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Norepinephrine (NE) is a neuromodulator that in multiple ways regulates the activity of neuronal and non-neuronal cells. NE participates in the rapid modulation of cortical circuits and cellular energy metabolism, and on a slower time scale in neuroplasticity and inflammation. Of the multiple sources of NE in the brain, the locus coeruleus (LC) plays a major role in noradrenergic signaling. Processes from the LC primarily release NE over widespread brain regions via non-junctional varicosities. We here review the actions of NE in astrocytes, microglial cells, and neurons based on the idea that the overarching effect of signaling from the LC is to maximize brain power, which is accomplished via an orchestrated cellular response involving most, if not all cell types in CNS.
The ability of an animal to rapidly respond to important environmental changes is fundamentally dependent upon swift changes in neuronal connectivity and excitability. In order to execute appropriate responses, these connectional changes must involve rapid reorganization of network activity, increasing and suppressing activity in different regions, and a host of other physiological changes that are necessary to respond successfully. Though these changes alter the way in which inputs are perceived and handled, their effects must occur across very large regions of the brain in order to facilitate a flexible, adaptive response. Beyond this, behavioral adaptation requires a bridge from immediate events to long term responses. Due to its broad activity and effects on most cell-types of the brain, this review will argue that norepinephrine (NE) plays a major role in optimizing and facilitating these responses.
To begin to understand how this function can arise from a single transmitter system, it is important to consider the anatomy of NE signaling. The exclusive source of NE in the cortex, the locus coeruleus (LC), is a small, pontine nucleus made up of approximately 1,500 noradrenergic neurons in the rat [1] with broad projections that pervade the cortex. These projections have been shown to primarily consist of non-junctional varicosities that may release NE into the extracellular space, with molecules diffusing to nearby receptors [1, 2]. This process of volume transmission, conceived by Agnati et al. [3], permits the activation of receptors over a broad field, promoting coordinated responses from many cells within a given diffusion zone. With more than 1.2 million varicosities per LC neuron [4], LC activation drives NE release over a broad area of cortex [5]. As a result, LC signaling can be seen as a global regulator of the brain, although, functionally, there is likely some selectivity in release to permit more specific sculpting of responses in the brain.
This broad release is coupled with two primary modes of NE release; tonic and burst firing of the LC. These modes have been associated with tonic control of wakefulness [6], as well as novelty and behaviorally driven phasic firing [6–9]. While phasic firing can be considered a mechanism of rapid reorientation and control during behaviorally-relevant moments, NE is also able to optimize responses to benign and pathological stimuli by controlling the state of the brain. Through tonic firing, NE exerts effects on sleep, attention, stress, inflammation and many other processes. This activity helps to integrate internal physiological demands with how external environmental inputs are gated. As such, NE has the potential to alter cortical responses both to slow changes in physiological function and critical moments of behaviorally-relevant stimuli.
To accomplish this feat, the noradrenergic system relies upon differential expression of several receptor types in both neurons and glial cells throughout CNS. This complexity extends even within fairly similar cell types, with expression depending on brain layer, neuron firing pattern, and other seemingly minor cellular differences. It is through this complexity that NE is able to simultaneously, and differentially, induce major changes in network connectivity, behavioral outcomes, inflammatory responses, and other system-wide changes.
The effects of NE in the brain are driven largely by changes in the responses of local circuits to inputs, with very little specific targeting of individual cells. As NE varicosities are preferentially associated with perivascular astrocytic endfeet [10–12] and microglia express receptors for and respond to NE [13, 14], NE's effects are realized through glia as well as neurons. Through this targeting, NE is able to change a myriad of processes, including metabolic activity, glutamate and potassium buffering, inflammatory activity and a host of other functions that alter gating across large populations of cells.
With these functions in mind, and given the astounding breadth of research on the effects of NE in all cell-types in the brain, this review can only begin to approach the question of how NE exerts its effects on the brain. To do so, we will first address some of the known effects of NE on individual cell types, including astrocytes, microglia and neurons. With a basic understanding of how NE can exert its adaptive influences on these cell-types this review will then address the broader question of how NE promotes rapid responses to behaviorally-relevant stimuli on both a cellular and network scale. Finally, we will look at how NE facilitates some of the long-term changes necessary to transform transient events into long-term plastic and homeostatic changes. Throughout this discussion emphasis will be placed on understanding how these processes interact to permit neuroglial networks to optimally respond and adapt.
Astrocytes are electrically non-excitable cells that reside within the central nervous system. Astrocytes express primarily α1, α2 and β1 adrenergic receptors and their activation have all been linked to robust downstream effects on the supportive functions of astrocytes [15, 16]. Astrocytes serve crucial housekeeping roles, which include ion homeostasis, neurotransmitter clearance, and distribution of energy and neurotransmitter precursors such as lactate and glutamine for neurons [17, 18]. When applied in vivo, NE and adrenergic agonists cause dose-dependent modulation of key functions. Especially well documented are the effects of NE on glutamate uptake, glycogen metabolism, and production of lactate and glutamine. NE enhances glutamate uptake, increases production and breakdown of glycogen [15, 18]. Thus, NE can be viewed as a booster of the critical supportive functions of astrocytes in anticipation of increased demand.
Several groups have shown that astrocytes express both α1 and α2-adrenergic receptors and that activation of these receptors increased glutamate uptake and glycogen production respectively. Hertz et al. [16] reported robust expression of α1-adrenergic receptor mRNA in astrocytes consistent with earlier studies demonstrating binding of a radiolabeled α1-adrenergic receptor agonist [19]. It has also been demonstrated that phenylephrine, an α1 agonist, induces transient increases in intracellular Ca2+ in vibrodissociated cortical astrocytes [20]. In vivo, stimulation of LC neurons trigger transient increases in cortical astrocytic Ca2+, which can be blocked with the non-specific α-adrenergic receptor blocker, phentolamine [21].
α1-Adrenergic receptors are positively coupled to phospholipase C (PLC), which catalyzes the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4,5-bisphosphate (PIP2) [22]. IP3 is released into the cytosol and putatively binds to the IP3 receptor (InsP3R), a transmembrane glycoprotein found on the endoplasmic reticulum (ER), which acts as a Ca2+ channel. The resulting conformational change in InsP3R leads to the release of Ca2+ from the ER into the cytosol [23]. As IP3 is released into the cytosol, DAG remains trapped in the membrane and is now free to positively regulate protein kinase C (PKC). Astrocytes are considered the main cell type responsible for glutamate uptake in the CNS as they robustly express the excitatory amino-acid transporters GLT1 and GLAST [24]. The α1-adrenergic receptor agonist phenylephrine was shown to increase uptake of glutamate in brain in vivo and this effect was blocked by the non-specific α-adrenergic receptor antagonist phentolamine [15]. Thus, activation improves glutamate re-uptake and thereby optimizes the temporal resolution and signal-to-noise ratio of glutamatergic transmission.
The primary function of α2-adrenergic receptors is to increase glycogenesis from glucose as part of the glycogen shunt during quiescent periods of neuronal activity [18]. Several groups have found expression of α2-adrenergic receptor on astrocytes in situ [25–27]. Cahoy et al. [28] found α2-adrenergic receptor expression on astrocytes was 2–3 times higher than that of neurons. Via the inhibitory G-protein (Gi/o) and its α subunit the α2-adrenergic receptors are negatively coupled to cAMP, which decreases adenylyl cyclase activity [29], promoting glycogenesis. However, via its βγ subunit it is coupled to PKC and Ca2+ transients [30], which may permit glycogenolysis under certain conditions. As such, while α2-adrenergic receptor activation of astrocytes, the main site of glycogen storage in the brain [18], can lead to a net increase in glycogen production via decreased cAMP activity, it may also act paradoxically to drive glycogenolysis through signaling of the α2 associated Gi/oβγ. Control of glycogen formation and degradation is critical, as ATP generated through glycogenolysis is kinetically faster than ATP generated through hexokinase-mediated glycolysis [18]. This allows for the rapid clearance of glutamate, which is necessary for maintaining high fidelity communication between neurons. Moreover, glycogen is stored throughout the cell body of astrocytes, including their processes, making it easily available during critical periods of high demands [31].
Stimulation of α2-adrenergic receptors by α2 specific agonists dexmedetomidine or clonidine also leads to increased pyruvate dehydrogenase activity, a rate-limiting step in the TCA cycle, as demonstrated by increased rate of production of radiolabeled 14CO2 in the presence of [1-14C] pyruvate [32, 33]. Hence α2-adrenergic receptor stimulation leads to increased glycogen turnover in the brain, with astrocytes as the exclusive site of glycogen storage and increased glucose metabolism to match the increased energy needs of a brain under circumstances requiring increased sympathetic tone, i.e. fight or flight. This will allow for kinetically faster energy production to help maintain stable ATP levels during periods of increased demand.
The primary function of β-adrenergic receptors in astrocytes is to trigger the breakdown of glycogen in astrocytes during increased local neuronal activity. In mammals, β1-adrenergic receptors are the primary mediators of this process judging from the magnitude of effect β1 agonists/antagonists have on the glycogenolytic pathway in slices from murine cerebral cortex [34]. This works via activation of the G-protein (Gs) which subsequently leads to an increased production of cAMP, leading to protein kinase A (PKA) mediated phosphorylation of phosphorylase kinase (PhK), and consequent phosphorylation of glycogen phosphorylase (GP), causing increased glycogenolysis [29]. β1-Adrenergic receptors are unequivocally expressed on astrocytes as demonstrated by astrocytic expression of β1 mRNA [16]. Clearance of extracellular K+ has largely been attributed to astrocytic Na+/K+-ATPase activity, which plays the key role in maintaining the ionic milieu inside and outside of cells [35]. This is especially important within the brain where subtle changes in ionic concentrations, especially K+, can have significant effects on neuronal firing. Na+/K+-ATPase is enhanced in the presence of the non-selective β-adrenergic receptor agonist isoproterenol [36, 37], suggesting β-adrenergic receptor stimulation can optimize K+ clearance in times of increased neural activity (Fig. 1). This allows for priming of astrocytes to effectively clear extracellular K+ under conditions of high neuronal activity.
Through the effects of these receptors, astrocytes are able to optimize many key support functions during periods of increased demand. By driving α1-adrenergic receptor activity, NE induces astrocytic calcium waves and promotes enhanced glutamate uptake—thereby enhancing synaptic efficacy. This is coupled with the strong effects of the α2-adrenergic receptor, wherein effects on cAMP, PKC (via activity of its associated Giβγ protein subunit), and increased pyruvate dehydrogenase activity all serve to enhance glycogen turnover in the brain during periods of LC signaling. These signaling pathways are integrally related to increased glycogenolysis from β-adrenergic receptor activation. Finally, β-adrenergic receptors enhance Na+/K+-ATPase activity. These effects strongly support the hypothesis that the overarching role of adrenergic receptors on astrocytes is to optimize their supporting roles to anticipate changes in demand to coordinate with other effects of NE on the brain.
Microglia, often thought of as the primary immune effector cells of the CNS, represent a major target of NE signaling in the cortex. Though microglia's best elucidated, and most established role, is in mediating injury and immune responses within the brain, recent studies have suggested that these cells may play an active role in regulating brain function under normal conditions [38]. The role of microglia in both pathological and normal conditions revolves around three major processes: surveillance and migration, phagocytosis, and expression of cytokines and neurotrophic factors [39]. While most of these processes have been shown to be largely mediated by purinergic signaling, tonic levels of NE resulting from activity of the LC is a necessary modulator, playing a critical permissive role [40].
Within the cortex, there is overwhelming evidence that β1 and β2 receptors are the only functionally significant adrenergic receptors in microglia [40–44]. Of note, the expression of the β2-adrenergic receptor is highly enriched in microglia compared to other cell types in the brain according to our genomic analysis (Table 1). It is also through activation of β2-adrenergic receptors that most of NE's effects on microglia are realized.
As mentioned above, microglia are highly ramified cells that possess motile processes that constantly survey the parenchyma for tissue injury [45, 46]. Upon detection of tissue damage, microglia abandon their "resting" ramified state and undergo a dramatic morphologic change to adopt an "activated" state, featuring an enlarged soma and fewer, thicker processes [47]. In the activated state, microglia rapidly respond to injury in various ways, many of which appear to require β2-adrenergic receptor activation. First, microglia extend their processes and migrate their somas towards the injury site. While process extension, which occurs within tens of minutes of an insult, has been shown to be dependent on ATP activation of P2Y12 receptors [45], soma migration occurs roughly 24 h after injury and is dependent on NE levels. There is both in vitro and in vivo evidence that NE depletion results in suppressed microglia migration [40].
Microglia are also noted for their ability to phagocytose cellular debris and harmful molecules such as amyloid-β plaques. In addition to evidence showing that the nonselective β-adrenergic receptor agonist isoproterenol enhances microglia migration towards amyloid β plaques in culture [39], phagocytosis of amyloid β plaques is similarly enhanced, though not directly mediated, by β2-adrenergic receptor activation [40, 48]. Furthermore, after migrating to the site of injury, microglia proliferate [49, 50]; interestingly, proliferation is suppressed by β2 receptor activation [51] (Fig. 2).
As such, NE, through β2-adrenergic receptor activation, works as a master-regulator of microglia disease response by modulation of three key microglia actions: migration, proliferation, and phagocytosis, while more specialized functions are driven by purinergic signaling [52]. Given the long timescales of these responses, NE modulation of microglia response is likely due to tonic rather than phasic release of NE. This release of NE keeps microglia primed for rapid, optimized responses to pathological insults.
Norepinephrine is widely recognized for its role as a neuroprotectant [53]. The neuroprotective effects of NE are orchestrated by activation of two parallel pathways: the suppression of inflammatory gene transcription concomitant with the enhancement of neurotrophic factor production. Both of these pathways feature glia as central players. Neuroinflammation is an increasingly appreciated feature of virtually every pathological condition of the CNS [54]. It is mediated by astrocyte gliosis and microglial activation [55, 56].
During neuroinflammation, astrocytes and microglia increase inflammatory gene expression [57–59] and NE has the capacity to suppress this response thereby diminishing the amplitude of the inflammatory processes throughout CNS [40, 42, 60, 61]. This anti-inflammatory action was first acknowledged when it was shown that astrocytes can express Class II major histocompatibility complex (MHC) in culture and this expression was attenuated by application of NE, via a β2-adrenergic receptors and cAMP dependent pathway [41]. Because astrocytic cultures are always contaminated with microglia cells [62], it cannot be ruled out that this observation was at least in part due to microglia. In fact the anti-inflammatory capabilities of glial cells may be predominately due to microglia, as microglial β2-adrenergic receptor expression is significantly higher relative to astrocytes (Table 1). Thus, the anti-inflammatory effect of NE could be largely driven by microglia.
More recently, other anti-inflammatory effects of NE have been demonstrated, including the suppression of iNOS [60, 63], IL-1β [64], TNFα [42], and ICAM-1 (which itself can increase production of TNFα and IL-1β) [65], among other pro-inflammatory cytokines in astrocytes and microglia. These cytokines have a variety of negative effects on the CNS: they are thought to contribute to cell damage, excitotoxicity, and the production of free radicals. The persistent activation of microglia can lead to self-regulating cytokine cycle and eventually chronic neuroinflammation, which has been implicated as a risk factor for a number of conditions, particularly in various forms of dementia [66–68]. The mechanism by which NE reduces the expression of pro-inflammatory cytokines is still a topic of debate but may revolve around the regulation of the NFκB:IκB signaling system by β2-adrenergic receptor driven increases in cAMP [61]. Regulation of these pathways may be closely related to the interaction between NE, inflammatory cytokines, and sleep. TNFα and IL-1β are known to be involved in the regulation of sleep, specifically in their ability to induce non-REM sleep [69]. Consistent with this idea, tonic firing rates of the LC are appreciably reduced during sleep [70] resulting in reduced cortical levels of NE and therefore greater production of cytokines from both astrocytes and microglia. This suggests that NE mediated control of inflammatory cytokines plays an important role in both regulating brain responses to pathology, and in normal physiology.
In addition to suppressing production of inflammatory cytokines, NE also enhances neurotrophic factor production, namely brain-derived neurotrophic factor (BDNF) [71]. Since its discovery, BDNF has been shown to play an important role in neuronal survival, neuroplasticity, and neurogenesis [72]. In astrocytic cultures, NE application (and to a lesser degree 5-HT and DA application) results in a dramatic increase in cellular BDNF expression mediated by the activation of β1/β2-adrenergic receptors as well as α1-adrenergic receptors [73, 74]. The mechanism by which this occurs is remarkably similar to the mechanism by which NE suppresses inflammatory gene production, suggesting these two neuroprotective pathways are activated in parallel. Microglia can also produce BDNF, possibly under the regulation of astrocyte-derived ATP [75]. Taken together, these observations suggest that NE acts via two parallel pathways, (1) suppression of expression of inflammatory genes and (2) enhancement of BDNF expression to promote neuronal survival. These two pathways are important in injury responses while also requiring tonic NE activity to maintain baseline function. As such, NE mediated effects on cytokine and neurotrophin activity permits normal physiological activity while also keeping microglia primed to respond rapidly to pathological insults (Fig. 2).
Norepinephrine may also influence glial-facilitated homeostatic synaptic scaling, a form of synaptic plasticity that increases or decreases the strength of all of a neuron's synaptic inputs as a function of activity [76]. This mechanism depends on the ability of a neuron to sense its own activity and subsequently modify its own excitability [77]. In this way, neuronal networks can tune themselves to increase stability and efficiency while preventing signal saturation [78]. One of the pathways by which synaptic scaling is mediated is through TNFα, which has been shown to increase the surface expression of AMPA receptors (Fig. 2) [79] while decreasing surface expression of GABAA receptors by binding to neuronal TNFR1 receptors [80]. This "scaling up" of a neuron's excitability occurs in response to prolonged absence of stimulation by blocking action potentials with tetrodotoxin [81]. Furthermore, the source of TNFα required for this type of scaling has been conclusively shown to be of glial origin [81]. The predominating view is that reduced levels of glutamate released from neurons are sensed by glia, which leads to an increase in glial release of TNFα [78]. Interestingly, exogenous BDNF prevents the scaling up phenomenon and incubating cultures with a soluble high-affinity BDNF receptor has an identical effect as an activity blockade [82]. However, enhanced BDNF levels do not result in a scaling down of the network [83], suggesting that BDNF acts as a brake on the TNFα-mediated scaling up phenomenon rather than as an opposite driving force. As stated above, NE enhances the expression of BDNF in astrocytes and suppresses the expression of TNFα in microglia. It is therefore likely that NE is heavily involved in regulating the scaling up phenomenon, perhaps by constitutively preventing it through enhancing the BDNF brake and suppressing TNFα.
Norepinephrine signaling in cortical neurons is highly diverse, likely acting on all neuronal populations [10, 84, 85]. This section will describe the primary effects NE on the membrane properties of excitatory and inhibitory neurons, with a focus on how NE differentially modulates neuronal circuits throughout several cortical areas.
A powerful consequence of NE signaling that it shares in common with other neuromodulators is its ability to limit spike frequency adaptation in cortical neurons [86]. NE, through β-adrenergic receptor activation, facilitates transmission of action potential trains by suppressing Ca2+ activated K+ channels (SK) and its after-hyperpolarization conductance (IADH) in a cAMP and PKA dependent pathway [87–90]. Additionally, emotional stress and non-selective activation of β-adrenergic receptors have a profound effect on synaptic strength by increasing postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) insertion. [91]. Furthermore, in prefrontal cortex NE activates α2-adrenergic receptors and closes hyperpolarization-activated cyclic nucleotide-gated channels (HCN), a nonselective cation channel, by decreasing intracellular cAMP levels. Closure of HCN channels decreases the threshold for action potential generation in spatially tuned delay-related prefrontal cortical neurons resulting in increased network connectivity, which is implicated in spatial working memory [92, 93]. In conclusion, the augmented excitatory effects of NE are predominantly due to its modulation of SK and HCN channels with concurrent increases in AMPA receptor trafficking.
However, NE also plays an essential role in decreasing excitatory transmission. Activation of α2-adrenergic receptors decreases calcium (Ca2+) entry though voltage gated Ca2+ channels (Cav2.2, N-type calcium channels) and limits neurotransmitter release [94–96]. This effect is mediated by the βγ G-protein subunit and is independent of intracellular cAMP concentrations. The activation of α1-adrenergic receptors, however, may act to prevent α2-adrenergic receptor inhibition of Cav2.2 by PKC mediated phosphorylation of the α2-adrenergic receptor's G-protein's βγ subunit binding site[97, 98]. This may act like a negative feedback mechanism in which α1-adrenergic receptors suppress the ability of α2-adrenergic receptors to inhibit neurotransmitter release. Lastly, activation postsynaptic β-adrenergic receptors enhances postsynaptic GABAA currents in pyramidal neurons, thereby sensitizing cortical networks to inhibitory input [99]. In summary, NE acts on multiple receptors to decrease cortical activity by either limiting neurotransmitter outflow or by increasing the sensitivity to inhibitory signaling (Fig. 3).
Similar to excitatory neurons, interneurons express all adrenergic receptors with possibly the exception of the α2-adrenergic receptor [84]. The activation of α1-adrenergic receptors on interneurons are likely responsible for NE's robust antiepileptic nature in vivo [100–102]. However the exact mechanism of α1-adrenergic receptor mediated inhibitory activity on neuronal networks is not well understood. Hippocampal interneurons are most likely depolarized by α1-adrenergic receptor agonists by inhibition of resting K+ leak conductances, though the exact mechanism and channels have not been further characterized [103]. In the prefrontal cortex, entorhinal cortex, and hippocampus, α1-adrenergic receptor activation leads to an increase in the frequency and amplitude of spontaneous IPSC independent of PKC and intracellular Ca2+ mobilization [104–106]. Additionally, there is evidence suggesting that application of NE can modulate the ability of evoked IPSCs to inhibit synaptic transmission depending on spatial inputs from different cortical layers in the auditory cortex however the adrenergic receptors responsible for this phenomenon remain unclear [107]. While this suggests that strengthening inhibitory circuits is a major role of NE in the brain, further work needs to be undertaken in order to understand if the other adrenergic receptors have any functional significance in regulating interneuron membrane properties.
The functional effect of NE signaling in a neuronal network is the result of a fine balance between its excitatory and inhibitory actions. [108–110]. One of the predominant features in many cortical regions, is that α1-adrenergic receptor activation opposes the effects of β-adrenergic receptor activation. NE activation of α1-adrenergic receptors in temporal and visual cortex results in decreased evoked excitatory responses, while β-adrenergic receptor activation increases those responses [111–113]. The opposite is true in prefrontal and somatosensory cortex where α1-adrenergic receptors increase excitatory transmission while in somatosensory cortex, β-adrenergic receptor activation decreases glutamate induced EPSPs [108]. Consequently, arriving at a simple mechanism for the effects of NE responsible for the observed region differences in α1 and β-adrenergic receptor activation is difficult and is likely the result of dynamic interplay between neuronal subpopulations and glia expressing diverse adrenergic receptors. In summary, despite complex interactions, a major prevailing feature of cortical adrenergic receptor activation is the opposing nature of α1 and β receptor actions on neuronal firing.
While the effects of NE on neurons is extremely complex, NE's overarching role appears to be to dampen most activity while promoting activity on specifically activated neurons. Through α2-adrenergic receptor mediated closure of HCN channels, NE reduces the threshold for action potential generation and promotes firing. However, activation of α1 and β-adrenergic receptors can lead to enhanced GABAA currents and interneuron firing, potentially suppressing activity, although this effect appears to be strongly dependent on local glial actions as well. Though it is possible that these receptors are activated only at distinct times, due to its global release, NE signaling could be using the differential activities of these receptors to drive many of its well established network effects.
Across the cortex NE signaling in the cortex is characterized by both tonic and phasic periods of LC activity. While tonic LC activity drives microglial responses, as mentioned above, and has been associated with different levels of wakefulness [6], phasic firing of the LC is the critical driver of NE's role in responding to novelty and important behavioral stimuli [6, 7, 9, 114]. Through phasic firing, the LC increases neuronal activity in response to arousing [108], rewarding [115, 116] and aversive stimuli [8, 21, 117]. By altering the pattern of network activity throughout the brain, the LC is able to affect focus, attention and consequent performance in a variety of tasks [6, 118]. As such, the NE signaling plays a central role in regulating how the brain reacts to important stimuli. These behavioral effects are critically dependent on NE's ability to drive changes in neuronal excitability and inhibitory tone. However, while the importance of LC activity in behavior has been thoroughly studied, the correlation between these effects and actions on individual cells is much less well understood.
In sensory cortex, one of NE's primary effects is to enhance population tuning by improving the signal-to-noise ratio [114, 119]. Early demonstration of this effect comes from historical studies which showed that the application of NE reduces neuronal spontaneous activity while retaining evoked responses [120, 121]. This result is partly mediated by altered postsynaptic responses to glutamate, with α1-adrenergic receptor activation facilitating and β-adrenergic receptor activation inhibiting neuronal responses [108]. This effect parallels the α1-adrenergic receptor driven increase in astrocytic glutamate uptake mentioned above [15], reaffirming that NE's effect is to coordinate network responses through multiple cell types.
Norepinephrine further induces significant increases in thalamocortical sensory suppression. This broad inhibition of thalamic activity only minimally alters strong evoked responses, creating an environment that permits high-frequency evoked signals to pass into the cortex with minimal noise [114, 119, 122]. As above, these responses are dependent upon differential α and β-adrenergic receptor activation, with regional differences playing a strong role in how specific parts of the network will respond to a given stimulus. The net result of this activity is enhanced responsiveness to a relevant stimulus, with NE suppressing weak sensory inputs while enhancing the responses of highly active cells; thereby sharpening population tuning and effectively optimizing the regional response to an input.
In higher-order processing areas, NE has been shown to alter network activity in attention and working memory. Persistent activation of the frontoparietal network is critical for sustained attention [123]. To understand the effect of NE on attention and working memory circuits, many studies have reduced cortical NE levels by application of the α2A-adrenergic receptor agonist clonidine to the LC, an effect shown in slice, where α2A-adrenergic receptor activation in the LC was shown to reduce neuronal firing, while, in contrast, α1-adrenergic receptor activation caused a delayed increase in activity [124, 125].
In rats, reduction of NE levels via clonidine injection into the LC has been shown to decrease frontoparietal network activation and impair attention [126]. In contrast, a PET imaging study in humans using i.v. clonidine enhanced frontoparietal connectivity when subjects were focused on a task, while reducing activity when subjects were resting with eyes closed [127]. These studies indicate that NE plays an important role in modulating attention via the α2A-adrenergic receptor.
Working memory similarly relies on persistent network activation, particularly of the excitatory neurons of the dorsolateral prefrontal cortex [128]. Within the prefrontal cortex, direct application of clonidine has been shown to impair working memory performance in monkeys [93]. This effect is driven by the α2A-adrenergic receptor mediated suppression of cAMP signaling mentioned above, a process recently linked with working memory decline in aging [129]. In contrast to the α2A-adrenergic receptor's strong effects on driving sustained activity, studies have shown that under basal conditions, α1 and β-adrenergic receptor antagonism, using the α1-adrenergic receptor antagonist prazosin and the non-specific β-adrenergic receptor antagonist propranolol, has little influence on prefrontal cortex function [130]. Since α1 and β-adrenergic receptor activation may depend upon higher levels of NE than the α2A-adrenergic receptor, these receptors may only become active under stress or other high NE states. This differential activity of α2A and α1/β-adrenergic receptors in working memory reflects the complexity of NE driven network modulation, with specific α2A activity promoting sustained attention and α1 and β-adrenergic receptors activating only in response to very strong NE signals.
While the effects mentioned above have focused on the immediate effects of NE on network connectivity, activation of adrenergic receptors has also been shown to elicit slower, longer lasting shifts in how these networks function. In particular, a large body of evidence suggests that NE orchestrates various parts of the stress response, as the β1-adrenergic antagonist, betaxolol, improves working memory [131] while the α1-adrenergic receptor antagonist, urapidil, attenuates stress-induced working memory impairments [132]. In a recent study in humans, β-adrenergic receptor activation was shown to induce substantial, prolonged changes in neural network coupling [133]. As these receptors have a lower affinity for NE than the α2A-adrenergic receptor [132, 134], it has been postulated that their activation is driven by high levels of NE in stress [135].
Beyond stress, elevated α1-adrenergic receptor activation has also been shown to enhance performance in rats undergoing attentional-shift dependent tasks [136]. α1 is also necessary for rapid large-scale induction of LTD in mouse visual cortex in response to heavily patterned visual stimuli [137]. These results suggest that NE plays a role in both focusing attention on a behaviorally relevant task and in rapidly reorienting the brain in response to important events. While lower levels of NE predominately drive α2A-adrenergic receptor mediated suppression of irrelevant activity, behavior-critical events can drive substantial increases in NE, obliterating ongoing processes and permitting new patterns to become established. NE's role in this 'network reset' switch is likely to allow disruption of ongoing activity in order to permit relevant stimuli to elicit rapid behavioral adaptation [138].
The roles discussed above elucidate a small part of the role NE plays in shaping how the brain reacts to a variety of behavioral inputs. In response to an arousing or emotionally salient input, the LC releases a burst of NE across the brain, sharpening sensory responses to the specific environmental stimuli and reconfiguring the network pattern of the brain. As such, NE plays a role in optimizing performance during important tasks [118]. This input optimization is coupled with NE's ability to rapidly alter network connectivity across the brain. These effects are dependent on internal variables such as wakefulness and voluntary attention as well as how behaviorally-relevant an incoming signal is. Thus, NE's role in behavior is to flexibly adapt networks to enhance performance on whatever task is immediately relevant.
While the role described above focused on immediate effects of NE within neuronal networks, the effects of NE on the brain are far more wide reaching. A substantial amount of evidence has demonstrated that NE plays a critical role in modulating plasticity within the brain as well. These effects can be viewed as a longer term adaptation to behaviorally important stimulus. Though it is critical for an organism to reorient and react rapidly to important events, these effects would be far less useful if they did not lay the groundwork for long term behavioral adaption.
As mentioned, noradrenergic signaling also strongly affects the longer term processes of plasticity via long-term potentiation (LTP) and long-term depression (LTD). Within the hippocampus NE has been shown to facilitate LTP through activation of β-adrenergic receptors [139–141]. Burst firing of the LC in response to encountering novel objects potentiates neuronal responses in the rat dentate gyrus through a mechanism that is blocked by the β-adrenergic receptor antagonist propranolol [142]. The ability of NE to modulate LTP has been shown to occur regardless of reward outcome, as LTP following a tetanic stimulus is reinforced by both rewarding and aversive stimuli [143]. Propranolol has been shown to prevent this effect by blocking β-adrenergic receptor dependent protein synthesis [141] (for a review of NE effects on LTP in the Hippocampus see [140, 144], for an extensive review of NE in cognition see [145]). This form of LTP may be further related to NE-driven increases in AMPA receptor membrane insertion, mentioned above [91]. These functions, driven by β-adrenergic receptor activation, promote LTP and the formation of new memories in response to behaviorally-relevant experiences.
Norepinephrine signaling, however, is not limited to induction of LTP. In the visual cortex, α1-adrenergic receptor activation has been shown to promote the induction of LTD by paired-pulse facilitation [146]. Recent studies have also shown that NE signaling coupled with novel spatial arrangements of known objects can induce hippocampal LTD [147]. The β-adrenergic receptor antagonist, propranolol, was shown to block this effect, as well as LTP, demonstrating diverse functions for these receptors in plasticity. Furthermore, LTP decay and hippocampal depotentiation may be an active process, permitting the removal of behaviorally-irrelevant memories [148]. From the perspective of NE signaling, arousal and salience may thereby promote changes in memory storage; potentially promoting formation of behavior-relevant patterns while deemphasizing memories that are irrelevant to current behavior.
While LTP has long been considered an important step in the formation of memories, a growing body of evidence has demonstrated that LTP progresses through several stages from short-term potentiation and early-LTP to late LTP (greater than 3 or 4 h), a process that was proposed as early as the 1980s [149]. These phases have been associated with distinct neuronal processes, with later forms of LTP being dependent on new protein synthesis [150, 151]. The transformation of early-LTP to late LTP is can be driven by heterosynaptic inputs, where activation of neuromodulatory inputs transforms early-LTP to late-LTP at synapses 'tagged' via glutamate transmission [152, 153]. Noradrenergic signaling has been shown to facilitate this process through β-adrenergic receptors in the hippocampus [140, 141, 154]. A similar process of heterosynaptic LTD has been shown to occur via α1-adrenergic receptors in the bed nucleus of the stria terminalis [155]. This transformation from early to late-LTP may play an important role in encoding memories. Specifically, neuromodulators, including NE, may act as a behavior-reinforcement cue [149] to enhance memories that are associated with important behavioral outcomes.
Given the effects of both α1 and β-adrenergic receptors in modulating the induction and maintenance of LTP and LTD, NE appears to play a major role in translating behaviorally relevant stimuli into long-term changes in synaptic strength. This effect can be viewed as critically dependent upon the effects mentioned above, particularly enhanced astrocytic support and decreased synaptic scaling, as the maintenance of LTP requires the synthesis of new proteins and active scaling of synapses could potentially interfere with simultaneous induction of LTP in a network. Thus the plastic processes mentioned here, NE helps to sculpt network changes that promote future responses based on previous behavioral inputs.
Following a learning task in the mammalian brain, memory conventionally progresses through a short-term, protein synthesis-independent phase that generally lasts a few hours, and is followed by a protein synthesis-dependent long-term memory. In the newly hatched chick, the protein-synthesis-independent short-term memory has been divided into several phases: short-term memory (<10 min) and intermediate-term memory A and B (10–30, 30–55 min, respectively), which—as in mammals—is followed by protein-synthesis-dependent long-term memory from 60 min after training (Fig. 4). The transition points between these phases of consolidation are of critical importance to memory formation, and this has been linked to noradrenergic signaling [156]. In particular, a growing body of evidence, led by the work of Leif Hertz and Marie Gibbs, has shown that these points are reliant upon astrocyte metabolic signaling. In studies of learning in the chick bead discrimination task, propranolol injection into the intermediate medial mesopallium, the avian equivalent of the mammalian brain's cortex, prevented memory formation only when it occurred between 5 and 25 min after training. Further work using the selective β1 and β2, agonists, RO363 and zinterol, demonstrated that this effect was dependent on β2, but not β1-adrenergic receptors [157]. These effects parallel studies showing that injection of the glycogen phosphorylase inhibitor DAB prevents learning when applied 5 min before, 25–35 and 60 min after learning [158]. In addition, α2-adrenergic antagonist application prevents learning [159], specifically when applied at 10–20 or 40–50 min post-learning [160]. This alternating pattern of activity fits closely with the effects of adrenergic receptors on astrocyte metabolism mentioned above. During critical periods, β2-adrenergic receptor activation drives glycogenolysis, supporting the metabolic demands of high activity. During these periods, glycogen levels are maintained by enhanced glycogenesis via activation of the βγ subunit of the G-protein (Gi) coupled with the α2-adrenergic receptor. These periods thereafter alternate with recovery periods, wherein α2-adrenergic receptor activation drives glycogen formation via the coupled G-protein subunit, Giα.
The necessity for increased astrocyte glycogenolysis has been associated with its role in supporting regionally increased glutamate and glutamine synthesis following learning, at both 5 min [160] and 30 min [161, 162] post-training. (For a comprehensive review of this pathway in memory see [160] and for an overview of the inhibitors studied see [163].) That glutamine synthesis in spite of adequate supply of glucose was inhibited by the glycogenolysis inhibitor DAB was demonstrated in a study in 2005 by Marie Gibbs [163]. The same study showed that DAB induced memory impairment at specific times after training can be rescued by application of lactate or of the astrocyte-specific metabolic substrate acetate together with aspartate. These act as a precursor for oxaloacetate, which is needed because acetate alone cannot support pyruvate carboxylation [160, 164]. The glutamate precursor glutamine also rescued DAB induced memory impairments as well as the impairment induced by propranolol or by the glutamine synthetase inhibitor MSO. This provides strong evidence for the necessity of astrocytic β-adrenergic receptor mediated glycogenolysis. This glycogenolysis leads to glutamine formation, which, once shuttled to neurons, provides a necessary precursor for increased glutamate formation [159, 163]. This work thus strongly suggests that a critical component of memory consolidation is the formation of glutamate and glutamine via astrocytic glycogenolysis.
Beyond glutamine formation, glycogenolysis driven ATP formation may support the β-adrenergic receptor mediated increase in K+ and glutamate clearance discussed earlier. Additionally, it has been theorized that astrocyte-derived lactate provides a metabolic support for neurons via a putative astrocyte-neuron lactate shuttle (ANLS) [165]. While this intriguing hypothesis remains somewhat contentious, it appears likely that glycogenolysis drives a myriad of processes that support network optimization and memory consolidation. Taken together, these effects demonstrate a major role for astrocytes in mediating NE-driven network responses. During periods of high neuronal activity, astrocytic β1/2-adrenergic receptors can drive (1) neuronal glutamate supply (see above); (2) optimal glutamate and potassium uptake (mentioned above and in [18, 166]); and (3) metabolic support for these functions. Critically, because of the rapid rate of energy formation from these processes, these supporting mechanisms can occur within a timeframe that is relevant to transient increases in neuronal activity. Moreover, activation of the βγ subunit of the G-protein (Gi) by α2-adrenergic activity in the chicken 'brain cortex' (IMM) drives glycogen synthesis at those times when NE is released (Fig. 4), but not in the period immediately following training, during which glycogenolysis is triggered by serotonin [164], which does not stimulate glycogenesis. Over larger time-scales, the coupling of this activity with recovery periods, mediated by G-protein subunit, Giα, activation via the α2-adrenergic receptor, perhaps most importantly in the LC, clearly illustrates that NE plays a role in optimizing network responses through both low and high activity periods. More broadly, NE signaling links memory consolidation to behavioral reinforcement, driving long-term adaptation.
The preceding studies demonstrated the strong link between NE driven astrocytic glycogenolysis and memory consolidation. However, the processes by which LTP and LTD relate to memory consolidation are still being uncovered. In a recent paper, Suzuki et al. [167] was able to demonstrate that DAB inhibition of astrocytic glycogenolysis prevents the maintenance of LTP beyond 30 min, an effect rescued by exogenous L-lactate. By further demonstrating that this inhibition of LTP maintenance was coupled with a loss of long-term memory formation, the authors provided strong evidence for a correlation between LTP and memory consolidation.
These studies show that NE signaling to astrocytes is necessary to drive the transformation of memory from short to long-term stores. Specifically, NE driven activation of α2 and β-adrenergic receptors is needed at specific times post-training to permit the consolidation of memories in the chicken. This effect is mediated primarily through control of glycogen turnover and glutamate formation, though other astrocytic support functions are also likely involved. Given the role of NE in mediating astrocytic glycogenolysis and subsequent processes, NE may play a further role in controlling both the induction of LTP/LTD and coordinating the metabolic response necessary to support the plastic changes necessary for long-term, 'late-associative' LTP formation. As such, NE signaling is important for supporting processes that bridge short to long term behavioral adaptation.
Together, NE's effects on network gating, plasticity and memory consolidation demonstrate a huge breadth of effects on cognition. By actively streamlining which inputs have priority in a given behavioral state, NE controls immediate potentiation of synapses and overlays a level of expectation on the system. By facilitating both LTP and LTD, NE acts as a switch to determine how a given part of the network reacts to diverse stimuli based on the behavioral state of the animal. Furthermore through broad changes in network excitability via effects on microglia and synaptic scaling, and through the syncing changes in neural activity to changes in metabolic rate, NE exerts a profound effect on driving optimal functional responses. Perhaps most importantly, these changes are able to occur on both immediate and long-term timescales, providing a substrate for the transformation of behaviorally relevant events into permanent changes in brain function and behavior.
Given the broad local effects of NE, including changes in potassium homeostasis, glutamate uptake, synaptic scaling and many other recently elucidated glial functions, astrocytes and microglia may be critical in regulating the behavioral responses of NE signaling. Beyond the very limited survey of NE's effects on behavior and plasticity above, evidence suggests that α1-adrenergic receptor activation may promote memory formation via astrocytic calcium signaling [168]. α1-Adrenergic receptor activation has further been shown to elicit long term plastic and behavioral changes. With data suggesting NE plays a prominent role in BDNF signaling, TNFα production, NGF transactivation, and a host of other pathways (Fig. 3), the specific role of astrocytes within this system is just beginning to be determined. The broad-reaching effects support the hypothesis that NE plays a critical role in modulating both immediate and long-term responses to certain behaviorally relevant stimuli. Given that most of those roles addressed here are focused on broad changes in homeostasis, trophic support and other effects on specific local environments, glia may be the predominate target of noradrenergic mediated network optimization.
This study was supported by funding from NIH/NINDS (NS075177 and NS078304), the W. M. Keck Foundation, and the Dana Foundation. We thank Leif Hertz for comments on the manuscript.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's Canada Institute for Scientific and Technical Information in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Hotel Hesperia
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- Continental Breakfast
- Room service
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TravelPod Member ReviewsHotel Hesperia Venice
For us this quaint old hotel was perfect. Nice and clean and full of character with a very friendly staff manning the reception desk. Our room is sort of a little annex, down the ha;;, through a door and down a few steps, it looks like a former rooftop patio turned into a room and although the building may be old all the fixtures appear to be new and up to date. Furthermore, every hotel should have bath towels this generously sized! Love 'em.
Our price included continental breakfast which was basic but nice. The bread, cheese and salami were fresh, the juice was cold, and there were a number of choices to satisfy different tastes.
There are a few negatives. This is an old building with no elevator and the rooms are tiny so if you want luxury this isn't the place for you. We notice a sewer smell at different times in this city and this hotel, being right on the canal, is not immune. Also, the shower in our room would be impossible for someone of any great height and it was impossible to shower without getting the floor wet.
This review is the subjective opinion of a TravelPod member and not of TravelPod.com.
Historical Traveler Reviews Hotel Hesperia Venice
Great location
We stayed at the Hesperia in May 2005. The location is excellent, 5-10 minutes from the Piazzale Roma where the buses from the airport come in. It is located in Cannaregio on the Cannaregio Canal, a few minutes walk from the western end of the Grand Canal. Vaporetti stops (San Marcuola to the east and Ferrovia to the west) for the Grand Canal are a short walk away. There is also a stop (Guglie) close to the hotel. The area around the hotel is more relaxed than the more obvious tourist areas, less crowded but still with lots going on. We ate at the Hotel Marte on our first night (on the corner by the bridge) and unfortunately felt we were ripped off (87 euros for two for one not very good course and wine and staff who were friendly enough but didn't seem to like tourists much). However some might say we paid for the canalside location. Watch the mosquitos if you sit by the canal. On our second night we asked the hotel staff for a recommendation and had a much better meal. Hotel staff are multilingual, helpful and friendly. Our room was fairly basic but clean and comfortable. Highlights of our trip were coffee in Caffe Florian in St Mark's Square (orchestra, waiters in white coats, expensive but worth it), going up the Campanile in St Mark's Square and having a 360 degree view all over Venice and beyond and a swim in the Adriatic from Lido island. Prices for food and drink on the Lido are MUCH cheaper than in Venice itself. Watch out for cars though - it was a bit of a shock after pedestrian Venice.
Excellent value for money!
This friendly family-run hotel is in a peaceful location away from the crowds but only a few minutes walk from the train station & Grand Canal. Our room was light & airy & spotlessly clean, bathroom was small but well equipped & again immaculately clean. Breakfast was very good & included fresh croissants, cereal, fruit, yoghurt, juice, coffee etc. We would happily stay here again for the friendly service & quiet location, not to mention the excellent value for money compared to many other hotels in Venice!
Stellar service and great location
We stayed at this little family run gem in September of 04 after having found it on this site and really couldn't have been more pleased. Charming, VERY convenient to the termini and the water bus lines, comfortable and cozy. Terrific, knowledgeable and amiable service from the proprietors as described in other reviews. Bathroom was postage stamp size, but who cares? You're in Venice in a room overlooking the Canareggio canal! Highly recommended.
The best
we have just come back from venice on the 31st of jan 05 .We have been to venice four times in two years and we would not stay anywhere but the Hesperia ,staff are great and the two sisters and there dad who run the hotel are very warm and helpfull we went with are small children this time and thay where just great. ThankS girls we love you all ,see you again in july suzanne caulton and kids
PS rooms are very clean and breakfast is great .
Not very accommodating
I am posting the following to share the experience my wife and I had
with Hotel Hesperia in Venice Italy:
We had a trip planned to Italy and then along came the events of September 11. There were warnings from the United States State Department warning Americans traveling abroad and especially to Italy of possible terrorist activity. So, based on these events and warnings we decided it was best to postpone our trip. We telephoned the airlines (United), hotels, and the car rental agency to cancel; every one of these places was gracious and understanding and had no problem with our cancellations; there is one exception...HOTEL HESPERIA in Venice Italy. This hotel refused to return our deposit; when my wife called to further explain why we had postponed they were very rude. After several communications with them they have still refused to return our deposit, so I thought a posting here may help others planning trips to, or in the selection of accommodations in Venice, Italy.
Helped to make it a wonderful break
A lovely hotel that comes complete with lovely owners set in a cosmopolitan and bustling area.
So convenient for the the main Waterbus routes, just over the other side of the Cannareggio Canal, that you can be anywhere on the island or the lagoon within minutes.
We've promised to go back and I don't break a promise.
Kind, knowledgeable and pleasant
Small warm hotel serviced by kind, helpful and knowledgeable people. The rooms are really clean, during the winter a little cold--but they provide tons of blankets. While we were there a transit strike occurred, we wouldn't have known if the people at the front desk hadn't mentioned it to us. They were always very willing to explain anything and everything, since it was our first time in Italy. Breakfast was really good, and there's a pay phone as well as small stores located around the corner from the hotel, so you're not really isolated from "it all". Great experience!
A great location and value to boot
The hotel, even though it is located in the north off the Grand Canal is a top notch place from top to bottom. It's a small hotel, great breakfast and staff. Within a five minutes walk to the train station and 10 minutes from the Parking area using the water taxi on Rt 51. The hotel rooms overlook one of the canals and if you are looking for that nice place and a decent value, then this is the place to go.
Charming, relaxed, lovely & a value
A friend living in Murano investigated hotels for us and recommended the Hesperia. This family owned and operated hotel was great. We'd been told to avoid 2 star hotels but we would have no qualms about recommending this one to anyone looking for a good value. Spotless. Generous and accommodating. Lovely continental breakfasts. We had a view of the canal. The only concern for some might be the lack of an elevator.If you're looking for elegance with all the features of a Ritz Carlton this is not the place for you. But if you'd rather spend your time and money exploring the city it's perfect and you'll be sharing the hotel with many Europeans and far less Americans but the owners speak English so it's not a problem if your Italian is not up to par.
Good Enough for Me
I was pleasantly surprised with the quality of the room. It was small but spotless. The bathroom facilities were some of the best I've run across in Europe. The staff can't be helpful enough. The location was good for me. It's within easy walking to the train station and close to the water taxi. Good English skills and great hot chocolate. Try it, you'll love it!
TripAdvisor Reviews Hotel Hesperia Venice
Travel Blogs from Venice
Let's leave the Airport!
Today we undertook a first for both Lisa and me, we took a boat from the airport to our hotel in the old part of Venice. In doing so we quickly noticed one of the first contrasts between Vancouverites and Venitians. In Vancouver 50 or 60 people line up for a bus that clearly can't hold them all. When the full bus drives away those remaining on the …
Ciao Italia
... an hour later it eased off, so we jumped in line to go inside the Basilica Di San Marco. The line was long but moved quickly. The inside was dark but stunning. Small gold mosaic tiles covered the walls and ceiling. At the very back of the basilica is an incredibly large, gold covered, jewel encrusted decorative piece. I'm sure it has some meaning behind it but I couldn't tell you. By the time we left the basilica ...
Bare shoulders equals floozy
... popping into so many shops ... But I completely want to shop!! However I am resisting the temptation as this is just day two! I end up inside a small church on my walk that one of the most impressive ceilings I've ever seen. I can't read the info as its in Italian. However I have googled it since being back at the hotel. I was that chiesa do San Pantaleone. This 17th century church has the worlds largest painted canvas ceiling. ...
Venezia - Gondolas and Masquerades
... appropriate but comfy as well. There were times where I would see other girls on tour wearing heels or wedges while I'm wearing my chucks or flats. Then I thought, I actually don't care. I'm comfortable and thats all the matters.
Try packing things that you can mix and match, no one cares what you wear. Everyones there for the same reason, to meet some new people and see the sights.
"When one is travelling, everything looks brighter and lovelier"
Venice day 3
... again, desperately hoping not to look like a burglar or an idiot in front of a local group of Italian men standing on the street corner, all the while Billy is still asleep in bed two floors up with no phone contact. Finally after 20 minutes with no avail, she requested the help of one of the Italian men. He gladly came to help, took the keys, and opened the door...to the next apartment. Nikki had fervently been trying to get into ...

subset: commoncrawl


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3251 La Salle in Ann Arbor is for sale. [Tweet "If you are looking for a home in Ann Arbor with more square feet than normal in this price range, then look no further."] This is a spacious two-story home providing more than enough living space for comfort…
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The doctors said nobody comes back from the hemorrhage she had. Yet here she is.
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You won't get lost in a crowd here, as there are fewer than 20 rooms. This is a great location for walking to landmarks such as Rembrandtplein, Waterloo Square and The Portuguese Synagogue. For a memorable Amsterdam visit, be sure you see Skinny Bridge. A museum visit can be fascinating; try the nearby Museum Van Loon or Hermitage. Business visitors appreciate the property's convenient location near Royal Theatre Carré.
For 2 rooms in Amsterdam, Charles Apartment is a good choice.
A weekly housekeeping service is available at Charles Apartment. The establishment has wireless high-speed Internet access (complimentary). A Premium bedding set makes for comfortable nights. Kitchen equipment in some rooms includes a microwave, a coffee/tea maker and a stove.
|From 15:00 Check-out: Until 11:00
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|Note: It is the responsibility of the hotel chain and/or the individual property to ensure the accuracy of the photos displayed. We are not responsible for any inaccuracies in the photos.
Please provide this reference number to our customer service center representative on request, so we can help you better


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I just returned from attending the Annual Meeting of two groups: the Society of Biblical Literature and the American Academy of Religion. Each organization holds its annual meeting jointly in the same place. This year it was held on November 22-25 at the Convention Center in San Diego. It was such a delight to be there. Many of the most famous theologians and biblical exegetes in the world attend this convention every year. Because of it, I have the privilege of knowing many of them. The Society … [Read more...]
The Annual Meeting of the Society of Biblical Literature–2014
See My Redesigned Website kermitzarley.com
Check out the new look at kermitzarley.com. My eldest daughter, Christy Eller, has a website business at iamchristyeller.com, and she is good at it. I'm so proud of her. She redesigned my website kermitzarley.com that I've had for nearly 18 years and just launched this redesign of it today. It has lots of photos of me, most of them regarding my career as a professional golfer on the PGA Tour and Champions Tour. And the ten update articles about my book Palestine Is Coming are better than reading … [Read more...]
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Is Church Membership Necessary?
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What Does "Your Kingdom Come" Mean in "the Lord's Prayer"?
According to the gospels of Matthew and Luke, Jesus taught his disciples how to pray. This model prayer has been popularly called "the Lord's Prayer," with "Lord" referring to Jesus. Both Matthew and Luke provide a similar version of it, with Luke's being shorter (Matthew 6.9-13; Luke 11.2-4). Both prayers begin by addressing God as "Father." That was Jesus' favorite way of referring to God. Calling God "Father" obviously is a recognition of an relationship with God similar to what a son or a … [Read more...]


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Most Recent Articles In Jewelry
Latest Jewelry Articles
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Special IssueWWD Accessory issue 08/04/2008
Childhood musings have worked their way into fall accessories, with designers stringing whimsical memories up as charms, brooches and bracelets. Consider Chanel's carousel necklace (left), a shrunken version of its fall runway set and a luxe ode to the carefree playground days of yesteryear. Meanwhile, Servane Gaxotte gets girly with tutu pins and scribbled heart pendants, while Alexandra François channels childhood surrealism with a collection inspired by the characters of Alice in Wonderland.
"Alice," says François, "was perfect for me, a very pretty girl in a very nice dress mixed with a very strange story in a very fantastic world with bizarre characters."


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Like most animals and some people, wine needs to breathe. Enjoy fully oxygenated flavor with this Groupon.
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During a 60-minute tour of the vineyard, guides describe the winemaking process from planting and harvesting to crushing and bottling. While learning, guests enjoy six tastings to further their understanding of the different varietals. Next, a 90-minute educational wine class explores the art of discerning flavors by tasting six additional wines paired with bites of artisanal cheeses, crackers, fruits, and chocolates.
Europa Village
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Good News AC/DC Fans, You Can Now Stream The Band's Catalog on Apple Music
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Details of AC/DC's Phil Rudd's Alleged Threats Released
Rudd reportedly called both of the people threatened, a contractor and his daughter, and restated the threats.
AC/DC's Phil Rudd Due in Court Again for Allegedly Threatening a Witness in His Trial
He may have just dug his hole a bit deeper by starting a fight with a witness in his own case. He's due back in court on Feb. 10.
AC/DC Drummer Phil Rudd Pleads Not Guilty to Charges of Threatening to Kill
He also pleaded not guilty to additional charges of holding drugs.


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I have not had a problem with this yet and if your into these old tv shows it worth buying.Published 7 months ago by Melano
I really like the first season which was not preachy or give that self-righteous toothpaste moral values that so many classic comedies are embedded with; it appears genuine and... Read morePublished 13 months ago by albert mike
This is a nice and funny sitcom. I have not seen these episodes for several years so I was happy to have this in my collection now.Published 14 months ago by Audrey Chaney
This show was funny. I heard about it from a family member but I had never seen it. I looked it up on Amazon and they had it for a good price. Read morePublished 17 months ago by M.S.
Enjoyed this classic from start to finish. Brought back many fond memories of the series and some similarities of my own family. Just great!Published 20 months ago by Lenore Southerland


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|Robbers drove late model BMW with no license plates
HydroCabron says CaptainShuddup says I bet he wasn't wearing a confederate flag. No one who flies the Confederate flag ever hurt anyone.
|Supreme Court Justice Sotomayor to speak in Stockton
Ceffer says Scalia is the one who keeps chickens in his office.
|What if Donald Trump is actually a good guy ?
Cull it Crazy says CaptainShuddup says Rules for hatred #1 honkeys are loathed by everyone Spoken like a practiced victim. Someone please cry about the white people!
|Insulting Mexicans is not insulting the Latin community.
CaptainShuddup says
|Grateful Dead is just huge pathetic money grab
Ceffer says The Grateful Dead changed their minds, they are changing their name to "The Greedy Dead". They have copyrighted all of their music retroactively and sold it to Apple for a billion cool. The...
|What's killing your career may be the obvious
Cull it Crazy says BayAreaObserver says CaptainShuddup says I look like sound, it hasn't hurt me none. If you look like you sound and vice versa and think it hasn't hurt you - have you...
|Reddit Blowing Up
HydroCabron says Patrick says How should I change Patrick.net do to that? Post and comments are listed in order of karma score: likes minus dislikes. Most wingnut drivel and personal attacks never make it near...
|Wells Fargo economy expert: Stash cash now
iwog says BayAreaObserver says This was one of my favorites - you stated that HIV is practically non-existent. Where do you come up with this shit ? You might consider checking your facts on that...
|Trump vindicated?
HydroCabron says More amazing to me is that some commentators have referred to the victim as "white." Do they really think other whites are all like her? How can they not know the different lineages...
|They are raping the white women, for the sake of humanity!
My neighbor's girl's two year old has a full mustache! Looks like Cheech Marin! Jumping Jimminy, won't someone do something!!?? White women in trouble! White women in trouble! "Given the importance of the topic, a...
|Hot beach porn and the return of the manssiere.
HEY YOU says Followers of Patnet? lol
|Eurozone is Toast. Wanted IMF Report Favorable to Greece BLOCKED!
Strategist says bgamall4 says Eurozone is Toast. Wanted IMF Report Favorable to Greece BLOCKED! Greece is toast. The Eurozone will be better off without the moochers.
|Austerity is life or death issue for Greeks
HEY YOU says iwog says:"Get ready for Greece II brought to you by the Republican party." The Rep/Con/Teas think that austerity will only affect those on the Left.
|Remember that senseless, bloody war we lost
http://news.yahoo.com/obama-ho Washington (AFP) - The head of Vietnam's Communist Party will make a first-ever visit to the White House next week, meeting President Barack Obama on the 40th anniversary of the end of the war...
|Greece "Defaulted" on IMF Payment a few minutes ago
Strategist says Heraclitusstudent says That's cause Germans don't expect to earn their living from their appreciating house. They're not as smart as I thought they were. Heraclitusstudent says Angela has Tsipras by the 'nads and...
|PG&E: Small users will subsidize big users
DieBankOfAmericaPhukkingDie says ASSHOLES!
|Miami condo builders seek Chinese buyers
CaptainShuddup says Hopefully we're too far away.
|Friday Humor: Hillary Trying To Use A Fax Machine
DieBankOfAmericaPhukkingDie says Hillary sends all her love letters to Rosie O'Donnell this way, whenever she isn't riding Huma's face or being face-fucked savagely by her patron Lloyd Blankfein.
|Are All Hipsters Snobs?
DieBankOfAmericaPhukkingDie says The clinical term is effete fuckwit.
|Single payer - no! Oligopoly payer - yes!
CaptainShuddup says It amazes me that in this day and people don't know the definition of a Monopoly.
home top share link sharer users register best of about questions or suggestions? write firstname.lastname@example.com


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Gunmetal Black Ep 01
episode 14.24 / 5.00 4,705 Views
Lucina's First Day
A look at the first day of Lucina in Super Smash4.24 / 5.00 15,025 Views
BATMAN v SUPERMAN final showdown
SPOILERS!!4.17 / 5.00 13,828 Views
great job Concerse!
For something made in 5 hours this was pretty good! 5iven' por voo!
Haha, awesome
I liked it, "It sounds a little sharp, what's this?" "Oh shit!" Awesome. Fifen'd.
I LOVE LOCK DAY 06 !!! And Also The Bloodhound Gang Music Makes It All The Better !!!
Very funny movie!
Short but sweet. Still, very funny movie! Keep up the good work.
ROFL! does the trojan man lubricate your slide?
dude, I gotta know now: A) what the hell was up with the trojans, B) does the trojan man have a place in your wallet too? or is it the trojan woman that you love?


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Kenneth Jay Lane
Turquoise & Crystal Teardrop Drop Earrings
- Color:
- turquoise
Qty: 1
- 1
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Please select an available size.
Please select a size.
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Description: 22K yellow gold-tone base metal teardrop-shaped drop earrings with turquoise resin details and glass crystal accents
- Clip-on closure
Measurements: 3" long, 1¼" at widest point
Material: 22K yellow gold-tone base metal, resin, and glass
Brand: Kenneth Jay Lane
Origin: Imported


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Morris, A.J. and Bailey, C.M. and Dillon, I.A. and Gruar, D.J. and Westbury, Duncan (2010) Improving Floristically Enhanced Field Margins for Wildlife. In: Agri-environment Schemes - What have they achieved and where do we go from here?, 27th - 29th April 2010, University of Leicester, Oadby, UK. ISSN 0265-1491Full text not available from this repository. (Request a copy)
Official URL: http://www.aab.org.uk/contentok.php?id=395
|Item Type:
|Conference or Workshop Item (Paper)
|Additional Information:
Conference proceedings: Agri-environment Schemes - What have they achieved and where do we go from here? in conjunction with the British Ecology Society Agricultural Ecology Group. University of Leicester, Oadby, UK 27-29 April 2010
|S Agriculture > S Agriculture (General)
Q Science > QH Natural history > QH301 Biology
|Academic Departments > Institute of Science and the Environment
|Related URLs:
|Depositing User:
|Janet Davidson
|Date Deposited:
|05 Jul 2011 13:55
|Last Modified:
|21 May 2015 12:00
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Broadcast Sports Inc. (BSI) recently helped SPEED capture nearly 40 hours of dynamic coverage from the Barrett-Jackson Collector Car Auction in Scottsdale, AZ. The auction, the first of four that will be held across the U.S., sprawled out over 16 acres and encompassed more than 700,000sq ft of total tented space. The BSI team provided SPEED with expert RF and communications services that allowed the network to deliver seamless coverage of the tents, buildings and outdoor display areas.
The Barrett-Jackson events involve the simultaneous coverage of multiple points across an expansive indoor and outdoor environment. BSI's proprietary equipment and personnel address the complexities of this scenario and are able to produce a strong, reliable, and consistent wireless signal environment throughout each event. The resulting infrastructure allows multiple audio and video components the flexibility to roam the grounds and capture compelling footage of each car from almost any angle.
For the Scottsdale car auctions, BSI provided six digital HD RF links and six UHF camera control systems; five BSI talent packs with on-air switchable MIC1500 Blue Steel wireless audio systems; two ENG wireless microphone packages; two fish pole-style wireless microphone packages; two shotgun-style wireless microphone packages; three half-duplex PL base stations; eight full-duplex PL belt packs and headsets; two full-duplex UHF PL with RTS; 24 handheld radios and accessories; six diversity receive sites; eight Stratos HD/SD HD-SDI fiber links; an Adder 162 multiplexer; two Viper systems; and a BSI mobile unit. BSI will provide similar equipment packages for the other Barrett-Jackson Collector Car Auctions throughout 2012.
Touted as the world's most prestigious and anticipated collector car auctions, the Scottsdale auction remained true to its reputation by attracting more than 270,000 attendees and generating more than $92 million in sales. The three remaining Barrett-Jackson Collector Car Auctions will air live on SPEED.
An Inside Look at Four Virtual Reality Start-Ups
What Moves the Social TV Needle?
Mark Kudsi Directs 'Art of Patron Virtual Reality Experience'
BT Renews Intelsat Deal
Top Twitter TV Shows for 2014-15 Season Unveiled
comScore Introduces MobiLens Plus
North Korean Propoganda Art Inspires the Credits of 'The Interview'
Imaginary Forces Creates Kaleidoscopic Titles for 'Bosch'
Filmmaker Embraces Short Documentary Format with Oscar-Nominated 'Crisis Hotline'
North Metro Television Goes Wireless with Comrex LiveShot
Spectra Logic and HauteSpot Networks Introduce Body-Worn Camera Video Surveillance Solution
Huge Ultra HD Display Lights Up Times Square


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Fender style. Plays great. Has three pickups. Comes with a stand. 909-996-6177
Jul 3 - Sun City - Musical instruments
1961 Fender Stratocaster Guitar black / white excellent condition with original red crush velvet case Deluxe klussons tuning keys . Original Duco black lacquar paint 21 frets SER # 57796 .... BLACKIES made from 1960 thru 1964 Only ! by LEO FENDER .. . .All decals ,letters and dots ledgable excellent condition ! ....
Jun 28 - Apple Valley - Musical instruments
40 in. Acoustic guitar with prison style art. By an original artist, made with black ink. For show only. Similar guitar art, by same artist, sold to guitarist, Tom Petty.
Jun 27 - San Bernardino - Everything else
Previous owner drilled the bottom peg hole to make it larger and the guitar cracked up the back and sides. Cracks were repaired once in 1982. Cracks have become visible again. This is not affecting the tone or sound quality. Because there is no stamp, seal or numbers on this guitar, I have only been able to research the details and determin this to be a late 1940's/early 1950's model J-45. ...
Jun 15 - Yucaipa - Musical instruments
Sunburst guitar plays great. Good for a beginner. Comes with case. 909-996-6177
Jun 6 - Sun City - Musical instruments
1987 Leo Fender Signature G & L ASAT DELUXE Telecaster Guitar Blondie with original blue crushed velvet case original pristine MINT condition serial # G 023000 SUPER DEAL !!!!
May 28 - Apple Valley - Musical instruments
Overview Great for mobile DJs or a Karaoke nightclub. Compact, powerful, and portable the MATRIX-200 Active Speaker PA System delivers clean, accurate sound ideal for both stage and music playback applications. The MATRIX-200 has a true 200W stereo amplifier, built-in five-channel mixer, studio-quality digital effects, phantom power, and numerous patch ...
May 16 - San Jacinto - Everything else
This is a rare 90's Teisco Spectrum 5, in pearl white. Very rare color. It is in excellent condition, and comes with the original case. Beautifully set up. This guitar is a dream! Serious inquiries only. MIJ. No offers accepted. This guitar is worth more than what I am asking.
Jul 4 - Los Angeles : Los Angeles - Musical instruments
Crate FXT120 Electric Guitar Amplifier Includes channel selector foot-switch. Excellent, like-new condition. This amp is incredible. 2x12. 120 Watts of crystal clear sound. It has a clean and an overdrive channel, sounds excellent either way. Lots of different effects built in, and you can control the effects from the foot-switch. There is also a built-in tuner that remains on as long as the ...
Jul 2 - Los Angeles : Whittier - Musical instruments
PRODUCT DESCRIPTION Metal: 14K White Gold Pendant w/ Yellow Gold String & 14k White Gold Chain Hallmarked 14K Quantity: 1 set Condition: New Pendant Weight: Approx. 3.10 grams Approx. Necklace Length 16" inches box chain Approx. Pendant Height 21.00mm including the bail Approx. Pendant Width 28.42mm Approx. Pendant Thickness 4.14mm Measurements All Approximate DIAMOND DESCRIPTION Diamond ...
Jun 24 - Los Angeles : Los Angeles - Jewelry & watches
PRODUCT DESCRIPTION Metal: 14K Yellow Gold Pendant w/ White Gold String & 14k Yellow Gold Chain Hallmarked 14K Quantity: 1 set Condition: New Pendant Weight: Approx. 3.40 grams Approx. Necklace Length 16" inches box chain Approx. Pendant Height 21.00mm including the bail Approx. Pendant Width 28.41mm Approx. Pendant Thickness 4.04mm Measurements All Approximate DIAMOND DESCRIPTION Diamond ...
Jun 24 - Los Angeles : Los Angeles - Jewelry & watches
Fender Telecaster Blond Tolex Thermometer Case - Brand New !!! This is a genuine Fender handcrafted case, MADE IN THE USA, NOT a cheap, flimsy, no-name knockoff from China. Perfect for original, vintage and ALL Fender Telecaster guitars, any year. Fits leftys too !!! Fender badge/logo on the front edge of the case. Heavy-duty, deluxe, Fender Blond Tolex exterior !!! Plush Green Poodle ...
Jun 24 - Los Angeles : Long Beach - Musical instruments
Functions: Ring modulator Voltage-controlled carrier oscillator Voltage-controlled dual-waveform LFO Used with guitars, basses, keyboards, samples or recorded tracks. Can create subtle or completely over -the-top effects. Never been used. PICK UP LOCATION - HAWTHORNE, CA Can call or text me any further questions.
Jun 23 - Los Angeles : Hawthorne - Musical instruments
Guitar tracks Pro recording software designed for guitarists by cakewalk v4.0 Includes; Installation DVD, Manuals & Original Box
Jun 21 - Orange County : Anaheim - Musical instruments
FULLBORE METAL DISTORTION PEDAL FROM MXR BRAND NEW AND IN ORIGINAL PACKAGE 3 band EQ with midrange sweep Turbo charges your guitar signal. Power: Dunlop ECB003 AC adapter or single 9 volt battery. PICK UP ONLY - HAWTHORNE, CA
Jun 20 - Los Angeles : Hawthorne - Musical instruments
C9 ORGAN MACHINE GUITAR EFFECTS PEDAL Transforms the tone of a guitar or keyboard. Provides 9 more definitive ORGAN and keyboard sounds Provides control over percussive attack level, modulation speed, ORGAN and dry volume. PICK UP ONLY - Hawthorne, CA
Jun 20 - Los Angeles : Hawthorne - Musical instruments
I have several BRAND NEW Guitar hard cases for sale: - Exterior dimension: 44" L x 18" W x 7.5" H - Interior dimension: 42" L x 16" W x 6" H - extra thick foam cushion inside to protect your guitar - lockable with key - built in pouch to store accessories You can pick it up at Baldwin Park or Chino Hills, whichever you prefer. Please reply to this posting, or text to (626) 888-223Five (text ...
Jun 18 - Los Angeles : Baldwin Park - Musical instruments
I have a Gibson Explorer electric guitar. With hardshell case. Guitar is in pretty good condition. Minimal use. Sounds awesome. Real heavy sound. Stock pick ups. 500T/496R Gibson pick ups. All black. Flat black paint. Plack pick guard. Black tuners. Case is ok outside. Perfect inside. It's a truly a fine piece of art. Hate to sell it but I don't play anymore. Asking$1300 willing to negotiate. ...
Jun 17 - Los Angeles : Los Angeles - Musical instruments
Real Harmonicas Recorders Keyboards Guitars Microphone & Music Toys Harmonicas and Recorders are $3 each or 2 for $5 See details of other MUSICIAL Instruments and decor at ebayclassifieds com/user/Tina4Music and eBay FUNdraising store MenagerieTreasures Dot Com HOME CLEARANCE SALE near HOAG hospital by appointment Much Love & BlesSINGs !!! &;-) ♪♫ >♥< ♪♫ TinaHoffman.Me "$ell your earthly ...
Jun 16 - Orange County : Newport Beach - Musical instruments
Please call or text (714) 317-1271 Acoustic Guitar Without Strings This is a Japanese made guitar Pre Lawsuit From late 1970s or early 80s Some damage to the finish in the back, otherwise in very good condition Comes with Vintage case, handle is broken
Jun 14 - Orange County : Garden Grove - Musical instruments
Fender Stratocaster/Telecaster Blond Tolex Case - BRAND NEW !!! Heavy-duty, deluxe, textured blond tolex exterior. Genuine, stitched-leather endcaps with matching leather handle and brass plated hardware. Comes with two keys. Fender badge/logo beneath the handle. Green Poodle Interior !!! Perfect for original, vintage and ALL standard, right-hand Fender Stratocaster and Telecaster guitars ...
Jun 5 - Los Angeles : Long Beach - Musical instruments
Chandler 5560 Guitar (pretty rare two-pickup model of 555 – I've actually never seen another) Blonde Finish Guitar has one concentric pot control (volume inner and blend in the middle position on the outer). This is easily reversible. 25.5" scale Thin neck, flattish radius (12") Upgraded with Lollar Firebird Pickups, bone nut, and metal saddles (Nut and saddles were a significant ...
Beatles' era Gibson J-160E in fantastic, incredible condition. This has the genuine finish coloration of that era. No belt buckle damage. And with original, like-new case. The Beatles swapped guitars around a lot. They often miked-up to combine the acoustic and the pickup sounds Beatles Lennon Acoutic-Electric Acoustic archtop Gibson Vintage Collectible
Les Paul style guitar – BRAND NEW!. Made in U.S.A. Set neck – not bolt-on. Very well made. Real FLAME (not "photo flame") Very nice 60s neck and action on this guitar


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10:00 PM ET, September 11, 2004
Stanford Stadium, Stanford, CA
Top Performers
Passing: T. Edwards (STAN) - 297 YDS, 3 TD
Rushing: J. Lemon (STAN) - 14 CAR, 61 YDS
Receiving: A. Smith (STAN) - 6 REC, 87 YDS, 1 TD
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Zakumi, the 2010 World Cup mascot, in Durban, South Africa, in March, 2010. Photograph by Laura Lane.
Send VF.com your Soccer Shots! Fair Play will post a soccer photograph each weekday through this summer's World Cup.
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Resting partly inside the counter and partly above-counter, this semi-recessed porcelain sink gives your bathroom a stylish, modern look. Its porcelain surface is nonporous for easy cleaning.Pair with your favorite single-hole faucet to complete the look.
Ships in 1 - 2 Business Days
Superb Quality for the MoneyWe purchased this sink about a year ago for part of a 1/2 bath complete overhaul. Despite the granite company having a difficult time measuring it properly, the sink has performed wonderfully. It looks great! Signature Hardware is SO easy to work with.
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