1b, right). In contrast, when we injected this virus into the dorsal striatum, we observed transfected SOM somata both in the dorsal striatum (Figure 1d, left) and in the cortex (Figure 1d, middle left and middle right). These data show that this inhibitory projection is unidirectional, arising preferentially from layer 5 and 6 SOM neurons in the cortex which project to the dorsal striatum.
Do corticostriatal somatostatin neurons inhibit striatal neurons?
To determine the connectivity pattern of CS-SOM neurons onto neurons in the dorsal striatum, we used an optogenetic approach in which we conditionally expressed channelrhodopsin-2 (ChR2) in SOM neurons by injecting AAV1.ChR2.Flex into the right AC of SOM-Cre transgenic mice (Figure 2a, b; injection site Figure 2c). After 3–4 weeks, we recorded from the right dorsal striatum, in which ChR2-positive axons could be observed (Figure 2d, right). These axons have been reported to remain photoexcitable even when severed from their parent somata (Petreanu et al., 2007; Rock and Apicella, 2015). To determine the synaptic properties of CS-SOM projections onto striatal neurons, we photoactivated CS-SOM ChR2-positive axons by flashing blue light (470 nm) for 2–5 ms during whole-cell recordings from striatal neurons. IPSCs (Figure 2f, red trace) were isolated by applying a command potential of 0 mV (the calculated reversal potential for glutamatergic excitatory conductance). The IPSCs onset of the photo-evoked response was 2.2 ± 0.11 ms (Figure 2g, left). This latency is consistent with the IPSCs being the result of a monosynaptic inhibitory input from the cortex and not a local striatal feedback inhibitory network recruited by cortical projections. Blocking excitatory neurotransmission by application of glutamate receptor antagonists NBQX and CPP did not abolish the CS-SOM-ChR2-evoked synaptic IPSCs (Figure 2f, magenta trace). In contrast, blocking inhibitory neurotransmission by application of gabazine (Figure 2f, black trace) completely abolished the CS-SOM-ChR2-evoked synaptic IPSCs, confirming they were elicited by direct cortical inhibitory transmission. Basic biophysical properties for CS-SOM-ChR2-evoked synaptic IPSCs (n = 16) included (Figure 2g,h,i): peak, 122 ± 26 pA; charge, 3.85 ± 0.67 pC; rise time, 1.64 ± 0.13 ms; decay time, 28.87 ± 2.76 ms. Biocytin-filled neurons were morphologically identified as SPNs post-hoc by the presence of dendritic spines (Figure 2e, right, white arrows). Eight out of 16 neurons were recovered after patching and were processed for imaging; all eight of these neurons showed a high density of dendritic spines at 40-63X magnification. These data reveal that a large proportion of striatal SPNs receive direct inhibitory input driven by CS-SOM neurons but does not exclude the possibility that other striatal neurons also receive inhibitory input from these projections.
To determine how CS-SOM neurons affect the output of striatal neurons, we took advantage of the same viral ChR2 approach described above. We obtained whole-cell recordings from SPNs while injecting a step of current causing the neurons to spike between 2–7 action potentials (Figure 2j, black traces). We then photoactivated CS-SOM ChR2-positive axons by flashing blue light (470 nm) for 2–10 ms starting 10–50 ms before the first action potential. Combining current injection with photoactivation of CS-SOM ChR2-positive axons, we observed a delay of the first action potential (Figure 2j, blue traces), with an average delay of 159.16 ± 66.45 ms (n=6) (Figure 2k). Overall, these results indicate that CS-SOM projections act directly on SPNs and have the ability to affect spike generation and timing in these neurons.
Cortical inhibition of direct and indirect spiny projection neurons
The dorsal striatum is characterized by two parallel networks: the direct and indirect pathways (Gerfen et al., 1990; Kawaguchi et al., 1990; Lei et al., 2004; Gerfen and Surmeier, 2011; Calabresi et al., 2014). Direct pathway SPNs (dSPNs) express D1-type dopamine receptors and are suggested to promote behaviors that have previously been rewarded. On the other hand, indirect pathway SPNs (iSPNs) express D2-type dopamine receptors and are suggested to suppress behaviors that have not previously been rewarded (Gong et al., 2003; Ade et al., 2011; Calabresi et al., 2014).
We examined how activity of CS-SOM neurons regulates activity in the direct and indirect pathways. To address this question we used an optogenetic approach in SOM-Cre-D1/D2 transgenic mice (Figure 3a) in which dSPNs and iSPNs are labeled with td-Tomato and GFP, respectively (Figure 3b left and middle). In these mice, AAV.ChR2.Flex injected in the AC induces ChR2 expression in CS-SOM neurons. Although both D1-type dopamine receptors and our ChR2 virus are tagged with tdTomato, ChR2-tdTomato-positive axons were detectable in the area of our recordings (Figure 3b, left and right panels, white arrows). To determine the relative strength of CS-SOM connections onto the two classes of SPNs, we recorded in coronal brain slices from a dSPN and a neighboring iSPN (~100 μm) in the dorsal striatum ipsilateral to the injection site. It has been reported (Ade et al., 2011) that in Drd1a-tdTomato and Drd2-EGFP mice, fluorescent labeling is restricted to SPNs (i.e. no fluorescent labeling of the three main classes of interneurons in the striatum: parvalbumin-expressing, somatostatin-expressing, and cholinergic). However, to ensure that the neurons we recorded from were in fact SPNs, we also identified them post-hoc by the presence of dendritic spines (Figure 3c, right, white arrow). Six out of fourteen neurons were recovered after patching and were processed for imaging; all six of these neurons showed a high density of dendritic spines at 40-63X magnification. All recordings were performed in the presence of NBQX and CPP (Figure 3d, red traces); CS-SOM-ChR2-evoked synaptic IPSCs were completely blocked by application of gabazine (Figure 3d, black traces). The peak and charge of the maximal IPSCs were used as measures of the strength of the CS-SOM projections to dSPNs (n = 7) and iSPNs (n = 7). IPSCs peak amplitude (dSPN: 149 ± 30 pA; iSPN: 130 ± 21 pA; p = 0.7 rank-sum test) and charge (dSPN: 6.26 ± 1.03 pC; iSPN: 5.24 ± 1.38 pC; p = 0.3 rank-sum test) were similar in dSPNs and iSPNs (Figure 3e). There were no differences in IPSCs rise times (Figure 3g; example IPSCs from iSPN Figure 3f), suggesting the CS-SOM synapses had similar somatodendritic distributions on dSPNs and iSPNs. Together, these results indicate that CS-SOM neurons do not preferentially innervate dSPNs vs. iSPNs in the dorsal striatum.
A general feature of the GABAergic corticostriatal connectivity pattern
So far we had only observed this projection from the AC to the dorsal striatum. We next asked whether CS-SOM projections from the cortex to the dorsal striatum are a general feature of the corticostriatal circuit organization, or if they are specific to the AC. To test this, we used a similar optogenetic approach in the motor cortex (MC), a cortical area which is not involved in sensory processing like the AC, but instead is involved in the planning, control and execution of voluntary movements.
We used the same methods as in the AC to transfect CS-SOM neurons in the MC with AAV.ChR2.Flex (Figure 4a,b; injection site Figure 4c). As before, we observed local transfection in the cortex (Figure 4c) as well as ChR2-tdTomato-positive axons in the dorsal striatum (Figure 4d, white arrows). Neurons in the dorsal striatum where ChR2-tdTomato-positive axons were present were chosen for recordings. We obtained whole-cell recordings from striatal neurons during photoactivation of CS-SOM ChR2-positive axons while recording IPSCs as in the AC (Figure 4f, red trace). Responses in this area of the dorsal striatum were similar to those seen in the region of the dorsal striatum receiving auditory CS-SOM projections. Again, application of NBQX and CPP did not abolish the CS-SOM-ChR2-evoked synaptic IPSCs (Figure 4f, magenta trace), while application of gabazine completely abolished the CS-SOM-ChR2-evoked synaptic IPSCs (Figure 4f, black trace). Basic biophysical properties for CS-SOM-ChR2-evoked synaptic IPSCs (n = 9) included (Figure 4g,h,i): onset, 2.4 ± 0.11 ms; peak, 91 ± 17 pA; charge, 3.58 ± 0.59 pC; rise time, 1.76 ± 0.14 ms; decay time, 32.96 ± 4.98 ms. Neurons were identified as SPNs post-hoc by the presence of dendritic spines (Figure 4e, right, white arrows). Three out of nine neurons were recovered after patching and were processed for imaging; all three of these neurons showed dendritic spines at 40-63X magnification. Overall, these results indicate that in MC, as well as in AC, CS-SOM projections act directly on SPNs.
In this study we test the hypothesis that the dorsal striatum is influenced by direct GABAergic projections from the cortex. Our results support this hypothesis and additionally conclude that both the motor and the auditory cortices send long-range GABAergic projections to the dorsal striatum, via CS-SOM neurons (Figure 5). Because of its presence in two such disparate cortical areas, this would suggest that the corticostriatal somatostatin projection connectivity pattern is likely a general feature of the corticostriatal network. We demonstrated that a class of corticostriatal long-range inhibitory neurons in the auditory and motor cortex of the mice are somatostatin-expressing neurons. Our results suggest that CS-SOM neurons provide a major GABAergic projection to the dorsal striatum, in agreement with a recent anatomical study in the mouse frontal cortex (Tomioka et al., 2015). However previous results from retrospinal and somatosensory cortex (Jinno and Kosaka, 2004) have provided anatomical evidence for expression of parvalbumin in glutamatergic and GABAergic pathways in mice suggesting that corticostriatal long-range inhibitory neurons are characterized predominantly by parvalbumin-expressing neurons. Moreover, recent results from prefrontal cortex (Lee et al., 2014), show that corticostriatal long-range inhibitory neurons are characterized predominantly by parvalbumin-expressing or vasoactive intestinal peptide (VIP)-expressing but not somatostatin-expressing interneurons. Overall, these suggest that corticostriatal long-range GABAergic projections may be characterized by heterogeneous subtypes of interneurons, and that additional studies are necessary to determine the subtypes and the physiological impact of long-range corticostriatal GABAergic projections on striatal neurons.
The main finding of the present study is that the cortex can exert a powerful direct inhibition of the dorsal striatum via CS-SOM neurons. Particularly, CS-SOM neurons target SPNs and have the ability to affect their spike timing and generation. In the cortex, interneurons target the somatodendritic compartment of pyramidal neurons (Somogyi et al., 1998). SOM cortical and striatal interneurons in particular target the dendrites of pyramidal neurons and SPNs, respectively; although not specifically tuft dendrites as is characteristic of their hippocampal analogue, OLM cells (Freund and Buzsaki, 1996; Kubota and Kawaguchi, 2000). This connectivity pattern may allow the dendrites to sum incoming activity over a broader window of time (synaptic integration) (Pouille and Scanziani, 2001). We suggest that a similar inhibitory mechanism might be applied to the corticostriatal long-range inhibitory circuit, in which CS-SOM neurons, by targeting the dendrites of SPNs, play a role in the integration of incoming cortical excitatory inputs to the striatum.
The dorsal striatum is characterized by two parallel networks: the direct and indirect pathways (Gerfen et al., 1990; Kawaguchi et al., 1990; Lei et al., 2004; Gerfen and Surmeier, 2011; Calabresi et al., 2014). Particularly, it is suggested that dSPNs promote behaviors that have previously been rewarded while iSPNs suppress behaviors that have not previously been rewarded (Gong et al., 2003; Ade et al., 2011; Calabresi et al., 2014). It is very well established that long-range glutamatergic/excitatory projections regulate the activity of dSPNs and iSPNs. However, how activity of CS-SOM neurons influences dSPNs and iSPNs has not been established. Our results show that the cortex provides an inhibitory projection to both direct and indirect pathway neurons, influencing the output of both striatal networks involved in action selection and suppression of action. The functional role of inhibition from CS-SOM neurons might be not in separating the activity of direct and indirect striatal pathways, but rather in shaping the output of both. This is reminiscent of the finding by Kress et al. (Kress et al., 2013) that long-range excitatory corticostriatal connections from intratelencephalic and pyramidal tract neurons in motor cortex are made onto both dSPNs and iSPNs in the mouse dorsal striatum.
The dorsal striatum is a brain structure where functionally distinct cortical regions (e.g. motor, auditory, visual, somatosensory) converge (Wilson et al., 1983; Schneider, 1991; Flaherty and Graybiel, 1993; Chudler et al., 1995; Reig and Silberberg, 2014; Wilson, 2014). Anatomical and physiological data have suggested that once this information reaches the dorsal striatum via the corticostriatal projection, it is either channeled into parallel functional segregated circuits (Alexander et al., 1986; Bordi and LeDoux, 1992; Bordi et al., 1993; Parent and Hazrati, 1995; Middleton and Strick, 2000) or integrated within these circuits (Nauta and Domesick, 1984; Hoffer and Alloway, 2001; Kolomiets et al., 2001; Reig and Silberberg, 2014). The existence of direct inhibitory cortical inputs to the dorsal striatum is likely to have profound consequences for corticostriatal mechanisms by which the AC regulates the output of the striatum and how auditory information is transformed into motor command (Znamenskiy and Zador, 2013). It is very well established that the dorsal striatum is characterized by activity-dependent plasticity (for review, see [Kreitzer and Malenka, 2008]). Particularly, striatal plasticity can alter the transfer of information throughout the striatum and may serve as a neuronal substrate for the transformation of sensory information and motor planning for flexible motor actions and procedural memory. Recently, Xiong et al. (Xiong et al., 2015) found that auditory corticostriatal projections are involved in the learning of an auditory frequency discrimination task. They found that neurons in the dorsal striatum of the rat are selectively potentiated by auditory corticostriatal neurons to promote the learned transformation of sounds into motor actions. Moreover, Chen et al. (Chen et al., 2015) demonstrated that motor learning is characterized by structural rearrangements of presynaptic boutons of cortical SOM interneurons. Further experiments are needed to understand the functional significance of this direct cortical inhibition to the dorsal striatum, but in combination with the two above mentioned studies it invites speculation that CS-SOM neurons might play a role in mechanisms underlying spine dynamics by inducing a specific reorganization of dendritic excitatory synapses on SPNs and have consequences on learning and/or memory retrieval.
Our results establish a previously unknown corticostriatal long-range inhibitory circuit (CS-SOM inhibitory projections → striatal SPNs) underlying the control of spike timing/generation in striatal spiny neurons and attribute a specific function to a genetically defined type of cortical neuron in corticostriatal communication. We have shown that the dorsal striatum receives not only glutamatergic excitatory inputs from the cortex, but also inhibitory inputs. This may suggest that the timing and ratio of excitation and inhibition, two opposing forces in the mammalian cerebral cortex, can dynamically affect the output of the dorsal striatum, providing a general mechanism for motor control driven by sensory stimuli.
Materials and methods
All animal procedures were approved by the Institutional Animal Care and Use Committee at the University of Texas at San Antonio. Procedures followed animal welfare guidelines set by the National Institutes of Health. Mice used in this experiment were housed in a vivarium maintaining a 12 hr light/dark schedule and given ad libidum access to mouse chow and water.
Transgenic mouse lines
The following mouse lines were used in this study:
SOM-Cre: Ssttm2.1(cre)Zjh/J [The Jackson Laboratory, stock number 013044]; ROSA-tdTomato reporter: B6.CG.Gt(ROSA)26Sortm14(CAG-tdTomato)Hze/J [The Jackson Laboratory, stock number 007914]; Drd1a-tdTomato/Drd2-GFP reporter: The two reporter lines, B6.Cg-Tg(Drd1a-tdTomato)6Calak/J [The Jackson Laboratory, stock number 016204; (Ade et al., 2011)] and Tg(Drd2-EGFP)S118Gsat/Mmnc [MMRRC, stock number 000230-UNC] were crossed to generate a reporter for both D1- and D2-expressing neurons. A male mouse positive for both Drd1a-tdTomato/Drd2-EGFP was provided to us by Dr. Carlos Paladini at UTSA.
SOM-Cre female mice were crossed with a ROSA-tdTomato reporter male mouse to generate a SOM-Cre-tdTomato line (somatostatin-containing neurons expressed both Cre and tdTomato). SOM-Cre female mice were crossed with a Drd1a-tdTomato/Drd2-GFP reporter male mouse to generate a SOM-Cre-D1/D2 line (somatostatin-containing neurons expressed Cre; D1 neurons expressed tdTomato; D2 neurons expressed GFP).
Stereotaxic injections
Basic surgical procedures
Mice were initially anesthetized with isoflurane (3%; 1 L/min O2 flow) in preparation for the stereotaxic injections detailed in the sections below. The mice were head-fixed on a stereotaxic frame (Model 1900; Kopf Instruments) using non-rupture ear bars. Anesthesia was maintained at 1–1.5% isoflurane for the duration of the surgery. A warming pad was used to maintain body temperature during the procedure. Standard aseptic technique was followed for all surgical procedures. Injections were performed using a pressure injector (Nanoject II; Drummond Scientific) mounted on the stereotaxic frame. Injections were delivered through a borosilicate glass injection pipette (Wiretrol II; Drummond Scientific) with a taper length of ~30 mm and a tip diameter of ~50 μm. Both male and female mice, P28-44 at the time of the injection, were utilized in these experiments.
Anterograde labelling of CS-SOM neurons
CS-SOM neurons in the auditory cortex were labelled using AAV1.CAG.Flex.EGFP.WPRE.bGH (AAV.GFP.Flex; Penn Vector Core) stereotaxically injected into the right auditory cortex of SOM-Cre and SOM-Cre-tdTomato mice. The injection pipette was positioned over the right auditory cortex (2.5 mm posterior and 4.25–4.35 mm lateral to bregma) and advanced to 0.9–1.2 mm below the surface of the brain. The pipette remained in place for 5 min before the injection began. ~50 nl of AAV.GFP.Flex was delivered over a period of 5–10 min. The pipette was allowed to remain in place for 5 min before being slowly withdrawn.
We injected in four locations in the motor cortex to increase the area of transfection. Stereotaxic coordinates for motor cortex injections: 1.0 mm, 1.2 mm anterior and 1.5 mm, 1.7 mm lateral to bregma; 0.9 mm below the surface of the brain.
Retrograde labelling of CS-SOM neurons
CS-SOM neurons in the auditory cortex were retrogradely labelled using AAV.GFP.Flex stereotaxically injected into the right auditory dorsal striatum of SOM-Cre mice (3 animals from 2 litters). Injections were performed as above, with the following modifications: Stereotaxic coordinates for the auditory dorsal striatum injection site were 1.45 mm posterior and 3.4–3.5 mm lateral to bregma. ~30–50 nl of AAV.GFP.Flex was delivered between two depths in the dorsal striatum, 2.9 mm and 2.7 mm below the surface of the brain.
Anterograde transfection of CS-SOM neurons with channelrhodopsin
CS-SOM neurons in the auditory cortex were transfected with channelrhodopsin (ChR2) using AAV1.CAGGS.Flex.ChR2-tdTomato.WPRE.SV40 (AAV.ChR2.Flex; Penn Vector Core) stereotaxically injected into the right auditory cortex of SOM-Cre mice (8 animals from 4 litters) and SOM-Cre-D1/D2 mice (4 animals from 1 litter). Injections were performed in the same manner as previous injections in the auditory cortex and using the same auditory cortex stereotaxic coordinates.
Motor cortex injections of AAV.ChR2.Flex followed the same basic procedure with motor cortex coordinates as previously mentioned in SOM-Cre mice (6 animals from 4 litters).
In vitro slice preparation and recordings
We allowed 2–4 weeks for expression of ChR2 or GFP. Mice were anesthetized with isoflurane and decapitated. Coronal slices (300 μm) containing the area of interest (auditory cortex, auditory dorsal striatum, or motor dorsal striatum) were sectioned on a vibratome (VT1200S; Leica) in a chilled cutting solution containing the following (in mM): 100 choline chloride, 25 NaHCO3, 25 D-glucose, 11.6 sodium ascorbate, 7 MgSO4, 3.1 sodium pyruvate, 2.5 KCl, 1.25 NaH2PO4, 0.5 CaCl2. These slices were incubated in oxygenated artificial cerebrospinal fluid (ACSF) in a submerged chamber at 35–37°C for 30 min and then room temperature (21–25°C) until recordings were performed. ACSF contained the following (in mM): 126 NaCl, 26 NaHCO3, 10 D-glucose, 2.5 KCl, 2 CaCl2, 1.25 NaH2PO4, 1 MgCl2; osmolarity was ~290 Osm/L.
Whole-cell recordings were performed in 31–33°C ACSF. Thin-walled borosilicate glass pipettes (Warner Instruments) were pulled on a vertical pipette puller (PC-10; Narishige) and typically were in the range of 3–5 MΩ resistance when filled with a cesium-based intracellular solution, which contained the following (in mM): 110 CsOH, 100 D-gluconic acid, 10 CsCl2, 10 HEPES, 10 phosphocreatine, 1 EGTA, 1 ATP, and 0.3–0.5% biocytin. Inhibitory postsynaptic potentials (IPSCs) were recorded in the voltage-clamp configuration with a holding potential of 0 mV (the calculated reversal potential for glutamatergic excitatory conductances). Intrinsic properties were recorded in the current-clamp configuration using a potassium-based intracellular solution at 31–33°C. Potassium-based intracellular solution contained the following (in mM): 120 potassium gluconate, 20 KCl, 10 HEPES, 10 phosphocreatine, 4 ATP, 0.3 GTP, 0.2 EGTA, and 0.3–0.5% biocytin).
Signals were sampled at 10 kHz and filtered at 4 kHz. Pharmacological blockers used were: CPP (5 μM; Tocris Bioscience), NBQX (10 μM; Abcam), and gabazine (25 μM; Abcam). Hardware control and data acquisition were performed by Ephus (www.ephus.org) (Suter et al., 2010).
ChR2 photostimulation
CS-SOM neurons transfected with ChR2 showed ChR2-tdTomato-positive axons in the dorsal striatum related to the cortical area where the virus was injected (auditory or motor). Because of variability both in ChR2 expression levels (number of ChR2 molecules per transfected neuron) and transfection efficiency (number of ChR2-expressing neurons per animal), to minimize the variability from experiment to experiment we performed the electrophysiological recording in the same dorsal striatum slices (identified by specific landmarks as slice 1 and 2) and with the highest density of ChR2 transfected axons. We recorded IPSCs from putative spiny projection neurons (SPNs) in the dorsal striatum during photoactivation of the CS-SOM ChR2-positive axon terminals. A 470nm wavelength blue LED (CoolLED pE excitation system) passed through a GFP filter cube (Endow GFP/EGFP longpass, C-156625; Chroma) and a 60X water-immersion objective was used to photoactivate CS-SOM ChR2-positive axon terminals.
Delay/silencing of first action potential in striatal neurons
We recorded from putative SPNs in the dorsal striatum in an area containing ChR2-tdTomato-positive CS-SOM axons. In current-clamp configuration, a step of current was injected to cause the striatal neuron to fire 2–7 action potentials. To determine the effect of CS-SOM projections on the output of striatal neurons, we photoactivated CS-SOM ChR2-positive axons by flashing blue light (470 nm) for 2–10 ms starting 10–50 ms before the first action potential. Combining current injection with photoactivation of CS-SOM projections delayed the current-evoked action potentials in striatal neurons. The action potential delay due to the combined current injection with photoactivation of CS-SOM projections was normalized to the onset of the first action potential measured during the current injection alone.
Identification of D1- and D2-receptor-expressing striatal neurons
D1- and D2-receptor-expressing neurons in the dorsal striatum were identified by the presence of fluorescent markers in the SOM-Cre-D1/D2 line of mice. Somatic expression of either tdTomato (D1-receptor-expressing neurons) or GFP (D2-receptor-expressing neurons) fluorescence was visualized under a 60X objective.
During whole-cell recordings, neurons were filled with an internal solution containing 0.3–0.5% biocytin. Filled neurons were held for at least 20 min, and then the slices were fixed in a formalin solution (neutral buffered, 10% solution; Sigma-Aldrich) for several days at 4°C. The slices were washed well in PBS (6 times, 10 min per wash) and placed in a 4% streptavidin (Alexa Fluor 488, 594, or 680 conjugate; Life Technologies, Carlsbad, CA) solution (498 μl 0.3% Triton X-100 in PBS, 2 μl streptavidin per slice). Slices were allowed to incubate in this solution at 4°C overnight, then washed well in PBS (6 times, 10 min per wash) and mounted with Fluoromount-G (SouthernBiotech) on a glass microscope slide. Confocal images were taken with a Zeiss LSM-710 microscope at varying magnifications (3-63X). The identities of SPNs recorded in the dorsal striatum were confirmed by the presence of spines on their dendritic processes when imaged at 40-63X magnification. Individual high magnification images were stitched together, when necessary, using XuvStitch software (XuvTools). Image adjustment was performed in ImageJ (National Institutes of Health) for brightness/contrast corrections and pseudocoloring.
Some filled neurons were processed for light microscopy. In brief, after overnight incubation in ABC-Elite solution (Vector Laboratories) at 4°C, slices were pre-incubated in 3′3-diaminobenzidine (DAB; Vector Laboratories) for 20 min at 4°C and visualized by adding H2O2 to the DAB solution. The reaction was stopped when dendritic and axonal processes were visible under light microscopy examination. After washing well in 0.1 M PB (6 times, 10 min per wash), a DAB Enhancing Solution (Vector Laboratories) was applied for 10–20 s to intensify the DAB reaction product in the stained section. Slices were washed again in 0.1 M PB, then mounted with Fluoromount-G on a glass microscope slide for light microscopy. Neurons were morphologically reconstructed in three dimensions using Neurolucida (MicroBrightField) and an upright microscope fitted with a 63X/0.85 oil-immersion objective.
Data analysis
Figure error bars represent SEM. Data analysis was performed offline using custom MATLAB (MathWorks) routines. Group comparisons were made using the Student's t-test if data were normally distributed and the rank-sum test if not, with significance defined as p<0.05.
- 1
Parallel organization of functionally segregated circuits linking basal ganglia and cortexAnnual Review of Neuroscience 9:357–381.https://doi.org/10.1146/annurev.ne.09.030186.002041
- 3
- 4
Sensory tuning beyond the sensory system: An initial analysis of auditory response properties of neurons in the lateral amygdaloid nucleus and overlying areas of the striatumJournal of Neuroscience 12:2493–2503.
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Direct and indirect pathways of basal ganglia: A critical reappraisalNature Neuroscience 17:1022–1030.https://doi.org/10.1038/nn.3743
Subtype-specific plasticity of inhibitory circuits in motor cortex during motor learningNature Neuroscience 18:1109–1115.https://doi.org/10.1038/nn.4049
- 10
Two input systems for body representations in the primate striatal matrix: Experimental evidence in the squirrel monkeyJournal of Neuroscience 13:1120–1137.
- 12
- 13
Modulation of striatal projection systems by dopamineAnnual Review of Neuroscience 34:441–466.https://doi.org/10.1146/annurev-neuro-061010-113641
- 15
The basal ganglia and adaptive motor controlScience 265:1826–1831.https://doi.org/10.1126/science.8091209
Building action repertoires: Memory and learning functions of the basal gangliaCurrent Opinion in Neurobiology 5:733–741.https://doi.org/10.1016/0959-4388(95)80100-6
Long-range gabaergic projection neurons in the cat neocortexThe Journal of Comparative Neurology 503:421–431.https://doi.org/10.1002/cne.21395
Subtypes of gabaergic neurons project axons in the neocortexFrontiers in Neuroanatomy 3:25.https://doi.org/10.3389/neuro.05.025.2009
Organization of corticostriatal projections from the vibrissal representations in the primary motor and somatosensory cortical areas of rodentsThe Journal of Comparative Neurology 439:87–103.https://doi.org/10.1002/cne.1337
A novel functionally distinct subtype of striatal neuropeptide Y interneuronJournal of Neuroscience 31:16757–16769.https://doi.org/10.1523/JNEUROSCI.2628-11.2011
Parvalbumin is expressed in glutamatergic and gabaergic corticostriatal pathway in miceThe Journal of Comparative Neurology 477:188–201.https://doi.org/10.1002/cne.20246
Projection subtypes of rat neostriatal matrix cells revealed by intracellular injection of biocytinJournal of Neuroscience 10:3421–3438.
Physiological, morphological, and histochemical characterization of three classes of interneurons in rat neostriatumJournal of Neuroscience 13:4908–4923.
Striatal interneurones: Chemical, physiological and morphological characterizationTrends in Neurosciences 18:527–535.https://doi.org/10.1016/0166-2236(95)98374-8
Gabaergic circuits of the striatumProgress in Brain Research 99:51–72.https://doi.org/10.1016/S0079-6123(08)61338-2
- 27
Segregation and convergence of information flow through the cortico-subthalamic pathwaysJournal of Neuroscience 21:5764–5772.
- 29
Convergent cortical innervation of striatal projection neuronsNature Neuroscience 16:665–667.https://doi.org/10.1038/nn.3397
Dependence of gabaergic synaptic areas on the interneuron type and target sizeJournal of Neuroscience 20:375–386.
Morphological and electrophysiological characteristics of pyramidal tract neurons in the ratExperimental Brain Research 57:177–190.https://doi.org/10.1007/BF00231144
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Synaptic transmission and modulation in the neostriatumInternational Review of Neurobiology 39:77–111.https://doi.org/10.1016/S0074-7742(08)60664-9
Distinct subtypes of somatostatin-containing neocortical interneurons revealed in transgenic miceJournal of Neuroscience 26:5069–5082.https://doi.org/10.1523/JNEUROSCI.0661-06.2006
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Organization of long-range inhibitory connections with rat visual cortexJournal of Neuroscience 13:768–781.
Subpopulations of somatostatin-immunoreactive non-pyramidal neurons in the amygdala and adjacent external capsule project to the basal forebrain: Evidence for the existence of gabaergic projection neurons in the cortical nuclei and basolateral nuclear complexFrontiers in Neural Circuits 6:46.https://doi.org/10.3389/fncir.2012.00046
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Basal ganglia and cerebellar loops: Motor and cognitive circuitsBrain Research. Brain Research Reviews 31:236–250.https://doi.org/10.1016/S0165-0173(99)00040-5
Afferent and efferent relationships of the basal gangliaCiba Foundation Symposium 107:3–29.https://doi.org/10.1002/9780470720882.ch2
Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loopBrain Research. Brain Research Reviews 20:91–127.https://doi.org/10.1016/0165-0173(94)00007-C
Channelrhodopsin-2-assisted circuit mapping of long-range callosal projectionsNature Neuroscience 10:663–668.https://doi.org/10.1038/nn1891
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Differential morphology of pyramidal tract-type and intratelencephalically projecting-type corticostriatal neurons and their intrastriatal terminals in ratsThe Journal of Comparative Neurology 457:420–440.https://doi.org/10.1002/cne.10541
Callosal projections drive neuronal-specific responses in the mouse auditory cortexJournal of Neuroscience 35:6703–6713.https://doi.org/10.1523/JNEUROSCI.5049-14.2015
- 50
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Changes in behavior-related neuronal activity in the striatum during learningTrends in Neurosciences 26:321–328.https://doi.org/10.1016/S0166-2236(03)00122-X
Salient features of synaptic organisation in the cerebral cortexBrain Research. Brain Research Reviews 26:113–135.https://doi.org/10.1016/S0165-0173(97)00061-1
Ephus: Multipurpose data acquisition software for neuroscience experimentsFrontiers in Neural Circuits 4:100.https://doi.org/10.3389/fncir.2010.00100
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Feedforward and feedback inhibition in neostriatal gabaergic spiny neuronsBrain Research Reviews 58:272–281.https://doi.org/10.1016/j.brainresrev.2007.10.008
Demonstration of long-range gabaergic connections distributed throughout the mouse neocortexEuropean Journal of Neuroscience 21:1587–1600.https://doi.org/10.1111/j.1460-9568.2005.03989.x
Long-distance corticocortical gabaergic neurons in the adult monkey white and gray matterThe Journal of Comparative Neurology 505:526–538.https://doi.org/10.1002/cne.21504
Corticofugal gabaergic projection neurons in the mouse frontal cortexFrontiers in Neuroanatomy 9:133.https://doi.org/10.3389/fnana.2015.00133
- 60
Morphology and synaptic connections of crossed corticostriatal neurons in the ratThe Journal of Comparative Neurology 263:567–580.https://doi.org/10.1002/cne.902630408
The Synaptic Organization of the Brain ( 5th)Oxford; New York: Oxford University Press.
The sensory striatumNeuron 83:999–1001.https://doi.org/10.1016/j.neuron.2014.08.025
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Decision letter
Sacha B NelsonReviewing Editor; Brandeis University, United States
In the interests of transparency, eLife includes the editorial decision letter and accompanying author responses. A lightly edited version of the letter sent to the authors after peer review is shown, indicating the most substantive concerns; minor comments are not usually included.
Thank you for submitting your article "An inhibitory corticostriatal pathway" for consideration by eLife. Your article has been favorably evaluated by Gary Westbrook (Senior editor) and three reviewers, one of whom, Sacha Nelson, is a member of our Board of Reviewing Editors.
The following individuals involved in review of your submission have agreed to reveal their identity: Charles Gerfen, Mitsuko Watabe-Uchida (peer reviewers).
The reviewers have discussed the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission.
The study by Apicella and colleagues characterizes an important recently identified inhibitory cortico-striatal pathway to striatal spiny projection neurons. The significance of this finding cannot be overstated as for over 30 years the assumption has been that cortical input to the striatum is exclusively excitatory. A few partial descriptions have previously indicated an inhibitory component to this project. Here the authors use modern state of the art optogenetic techniques to characterize the nature and physiological impact of this projection.
Essential revisions:
1) The authors should provide better documentation of the neuroanatomy in Figure 1. The main finding in this paper concerns SOM cortical neuron projections to the striatum. The one low magnification of the labeling in the striatum is inadequate, both a low and high magnification image of the distribution of the fibers in the striatum would be nice. Also, the low level images of the retrograde labeling of SOM neurons in the cortex should be added to with higher magnification images that allow one to get a sense of the numbers and laminar distribution of these neurons. It would also be nice if the authors were able to provide a Neurolucida drawing of an axon from one of the cortical neurons going into the striatum (although it is recognized this might be difficult).
2) The rigorous characterization of SOM neurons projecting from layer 5 and 6 of cortex to striatal D1 and D2 MSNs in this paper will be important for the field. However, because the existence of GABAergic projections from the cortex to the striatum, and the fact that some of them were SOM neurons (and PV neurons), have already been reported anatomically and physiologically, it is very important to show what proportion of these GABAergic projections are from SOM neurons and what proportion of MSNs in the striatum receive these projections.
3) The text (Introduction, Results, and Discussion) should more thoroughly discuss past studies of corticostriatal GABAergic projections. For example, are the present physiological results consistent with previous ones in the ventral striatum or different? "A class of GABAergic neurons in the PFC sends long-range projections to NAc and elicits acute avoidance behavior" By Lee et al. in J. Neuroscience 2014 (the most related, including electrophysiology), "Corticofugal GABAergic projection neurons in the mouse frontal cortex" by Tomioka et al. in Frontiers in Neuroanatomy 2015 (mapping of cortical GABAergic projection sites and identification as somatostatin neurons), and "Parvalbumin is expressed in glutamatergic and GABAergic corticostrial pathway in mice." by Jinno and Kosaka in J. Comp. Neurol. 2004 (probably original finding about GABA projection from cortex to striatum). Authors cited them briefly and improperly in the second paragraph of the Introduction and in the first paragraph of the Discussion.
[Editors' note: further revisions were requested prior to acceptance, as described below.]
Thank you for submitting your article "An inhibitory corticostriatal pathway" for consideration by eLife. Your article has been favorably evaluated by Gary Westbrook (Senior editor) and three reviewers, one of whom, Sacha B Nelson, is a member of our Board of Reviewing Editors.
The following individuals involved in review of your submission have agreed to reveal their identity: Charles R Gerfen (Reviewer #2); Mitsuko Watabe-Uchida (Reviewer #3).
Although the reviewers felt that most of the points raised were addressed, they did not feel that the slightly higher magnification view of the same image added much to Figure 1 and encourage you to provide an additional image (either as part of Figure 1 or as a supplementary figure) that actually shows greater detail as to the distribution of axons and cell bodies. We will not hold up acceptance of the manuscript on this point if you are unable to provide an additional image in a relatively short period, but all three reviewers felt this would be a significant improvement to the manuscript with relatively little additional effort.
An additional thing that needs to be corrected is the last sentence of the Abstract, "previously unknown" should be deleted as this pathway had been described before.https://doi.org/10.7554/eLife.15890.008
Article and author information
Author details
National Institute of Neurological Disorders and Stroke (NS072197)
- Charles Wilson
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
We are indebted to C Paladini for providing the Drd1a-tdTomato/Drd2-EGFP transgenic mouse line. We are grateful to G Gaufo for help with confocal imaging; S Lebby for help with single cell staining; S Song for providing SOM-Cre animals.
Animal experimentation: Apicella IACUC protocol number: IS00000135 All animal procedures were approved by the Institutional Animal Care and Use Committee at the University of Texas at San Antonio. Procedures followed animal welfare guidelines set by the National Institutes of Health. Mice used in this experiment were housed in a vivarium maintaining a 12 hour light/dark schedule and given ad libidum access to mouse chow and water. Mice were initially anesthetized with isoflurane (3%; 1 L/min O2 flow) in preparation for the stereotaxic injections.
Reviewing Editor
- Sacha B Nelson, Reviewing Editor, Brandeis University, United States
Publication history
- Received: March 10, 2016
- Accepted: May 8, 2016
- Accepted Manuscript published: May 9, 2016 (version 1)
- Version of Record published: June 13, 2016 (version 2)
- Version of Record updated: June 21, 2016 (version 3)
© 2016, Rock et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
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Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.


text:
A remarkable analysis linking the assassination of JFK and 9/11, and how both events were used to influence war policy. Peter Dale Scott examines the many ways in which war policy has been driven by "accidents" and other events in the field, in some cases despite moves toward peace that were directed by presidents. This book explores the "deep politics" that exerts a profound but too-little-understood effect on national policy outside the control of traditional democratic processes.
This is an ambitious, meticulous examination of how U.S. foreign policy since the 1960s has led to partial or total cover-ups of past domestic criminal acts, including, perhaps, the catastrophe of 9/11. Peter Dale Scott, whose previous books have investigated CIA involvement in southeast Asia, the drug wars, and the Kennedy assassination, here probes how the policies of presidents since Nixon have augmented the tangled bases for the 2001 terrorist attack.
"Full of Interesting Information, Hard to Follow"
Over a decade has passed since the World Trade Center attacks of September 11, 2001, and yet there are still many unanswered questions surrounding that fateful day, which changed a nation forever. Conspiracy theories attribute the planning and execution of the attacks to two parties other than Al-Qaeda and claim there was advance knowledge of the attacks amongst high-level government and military officials.
"Do not get this book if you can't handle the truth!"
Peter Dale Scott has written extensively on the Kennedy assassination and other dark corners of the American political scene. His encyclopedic knowledge enables him to connect the dots among the players, the organizations, and the unacknowledged collusions--the deep politics-- of our often troubled political system. Deep Politics on Oswald, Mexico, and Cuba, originally published in 1995, narrows the focus of Scott's earlier Deep Politics and the Death of JFK.
"For deeper Oswald research only"

subset: commoncrawl


text:
Red Hat Bugzilla – Bug 816837
preupgrade appears to work OK and offers reboot but in fact has failed
Last modified: 2012-08-07 12:21:15 EDT
Description of problem:
Doing a preupgrade for fc14 -> fc15 appears to operate normally on the GUI but actually gives a failure on the command line window. It says it has downloaded successfully and to reboot to complete the install but in fact doesn't.
Version-Release number of selected component (if applicable):
How reproducible:
Steps to Reproduce:
1. Run preupgrade on a Fedora 14 system with boot on /dev/md0
Actual results:
Fails with GUI dialog message indicating success.
Expected results:
GUI reflects the failure or can cope with upgraded a machine with RAID on the boot partition.
Additional info:
# preupgrade
Loaded plugins: blacklist, langpacks, whiteout
No plugin match for: rpm-warm-cache
No plugin match for: remove-with-leaves
No plugin match for: auto-update-debuginfo
Adding en_GB to language list
preupgrade-main (mirrorlist)
url: http://mirrors.fedoraproject.org/mirrorlist?repo=fedora-15&arch=$basearch
now: http://mirrors.fedoraproject.org/mirrorlist?repo=fedora-15&arch=x86_64
preupgrade (mirrorlist)
url: http://mirrors.fedoraproject.org/mirrorlist?path=pub/fedora/linux/releases/15/Fedora/$basearch/os/
now: http://mirrors.fedoraproject.org/mirrorlist?path=pub/fedora/linux/releases/15/Fedora/x86_64/os/
unknown metadata being downloaded: repomdXZwwBFtmp.xml
preupgrade-fedora (mirrorlist)
url: https://mirrors.fedoraproject.org/metalink?repo=fedora-15&arch=x86_64
now: https://mirrors.fedoraproject.org/metalink?repo=fedora-15&arch=x86_64
unknown metadata being downloaded: metalink.xml.tmp
unknown metadata being downloaded: repomdD3QrSYtmp.xml
preupgrade-rpmfusion-free (mirrorlist)
url: http://mirrors.rpmfusion.org/mirrorlist?repo=free-fedora-15&arch=x86_64
now: http://mirrors.rpmfusion.org/mirrorlist?repo=free-fedora-15&arch=x86_64
unknown metadata being downloaded: repomdUIj35dtmp.xml
preupgrade-rpmfusion-free-updates (mirrorlist)
url: http://mirrors.rpmfusion.org/mirrorlist?repo=free-fedora-updates-released-15&arch=x86_64
now: http://mirrors.rpmfusion.org/mirrorlist?repo=free-fedora-updates-released-15&arch=x86_64
unknown metadata being downloaded: repomdrf5Gtftmp.xml
preupgrade-rpmfusion-nonfree (mirrorlist)
url: http://mirrors.rpmfusion.org/mirrorlist?repo=nonfree-fedora-15&arch=x86_64
now: http://mirrors.rpmfusion.org/mirrorlist?repo=nonfree-fedora-15&arch=x86_64
unknown metadata being downloaded: repomdNwlU0Atmp.xml
preupgrade-rpmfusion-nonfree-updates (mirrorlist)
url: http://mirrors.rpmfusion.org/mirrorlist?repo=nonfree-fedora-updates-released-15&arch=x86_64
now: http://mirrors.rpmfusion.org/mirrorlist?repo=nonfree-fedora-updates-released-15&arch=x86_64
unknown metadata being downloaded: repomdOiwiSWtmp.xml
preupgrade-updates (mirrorlist)
url: https://mirrors.fedoraproject.org/metalink?repo=updates-released-f15&arch=x86_64
now: https://mirrors.fedoraproject.org/metalink?repo=updates-released-f15&arch=x86_64
unknown metadata being downloaded: metalink.xml.tmp
unknown metadata being downloaded: repomdyUs6omtmp.xml
unknown metadata being downloaded: MEMORY
Fetched treeinfo from http://mirror01.th.ifl.net/fedora/linux/releases/15/Fedora/x86_64/os//.treeinfo
treeinfo timestamp: Fri May 13 20:44:30 2011
unknown metadata being downloaded: MEMORY
Traceback (most recent call last):
File "/usr/share/preupgrade/preupgrade-gtk.py", line 259, in on_assistant_apply
File "/usr/share/preupgrade/preupgrade-gtk.py", line 278, in _do_main
File "/usr/share/preupgrade/preupgrade-gtk.py", line 497, in main_preupgrade
extra_args += " ks=%s" % self.pu.generate_kickstart()
File "/usr/lib/python2.7/site-packages/preupgrade/__init__.py", line 607, in generate_kickstart
return dev.bootpath_to_anacondapath(targetfile, UUID=True)
File "/usr/lib/python2.7/site-packages/preupgrade/dev.py", line 91, in bootpath_to_anacondapath
raise PUError, "/boot is on RAID device %s" % bootdev
preupgrade.error.PUError: /boot is on RAID device md0
This message is a notice that Fedora 15 is now at end of life. Fedora
has stopped maintaining and issuing updates for Fedora 15. It is
Fedora's policy to close all bug reports from releases that are no
longer maintained. At this time, all open bugs with a Fedora 'version'
of '15' have been closed as WONTFIX.
(Please note: Our normal process is to give advanced warning of this
occurring, but we forgot to do that. A thousand apologies.)
Package Maintainer: If you wish for this bug to remain open because you
plan to fix it in a currently maintained version, feel free to reopen
this bug and simply change the 'version' to a later Fedora version.
Bug Reporter: Thank you for reporting this issue and we are sorry that
we were unable to fix it before Fedora 15 reached end of life. If you
would still like to see this bug fixed and are able to reproduce it
against a later version of Fedora, you are encouraged to click on
"Clone This Bug" (top right of this page) and open it against that
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Although we aim to fix as many bugs as possible during every release's
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The process we are following is described here:


text:
Ten years ago, I was neck deep in a quagmire of confusion. What should I do with my life? What was my purpose? What was my mission?
With no answers to these vexing questions, I went for a run. Running always helped me clear my head. Running helped me find my way.
It turned out the answer to what to do with my life was right in front of me. Turning people into runners was the answer to all of these questions.
Thousands have become better people as a result of their experiences with Run Club. The reality is people are simply better when they run.
Whether you're notching your first mile, your first half marathon, looking to get faster, or simply want to meet some friends via this passion we call running, The Run Club team is here to make it happen. We're also here to make you a better person.
Marathon Matt - Club Director
Phone: 415-572-4437
Email: email@example.com


text:
In coal preparation plants, magnetic wet drum separators are used to recover for re-use, fine magnetite used in the sink/float heavy media process. Similar drums are also used for iron ore beneficiation.
Slurry containing the magnetic medium is passed under a revolving stainless steel shell inside which a stationary multi-pole magnet element is housed. As the slurry moves beneath the revolving drum shell magnetic particles are drawn to the drum surface and transported to a discharge point where the magnetic field decreases.
Drum styles, diameters and rotation direction vary according to specific duties. Serpent and Dove® Pty Ltd is a company with many year's experience with magnetic separation technology.


text:
Steve McNiven has been in the wars of late.
First, he painfully passed a kidney stone and then possibly as a result, threw out his back. This resulted in a two-months-plus month recovery period.
Because of this, Steve told folk at C2E2 that his comic with Mark Millar, Nemesis #2 has been indefinitely delayed, as he's still trying to complete the pages.
McNiven has no other competing projects. His recent appearance at C2E2 was part of a test to see how well he can cope with normal comic creator-type things with regularity again.
(UPDATE) While this story was based on reporting by a Bleeding Cool contributor talking to McNiven at C2E2, Mark Millar has repudiated the report on his board. Millar writes;
People have got in touch and asked what's happening as some nonsense online about Nemesis delayed indefinitely. Steve had a couple of health problems that slowed him down, but he's almost finished issue two and isn't doing anything else until he's finished issue four (the series finale). I don't know where this started (perhaps Chinese Whispers at Chicago), but issue two will be out in a few weeks and we're probably looking every two months for the remaining two issues.
PS We have our director and the deal is being ironed out this week. He's literally my number one choice and all the mods, who know who he is, are very excited. I've finished the comic series and the scripts are now in the hands of the director who will start adapting next month. HUGELY EXCITING!
Steve McNiven has also posted, stating;
Oh dear. I guess it's been a slow rumor day. Still, this supposed news story is very misleading and I don't want fans of Nemesis to be lead astray by some fool with an axe to grind. If I need to go into details, it wasn't the kidney stones that caused the delay but rather the herniated disc in my lower back resulting from writhing around in pain passing those buggers that dropped me for about three months. Now to make matters worse I have to post this stuff online to stop this crap from being taken seriously by the good folks who buy the stuff I work hard to create. For the record I am back at the drawing table (standing up though), getting stronger every day and am just finishing off the last few pages of Nemesis #2 as we speak, and I'm solely focused on finishing the series off. So enough of this 'indefinitely postponed' bullshit o.k.? Look, I don't like to have to post details of my personal life online but when someone makes it personal by attacking my livelihood without cause, I have no other recourse. Hopefully this will set the matter straight and I can get back to drawing. But before I do I just wanted to say thanks to all the fans of Nemesis for stopping by my table at C2E2 this weekend, your enthusiasm for the book and the medium as a whole makes all this worthwhile.
- Two TV Commercials From DC Comics For the New Age of Heroes Line - January 17, 2018
- For Those of You Still Reading Generation X… Something Special For Jubilee (#86 Spoilers) - January 17, 2018
- Brian Wood and Jorge Coelho's Robocop: Citizens Arrest Looks to Explore Social Justice - January 17, 2018
- Ludocrats from Kieron Gillen, David Lafuente, and Jim Rossignol is Coming Soon, Honest - January 17, 2018
- Now Glénat to Publish Conan Comics, as It's All Public Domain in Europe - January 17, 2018


text:
Consumers snapped up more than one million iPhone 3GS handsets over the weekend, according to Apple. The total, which represents device sales across all eight countries where the new turbocharged phone was available, exceeds analyst predictions, and is equal to the number of iPhone 3G handsets sold at launch last July.
Apple also said that six million iPhone and iPod touch owners had downloaded the iPhone 3.0 software that adds functionality such as copy and paste and landscape keyboards to all devices.
"Customers are voting and the iPhone is winning," said Steve Jobs, Apple's chief executive, in a statement. "With over 50,000 applications available from Apple's revolutionary App Store, iPhone momentum is stronger than ever."
The new iPhone 3GS is faster than its predecessor, the iPhone 3G, and features a three-megapixel camera which can record video, a digital compass, voice control and increased storage.
Analysts had predicted that the iPhone 3GS would be less popular with consumers than the iPhone 3G, as it featured evolutionary rather than revolutionary improvements. Many current iPhone owners are also still locked in to their iPhone 3G contracts with O2, and face a significant financial outlay if they choose to break that contract early in order to upgrade to the iPhone 3GS.
Gene Munster, an analyst with Piper Jaffray, believed Apple would sell around 750,000 iPhones during the opening weekend. He estimates that around 56 per cent of those US customers buying the iPhone 3GS were upgrading from a previous iPhone. "We believe this shows Apple is developing brand loyalty not enjoyed by other mobile phone makers," said Munster.
The launch of the iPhone 3GS has been overshadowed by news that Steve Jobs, Apple's chief executive, received a liver transplant earlier this year. The Apple co-founder has been on a leave of absence from the company since January following a period of ill-health. Significantly, though, the use of a quote by Jobs regarding the success of the iPhone 3GS could signal that his anticipated return to the company later this month is on schedule.


text:
Project Updates
|2017 Project Listing
|Cecil Street (Henry to Oak)
|Street, Utilities
|Cleveland Street (Reddin to Zemlock)
|Street, Utilities
|Edward Street (Western to John)
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|Helen Street (Western to John)
|Street, Utilities
|Industrial Drive (Enterprise to Bell)
|Higgins Avenue (Haylett to Cecil)
|Street, Utilities
|Yorkshire Road (Yorkshire Ct to Sunrise Bay)
|Whippoorwill Circle (Pendleton)
Project Pictures
Click here to view photos of construction projects.
Sign-up for Construction Project Updates
Click here to sign up for our Construction Project Updates Newsletter!
Bid Documents
All construction bid documents available for download at QuestCDN.
|2017 Projects
|Ad for Bid
|Bid Form
|Bid Date
|Contract 1-17 Sewer and Water Main Construction and Street Construction on Cecil Street and Higgins Avenue
|Ad for Bid 1-17
|Bid Tab Doc 1-17
|Contract 2-17 Sewer and Water Main Construction and Street Construction on Cleveland Street/Edwards Avenue/Helen Street
|Ad for Bid 2-17
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|Contract 3-17 Parking Lot, Street and Trail Construction
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Perfect for RTP or UNC: $885/Month
- Gym
- Swimming Pool
- Wifi
- Parking
The Space
This apartment is perfect for a professional commuting to the RTP or UNC, as well as visiting graduate students. This is a spacious apartment for an individual, and plenty big for a small family. The office is easily used as a nursery, child's bedroom, or guest bedroom if required, or as a quiet study with extra closet space.
Guest Access
-Fully equipped kitchen
-Full-sized GE Washer and Dryer -GE Dishwasher
-Large bathroom with shower and tub -Lots of closet space
-Access to Private swimming pool and tennis court
-Code access to 24-hour clubhouse with recently renovated gym
-Very responsive and friendly maintenance/staff
Includes ALL Utilities:
-Free high speed internet with wi-fi
-Free access to Netflix via television in living room
Interaction with Guests
My family and I will be in Charleston for the summer, so I am accessible by phone or email. We are well connected in the area, however, and could easily provide advice on dining, community events, etc. I am happy to make a trip from Charleston if necessary, but also have relatives and friends who are available to take care of any urgent needs.
The Neighborhood
This neighborhood is great for young families, professionals, and students alike. There are nice schools and large homes in the area and an extensive greenway system close buy.
Getting Around
Chapel Hill has amazingly convenient AND free public transportation. There is never trouble finding public transit, taxis, or Uber in the Triangle in general.
Other Things to Note
We prefer to rent the apartment for the majority or entirety of the summer. We prefer not to rent out on a nightly or weekly basis, but may rent for periods two weeks and over.
- Kitchen
- Internet
- Essentials
- Heating
- Air Conditioning
- Washer
- Dryer
- Free Parking on Premises
- Wireless Internet
- Family/Kid Friendly
- Indoor Fireplace
- Pool
- Gym
- Smoke Detector
- Carbon Monoxide Detector
- First Aid Kit
- Safety Card
- Fire Extinguisher
Place's rules
Of course, please respect the property while we are away. We hope our family returns to a clean, undamaged apartment.
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In Sonnet 130 by Shakespeare, are most of the images auditory, olfactory, visual, or kinesthetic?
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When we think of imagery, we are talking about images that the author or poet creates using words that appeal to our senses to help us imagine them. Therefore, generally speaking, the most successful images are those that appeal to as many of our senses as possible. When we think of this poem, and the complete picture that the speaker builds up of his mistress and of her many imperfections, we can see that the imagery he employs does appeal to many of our senses. Consider, for example, the dominant sense of sight:
My mistress' eyes are nothing like the sun;
Coral is far more red than her lips' red;
If snow be white, why then her breasts are dun;
If hairs be wires, black wires grow on her head.
We have a very strong visual description of the eyes being "nothing like the sun," her lips not being like "coral" and her "breasts" being a "dun" colour. In addition, the last line points towards the feel of the mistress' hair, stressing the sense of touch as we can imagine the rather unpleasant feeling of the speaker as he goes to touch his mistress' hair.
There is a definite appeal to scent in the fragrance that the mistress exudes, as the "breath that from my mistress reeks" captures, and an auditory image is captured in the sound of her speech, even though "music hath a far more pleasing sound." Thus we can see that this poem successfully appeals to a number of the senses to create excellent imagery.
Most of the images in Shakespeare's Sonnet 130 are visual. Note that the first six lines all provide sight images, while the remaining 8 lines of the sonnet illustrate sound/auditory, smell/olfactory, kinesthetic/movement (my mistress walks on the ground.) Thus the majority of images are visual in this sonnet.


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The Edge of Dreams
- Format: Hardcover
- Copyright: 03/03/2015
- Publisher: Minotaur Books
Note: Not guaranteed to come with supplemental materials (access cards, study guides, lab manuals, CDs, etc.)
Extend Your Rental at Any Time
Need to keep your rental past your due date? At any time before your due date you can extend or purchase your rental through your account.
Molly Murphy Sullivan's husband Daniel, a captain in the New York City police force, is stumped. He's chasing a murderer whose victims have nothing in common—nothing except for the taunting notes that are delivered to Daniel after each murder. And when Daniel receives a note immediately after Molly and her young son Liam are in a terrible train crash, Daniel and Molly both begin to fear that maybe Molly herself was the target.
Molly's detective instincts are humming, but finding the time to dig deeper into this case is a challenge. She's healing from injuries sustained in the crash and also sidetracked by her friends Sid and Gus's most recent hobby, dream analysis. And when Molly herself starts suffering from strange dreams, she wonders if they just might hold the key to solving Daniel's murder case.
Rhys Bowen's characteristic blend of atmospheric turn-of-the-century history, clever plotting, and sparkling characters will delight readers in The Edge of Dreams, the latest in her bestselling Molly Murphy series.


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Alan Menken & Lynn Ahrens's gorgeous songs are the best of quite a few reasons to catch Actors Repertory Theatre Of Simi's holiday production of Charles Dickens' A Christmas Carol despite the disservice its multitalented hometown cast is done by some sour notes emanating from the orchestra pit.
Anyone familiar with Menken's Disney oeuvre (Aladdin, Beauty And The Beast, Enchanted, Hercules, The Hunchback Of Notre Dame, The Little Mermaid, Newsies, Pocahontas, and most recently, Tangled) not to mention his Broadway hits (Little Shop Of Horrors, Sister Act The Musical, and many of the aforementioned titles) can imagine how tuneful his A Christmas Carol songs will be even without having heard them during the musical's 1994-2003 holiday runs at Madison Square Garden or in its 2004 TV adaptation starring Kelsey Grammer as Scrooge.
Add to Menken's music the deft lyrics of Stephen Flaherty's most frequent collaborator (Once On This Island, Ragtime, Seussical, and many more) and you've got more than a dozen songs you'll want to hear again and again, among them the exquisite "A Place Called Home," not to mention uptempo numbers ("Link By Link," "Fezziwig's Annual Christmas Ball," and "Abundance & Charity" among them) sure to be dancing around in your head long after curtain calls.
Mike Ockrent and Ahrens' book opts wisely to stick close to the Dickens original (though why the writers renamed Belle Emily and omitted her key denunciation of the "golden idol" that ended up displacing Scrooge's childhood love is anyone's guess).
Under Jan Glasband and Becky Castells' able direction, Damian Gravino's Scrooge anchors the production in a performance that captures literature's most ultimately beloved miser in all his crotchety meanness—with a good deal of humor thrown in for holiday measure.
Supporting Gravino is a cast so huge, they merit extra marks simply for fitting onto the relatively compact Simi Valley Cultural Arts Center stage, in addition to the applause they deserve for executing Castells' energetic choreography, expressly tailored for their various talents.
Alyssa Deboisblanc (Fan, Tre Cratchit, Angel), Heather Baez (Rich Woman, Woman #2, Creditor), Katherine Bottoms (Emily), Cynthia Caldwell (Ghost Of Christmas Past), Kyle Cooknick (Fred), dance captain Tori Cusack (Wraith), Kevin Ellis (Ghost Of Christmas Past, Sandwichboard Man), Nicholas Ferguson (Marley's Ghost), Tyler Fraser (Tiny Tim, Scrooge at age 12), Autumn Jessel (Grace Smythe), Ally Kaplan, Kate Landro (Blind Old Hag, Mrs. Fezziwig), Genevieve Levin (Mrs. Cratchit, Scrooge's Mother), Rachel Levin, Austin Robert Miller (Young Ebenezer), Vinny Mohr (Scrooge at 8), Dawn Notagiacomo (Featured Dancer), Paul Panico (Old Joe, Poulterer), Grace Phenicie (Martha Cratchit), Brian Pletcher (Beadle, Mr. Fezziwig, Judge), Spencer Pletcher (Gravedigger), Jaclyn Plotkin (Sally Anderson), Jared Price (Young Marley), Gianberto Ridino (Mother Goose Leaflet Boy, Gravedigger), Camille Schwarz (Granny Pickwick, Bread Vendor), Julie Snyder (Mrs. Mops, Granny Chuzzlewit), and Timothy Velarde (Mr. Smythe) bring their talents and an abundance of enthusiasm to the entire endeavor, and under P. Matthew Park's musical direction, their harmonies are ear-pleasing indeed.
The same cannot unfortunately be said for an orchestra whose best efforts—and it's a sure bet that each and every member is giving his or her all—do justice neither to the cast's vocals nor to the score's symphonic arrangements. (I can only imagine how much better this Christmas Carol would sound with professionally recorded backup tracks.)
On a far more positive note, Castells' savvy choreography turns musical numbers like the taptastic "Abundance & Charity," the creepy-crawly "Link By Link" (with its cast of dancing corpses and some "Thriller" moves thrown in as a bonus), and the infectiously joyous full-cast Act One closer "Fezziwig's Annual Christmas Ball" into crowd-pleasers each and every one.
Kamenow's lighting is mostly first-rate, and though he might have gone even creepier in "Link By Link," he scores high marks for keeping projections vivid even during brightly lit scenes.
Caldwell's colorful period costumes are all-around winners, and scenic designer Seth Kamenow makes effective use of David Daniels' and his own projections to set various scenes (though we could be made better aware of the Cratchits' poverty in costuming, lighting, and set).
Kevin Kahm's sound design amplifies voices without a glitch. Brenda Miller does terrific work as prop mistress, assisted by Ben Deschaine's, Kamenow's, and her own specialty props.
Megan Tisler is stage manager. Others receiving program credit include producer Glasband, lightboard operator Brenda Goldstein, spot operators Luther Cockrill and Carrie Dean, and crew members Brandin Mitchell and Tara Suffolk.
Ultimately, it wouldn't be a year-end holiday season without at least one excursion into Charles Dickens land, and if only to hear Menken and Ahrens' songs performed live on stage, Actors Repertory Theatre Of Simi's A Christmas Carol is worth seeing.
Actors Repertory Theatre Of Simi, Simi Valley Cultural Arts Center, 3050 Los Angeles Avenue, Simi Valley.
–Steven Stanley
November 29, 2014
Tags: Actors Repertory Theatre Of Simi, Alan Menken, Charles Dickens, Lynn Ahrens, Ventura County Theater Review


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Dave Matthews Performance Video From MGM Grand Las Vegas
The Dave Matthews Band was here in Las Vegas on Saturday night and performed at the MGM Grand. Opening the show was Jason Mraz, before he headed over to the Palms Casino Resort for his own performance at the Pearl. From what I heard, the Dave Matthews concert was unreal. I lose sleep at the thought that I had a ticket, but was unable to make it! Check it out:
If you ignore the bobbing heads, you can see Boyd Tinsley jamming out on the violin during his solo part of "Dancing Nancies". About 2:15 minutes into the video, Carter jumps in on the drums, and the crowd goes wild.
Whether you like Dave Matthews band or not, if you like live music, you can imagine how this performance was a must see!
It all went down Saturday night at the MGM Grand Garden Arena with a live performance from the Dave Matthews Band.


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Linen Backing
The primary objective of Linen Backing is to restore and preserve a poster. It can be used to effectively remove folds, repair tears as well as restore missing parts. The process is 100% reversible meaning that if new developments in restoration and preservation were to be discovered, further work could be undertaken without damage.
We are now pleased to announce that a complete Linen Backing service is available. Please contact us for further information and pricing.


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Guys can answer too. Do you fellas fantasize about fatherhood, or getting the girl of your dreams pregnant, what it would be like to see her body change, what it will be like when the child arrives, ect. Ladies, do you fantasize about motherhood and what it would be like to be pregnant, and how you will look, how you will feel when the child arrives, ect. Have you even put a pillow underneath your shirt to see what you look like? lol... Although I know how to separate fantasy from reality, motherhood is something that I fantasize about. What about you?
Most Helpful Girl
Yes, a lot of times! Even though I'm not ready to see my body changing (I think it's going to be for worse in my case) , to feel so much pain and spend so many nights awake. But that's a part of being a mother, I will have to get used to it. I also have this fantasy: I imagine myself pregnant and having my boyfriend (or husband if I change my mind) kissing my pregnant belly. I know it's a silly idea, but it's something that I really want, if I got pregnant someday.22|00|0
Awee, I understand! :) Thank You !
You're welcome :)


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About Flagstaff House
Chef Mark Monette has been responsible for the culinary delights at the Flagstaff House since 1985. His unique style of cooking incorporates French cuisine with Asian accents, brought together by his training in several michelin three star restaurants in France and the Orient. Mark has worked with several master chefs including Bernard Hermman and Thomas Keller. At the Flagstaff House chef Mark has had the pleasure of preparing a special menu for the Emperor and Empress of Japan as well as the Prime minister of Japan and his foreign ministers. The restaurant has also hosted many dinners for notable culinary dignitaries including Paul Bocuse, Angela Gaja and Robert Mondavi. The Monette family has owned the Flagstaff House since 1971. The restaurant holds many prestigious awards including Colorado's longest holding Wine Spectator Grand Award. Please note our dress code prohibits shorts, t-shirts and athletic attire.
Boulder, CO 80302
Dining Style:
Fine Dining
American, Steak
Hours of Operation:
Dinner: Sunday - Friday: 6:00pm - 10:00pm, Saturday: 5:00pm - 10:00pm; Cocktails: Daily: 5:00pm - 10:00pm
Dress Code:
Business Casual
Price Range:
$50 and over
Payment Options
AMEX, Diners Club, Discover, MasterCard, Visa
Phone Number:
(303) 442-4640
Executive Chef:
Mark Monette
Private Party Facilities:
Whether you need space for as few as 12 or as many as 200 people, we can accommodate your private party needs. From our elegant world class dining atmosphere and fabulous menu, to the fresh mountain air and inspiring views of Boulder, Colorado.
Private Party Contact:
Jean Davis: (303) 442-4640
Banquet, Bar Dining, Bar/Lounge, Beer, Fireplace, Full Bar, Non-Smoking, Outdoor dining, Private Room, Takeout, View, Wine
Restaurant Photos
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Flagstaff House Ratings and Reviews
This is my favorite restaurant of all time. From the moment you open the door until they give you the breakfast bread to go, the Flagstaff House has the most amazing eye for detail, attention to service and spectacular food in Boulder, not to mention the killer view!
It is refreshing that some things never change. The Flagstaff House is just as wonderful as it has been for the last 15 years we have been going there. The chef and all the staff are spot on, not fussy and it is therapeutic to spend a magical evening there every once in awhile.
We absolutely loved it. I took my wife there for her birthday and they really made it special. The food was amazing and the service was exceptional. It was a very quiet restaurant, which is great, except we tend to be the loudest people in the room, so that was a bit weird, but we adapted.
Overall a nice dining experience. It was a special occasion, my wife's 50th.
Positives include service- from when we arrived until when we left the service was as good as it gets. Setting- clearly what sets this restaurant apart. The view of Boulder is awesome!
Negatives include food- the monk fish was okay, overcooked and lacking character. We both added the 1/2 lobster. Not at all worth it. Price- everything is obscenely overpriced. Ambiance-
the restaurant is in need of an update. Feels old and worn out.
I don't mind spending $300.00 (including tip) for two if it's an excellent experience. It was okay for sure, but nothing special.
Impeccable service in a unique atmosphere with an amazing view. The pear sausage soup, monkfish, terrine, salad and deconstructed chicken pot pie were amazing. They were also very accommodating with my gluten allergy. I may have to hit the seating at the bar just to order another bowl of soup. All the extras were so appreciated -- the bread! (that I couldn't eat but the whole table raved about), the sorbet, the dessert sample, the cranberry bread for breakfast tomorrow... we have not experienced that kind of service in the Denver area in quite some time. Definitely cannot wait to go again.
This was the BEST meal I can remember having in years!!! OMG order the lamb shank meal, you will go silent for 10 minutes into a bliss state. I was further delighted when we left to meet the man in the photo in the glass case. I asked him if he was the owner and he told me that he and his brother and their father were the owners from the beginning. He also said there were 13 grandchildren working that night - New Year's Eve. THAT's what I call a healthy classy family serving Boulder Colorado. It's expensive but well worth it.
We had never been to the Flagstaff House but we were excited for the view and the food. The view was amazing, the service was excellent, the staff were all extremely polite, the entrees were all delicious, and there were lots of little extras like free valet parking, taster appetizers, between-course sorbet, mini dessert (plus the dessert menu itself was great) and they even sent us home with a breakfast bread for the morning! Very reasonably priced for the experience.
The ambience of this venue is amazing as well as the service. Unfortunately, hidden behind their diverse wine selection, the execution of the back of the house food lacks passion and creativeness. Many simple details were missed including, lamb bone not being properly cleaned and over cooked white polent with too much truffle oil. Again, the place is great, but for anyone going there don't waste your money on the food just get wine, bread and maybe dessert.
My wife and I had our wedding reception at the Flagstaff House 39 years ago on a Saturday early afternoon, December 30th, which was extremely memorable. Whenever we are back in town from Alaska we make it a point to celebrate our anniversary here, as we did this year. The stafff went out of their way to make our dinner very enjoyable and memorable. The wine and spirits list are incomparable. Their wine steward that evening was very knowledgeable about the wines we were considering to compliment our meal and made a good selection for us. She also went out of her way to decant and filter a vintage port wine for us that had also aged 39 years. The free valet parking is a welcome convenience that is always very prompt. The view of the city and front range is fantastic and enhances an already memorable dining experience. However, be prepared to spend a pretty penny for your dining experience. Nevertheless, for all the reasons previously stated this is a dining experience worth paying for, at least for special occasions.
My husband's 50th birthday couldn't have been better! We had an amazing dinner at Flagstaff House with Andres waiting on us. The service was impeccable .. the views from our table were amazing and we were not directly at the window. The food was fabulous and there are several different courses that we were not even expecting. They also brought my husband a small tray of birthday goodies at the end of the meal. Highly recommend this restaurant for a special occasion.
Very great location with outstanding food and excelent service. We were sat in a back corner table so we never got to fully appreciate the view with the exception of getting up to use the restroom. For a $400 meal, I would have liked to experience the Flag staff house in its fullest and not have been in the back corner. They should honestly get rid of that table. Very cramped back there and when the people at the neighboring table got up there was little to no room so we were constantly getting bumped. Apart from that it was amazing.
The Flagstaff House is always special and fabulous. It's truly a restaurant for special occasions and celebrations. Have no fear in taking children--the kitchen and wait staff catered to our 8 year old grandson's requests and he exclaimed after dinner that it was his favorite restaurant.
Let me start by saying the Flagstaff House is great for celebrating any occasion and is certainly a special place. My partner and I visited for an anniversary and were so pleased with the experience. They made the occasion truly wonderful, with a specially designed menu and special deserts with a "Happy Anniversary" sugar heart display. The service was top notch.
Honestly, the most disappointed part of the night was the entrees, which is a bummer when that is the most expensive part of your meal. The starters we ordered we great, as were the complimentary bread selections and transition and palette cleansing plates but both entrees fell flat and were not worth the $$$$. However, it was a wonderful evening and I returned a week later with my parents for drinks and starters at the bar. This, in my opinion, was way better for my budget and style! We sat in the lounge area, which was wonderful, ordered a great bottle of wine with help from the sommelier (which is now one of my favorites!) and enjoyed the cheese plate. I would absolutely return to Flagstaff but will opt for a drink and starter selection.
Food, cocktails, ambiance and service all combined for a wonderful experience to celebrate my son's graduation. My duck was cooked perfectly, and the spicy risotto that was served on the side gave it the pop of flavor it needed. Prime rib and lamb were also reportedly excellent, as was a parsnip-apple soup. Thai-seasoned lobster bisque was one of the few misses, in my eyes, as it was light on lobster and too heavy on rice. Another area of improvement would be to include a few reasonably-priced bottles on the wine list. I went with a cocktail, instead, and my choice, "The Last Word", was delicious. The restaurant has a high vantage point, and even on a winter night, the sparkling lights of downtown Boulder provided a magical view. I would have preferred a window table, and tried to reserve one, but window tables are first come, first serve. This restaurant is more expensive than my usual choices, but is worth it for the overall dining experience, especially for a special occasion.
Perfect. The staff are professional, kind, and thoughtful. They value you as a customer and understand that this night is often something worked towards. They instantly put our party at ease. They made celebrating my partner's graduation a dream. I was thrilled by the cocktails and the champagne, and the food!! We were literally speechless at points, all staring across the table at one another, stars in our eyes. It was a beautiful night. The city below was a tapestry of light, and it was truly perfect.
It is an expensive meal. It is a meal for when you have time and attention, but for us, it was so, so worth it.
Thank you, Flagstaff House, for an unforgettable night!
We took our daughter there for college graduation and luckily got a window table overlooking city lights. First class food, wine & service. Easily one of the best dining experiences of our lives. Well worth the splurge & will come back for special occasions. Cheers!
We have used FH for special occasions for many years. It is time for a refresh. While the service is special and well done, and the extra touches also make it special, the food is only OK and the repetition of each same aspect is now tired. New look needed FH.
My wife and I celebrated our 50th wedding anniversary with tow other couples. We were given a corner window, the servers were knowledgeable, friendly and completely engaged in serving us. The dinner was superb with unexpected added appetizers. Inexpensive - no! High quality in all aspects - Yes! We had a great evening !
All that I can say is the service was impeccable. All the little details were handled with such professionalism. All I can say is we felt loved throughout the whole experience! Food was delicious as well. Very expensive but by the end of the evening it was all worth it!
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At Grand Rapids Masonry Contractors you are going to get affordable masonry work without losing out on service. Masonry brick, stone or block provide an unparallelled look and function to any project. If you are looking to update your house, build a new home or need some special or unique masonry done then look to Grand Rapids Mason Contractors. We have the expertise in stone, brick, cement block, and decorative blocks. As a masonry contractor we know how to make each project stand out! Below is a list of our basis services: Brick Masonry Stone Masonry Block Masonry
Diamond Cut Masonry has a reputation of having exceptional quality workmanship. We service all masonry needs from underpinning and waterproofing to concrete steps, natural stone, fire places and much more. Let our skilled Toronto masonry team help with your next project. We do it right the first time and explain to customers their options to cut unnecessary expenses.
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2000 · Tehran
by Mir-'Emadi, Manijeh (Nasseri)
Tehran: Iranian Art Publishing, 2000. Softcover. VG+ contents; light general wear to covers. Charcoal matte card wraps with bw illus.; peacock feather, and lavender-highlighted putty lettering. 304 pp. with color and bw illus. Text in a mix of English/Farsi. A beautiful, comprehensive publication covering topics in classic art, ceramic art, painting, Islamic art, theater, rising artists, music, architecture, cinema; with profiles, news, reports and reviews, obituaries, previews, critiques, exhibitinos, selected books, galleries, and more. Distributed outside Iran by MIR Enterprised, New York. (Inventory #: 154836)


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Chatham Bars Inn
Phone: 508-945-0096
Main dining room: (Jacket and tie required at dinner) Breakfast is served daily from 7:00 a.m. to 11 a.m. Sunday Brunch 12p.m.-2:30p.m. Dinner 6p.m.-10p.m.
Tavern: All Day Dining 11a.m.-9p.m. Bar Service: 11a.m.-1a.m. daily.
Beach House Grill: Open Seasonally. Lunch 11:30-3. Dinner 6-10.
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|Family Friendly, Fine Dining, Casual Dining, Pub or Bar
|Food Types
|American, Seafood