Norepinephrine and the dentate gyrus

H.E. Scharfman (Ed.) Progress in Brain Research, Vol. 163 ISSN 0079-6123 Copyright r 2007 Elsevier B.V. All rights reserved

CHAPTER 18

Norepinephrine and the dentate gyrus Carolyn W. Harley Department of Psychology, Memorial University of Newfoundland, St. John’s, NL, A1B 3X9, Canada

Abstract: Norepinephrine’s role in the dentate gyrus is assessed based on a review of what is known about its innervation and receptor patterns and its functional effects at both cellular and behavioral levels. The data support seven hypotheses: (1) Norepinephrine’s functional actions are primarily mediated by b adrenoceptors and include electrophysiological enhancement of responses to excitatory input and glycogenolytic metabolic support of excitatory synaptic activity. (2) At the cellular level, locus coeruleus burst release of norepinephrine transiently inhibits feedforward interneurons and either excites or inhibits subpopulations of feedback interneurons. Consistent with reduced feedforward inhibition, granule cell firing is transiently increased. Concomitant EEG effects include transient increases in theta power and decreases in beta and gamma power. (3) Norepinephrine selectively promotes the processing of medial perforant path spatial input. This effect is mediated both through short- and long-term potentiation of cell excitability and through delayed potentiation of synaptic input. A critical level of norepinephrine release is required for long-term effects to norepinephrine alone. Norepinephrine release switches early phase frequency-induced long-term potentiation of perforant path input to an enduring late phase form and can reinstate decayed long-term potentiation. Norepinephrine also promotes frequency-induced potentiation of granule cell output at the mossy fiber to CA3 connection. (4) Local increases in norepinephrine accompany glutamate release and release of other neurotransmitters providing a mechanism for norepinephrine enhancement effects independent of locus coeruleus firing. (5) Stimuli, such as novelty and reward and punishment, which activate locus coeruleus neurons, enhance responses to medial perforant path input and engage late phase frequency-induced long-term potentiation through b adrenoceptor activation. (6) Behavioral studies are consistent with the mechanistic evidence for a norepinephrine role in promoting learning and memory and assisting retrieval. (7) The overall profile suggests lower levels of norepinephrine may facilitate pattern completion or memory retrieval while higher levels would recruit global remapping and promote long-term episodic memory. Keywords: locus coeruleus; LTP; LTD; novelty; glycogen metabolism; theta EEG; gamma EEG; global remapping; feedback inhibition; feedforward inhibition; alpha adrenoceptors; beta adrenoceptors; medial perforant path; lateral perforant path; synaptic plasticity DG cells, and reviews NE’s role in promoting long-term plasticity, based primarily on rodent data.

The present chapter examines norepinephrine (NE) innervation and receptor patterns in the dentate gyrus (DG), considers NE’s effects on Corresponding author. Tel.: +1 709 737 7974; Fax: +1 709 737 4000; E-mail: [email protected] DOI: 10.1016/S0079-6123(07)63018-0

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NE innervation Blackstad first characterized NE innervation of the rat hippocampus, reporting the densest NE innervation in the hilus of the DG, particularly the subgranular zone (Blackstad et al., 1967). NE fibers were less common in cell body layers, suggesting axodendritic contacts. Within the molecular layer, the dendritic zone of DG granule cells, NE fibers were denser in the middle molecular layer, a target of medial perforant path fibers from the medial entorhinal cortex, as compared to the outer molecular layer, the target of lateral entorhinal fibers. With retrograde tracing, the origin of the DG NE innervation was identified as multipolar and fusiform cells in the dorsal part of the dorsal pontine locus coeruleus (LC) (Haring and Davis, 1985). Electron microscope (EM) images of the NE fibers in DG reveal small granular vesicles, indicating NE content in
0.4–1.2 mm diameter varicosities. Each varicosity contains
20 vesicles, of which 55% can be classified as small granular vesicles. Large granular vesicles (6%) and a few mitochondria are also present (Koda and Bloom, 1977; Milner and Bacon, 1989b). Intervaricosity axons are 0.1–0.15 mm in diameter (Milner and Bacon, 1989b). In 6600 mm2 samples, the hilus has 1 NE bouton (varicosity) for every 400 boutons of other types; while the granule cell layer has 1/500, and the molecular layer has 1/ 4000 NE boutons. Total NE bouton density differs among regions. An average of 1500 and 2000 boutons are located in hilar and molecular layer samples, respectively, while only 500 boutons are present in each granule cell layer sample (Koda and Bloom, 1977). These estimates of NE innervation density may be compared to estimates of 1/8800–1/14,500 boutons for the neocortex (Lapierre et al., 1973). The majority of NE axon contacts in DG end on small dendrites in the subgranular layer where a third make symmetric synapses, a third form asymmetric synapses, and a third type make close associations without specializations. Terminals in the molecular layer have a similar typology. Thirty percent of terminals end at spines and do not have specialized synaptic profiles. On large dendrites

and granule cell somata, symmetric synapses and appositions are typical (Milner and Bacon, 1989b). Biochemically, NE content in the hippocampus is highest in DG (about twice that in CA1) with higher levels in ventral (600 ng/g) compared to dorsal DG (360 ng/g) (Loy et al., 1980) or similar values (500 ng/g) in both regions (Hortnagl et al., 1991) depending on the study. Quantification of varicosities in DG (2.4 million/cubic mm) also suggest twice as many varicosities there as in CA1 (Oleskevich et al., 1989); however when divided by cell number, the ratio of NE varicosities to cells (20–40/1) is smaller in DG than CA1 (180/1). The ratio is lowest in the granule cell layer itself (2–4/ 1), consistent with the low total number of varicosities in this layer. Seventy percent of the input from the LC to DG courses through the cingulum, with the fornix and ventral amygdaloid pathways each accounting for
15% (Loy et al., 1980). Developmentally, the NE input, as characterized by dopamine-b-hydroxylase immunocytochemistry, is very sparse in the DG at four days postnatal, and is heaviest at this time point in CA1. By 10 days postnatal, a band of fibers in the subgranular zone becomes detectable (Moudy et al., 1993). By 21 days, a mainly adult-like pattern is developed.

Adrenoceptor distribution Both a and b adrenoceptors occur in DG. In an early study using several methods to assess adrenoceptors, Crutcher and Davis (1980) reported b adrenoreceptors at uniform levels in the dentate (146 fmol/mg) and hippocampal gyri (178 fmol/ mg), while a1 receptors were more concentrated in the DG (269 fmol/mg). The uniformity of b adrenoceptor distribution led the authors to suggest these receptors might occur separately from LC terminals, while a1 adrenoreceptors showed better correspondence with LC innervation. Both receptors occurred most densely in the synaptosomal/ mitochondrial fractions. The a1 receptor population was not changed by 6-OHDA lesions (U’Prichard et al., 1980) suggesting a postsynaptic localization.

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b Adrenoceptors Milner’s more recent work (Milner et al., 2000) using both EM and light microscope methodologies, suggests NE adrenoceptor distribution is best identified using EM. Her quantified EM receptor counts show laminar differences in b adrenoceptors that were not evident in light microscope studies. Approximately 500 b adrenoceptor-immunoreactive profiles per 6000 mm2 sample occur in the middle molecular layer, while only
250 profiles are seen in the inner and outer molecular layers, and in the subgranular and hilar zones;
125 b adrenoceptor-immunoreactive profiles/sample occur in the granule cell layer. The molecular layer distribution shows interesting parallels with b adrenoceptor physiological effects (see Physiology, below) and is consistent with Blackstad’s initial description of NE fiber innervation. Granule cell somata express b adrenoceptor immunoreactivity in the endoplasmic reticulum, consistent with granule cell production of b adrenoceptors. A few hilar interneurons, including those reactive for parvalbumin, which marks basket cells (Kosaka et al., 1987; Ribak et al., 1990, 1992), are also immunoreactive for b adrenoceptors. In the molecular layers, 40–50% of the b adrenoceptor reactive profiles are associated with dendrites, and 50–60% with astrocytes. In the granule cell layer, 30% are somatic, dendritic and astrocytic, respectively. In the subgranular region (an
55 mm zone below the granule cells), 65% are astrocytic, while 25% are dendritic. Below the subgranular zone, in the hilar region, 30% of the b adrenoceptor reactive sites are in axons or axon terminals and over 50% are in astrocytes. Some b adrenoceptors are present within parvalbumin-immunoreactive terminals. Reactive sites in axons are less common outside the hilar region, comprising only 2–10% of the b adrenoceptor-reactive sites in other layers (Milner et al., 2000). Dendritic receptors are associated with postsynaptic densities on both large (inner molecular layer) and small (middle and outer molecular layers) dendritic profiles. Immunoreactive sites also

occur in spines. Axonal b adrenoceptors occur in both axons and in axon terminals ending on spines (Milner et al., 2000). The b adrenoreceptors on astrocytes are usually next to terminals that make asymmetric synapses on dendrites and which are thought to be excitatory inputs. Many of the receptors on astrocytes are closely apposed to the terminals that form synapses on spines (Milner et al., 2000). The astrocytic adrenoceptor distribution, in close association with synapses, may support glycogen breakdown at active synaptic sites (see Physiology, below). Astrocytic b adrenoceptors also occur around blood vessels. NE axons, identified by tryrosine hydroxylase immunoreactivity, occur close (1–2 mm) to both astrocytic and dendritic b adrenoceptors, but direct contacts were not observed (Milner et al., 2000). The b adrenoceptors in DG are wellplaced to modify granule cell function, and some interneurons, either directly through postsynaptic receptors or indirectly, through effects on glial processes near synapses. The common postsynaptic location of b adrenoceptors on the dendrites of granule cells near, or with, asymmetric synaptic input and their predominance in the middle molecular layer, is consistent with a selective modulation of responses to glutamatergic input from the medial entorhinal cortex to the DG (see Physiology, below). Activation of presynaptic axonal b adrenoceptors and, possibly, astrocytic b adrenoreceptors, may play a role in the increase in glutamate release also reported with b-adrenoceptor activation (see Physiology, below). Molecular and binding studies suggest the majority of b adrenoceptors in the DG are b1 adrenoceptors (Minneman et al., 1979; Rainbow et al., 1984), but both b1 and b2 adrenoceptors occur in the molecular layer and hilus (Duncan et al., 1991; Booze et al., 1993) and granule cells produce mRNA for both b1 and b2 adrenoceptors with a stronger signal from the b2 mRNA probe (Nicholas et al., 1993b). The hippocampus has a high proportion of high-affinity b adrenoceptors, consistent with a strong functional role for these receptors (Arango et al., 1990).

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a Adrenoceptors Three a1 receptor subtypes are recognized. Specific probes for each (a1a, a1b, a1d) reveal that granule cells have an intense mRNA signal for the a1d subtype (Pieribone et al., 1994; Day et al., 1997), but do not contain the a1b subtype mRNA. The a1a subtype is restricted to polymorph cells of the hilar region (Day et al., 1997). The a1 receptor is described as half as dense in hippocampus as in neocortex, despite the fact that the hippocampus has twice the NE innervation density of neocortex (Zilles et al., 1991). Zilles reports that a1 receptors are more concentrated in the inner 2/3rd of the molecular layer, but that overall a1 receptor density is similar in molecular, granule and hilar zones and does not correspond with NE innervation (both a1a and a1b receptors are represented at similar levels in contrast to the mRNA data). Zilles’ a1 pattern differs from earlier work using a different a1-ligand in which a1-receptor density closely followed NE fiber density (Jones et al., 1985). Since neither a2a nor b adrenoceptors are in clear synaptic association with NE terminals, a1 adrenoceptors are candidates, by default, for sites of synaptic specialization for tyrosine hydroxylase fibers. No a1 adrenoceptor subtype distribution has been described at the EM level in DG. Milner (Milner et al., 1998) characterized the a2a receptor at the light microscope and EM levels and describes its distribution as complementary to the b adrenoceptors in that the majority of receptors are presynaptic — in axons and axon terminals — rather than postsynaptic. Nonetheless, a2a receptors exist both pre- and postsynaptically, and while a2a receptors are implicated in the negative feedback regulation of NE release, most presynaptic profiles are in unmyelinated non-noradrenergic axons. Granule cells demonstrate immunoreactivity for a2a-like receptors in association with endoplasmic reticulum, suggesting granule cell synthesis of a2a receptors. The a2a-immunoreactive sites are evenly distributed in the middle and outer molecular layers with about 40% on axons, 30% on astrocytes and another 30% on dendrites or spines. There are about 1/3rd fewer immunoreactive a2a receptors in the inner molecular layer with only

10% on axons, 50% on dendrites and 40% on glia. Throughout the molecular layer, a2a receptors on dendrites are primarily on spines at asymmetric synapses. Astroctyic a2a receptors are also near asymmetric synapses. No direct synaptic contacts between the postsynaptic a2a receptors and tyrosine hyroxylase reactive axons are observed. The granule cell layer has the fewest a2a profiles (2/3rd less than the molecular layer) and 50% are somatic profiles. In the subgranular zone, there is a paucity of dendritic profiles, with mainly axonal (44%) and glial (46%) profiles. In the hilar region 60% are in axonal elements. The remaining a2a profiles are in glia. The axonal profiles throughout are predominantly in non-noradrenergic axons. A small subpopulation of hilar interneurons, with characteristics of the somatostatin interneuron subtype, contained a2a receptors (Milner et al., 1998). In situ studies examining mRNA for the three a2 receptor subtypes report more of a2c subtype in DG granule cells than a2a (Nicholas et al., 1993a; Scheinin et al., 1994) and none of a2b subtype. A mouse study did find evidence of granule cell a2b receptor expression, with the most signal in more mature granule cells (located at the border with the inner molecular layer) and none in the subgranular zone (Wang et al., 2002). Developmental studies report that the a2a mRNA signal is moderate at 1–3 days postnatal and then becomes weak after maturity (Winzer-Serhan et al., 1997a), while the a2c signal intensity is high from 11 to 14 days postnatal, and remains a moderately-intense signal through adulthood (Winzer-Serhan et al., 1997b). It would be of interest to know the localization of a2c receptors.

Physiology Glycogen metabolism The astrocytic metabolic enzyme, glycogen phosphorylase, which breaks down glycogen to glucose, is strongly activated by NE in DG, as demonstrated pharmacologically using an a2 adrenoceptor antagonist (Fara-On et al., 2005), or physiologically, using glutamate activation of the

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LC (unpublished observations). In 1971, Phelps found high levels of glycogen accumulation in astrocytic processes near synapses in the DG in barbiturate-treated mice (Phelps, 1972). Earlier evidence that NE release depleted glycogen, while suppression of NE release increased glycogen, led Phelps to hypothesize that NE controlled glycogen breakdown in the DG at sites of synaptic activation through b adrenoceptors. This hypothesis is consistent with the common association of astrocytic b adrenoceptors and asymmetric synaptic contacts. At the light microscope level, a patchy, modular distribution of glycogen phosphorylase, which coexists with glycogen, is evident in the DG. Patches are more numerous during the dark phase of the daily cycle, when rodents are aroused, and predominate (
60%) in the middle molecular layer, with the remaining patches equally divided between inner and outer layers (Harley and Rusak, 1993). Glycogen phosphorylase activity is reduced during the theta EEG state, possibly in relation to a higher overall inhibition in the DG during theta rhythm (Uecker et al., 1997). NE activation of glycogen phosphorylase and glycogenolysis in vitro requires b adrenoceptor coupled cAMP activation (Edwards et al., 1974; Nahorski et al., 1975; Quach et al., 1978). NE also increases astrocyte metabolism through a adrenoceptor activation (Subbarao and Hertz, 1991).

Intracellular recording Granule cells Three studies have examined NE effects in vitro. Haas and Rose found that NE and the b adrenoceptor agonist, isoproterenol, produced a small depolarization of the membrane potential, an attenuated afterhyperpolarization, and a decrease in accommodation (Haas and Rose, 1987). The attenuated afterhyperpolarization was attributed to a cAMP-mediated block of Ca++-activated K+ currents. In a few granule cells, a b adrenoceptor initiated block of the transient outward K+ current (A-type current) was reported. Blocking the slow Ca++-activated afterhyperpolarization slows the

decay of excitatory postsynaptic currents (EPSCs) and increases temporal summation in other hippocampal principal cells (Lancaster et al., 2001). Gray and Johnston blocked K+ currents and showed that b adrenoceptor activation increased a voltage-dependent Ca++ current, which is activated when cells are depolarized to at least 15 mV, and is therefore likely to be L-type current (Gray and Johnston, 1987). They showed an increase in Ca++ channel open times and a dependence on cAMP elevation. No changes in the N-type Ca++ current were reported. The a2 agonist, clonidine, was without effect. NE also produced an increase in the amplitude and duration of Ca++-dependent action potentials, which contribute to back-propagating action potentials and spike-timing dependent plasticity (Dan and Poo, 2006). Thus, NE might be expected to enhance this form of plasticity. Intracellular calcium is also increased in granule cells by dose-dependent activation of a1 adrenoceptors (Kusaka et al., 2004). Lacaille and Schwartzkroin used focal application of a b adrenoceptor agonist in hippocampal slices to evaluate the effects of NE. They replicated the depolarization of the granule cell membrane potential (Lacaille and Schwartzkroin, 1988). They also showed that the depolarization was accompanied by an increased input resistance, which they attributed to a blockade of K+ channels that are open under normal conditions. Collectively, one would predict that these b adrenoceptor effects would enhance the excitability and responsivity of granule cells to afferent input. No other adrenoceptor subtype has been implicated in direct modulation of granule cell membrane characteristics.

Hilar interneurons Misgeld and Bijak sampled hilar interneurons in the subgranular zone (Bijak and Misgeld, 1995). Aspiny interneurons, which are GABAergic and inhibitory, have strong afterhyperpolarizations and little spike accommodation. EM studies show they receive NE input (Milner and Bacon, 1989a). Spiny hilar neurons, which are glutamatergic and

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excitatory (mossy cells), have strong accommodation and little afterhyperpolarization. NE blocked both aspiny neuron afterhyperpolarizations and spiny neuron accommodation through b adrenoceptors. NE, or a b adrenoceptor agonist, increased the firing frequency of the excitatory spiny neurons to current injection, but did not alter the response of the aspiny inhibitory interneurons to current injection. Spontaneous firing of both interneuron types increased with NE or b adrenoceptor activation, as did the frequency of excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs). IPSPs increased in neighboring granule cells with increased activity in inhibitory interneurons. With glutamate release blocked, GABA-A receptor-mediated IPSPs still increased in granule cells, but NE no longer increased inhibitory interneuron firing. a adrenoceptor agonists suppressed inhibitory interneuron activity. Thus, NE activation of both b adrenoceptors and a adrenoceptors either did not change or else suppressed, inhibitory interneurons. The enhancement of spontaneous IPSPs, without increased inhibitory interneuron firing, suggests presynaptic b adrenoceptors enhance GABA release. Presynaptic b adrenoceptors also appear to enhance glutamate release. The outcome of natural NE release on inhibitory interneurons, and network inhibition, will reflect the balance of a and b adrenoceptor activation on all elements of the circuit. Extracellular unit recording (see Extracellular unit recording, below) shows that the effects of NE naturally released include decreases and increases in inhibitory interneuron firing, depending on the subtype of the interneuron.

Extracellular unit recording Segal and Bloom were the first to record changes in unit activity in DG in response to electrical stimulation of the LC (Segal and Bloom, 1976a). The cells they monitored had relatively high firing rates and therefore were likely to be interneurons (Jung and McNaughton, 1993). LC stimulation inhibited this cell type in anesthetized rats. In awake rats, a loud tone also inhibited these DG

cells, but when paired with sweet milk it evoked excitation; LC stimulation enhanced the cell excitation as well as inhibition (Segal and Bloom, 1976b). This suggests a circuit-dependent LC modulation of interneuron responses. The inhibition appeared to be a direct effect of NE release, since LC cells transplanted to a denervated hippocampus also inhibited spontaneously active units in the DG. A brief stimulus train to the LC transplant inhibited DG cell firing for
30 s (Bjorklund et al., 1979). This inhibition was antagonized by a b adrenoceptor antagonist. In two pharmacological studies, theta interneurons (putative inhibitory interneurons) in the hilus and near the granule cell layer were excited by NE and by a2 and b agonists, while granule cells were inhibited by NE and by a1 agonists, but excited by a2 and b agonists (Pang and Rose, 1987; Rose and Pang, 1989). The excitatory effects of a2 receptors appeared to be postsynaptic, since they occurred in the presence of high concentrations of magnesium in the extracellular buffer. A more recent study using glutamatergic activation of LC neurons demonstrates both inhibitory and excitatory effects on subgranular and hilar interneurons with natural NE release (Brown et al., 2005). Using NE release from LC activation (natural NE release) has the advantage of revealing in situ actions of NE rather than pharmacological actions, but non-NE effects may also be recruited. The nature of the LC-NE effect depended on the physiological identity of the interneurons. Feedforward interneurons, activated by perforant path input from the entorhinal cortex and firing with a lower threshold than granule cells, were consistently inhibited (
60 s) by brief LC activation (see Fig. 1). Feedback interneurons, recruited only after granule cells discharged, were either excited or inhibited, suggesting differences between subpopulations. Consistent with inhibition of feedforward interneurons was the observation of a strongly increased granule cell response after LC activation. These results reveal that natural release of NE produces selective modulation of DG circuitry. More work is needed to classify the feedback interneurons that respond differentially to NE release.

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Fig. 1. Normalized firing rate of 16 feedforward interneurons in the dentate gyrus following ejection of glutamate in the locus coeruleus demonstrated the robust effects on this cell type. Glutamate was ejected at 0 min. Adapted with permission from The Society for Neuroscience, 2005.

EEG recording In the same study (Brown et al., 2005), LC activation enhanced DG EEG theta in the 4–8 Hz range while suppressing beta (12–20 Hz) and gamma (20–40 Hz) frequencies (see Fig. 2). This result appears consistent with concomitant inhibition of the feedforward interneuron population, which potentially mediates the more distant influences implicated in beta oscillations (Kopell et al., 2000), and excitation of a feedback subpopulation enhancing theta amplitude as reported for 5-HT modulation (Nitz and McNaughton, 1999). Gray originally proposed that LC activation increases hippocampal theta power specifically in a 7.5–7.8 Hz range in awake rats (Gray and Ball, 1970). He observed this increase when rats were responding to novelty or a disconfirmation of expectation. The low driving threshold for this frequency range was lost following NE depletion or blockade (Gray et al., 1975). We have observed that this theta frequency (7.5–7.8 Hz) increases with LC activation in awake rats (unpublished observations). Segal reported that electrical LC stimulation induces theta burst firing in medial septal neurons (Segal, 1976). Berridge and Foote later showed that tonic cholinergic LC activation produces a dramatic increase in hippocampal theta in anesthetized rats (Berridge and Foote, 1991), which depends on b adrenoceptors in medial septum (Berridge et al., 1996).

A pattern of enhanced theta and suppressed beta/gamma activity is consistent with the hypothesis that disengagement from established representations and enhancement of processes that promote incorporation of new information is an effect of LC activation (Brown et al., 2005). Consistent with this view, Bouret and Sara have proposed ‘network resetting’ as a primary LC function (Bouret and Sara, 2005).

Evoked potential recording NE potentiates the perforant path-evoked population spike both transiently, and in a sustained manner, depending on the degree of NE exposure in the DG. Transient potentiation of the perforant path-evoked population spike amplitude, which is b adrenoceptor-dependent, has been reported in numerous in vivo experiments after either exogenous NE application (Neuman and Harley, 1983; Winson and Dahl, 1985; Babstock and Harley, 1993; Harley et al., 1996; Chaulk and Harley, 1998) or activation of LC (Dahl and Winson, 1985; Harley and Milway, 1986; Harley et al., 1989; Washburn and Moises, 1989; Babstock and Harley, 1992; Frizzell and Harley, 1994; Klukowski and Harley, 1994). NE or b adrenoceptor agonists in vitro increase the perforant pathevoked EPSP slope, as well as the population spike, although enhanced E-S coupling is also observed (Lacaille and Harley, 1985). The duration

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Fig. 2. Frequency-dependent increases and decreases in dentate gyrus EEG in the 4–40 Hz range following ejection of glutamate in the locus coeruleus. Asterisks indicate significant effects at po0.05. Upward arrow denotes time of ejection. Adapted with permission from The Society for Neuroscience, 2005.

of in vitro effects are transient when agonist concentrations are low or briefly applied (Lacaille and Harley, 1985; Stanton and Sarvey, 1985c). The discovery of sustained NE-induced increases in the perforant path-evoked potential or NE-induced long-term potentiation (NE-LTP) (Neuman and Harley, 1983) was the first direct evidence that LC-NE could provide a heterosynaptic signal to initiate long-lasting increases in DG responses to glutamate-mediated information. NE-LTP is consistent with Kety’s early hypothesis, based on pharmacological and behavioral evidence, that LC-NE strengthens brain responses to significant stimuli (Harley, 1987), and NE-LTP will be examined in detail in the next section.

NE-induced plasticity Spike potentiation in anesthetized rats While studies at the cellular and EEG level suggest transient LC-NE modulation of the DG network, studies of the perforant path-evoked potential, as noted, reveal a sustained component of LC-NE modulation of the DG response to entorhinal input. Iontophoresed NE was first reported in 1983 to produce a long-lasting potentiation of the perforant path-evoked DG population spike in anesthetized rats that endured for hours (Neuman and Harley, 1983). NE-induced LTP of the population spike has been repeatedly confirmed in vivo using

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direct NE application (Winson and Dahl, 1985; Harley et al., 1996; Chaulk and Harley, 1998), LC activation by glutamate (Harley and Milway, 1986; Harley and Sara, 1992; Klukowski and Harley, 1994; Walling and Harley, 2004) and LC activation by orexin (Walling et al., 2004). Repeated LC electrical stimulation can also induce LTP of the perforant path-evoked potential (Harley et al., 1989). LC electrical stimulationinduced potentiation is controversial, however, with respect to dependence on b adrenoceptor activation. There is evidence both for (Washburn and Moises, 1989) and against (Harley et al., 1989) such dependence. DG evoked response potentiation associated with glutamate- or orexin-induced activation of LC neurons is consistently blocked by b adrenoceptor antagonists, either systemicallyadministered (Harley and Milway, 1986; Harley et al., 1989; Babstock and Harley, 1992; Walling and Harley, 2004; Walling et al., 2004) or locally-delivered to the DG (Harley and Evans, 1988). The requirement for DG b adrenoceptor activation is consistent with the intracellular evidence that b adrenoceptor activation increases the excitability of granule cells to exogenous input. NE-LTP does not depend, however, on continued exposure to NE, as demonstrated by the efficacy of brief iontophoretic applications (Neuman and Harley, 1983; Winson and Dahl, 1985) and by measurement of hippocampal NE during NE-LTP induced by exogenous NE application (Harley et al., 1996) or LC activation (Walling et al., 2004). (For further discussion, see LC firing and NE release patterns, below).

Synaptic and spike potentiation in vitro In vitro studies of NE and perforant path stimulation differ from in vivo studies because potentiation of both synaptic and population spike components of the perforant path-evoked potential occurred consistently in vitro but not in vivo (Lacaille and Harley, 1985; Stanton and Sarvey, 1987). In vitro NE-LTP depends on concomitant NMDA receptor activation (Burgard et al., 1989; Sarvey et al., 1989), as well as on b1 adrenoceptor activation and protein synthesis (Stanton and

Sarvey, 1985c), strongly suggesting an associative component to NE-LTP. However in vitro studies failed to find evidence that pairing electrical stimulation of perforant path input with NE bathapplication was critical for NE-LTP (Lacaille and Harley, 1985; Dahl and Sarvey, 1990) (but see Spike potentiation and pairing requirements, below). Frizzell and Harley found an NMDA receptorindependent potentiation of EPSP slope and population spike using LC-NE activation and ketamine anesthesia in vivo, but potentiation was typically short-lived (Frizzell and Harley, 1994). In vitro, Dahl reported that two applications of a low b adrenoceptor agonist dose (75 nM), spaced by 30 min, which, individually, elicit only weak transient potentiation, induce NE-LTP of the perforant path population spike only, and NMDA receptor activation was not required (Dahl and Li, 1994). This effect of a spaced NE agonist suggests a mechanism by which LC-NE might contribute to a stronger memory with spaced training.

Pathway selectivity The in vitro NE-LTP of EPSP slope occurred only for medial perforant path input, while the same application of NE with an a adrenoceptor antagonist, or of a b adrenoceptor agonist alone, produced a long-term depression (LTD) of the lateral perforant path EPSP slope (Dahl and Sarvey, 1989). It may be relevant for this selective effect that b adrenoceptors are densest in the terminal zone of the medial perforant path (Milner et al., 2000) and that enhancement of back-propagating calcium spikes by NE would be more likely to induce LTP in the adjacent medial perforant path target than the more distal lateral perforant path target (Dan and Poo, 2006). A possible explanation for the failure to induce NE-LTP of the field EPSP in vivo could be that stimulation in vivo, particularly the stronger stimulation that is required to evoke a DG population spike, would activate a mixture of medial and lateral perforant path fibers. NE-LTP in vivo occurs for short-latency population spikes, which reflect medial perforant path activation. In one attempt to examine the selectivity of the

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NE effect in vivo, lateral perforant path input was activated by stimulating the lateral olfactory tract. The synaptic input produced by lateral olfactory stimulation was decreased by pairing with paragigantocellularis stimulation, a major glutamatergic afferent pathway to the LC (Babstock and Harley, 1993). Depression of the lateral perforant path input depended on b adrenoceptor activation. Since paragigantocellularis stimulation enhances the medial perforant path population spike through a b adrenoceptor-dependent mechanism (Babstock and Harley, 1992), the combined results are consistent with enhanced medial perforant path input and depressed lateral perforant path input with LC-NE activation in vivo. One functional interpretation of selectivity is suggested by a new perspective on the entorhinalhippocampal complex, which suggests two forms of spatial mapping occur in hippocampus. Global remapping, reflecting a completely new context, is associated with changes in medial perforant path ‘grid cell’ input; while rate remapping, which reflects firing changes in the same place cell map, is ascribed to alterations in nonspatial sensory input mediated by the lateral perforant path (McNaughton et al., 2006). If strong LC-NE activation potentiates medial, and depresses lateral, perforant path inputs, it would favor global remapping in DG over rate remapping. Global remapping would provide a new context for memory storage. It should be noted that high frequency-induced LTP of either the medial or lateral perforant path requires b adrenoceptor activation (Bramham et al., 1997). Thus, while b adrenoceptors may gate weaker inputs to favor the medial perforant path, when signals are strong, plasticity should be promoted by b adrenoceptor activation in both pathways similarly.

Spike potentiation and pairing requirements In vivo experiments provide evidence that LC-NE activation induces long-lasting increases in the medial perforant path-evoked population spike, suggesting that excitability in the postsynaptic

granule cells increases. Although mixed medial and lateral perforant path input is a possible explanation of the lack of EPSP potentiation observed in vivo, the ubiquity of studies that see no change in EPSP slope suggests an increase in E-S coupling, or granule cell excitability, is a prominent feature of LC-NE modulation. Recent evidence provides support for the hypothesis that an increase in intrinsic excitability, through such mechanisms as reduced K+ conductance in activated dendrites (Frick et al., 2004), is an important component of associative plasticity functioning similar to, and independent of, increases in synaptic drive per se (Daoudal and Debanne, 2003). Evidence for associative plasticity in LC-NE activation effects on DG has been lacking. In vitro studies have not found that NE-LTP requires concurrent pairing of bath-applied NE and perforant path stimulation (Lacaille and Harley, 1985; Dahl and Sarvey, 1990). However, we have recently found that pairing of LC glutamate activation and perforant path input is critical for NE-LTP in vivo (Reid and Harley, 2005). With LC activation 10 min after cessation of perforant path stimulation and 10 min prior to resumption of perforant path stimulation, no NE-LTP occurs. The same LC activation during concurrent perforant path stimulation produces reliable NE-LTP. Both EPSP slope and spike potentiation occurred in our in vivo study (Reid and Harley, 2005). The importance of timing in LC-NE activation for potentiation effects is consistent with evidence that conduction velocity in LC-NE axons varies across species to maintain a constant delay-to-signal arrival in forebrain structures (Aston-Jones et al., 1985). Two differences may be noted between the in vitro and in vivo pairing experiments. First, there was no delay between the offset of perforant path stimulation and the beginning of NE perfusion in the in vitro studies. Second, in vitro bath application of NE is associated with an extended elevation of cAMP levels in DG, permitting perforant path interaction with cAMP effects even at late time points (Stanton and Sarvey, 1985b). This is unlikely to be the case with LC activation (Siggins et al., 1973).

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Delayed long-term synaptic potentiation in awake rats In contrast to the evidence that NE induces rapid potentiation of perforant path synaptic input from in vitro studies is new in vivo data from awake rats in which potentiation of perforant path synaptic input is first observed 24 h after LC activation (Walling and Harley, 2004). In the Walling and Harley study, LC burst activation initially had no effect on synaptic input, but induced the usual rapid and enduring potentiation of the perforant path-evoked population spike. Twenty-four hours later, both the perforant path field EPSP and the population spike were strongly potentiated (Fig. 3). The 24 h increase in field EPSP slope predicted the 24 h increase in population spike amplitude. This delayed NE-LTP of EPSP slope and population spike amplitude depended on b adrenoceptor activation at the time of LC activation, and on protein synthesis. Aplysia also demonstrates a 24 h delayed potentiation of synaptic input in response to heterosynaptic activation of a cAMP-dependent cascade (Brunelli et al., 1976; Schacher et al., 1988). Walling and Harley suggest mammalian delayed synaptic potentiation implies a special role for DG NE modulation in long-term memory. Such an association is likely to require relatively strong NE release. NE applied intracerebroventricularly and

measured by microdialysis in the DG is only associated with NE-LTP in the DG when the NE increase exceeds a critical threshold, estimated to be
400 nM, intrasynaptically (Harley et al., 1996).

LC firing and NE release patterns LC neurons fire tonically at rates from less than 1 to 5 Hz (Aston-Jones and Bloom, 1981b) as a function of level of arousal. They also fire phasically in bursts in which 2 or 3 spikes occur in rapid succession (10–15 Hz) followed by 200–500 ms pauses (Aston-Jones and Bloom, 1981a). Burst events are typically associated with responses to environmental stimuli (Aston-Jones and Bloom, 1981a). Harley and Sara have shown that glutamate activation of LC produces a strong burst followed by a pause, lasting minutes, in LC firing (Harley and Sara, 1992). Higher levels of NE release are associated with phasic rather than tonic firing patterns (Florin-Lechner et al., 1996). Glutamate administration to the LC in vivo increases NE release in hippocampus by
200%, measured by microdialysis, in the first 20 min after LC activation, subsequently, NE levels return to baseline (Walling et al., 2004). Orexin A is also a potent activator of LC neurons, and its administration to the LC led to a similar increase in NE, restricted to the first 20 min (Walling et al., 2004).

Fig. 3. Delayed potentiation of the perforant path-evoked field EPSP with immediate and delayed potentiation of the perforant pathevoked population spike in awake rats following infusion of glutamate in the locus coeruleus at the arrow. Adapted with permission from The Society for Neuroscience, 2005.

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Both orexin A and glutamate activation of LC produce a b adrenoceptor-dependent increase in population spike amplitude that lasts for hours and is thus triggered, but not maintained by, hippocampal NE release. High frequency electrical stimulation of the perforant path also increases NE release in the DG (Bronzino et al., 2001), and may contribute to the level and duration of LTP induced (Bronzino et al., 1999). Voltammetry provides better temporal resolution of NE release. Electrical stimulation of the LC for 2 s at 50 Hz induces a 10 fold increase in oxidation signal in the DG (maximal extracellular signal
0.18 mM NE), appearing immediately after stimulation and returning to baseline within 10–15 s (Yavich et al., 2005). Repeated stimulation at 5 min intervals yields stable NE signals, while stimulation at 30 s intervals shows decreasing responses, suggesting a slow rate of vesicle refilling. Natural stimuli that activate LC (tail pinch or vibrissae stimulation) do not produce a visible NE signal without enhancement of NE release using the a2 receptor-antagonist, idazoxan. Glutamate activation of LC produces an average increase of
0.1 mM in hippocampal NE beginning 30 s after glutamate infusion, peaking at 1.5 min and returning to baseline by 7 min in urethane-anesthetized rats (Palamarchouk et al., 2000). NE patterns in awake rats with glutamate infusion were similar but peaked at 5 min and returned to baseline within 20 min (Palamarchouk et al., 2002).

NE release modulation by glutamate and vice-versa: local effects Both NMDA and AMPA receptors are present presynaptically on NE axon terminals in hippocampus, and when activated by glutamate or glutamate agonists, induce an increase in NE release (Pittaluga and Raiteri, 1992; Raiteri et al., 1992). NMDA-induced NE increases are greatest in DG microslices (Andres et al., 1993). Nictotine and somatostatin receptors are also present on NE terminals in hippocampus and induce NE release alone (nicotine) or in concert with NMDA receptor stimulation (nicotine and somtatostatin) in the

presence of normal magnesium levels and without membrane depolarization (Pittaluga et al., 2000, 2005; Risso et al., 2004). This provides a mechanism for local NE release in the absence of direct terminal activation. Finally, cognitive enhancers significantly facilitate NE release in response to glutamate, even in the presence of the endogenous NMDA receptor antagonist, kynurenate (Pittaluga et al., 1997). This facilitation is suggested to be an important mediator of cognitive enhancement (Desai et al., 1995; Pittaluga et al., 2001). Conversely, NE enhances glutamate release in DG, an effect which depends on presynaptic b adrenoceptors (Lynch and Bliss, 1986). NE can also enhance GABA release in hippocampus through a2 adrenoceptor activation (Pittaluga and Raiteri, 1987; Maura et al., 1988). Reversible EPSP slope potentiation of perforant path input to the DG has been related to b adrenoceptormediated phosphorylation of the presynaptic proteins synapsins I and II (Parfitt et al., 1991, 1992). The positive feedback between NE and glutamate release further suggests local increases in NE could occur independently of LC activation. The release of NE by glutamate and other neurotransmitters may explain extended limbic NE elevation when rats receive shock in a novel context (McIntyre et al., 2002). Suggestively, memory for the context correlates positively with NE levels at the time of acquisition. LTP of perforant path fibers also evokes longer lasting increases in NE release than LC activation alone (Bronzino et al., 1999, 2001).

LC-NE modulation of DG in relation to environmental events Novel objects investigated by a rat using a board with objects contained in holes (holeboard) elicit LC bursts (Vankov et al., 1995). Perforant pathevoked population spikes are potentiated for
1 min after a rat places its nose in a hole in response to a novel object (nose poke). Spike potentiation depends on b adrenoceptor activation (Kitchigina et al., 1997); as does the enhanced exploration of novelty (Sara et al., 1995). Prolonged spike enhancement occurs upon first exposure to

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the novel holeboard environment, possibly because the novel environment elicits a larger LC response (Kitchigina et al., 1997). These effects appear to model the attentional (Berridge and Waterhouse, 2003), rather than the memory, effects of NE. Novel environment exposure can promote memory-like effects when a weak, high-frequency LTP stimulus is also presented (Straube et al., 2003). Placement in a novel environment converts earlyphase LTP to late-phase LTP in the DG. This conversion depends on b adrenoceptor activation, suggesting LC-NE activation by novelty induces an enhancement of the weak LTP stimulus. NE in the ventricles mediates a similar conversion of early to late-LTP in the DG (Almaguer-Melian et al., 2005). b adrenoceptor activation is critical for late DG LTP both in vitro (Stanton and Sarvey, 1985a) and in vivo (Straube and Frey, 2003). Only the use of strong LTP protocols (for example, 15 0.25 ms pulses at 200 Hz every 10 s for 200 s) with repeated 15 pulse protocols twice within 5 min can produce LTP in vivo that is independent of b adrenoceptor activation (Straube and Frey, 2003). In addition to facilitation by NE of enduring LTP in the entorhinal cortex-to-granule cell perforant pathway, there is LTP facilitation in the granule cell-to-CA3 pathway when subthreshold LTP stimuli are combined with b adrenoceptor activation (Hopkins and Johnston, 1984). Thus, weak patterns for LTP recruit enduring LTP in both the input and output components of DG circuitry when NE is elevated. Reward also promotes the conversion of early phase perforant path-LTP to late phase perforant path-LTP (Seidenbecher et al., 1997), and is known to activate LC neurons (Sara and Segal, 1991). Punishment has similar effects on activation of LC (Sara and Segal, 1991) and the conversion of early to late DG LTP. Conversions of early to late LTP by reward and punishment depend b adrenoceptor activation (Seidenbecher et al., 1997). These results suggest reward- or punishment-related LC activation ‘reinforces’ plasticity in the DG. LC-NE may also contribute to long-lasting circuit changes through the promotion of the survival of new neurons in DG (Rizk et al., 2006) and/or the promotion of neurogenesis (Kulkarni et al., 2002).

Restoration of recently-decayed LTP in the DG occurs following electrical stimulation of the LC (Ezrokhi et al., 1999). This phenomenon may relate to other evidence for a role of NE in memory retrieval (Sara and Devauges, 1989; Devauges and Sara, 1991; Murchison et al., 2004). NE’s promotion of theta EEG and the reported dependence of engram spread on b adrenoceptor activation could also contribute to retrieval processes (Flexner et al., 1985; Givens, 1996). Aston-Jones and Cohen’s proposal that phasic LC-NE optimizes decisiondriven behavior and decision-driven memory representations provides further theoretical support for an NE retrieval function (Aston-Jones and Cohen, 2005). Exploratory behavior is increased with DG NE infusions (Flicker and Geyer, 1982) and this effect is blocked by a b adrenoceptor antagonist. A tonic LC-NE driven modulation of diversive exploration (Usher et al., 1999; Mansour et al., 2003) is consistent with lesion evidence suggesting the DG has an important role in encoding spatial novelty (Lee et al., 2005; Jerman et al., 2006). Vasopressin in the DG facilitates memory for passive avoidance and increases NE turnover in DG (Kovacs et al., 1979b). Both consolidation and retrieval are enhanced, and these effects require intact LC-NE innervation (Kovacs et al., 1979a). Vasopressin in dorsal hippocampus also facilitates memory for spatial learning (Paban et al., 2003). NE dependence of this effect remains to be assessed. Corticotrophin releasing factor infused in the DG also enhances passive avoidance memory, while loss of local NE innervation, or blockade of local b adrenoceptors or NMDA receptors, prevents this memory enhancement (Lee et al., 1993). Lee et al. suggested that b adrenoceptors promote NMDA-mediated synaptic plasticity to support passive avoidance memory. A dependence of NEinduced plasticity on NMDA receptors was also described in some in vitro studies (Sarvey et al., 1989). As we come to better understand the behavioral role of DG, new probes of NE’s function in the DG should emerge. Aston-Jones and Cohen have proposed, based on data from primates, that phasic LC-NE activation facilitates decision-driven

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responses or memories, while tonic LC-NE activity facilitates exploration (Aston-Jones and Cohen, 2005). The latter hypothesis is supported by increased exploration following NE infusion in DG (Flicker and Geyer, 1982), but the relation of phasic activation to decision-driven behavior and/or memory is unclear with respect to DG activity. Bouret and Sara’s more general description (Bouret and Sara, 2005) of the function of the LC-NE system as ‘network resetting’ is broadly consistent with NE-associated changes in EEG and with the promotion of long-term synaptic plasticity in DG input and output. The promotion of frequency-induced long-term potentiation (Dragoi et al., 2003) by NE reviewed above and the selective enhancement of the spatial map matrix input from the medial entorhinal cortex (Hafting et al., 2005) described earlier (see Pathway selectivity) lead to the prediction that, for the DG, strong activation of NE input would promote global remapping of spatial context. Weaker activation of NE input and an associated transient reduction in network inhibition (see Extracellular unit recording, above) might enhance input generalization, or pattern completion to assist retrieval, but strong activation would alter the DG map. Global remapping provides a new framework for the encoding of associative learning, reducing interference among associations and increasing memory capacity. Global remapping is assumed to underlie episodic memory. The prediction that strong LC-NE activation recruits global remapping in DG is consistent with the hypothesis that activation of the LC and the related sympathetic system is part of a response to strongly significant events that promotes long-term memories for significant events (Cahill et al., 1994). Global remapping with novelty exposure has been shown for CA3 cells (Leutgeb et al., 2006), which like DG (Chawla et al., 2005; Rolls and Kesner, 2006), are implicated in sparse encoding and orthogonal environmental representations. The occurrence of global remapping in DG concomitant with strong LC activation remains to be demonstrated, but is suggested by the data reviewed here. In summary, evoked potential and cellular data support various effects of NE on information processing in the DG. Transient effects of phasic

NE release include reduction of feedforward inhibition and increases in granule cell excitability, such that granule cell responses to entorhinal input increase. NE’s modulation of feedback interneurons enhances theta to facilitate throughput and associative change in synaptic strength depending on theta phase (Pavlides et al., 1988; Orr et al., 2001). NE enhances and depresses inputs in a pathway-dependent manner and recruits glial metabolic support for neuronal activation. Strong NE input engages processes that recruit long-term modifications of excitability and/or delayed increases in synaptic strength in the DG pathway. Together these effects support both attentional and memory roles for DG NE.

Acknowledgment The author wishes to express appreciation for the support of Canada’s NSERC Granting Council via Grant A9791.

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