Priming locus coeruleus noradrenergic modulation of medial perforant path-dentate gyrus synaptic plasticity

Neurobiology of Learning and Memory xxx (2016) xxx–xxx

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Priming locus coeruleus noradrenergic modulation of medial perforant path-dentate gyrus synaptic plasticity Ramamoorthy Rajkumar a,b,c, Jigna Rajesh Kumar a,b,c,d, Gavin S. Dawe a,b,c,d,⇑ a

Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 117600, Singapore Neurobiology and Ageing Programme, Life Sciences Institute, National University of Singapore, 117456, Singapore c Singapore Institute for Neurotechnology (SINAPSE), 117456, Singapore d NUS Graduate School for Integrative Sciences and Engineering (NGS), National University of Singapore, 117456, Singapore b

a r t i c l e

i n f o

Article history: Received 5 May 2016 Revised 30 June 2016 Accepted 6 July 2016 Available online xxxx Keywords: Priming Metaplasticity Long-term potentiation Stress Locus coeruleus Hippocampus

a b s t r a c t Priming phenomenon, in which an earlier exposure to a stimulus or condition alters synaptic plasticity in response to a subsequent stimulus or condition, known as a challenge, is an example of metaplasticity. In this review, we make the case that the locus coeruleus noradrenergic system-medial perforant pathdentate gyrus pathway is a neural ensemble amenable to studying priming-challenge effects on synaptic plasticity. Accumulating evidence points to a tyrosine hydroxylase-dependent priming effect achieved by pharmacological (nicotine and antipsychotics) or physiological (septal theta driving) manipulations of the locus coeruleus noradrenergic system that can facilitate noradrenaline-induced synaptic plasticity in the dentate gyrus of the hippocampus. The evidence suggests the hypothesis that behavioural experiences inducing tyrosine hydroxylase expression in the locus coeruleus may be sufficient to prime this form of metaplasticity. We propose exploring this phenomenon of priming and challenge physiologically, to determine whether behavioural experiences are sufficient to prime the locus coeruleus, enabling subsequent pharmacological or behavioural challenge conditions that increase locus coeruleus firing to release sufficient noradrenaline to induce long-lasting potentiation in the dentate gyrus. Such an approach may contribute to unravelling mechanisms underlying this form of metaplasticity and its importance in stress-related mnemonic processes. Ó 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction Prior experience can modulate subsequent capacity to learn. In particular, exposure to stress or conditions evoking anxiety can alter subsequent behavioural plasticity. Metaplasticity describes plasticity in the ability to induce subsequent synaptic plasticity (Abraham & Bear, 1996; Abraham & Tate, 1997). Priming phenomena in which an earlier exposure to a stimulus or condition alters subsequent induction of synaptic plasticity in response to a challenge stimulus or condition can be viewed as a form of metaplasticity. Stress-induced metaplasticity may have important implications for understanding behaviour (Schmidt, Abraham, Maroun, Stork, & Richter-Levin, 2013). In the current review, we explore priming of locus coeruleus noradrenergic - modulation of medial perforant path-dentate gyrus synaptic plasticity weeks

⇑ Corresponding author at: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Building MD3, #04-01Y, 16 Medical Drive, 117600, Singapore. E-mail address: [email protected] (G.S. Dawe).

later as an example of metaplasticity. This phenomenon was first reported for nicotine priming and challenge but likely reflects mechanisms that can be induced by any stimulus inducing locus coeruleus tyrosine hydroxylase expression combined with any challenge activating locus coeruleus firing. As such non-reward frustration, anxiety or stress may induce this form of metaplasticity. The locus coeruleus, comprised of only approximately 1500 densely packed projection neurons bilaterally in the rodent brain, is the sole source of noradrenergic innervation of the mammalian forebrain, including the hippocampus and prefrontal cortex. The neurons of the locus coeruleus express tyrosine hydroxylase. Tyrosine hydroxylase is the rate-limiting enzyme in synthesis of catecholamines, including noradrenaline and dopamine. The roles of the locus coeruleus and its noradrenergic projections in attention, arousal, working memory and other aspects of cognition have been extensively investigated (for reviews see Ramos & Arnsten, 2007; Sara, 2009; Sara & Bouret, 2012). The noradrenergic system has been proposed as a target for treatment of cognitive dysfunction, for example in schizophrenia, attention deficit hyperactivity disor-

http://dx.doi.org/10.1016/j.nlm.2016.07.003 1074-7427/Ó 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Rajkumar, R., et al. Priming locus coeruleus noradrenergic modulation of medial perforant path-dentate gyrus synaptic plasticity. Neurobiology of Learning and Memory (2016), http://dx.doi.org/10.1016/j.nlm.2016.07.003

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der and Alzheimer’s disease (for review see Arnsten, 2004; Arnsten & Jin, 2012; Chalermpalanupap et al., 2013; Harvey, 2009). The locus coeruleus expresses corticotrophin releasing factor (CRF) receptors and is strongly activated by stress (Page & Valentino, 1994; Valentino, Foote, & Aston-Jones, 1983). CRF-mediated activation of locus coeruleus may facilitate shifting of attention between diverse stimuli (Snyder, Wang, Han, McFadden, & Valentino, 2012). Moderate levels of noradrenaline release may enhance working memory and prefrontal cortical function via high affinity alpha-2 adrenoceptors but high levels of noradrenaline release during stress impair prefrontal cortical function via low affinity alpha-1 adrenoceptors and perhaps also beta-1 adrenoceptors (Birnbaum, Gobeske, Auerbach, Taylor, & Arnsten, 1999; Ramos & Arnsten, 2007; Wang et al., 2007). Impairment of prefrontal cortex structure and function by stress signalling pathways may contribute to mental illness (for review see Arnsten, 2009). Medial perforant pathdentate gyrus monosynaptic pathway is a reliable model to study mechanisms of mnemonic processing. Specifically, the medial perforant path plays a role in spatial information processing along with the dorsal hippocampus (Hargreaves, Rao, Lee, & Knierim, 2005; Hunsaker, Mooy, Swift, & Kesner, 2007; Naber, Witter, & Lopez da Silva, 1999). Lesioning of the medial perforant path impaired water maze learning (Ferbinteanu, Holsinger, & McDonald, 1999) and caused a path integration deficit (Van Cauter et al., 2013). N-methyl-D-aspartate (NMDA) receptors in the pathway are predicted to control the direction of plasticity change (Luscher & Malenka, 2012). Nicotine delivered by tobacco smoking has long been associated with transient improvements in attention and cognitive function but has many adverse effects. Nicotine is the principal neuroactive alkaloid in tobacco and appears to be largely responsible for addiction to smoking (Jaffe & Kanzler, 1979; Pich et al., 1997; Pontieri, Tanda, Orzi, & Di Chiara, 1996; Stolerman & Jarvis, 1995). During abstinence from smoking, heavy smokers are reported to experience cognitive impairment (Abrous et al., 2002). Despite recognition of the liability for abuse and the harmful effects of nicotine, there continues to be interest in the potential for beneficial cognitive enhancing effects (Changeux et al., 1998; Everitt & Robbins, 1997; Levin, 2013; Robbins, McAlonan, Muir, & Everitt, 1997). Nicotine exposure induces persistent neuroplasticity by various mechanisms, including changes in the expression and sensitivity of nicotinic acetylcholine receptors in the midbrain dopaminergic neurons projecting to the dorsal striatum, ventral striatum and nucleus accumbens and prefrontal cortex (for review see Korpi et al., 2015). In addition, nicotine administration produces an intriguing priming effect on locus coeruleus neurotransmission that amplifies responses to subsequent nicotine challenge and enables induction of noradrenaline-dependent synaptic plasticity in the dentate gyrus of the hippocampus.

2. Nicotine priming up-regulates tyrosine hydroxylase expression and noradrenaline release Acute, systemic administration of nicotine (0.4 mg/kg or 0.8 mg/kg) increased 2-amino-3-(3,4-dihydroxyphenyl)propanoic acid (DOPA) accumulation (a marker of catecholamine synthesis) in the rat nucleus accumbens, hypothalamus and hippocampus but not in several other regions including the frontal cortex (Mitchell, Brazell, Joseph, Alavijeh, & Gray, 1989). The increase in noradrenaline synthesis in response to nicotine appears to be specific to the locus coeruleus projections via the dorsal noradrenergic bundle (Mitchell, Brazell, Schugens, & Gray, 1990). Chronic, systemic nicotine administration (0.8 mg/kg/day) for 28 days further increased DOPA accumulation in the hippocampus in response to a subsequent challenge systemic administration of nicotine

(0.4 mg/kg) (Mitchell et al., 1989). Thus chronic nicotine treatment enhanced the subsequent catecholaminergic responses to nicotine treatment in the hippocampus. Chronic nicotine treatment (0.8 mg/kg/day) for 28 days increased tyrosine hydroxylase expression in the hippocampus (Joseph et al., 1990). Subsequently, it was shown that a single, systemic dose of nicotine (0.8 mg/kg) increased tyrosine hydroxylase mRNA 2–6 days later in the noradrenergic locus coeruleus but not in the dopaminergic substantia nigra and ventral tegmental area (Mitchell, Smith, Joseph, & Gray, 1993). By 28 days after nicotine injection, an increase in noradrenaline release in response to systemic administration of a nicotine challenge (0.4 mg/kg) was detected. However, the nicotine priming did not increase the hippocampal release of noradrenaline in response to direct intrahippocampal administration of a nicotine challenge (250 lM) (Mitchell et al., 1993). This suggests that priming might augment nicotinic stimulation of locus coeruleus activity-driven norardrenaline release to a greater extent than it augments presynaptic nicotinic receptor-triggered release at noradrenergic terminals within the hippocampus. Why this is the case if the effect is dependent on tyrosine hydroxylase transport to the noradrenergic terminals, requires further investigation. Together, these data suggest that nicotine increases tyrosine hydroxylase expression in the locus coeruleus and that there is subsequently a time-dependent anterograde transport of the tyrosine hydroxylase to the terminals of the locus coeruleus projections. The tyrosine hydroxylase reaches the hippocampus at least by 28 days and is accompanied by increased synthesis and release of noradrenaline in the hippocampus. Further studies are required to determine the time course of transport of tyrosine hydroxylase in greater detail. The effect on tyrosine hydroxylase expression and noradrenaline release in cortical regions, including the prefrontal cortex implicated in dysfunctions in selective attention and cognition in schizophrenia, has not been investigated but it might be hypothesised that tyrosine hydroxylase is also transported to the locus coeruleus terminals projecting to the cortex. Due to the longer distance to the prefrontal cortex, the tyrosine hydroxylase and the accompanying increase in capacity to release noradrenaline might be expected to arrive later than in the hippocampus. The role of nicotine-induced changes in locus coeruleus innervation of prefrontal cortex is an interesting avenue of research.

3. Role of locus coeruleus noradrenergic projections in cognitive function The locus coeruleus, and in particular the dorsal noradrenergic bundle to which the nicotine-induced increase in noradrenaline synthesis appears to be more specific (Mitchell et al., 1990), has been associated with attention. Early work proposed an attentional theory of dorsal noradrenergic bundle function (Mason & Iversen, 1977, 1978a, 1978b, 1979). Similarities between the effects of dorsal noradrenergic bundle lesions and hippocampal lesions on filtering out irrelevant and redundant information suggested that the role of the dorsal noradrenergic bundle on selective attention may, in part, be mediated by modulation of hippocampal function (Tsaltas, Preston, & Gray, 1983) and that the behavioural inhibitory functions of the dorsal noradrenergic bundle may involve projections to the septohippocampal system (Salmon, Tsaltas, & Gray, 1988). A role in behavioural response inhibition continues to be supported by more recent findings (for review see Bari & Robbins, 2013) that electrophysiological activity of locus coeruleus neurons is strongly modulated by drugs, such as methylphenidate and atomoxetine (Bari & Aston-Jones, 2013; Devilbiss & Berridge, 2006), known to improve response inhibition and suggested to improve communication within and between brain regions

Please cite this article in press as: Rajkumar, R., et al. Priming locus coeruleus noradrenergic modulation of medial perforant path-dentate gyrus synaptic plasticity. Neurobiology of Learning and Memory (2016), http://dx.doi.org/10.1016/j.nlm.2016.07.003

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involved in executive control functions (Arnsten & Dudley, 2005; Bari & Aston-Jones, 2013; Gamo & Arnsten, 2011; Gamo, Wang, & Arnsten, 2010; Robbins & Arnsten, 2009). Bari and Robbins (2013) point to converging evidence indicating a role for the locus coeruleus noradrenergic projection system in executive-oriented shifts of attention and behaviour by facilitation not only of stimulus detection (Aston-Jones & Bloom, 1981; Robbins & Everitt, 1982), but also of rearrangement of cognitive and neural resources (Corbetta, Patel, & Shulman, 2008; Hermans et al., 2011; Sara & Bouret, 2012). While CRF administration into locus coeruleus induced c-Fos and p44/42 ERK expression in a biphasic pattern that correlated with extradimensional set-shifting behaviour (Snyder et al., 2012), unilateral optogenetic silencing of locus coeruleus, caused marked impairments in extradimensional set-shifting and reversal learning in mice. These results indicate that the locus coeruleus, via its connections with medial prefrontal cortex, may modulate cognitive flexibilty (Janitzky et al., 2015). However, in humans, blocking the b-adrenoceptors by acute administration of propranolol did not affect the time taken in a task switching paradigm (Steenbergen, Sellaro, de Rover, Hommel, & Colzato, 2015) indicating that the adrenergic projections of locus coeruleus to the cortex may not participate in the cognitive flexibility required for task switching. Collectively, the emerging picture (Bari & Robbins, 2013) is that the locus coeruleus projection system is a modulator of inhibitory processes acting at multiple levels controlling stimulus detection, behavioural orienting, attentional shifting and conflict detection (Aston-Jones & Cohen, 2005; Aston-Jones, Rajkowski, & Cohen, 1999; Berridge & Waterhouse, 2003; Bouret & Sara, 2005; Corbetta & Shulman, 2002; Sara, 2009; Yu & Dayan, 2005). It is proposed that arousal-induced noradrenaline released from the locus coeruleus amplifies selectivity in perception and memory, biasing perception and memory in favor of salient, high priority representations at the expense of lower priority representations (Mather, Clewett, Sakaki, & Harley, 2015). These processes may in part involve noradrenergic modulation of hippocampal function. The locus coeruleus is known contribute to behavioural reinforcement. ICV administration of noradrenaline mimics the effects of stimulation of locus coeruleus, septum and basolateral amygdala or behavioural reinforcement, in prolonging early long-term potentiation (LTP) in the dentate gyrus of freely moving rats (Almaguer-Melian et al., 2005) and this demonstrates the role of locus coeruleus in mediating the reinforcing effect. Interrupting or lesioning the fimbria-fornix abolishes reinforcing effects of stimulating the BLA or behavioural motivation (Almaguer-Melian, Rosillo, Frey, & Bergado, 2006; Jas, Almaguer, Frey, & Bergado, 2000). It is important to note that the afferents from the fimbriafornix to the dentate gyrus include fibres from the noradrenergic locus coeruleus, in addition to the GABAergic and cholinergic fibres from the septum (Cassel, Duconseille, Jeltsch, & Will, 1997; Vizi & Kiss, 1998). The cholinergic afferents to the locus coeruleus, the noradrenergic projections from the locus coeruleus to the dentate gyrus and the medial septum and projection from the medial septum to the dentate gyrus together form the functional neuronal ensemble that underlies basolateral amygdala stimulation mediated reinforcement in the dentate gyrus (Bergado, Frey, Lopez, Almaguer-Melian, & Frey, 2007). b-adrenoceptor activation during periods of novel experience is able to fine-tune the degree and duration of LTP and long-term depression (LTD) processes occurring in the hippocampus, while the timing and level of activation of the locus coeruleus strongly shapes the information storage process (Hansen & Manahan-Vaughan, 2015). Single electrical tetanus-induced LTP at Schaffer collaterals (SC)-CA1 synapses is promoted by activation of alpha-1 adrenoceptors, whereas beta-receptor ligands had no effect (Izumi & Zorumski, 1999). Multitrain tetanus has been shown to activate

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beta-adrenoceptors and rescue LTP in genetically diverse inbred mouse strains (129S1/SvImJ, BALB/cByJ and C3H/HeJ) with inherently reduced brain noradrenaline levels and impaired LTP (Schimanski, Ali, Baker, & Nguyen, 2007). On the other hand, beta-adrenoceptor activation enhances induction and maintenance of low frequency stimulation (LFS)-induced SC-CA1 LTP in vitro and rescues maintenance of high frequency stimulation (HFS)-induced LTP in protein kinase A (PKA)-deficient mice (Gelinas, Tenorio, Lemon, Abel, & Nguyen, 2008). These findings demonstrate that noradrenaline release and subsequent beta-adrenoceptor activation can promote formation of memories that may not normally occur, highlighting the modulatory role of noradrenergic system on PKA-dependence in synaptic plasticity (Gelinas et al., 2008). Likewise, in freely behaving rats, coupling of stimulation with test pulse in the SC-CA1 pathway induced LTD and transitory suppression of theta that were NMDA receptor and beta-adrenoceptor dependent and in addition locus coeruleus stimulation caused increased spatial memory associated with elevated CA1 noradrenaline levels (Lemon, Aydin-Abidin, Funke, & ManahanVaughan, 2009). A recent in vitro study demonstrated the metaplasticity phenomenon induced by noradrenaline in SC-CA1 and explained that activation of beta1-adrenoceptors by noradrenaline has a priming effect that involves transcription and translation to generate new mRNAs and plasticity-related proteins and epigenetic mechanisms (histone-3 acetalylation and phosphorylation) required for the maintenance of LTP (Maity, Jarome, Blair, Lubin, & Nguyen, 2016; Maity, Rah, Sonenberg, Gkogkas, & Nguyen, 2015). These findings represent the role of the locus coeruleus noradrenergic system in modulating metaplasticity in the CA1 hippocampal region. Pairing of glutamate activation of locus coeruleus with perforant path stimulation showed persistent potentiation of the population spike in the dentate gyrus of anaesthetised rats, whereas only a transient enhancement in the population spike was noted in a non-paired condition (Reid & Harley, 2010). It has been argued that noradrenergic and locus coeruleus modulation of the perforant path-evoked potentials in rat dentate gyrus supports a role for the locus coeruleus in attentional and memory processes that are linked to arousal (Harley, 1991).

4. Role of locus coeruleus noradrenergic projections in induction of hippocampal dentate gyrus synaptic plasticity Noradrenaline is known to induce synaptic plasticity in the hippocampal dentate gyrus (Harley, 1991, 1998, 2007) (Fig. 1). Iontophoretically applied noradrenaline was found to induce both short-term and long-lasting potentiation of perforant pathevoked potentials, in particular population spikes, in the dentate gyrus of urethane anaesthetised rats (Neuman & Harley, 1983). Since this form of potentiation was produced without tetanus it was described in the early literature as a long-lasting potentiation to differentiate the phenomenon from tetanus-induced LTP. For consistency with the earlier references cited, in the current review we will continue to refer to the phenomenon as a long-lasting potentiation. However, with broader usage of the term LTP and increasing acceptance that the noradrenaline-induced dentate gyrus potentiation has many mechanisms in common with conventional LTPs, the phenomenon is now also described in the more recent literature as noradrenaline-induced LTP. While application of noradrenaline in vitro induced potentiation of both the population spike and EPSP in the dentate gyrus, the potentiation of the population spike exceeded that predicted by the increase in the EPSP (Lacaille & Harley, 1985). Moreover, it was demonstrated that the noradrenergic induction of the long-lasting potentiation required activation of b-adrenoceptors (Dahl & Sarvey, 1990;

Please cite this article in press as: Rajkumar, R., et al. Priming locus coeruleus noradrenergic modulation of medial perforant path-dentate gyrus synaptic plasticity. Neurobiology of Learning and Memory (2016), http://dx.doi.org/10.1016/j.nlm.2016.07.003

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Fig. 1. Locus coeruleus (LC) control of hippocampal plasticity. Pharmacological or physiological conditioning alter firing and tyrosine hydroxylase (TH) expression in the LC. Glutamate injection to locus coeruleus increases 4–8 Hz theta activity and long-term synaptic plasticity but decreases feedforward neuron inhibition and beta and gamma frequencies. Injection of orexin-A or glutamate infusion into the locus coeruleus or stimulation of nucleus paragiganticellularis (nPGi) causes noradrenaline (NA) release in the hippocampus. If NA levels are sufficiently elevated it can induce long-lasting potentiation (LLP) of medial perforant path-dentate gyrus evoked responses by mechanisms that are dependent on b-adrenoceptors and NMDA receptors, and require protein synthesis. Pharmacological treatments such as nicotine and atypical antipsychotics (AAPs) and behavioural stress activating CRF1 receptor mechanisms, cAMP response element (CRE) and/or glucocorticoid response elements (GRE) increase TH expression. On subsequent challenge with any condition increasing locus coeruleus firing there is increase NA release in the hippocampus facilitating induction of LLP. AAPs: Atypical antipsychotics; b: Beta-adrenergic receptors; CRE: cyclic adenosine monophosphate (cAMP) response element; CRF1: Corticotropin releasing hormone receptor type 1; GRE: Glucocorticoid response elements; NMDAR: N-methyl-D-aspartate receptors; LLP: Long-lasting potentiation; NA: Noradrenaline, TH: tyrosine hydroxylase.

Lacaille & Harley, 1985). Further in vitro experiments showed that noradrenaline induced a long-lasting potentiation of medial perforant path-evoked potentials and a long-lasting depression of lateral perforant path-evoked potentials in the dentate gyrus (Dahl & Sarvey, 1989; Pelletier, Kirkby, Jones, & Corcoran, 1994; Stanton & Sarvey, 1987) and that, although potentiation was most marked for the population spike, there was also potentiation of dendritic EPSPs (Stanton & Sarvey, 1987). The noradrenaline-induced potentiation of medial perforant path-dentate gyrus evoked potentials was found to be dependent on activation of NMDA receptors (Burgard, Decker, & Sarvey, 1989; Dahl & Sarvey, 1990) and required protein synthesis (Stanton & Sarvey, 1985). It was further confirmed in vivo that pressure ejection of glutamate into the locus coeruleus to activate locus coeruleus cells and release noradrenaline in the dentate gyrus was sufficient to induce long-lasting potentiation of perforant path-evoked population spikes both in anaesthetised rats (Harley & Milway, 1986) and awake rats (Klukowski & Harley, 1994). Experiments varying the amount of glutamate administered indicated that induction of burst firing in a certain threshold population of locus coeruleus cells was necessary for the induction of the hippocampal longlasting potentiation (Harley & Sara, 1992). This is consistent with the observation that burst activation of the locus coeruleus increased noradrenaline release, at least in the frontal cortex

(Florin-Lechner, Druhan, Aston-Jones, & Valentino, 1996). Stimulation of the nucleus paragigantocellularis, the major excitatory glutamatergic input to the locus coeruleus, likewise induced a b-adrenoceptor-dependent long-lasting potentiation of the perforant path-evoked population spike in the dentate gyrus (Babstock & Harley, 1992). Monitoring noradrenaline levels in urethane anaesthetised rats by microdialysis, it was estimated that induction of long-lasting potentiation in the dentate gyrus was associated with increases of noradrenaline levels to 30 times basal levels and that such levels would be sufficient to activate badrenoceptors near the sites of noradrenaline release (Harley, Lalies, & Nutt, 1996). More recently, it was shown that orexin-A infusion in the locus coeruleus triggers noradrenaline release and noradrenaline-induced long-lasting potentiation in the dentate gyrus (Walling, Nutt, Lalies, & Harley, 2004). Although the data point to the importance of threshold noradrenaline levels in triggering induction of the long-lasting potentiation (Harley et al., 1996), the potential contribution of input pairing cannot be excluded (Edison & Harley, 2012; Reid & Harley, 2010). However, collectively, the data suggest that any manipulation that increases locus coeruleus firing to a threshold level to release sufficient noradrenaline in the dentate gyrus is likely to induce longlasting potentiation of medial perforant path-evoked responses in the dentate gyrus.

Please cite this article in press as: Rajkumar, R., et al. Priming locus coeruleus noradrenergic modulation of medial perforant path-dentate gyrus synaptic plasticity. Neurobiology of Learning and Memory (2016), http://dx.doi.org/10.1016/j.nlm.2016.07.003

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5. Nicotine priming and challenge triggers noradrenalineinduced long-lasting potentiation in the dentate gyrus The hypothesis that release of a threshold level of noradrenaline in the dentate gyrus would likely induce long-lasting potentiation of medial perforant path-evoked responses in the dentate gyrus suggested the possibility that nicotine-induced priming of nicotine-induced noradrenaline release in the hippocampus could induce this hippocampal neuroplasticity. Four weeks after priming with 7 daily injections of nicotine (0.8 mg/kg s.c.), a challenge dose of nicotine (0.4 mg/kg s.c.) produced a long-lasting potentiation of medial perforant path-dentate gyrus evoked responses (Hamid, Dawe, Gray, & Stephenson, 1997). This challenge dose of nicotine was shown to increase locus coeruleus cell firing rates and induce burst firing (Markevich, Grigoryan, Dawe, & Stephenson, 2007). However, in animals receiving saline injections in place of the priming doses for nicotine, the challenge dose of nicotine (0.4 mg/kg s.c.) was not sufficient to induce any potentiation. The long-lasting potentiation induced by the nicotine priming and challenge was blocked by systemic administration of mecamylamine, a nicotinic acetylcholine receptor antagonist, or propranolol, a non-selective b-adrenoceptor antagonist, administered 30 min before but not 90 min after the challenge injection of nicotine (Hamid et al., 1997). This indicates that induction but not maintenance of the long-lasting potentiation was dependent on activation of nicotinic acetylcholine receptors and badrenoceptors. It is likely that prior to nicotine priming, the challenge dose of nicotine is insufficient to release noradrenaline in the hippocampus to the threshold level for induction of medial perforant path-dentate gyrus long-lasting potentiation. However, nicotine priming increases locus coeruleus tyrosine hydroxylase expression and after several weeks, when this tyrosine hydroxylase has been transported to the noradrenergic nerve terminals of the locus coeruleus projections to the hippocampus, injection of the challenge dose of nicotine now releases a greater amount of noradrenaline in the hippocampus, which is sufficient to trigger noradrenaline-induced long-lasting potentiation of the medial perforant path-dentate gyrus evoked responses (Fig. 2). If this hypothesis is correct, any other treatments similarly inducing increased expression of tyrosine hydroxylase would be predicted to produce a similar priming effect. However, additional effects of nicotine on other brain structures cannot be ruled out. In future studies, it will also be important to investigate how long the induced plasticity lasts.

6. Cross-priming with other treatments increasing tyrosine hydroxylase expression Subsequently, it was shown that the nicotine priming and challenge effect cross-primes with other treatments increasing tyrosine hydroxylase expression in the locus coeruleus. Activation of the locus coeruleus with glutamate to release noradrenaline in the hippocampus transiently inhibited feedforward inhibitory neurons and increased 4–8 Hz theta activity (Brown, Walling, Milway, & Harley, 2005). In a phenomenon known as septal driving of hippocampal theta or septal theta driving, stimulation of the medial septum can entrain hippocampal theta and drive its frequency (Gray, 1972; Gray & Ball, 1970; Holt & Gray, 1983). Septal theta driving at 7.7 Hz or 8.3 Hz is thought to mimic effects of nonreward or anxiety and produces a resistance to behavioural extinction or a response persistence in runway and leverpress paradigms (Glazer, 1974a, 1974b; Gray, 1972; Holt & Gray, 1983) and increases behavioural tolerance to the effects of electric shock (Holt & Gray, 1985). Non-reward in partial reinforcement schedules increases resistance to extinction, a phenomenon known as

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the partial reinforcement extinction effect. In both a discrete-trial fixed-ratio (FR) 5 leverpressing response task and a partial reinforcement extinction effect runway paradigm, theta driving at 7.7 Hz before acquisition of the task increased resistance to extinction (Snape, Grigoryan, Sinden, & Gray, 1996; Williams & Gray, 1996). Lesions of the septum or the locus coeruleus projections conversely increase resistance to extinction after continuous reinforcement, but decrease resistance to extinction after partial reinforcement and reduce the partial reinforcement extinction effect (for discussion see Gray, 1982; Holt & Gray, 1983). Thus theta at 7.7 Hz appears to act as a signal of non-reward or anxiety in a noradrenergic-dependent manner. Together with a large body of evidence from behavioural, pharmacological, lesion and electrophysiological studies, this suggests that the septohippocampal system plays a role in anxiety (Gray, 1982; Gray & McNaughton, 2000). The effect of theta driving was proactive and in some cases the resulting changes in behaviour were observed several weeks after the end of theta driving stimulation (Holt & Gray, 1983, 1985; Snape et al., 1996; Williams & Gray, 1996). Therefore theta driving at 7.7 Hz is thought to mimic effects of non-reward or anxiety and was shown to increase tyrosine hydroxylase activity in rat hippocampus 15–33 days later (Graham-Jones, Holt, Gray, & Fillenz, 1985). Thus theta driving at 7.7–8.3 Hz has a similar effect to nicotine on tyrosine hydroxylase activity. Two weeks after septal theta driving at 7.7 Hz for 20 min per day for 7 days, a challenge injection of nicotine (0.4 mg/kg s.c.) induced medial perforant path-dentate gyrus long-lasting potentiation in rats primed by theta driving but not in rats that did not receive theta driving (Markevich et al., 2007). However, at lateral perforant path-dentate gyrus synapses the challenge injection of nicotine-induced a long-lasting potentiation in animals that did not receive theta driving, but not in rats that received theta driving (Markevich et al., 2007). This abrogation of the long-lasting potentiation of lateral perforant path-dentate gyrus responses in the theta driving primed animals may be consistent with the previous reports of noradrenaline-induced long-lasting depression at lateral perforant path-dentate gyrus synapses. However, the mechanisms underlying the induction of long-lasting potentiation in lateral perforant path-dentate gyrus by 0.4 mg/kg nicotine, without the need of priming, require further investigation. The results in the medial perforant path, are consistent with the prediction that other manipulations increasing locus coeruleus tyrosine hydroxylase expression would prime induction of medial perforant pathdentate gyrus long-lasting potentiation in a manner similar to nicotine. Antipsychotic drugs are also known to activate the locus coeruleus and increase tyrosine hydroxylase expression. The superior clinical efficacy of clozapine has been suggested to be related to the increase in noradrenergic activity by blockade of the alpha2C adrenergic autoreceptors (Breier et al., 1998; Brunello et al., 1995; Kalkman and Loetscher, 2003). Chronic clozapine treatment activated locus coeruleus cell firing (Nilsson, Schwieler, Engberg, Linderholm, & Erhardt, 2005; Ramirez & Wang, 1986; Souto, Monti, & Altier, 1979) and increased tyrosine hydroxylase expression in the locus coeruleus (Verma, Lim, Han, Nagarajah, & Dawe, 2007). Although it has not specifically been demonstrated for clozapine, another atypical antipsychotic, olanzapine, that had similar effects on induction of locus coeruleus c-Fos expression, increased burst firing of locus coeruleus cells (Dawe et al., 2001). Rats primed with clozapine (30 mg/kg) daily for 7 days showed nicotine (0.4 mg/kg) challenge-induced medial perforant pathdentate gyrus long-lasting potentiation 21–28 days later (Rajkumar, Suri, Deng, & Dawe, 2013). Likewise, rats primed with clozapine (30 mg/kg) daily for 7 days showed clozapine (15 mg/ kg) challenge-induced medial perforant path-dentate gyrus longlasting potentiation 21–28 days later. Meanwhile, rats primed with

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Fig. 2. Locus coeruleus (LC) noradrenergic system priming-challenge phenomenon. Priming with nicotine, atypical antipsychotics (AAPs), septal theta driving and likely also behavioural stress causes increased expression of TH in the hippocampus. Likely, septal theta driving feeds back to the locus coeruleus to increase firing and trigger TH expression. The priming stimulation will likely release NA in the hippocampus but the release may be insufficient to induce medial perforant path-dentate gyrus long-lasting potentiation (MPP-DG LLP). There is delayed transport of the newly synthesized TH to the hippocampus. Weeks later when the TH has reached the hippocampus, challenge with nicotine or antipsychotics, or likely also behavioural stress, increases locus coeruleus firing and release of NA in the hippocampus. The release of NA may now be sufficient to induce MPP-DG LLP. Antagonism of nicotinic acetylcholine receptors (mecamylamine) or b-adrenoceptors (propranolol) was shown to prevent LLP induced by the nicotine treatment priming and challenge regimen and agonism at a2-adrenoceptors with clonidine, which acts at autoreceptors reducing locus coeruleus firing and NA release, was shown to prevent LLP induced by cross-priming and challenge by an AAP (clozapine) and nicotine. Nicotine challenge also induced LLP in rats primed by of septal theta driving. It is predicted that priming-challenge-induced increases in NA would also modulate plasticity in other pathways influenced by locus coeruleus noradrenergic projections such as at hippocampo-prefrontal cortical synapses (HP-PFC). AAPs: atypical antipsychotics; DG: dentate gyrus; HP: Hippocampus; LC: Locus coeruleus; LLP: Long-lasting potentiation; MS: Medial septum; MPP: Medial perforant path; TH: tyrosine hydroxylase.

nicotine (0.8 mg/kg) for 7 days showed clozapine (15 mg/kg) challenge-induced medial perforant path-dentate gyrus longlasting potentiation 21–28 days later. Thus there was complete crossover between nicotine and clozapine priming and challenge. Acute exposure to stress has been shown to increase tyrosine hydroxylase levels in the locus coeruleus while repeated stress leads to sustained elevation in the tyrosine hydroxylase levels in the terminal fibres (Kvetnansky, Sabban, & Palkovits, 2009; Sun, Chen, Xu, Sterling, & Tank, 2004) likely via activation of the CRF1 receptor which results in elevated tyrosine hydroxylase expression and neuronal firing in the locus coeruleus (Melia & Duman, 1991; Schulz & Lehnert, 1996). Interestingly, prenatal exposure to cocaine in rats results in increased density of tyrosine hydroxylase fibres in regions such as the hippocampus, anterior cingulate cortex and parietal cortex (Akbari & Azmitia, 1992). Prenatal cocaine treatment in addition to downregulating the presynaptic alpha2 adrenergic receptors in the locus coeruleus, elevated the noradrenaline turnover in the prefrontal cortex in response to mild shock (during postnatal days 40–42) and activation of the tyrosine hydroxylase positive neurons of the locus coeruleus in response to novel environment exposure (postnatal day 45) indicating enhanced noradrenaline neurotransmission due to prenatal cocaine and subsequent exposure to stressors (Elsworth et al., 2007). Electrophysiological studies on hippocampal slices showed that, while noradrenaline facilitated conversion of short-term potentiation to LTP in the dorsal but not in the ventral hippocampus, prenatal stress switched this facilitation to the ventral hippocampus (Grigoryan & Segal, 2013). Further, juvenile stress facilitated LTP and enhanced the action of isoproterenol (betaadrenergic agonist) in the ventral hippocampal slices (but not DH slices) along with increased beta-1 adrenergic receptors in the VH (Grigoryan, Ardi, Albrecht, Richter-Levin, & Segal, 2015). A recent study showed that repeated social stress during adolescence

causes a persistent elevation of locus coeruleus neuronal activity, decreased locus coeruleus-medial prefrontal cortex coherence in beta and gamma range but retained a strong coherence in the theta range that may compromise adaptability to future social challenges (Zitnik, Curtis, Wood, Arner, & Valentino, 2016). Prenatal stress, on the contrary decreased tyrosine hydroxylase expression in the locus coeruleus (Bingham, Sheela Rani, Frazer, Strong, & Morilak, 2013). It would be interesting to examine if adolescent/ juvenile rodents exposed to repeated stress have sustained tyrosine hydroxylase expression in the locus coeruleus and target structures such as ventral/dorsal hippocampus and prefrontal cortex. It will also be important to use pharmacological or optogenetic inhibition to confirm the involvement of the locus coeruleus. Such studies may qualify stress exposure as a method of priming and help us understand the influence of nature of the stress and age factor on priming as well. It will be interesting to examine if prenatal cocaine exposure augments firing and tyrosine hydroxylase expression in locus coeruleus to an extent where a submaximal challenge condition (cocaine/stress) achieves plasticity changes. Together these data suggest that pharmacological treatments such as nicotine alone or in conjunction with other stressful stimuli can induce tyrosine hydroxylase expression in the locus coeruleus resulting in delayed transport of tyrosine hydroxylase to the afferent terminal fields facilitating noradrenergically mediated synaptic plasticity. 7. Role of locus coeruleus cell activation in noradrenergic priming and mechanisms of induction of locus coeruleus tyrosine hydroxylase Clozapine priming and nicotine challenge-induced long-lasting potentiation of medial perforant path-dentate gyrus evoked responses was blocked by infusion of lidocaine into the locus coer-

Please cite this article in press as: Rajkumar, R., et al. Priming locus coeruleus noradrenergic modulation of medial perforant path-dentate gyrus synaptic plasticity. Neurobiology of Learning and Memory (2016), http://dx.doi.org/10.1016/j.nlm.2016.07.003

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uleus at the time of nicotine challenge injection (Rajkumar et al., 2013). The nicotine priming and clozapine or nicotine challenge and the clozapine priming and clozapine or nicotine challengeinduced long-lasting potentiation of medial perforant pathdentate gyrus evoked responses was also blocked by administration of the a2-adrenoceptor agonist clonidine (0.4 mg/kg), which activates autoreceptors to reduce locus coeruleus cell firing and noradrenaline release, 30 min before the challenge injection (Rajkumar et al., 2013). Together these data indicate that activation of the locus coeruleus at the time of the challenge injection is important. It will be important to confirm the involvement of the locus coeruleus by similar pharmacological means or by optogenetics in future studies. Direct administration of adrenoceptor antagonists in the hippocampus or other target structures and measurements of changes in noradrenaline levels in target structures will also be important. Nicotine and atypical antipsychotics, which induce tyrosine hydroxylase expression in the locus coeruleus and prime noradrenergic modulation of synaptic plasticity, are known to activate cell firing in the locus coeruleus (as we have also confirmed Dawe et al., 2001; Markevich et al., 2007). It remains to be determined whether septal driving of 7.7–8.3 Hz theta also activates locus coeruleus firing. In PC12 pheochromocytoma cells, nicotine treatment for 1–2 days upregulated tyrosine hydroxylase expression via a mechanism dependent on protein kinase A activity and a cAMP-mediated pathway involving a cAMP response element (CRE) in the 50 promoter region of the tyrosine hydroxylase gene (Hiremagalur, Nankova, Nitahara, Zeman, & Sabban, 1993). A number of other reports have confirmed that activation of the cAMP pathway activates expression of tyrosine hydroxylase (Kim, Lee, Carroll, & Joh, 1993; Kim et al., 1993; Kim, Tinti, Song, Cubells, & Joh, 1994; Lazaroff, Patankar, Yoon, & Chikaraishi, 1995). In the locus coeruleus, the cAMP response element-binding protein (CREB) was shown to contribute to maintenance of basal tyrosine hydroxylase expression and to be necessary for chronic morphine-induced increases in tyrosine hydroxylase expression (Lazaroff et al., 1995). We would predict that any pharmacological manipulation activating the cAMP/CREB pathways to induce CREmediated promotion of tyrosine hydroxylase expression could potentially prime the locus coeruleus noradrenergic system to release sufficient noradrenaline to induce medial perforant pathdentate gyrus long-lasting potentiation on subsequent challenge with any drug inducing firing of locus coeruleus cells. One study reported that chronic diazepam treatment enhanced hippocampal synaptic plasticity along with increased locus coeruleus activity (Perez, Nasif, Marchesini, Maglio, & Ramirez, 2001). Likewise, prenatal exposure to morphine in male rats increased tyrosine hydroxylase immunoreactivity in locus coeruleus (in addition to the paraventricular nucleus) but it was reported to be decreased in overectomised female rats indicating a sex-specific response to prenatal stress (Vathy, Rimanoczy, & Slamberova, 2000). The glucocorticoid, dexamethasone also activates tyrosine hydroxylase expression (Kim, Park, & Joh, 1993) and glucocorticoid response elements (GREs) are present in the tyrosine hydroxylase gene promoter region (Hagerty et al., 2001; Hagerty, Morgan, Elango, & Strong, 2001; Rani, Elango, Wang, Kobayashi, & Strong, 2009). A genome-wide Chromatin ImmunoPrecipitation combined with next generation sequencing (ChIP-Seq) search for glucocorticoid receptor binding sites in PC12 cells identified two glucocorticoid receptor binding sites upstream of the tyrosine hydroxylase gene in the putative promoter region (Polman et al., 2012). It is likely that non-reward frustration, anxiety and stress activate tyrosine hydroxylase expression via actions of endogenous cortisol at the GRE sites in the tyrosine hydroxylase promoter. Thus, we would predict that any drug or behavioural manipulation leading to GRE-mediated promotion of tyrosine hydroxylase expression

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could potentially prime the locus coeruleus noradrenergic system to release sufficient noradrenaline to induce medial perforant path-dentate gyrus long-lasting potentiation on subsequent challenge with any drug activating firing of locus coeruleus cells. 8. Concluding remarks and future directions The beta-adrenergic control of synaptic plasticity is different in subregions of the hippocampus (dentate gyrus, CA3 and C1) and differences in the pattern of release of noradrenaline by the locus coeruleus determines the type and persistence of the synaptic plasticity (Hagena, Hansen, & Manahan-Vaughan, 2016). The complexity is further increased under conditions of stress exposure. In the dentate gyrus, both pharmacological (nicotine and clozapine) and physiological (septal theta driving) manipulations that increase tyrosine hydroxylase expression in the locus coeruleus, prime the locus coeruleus noradrenergic projections to the hippocampus to induce long-lasting potentiation of medial perforant path-dentate gyrus evoked responses on challenge with drugs that increase locus coeruleus cell firing weeks later. The delay in the priming effect is consistent with transport of newly synthesized tyrosine hydroxylase to the terminals of the locus coeruleus projections to the hippocamapus. Further studies are required to test the hypothesis that this is a general mechanism whereby any manipulation inducing tyrosine hydroxylase expression in the locus coeruleus will be sufficient to prime the locus coeruleus projection system and any manipulation activating adequate locus coeruleus cell firing to induce a threshold level of noradrenaline release will be a sufficient challenge to induce long-lasting potentiation of medial perforant path-dentate gyrus evoked responses. It will be especially interesting to explore the potential for behavioural experiences alone to prime the locus coeruleus increasing tyrosine hydroxylase expression and challenge the system inducing locus coeruleus cell firing and release of sufficient noradrenaline in the hippocampus to induce long-lasting potentiation of medial perforant path synaptic inputs to the dentate gyrus. It would be expected that behavioural manipulations inducing non-reward frustration, anxiety or stress many be able to achieve this effect. In a post-traumatic stress disorder (PTSD) model triggered by single-prolonged stress, the tyrosine hydroxylase level in the locus coeruleus increases acutely in response to the stressor, returning to basal levels after 7 days, but increasing in response to a challenge such as a mild stressor. This latter increase is absent in animals not exposed to the priming stressor (Serova et al., 2013). This suggests the possibility of a further level of metaplasticity in the control of the expression of tyrosine hydroxylase itself, perhaps involving epigenetic mechanisms. Interestingly, the severity of PTSD in patients has been linked to the elevated levels of noradrenaline in the CSF, particularly during periods of trauma re-experience (Geracioti et al., 2001, 2008). Tyrosine hydroxylase elevation was observed in the locus coeruleus of suicide victims (Ordway, Smith, & Haycock, 1994) as well as in patients suffering from major depression (Zhu et al., 1999). It will also be of interest to investigate the behavioural significance of increased noradrenaline release in the hippocampus and the induction of medial perforant path-dentate gyrus long-lasting potentiation. Hippocampal dentate gyrus-dependent tasks of interest will be cheeseboard pattern separation task, Bussey-Saksida touchscreen pattern separation tasks and fear conditioning memory and pattern completion tasks (Gu et al., 2012; Kesner, 2007, 2013; Kheirbek et al., 2013). Specifically, based on Harley’s discussion of the role of noradrenaline in the dentate gyrus (Harley, 2007), we predict that moderate increases in dentate gyrus noradrenaline levels, such as would be induced by nicotine without priming, will facilitate pattern completion or memory retrieval; but that higher levels of noradrenaline release, such as would occur

Please cite this article in press as: Rajkumar, R., et al. Priming locus coeruleus noradrenergic modulation of medial perforant path-dentate gyrus synaptic plasticity. Neurobiology of Learning and Memory (2016), http://dx.doi.org/10.1016/j.nlm.2016.07.003

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on primed nicotine challenge, will recruit global remapping and promote long-term episodic memory. In the current review, we have focused on noradrenergic induction of long-lasting potentiation of medial perforant path-dentate gyrus evoked responses. However, noradrenaline has many other effects on synaptic plasticity and behavioural functions throughout the brain. For example, locus coeruleus-mediated plasticity in the olfactory bulb, observed from the persistent effects of noradrenaline release from locus coeruleus, was posited to underlie odour-related memories that are dependent on arousal (Eckmeier & Shea, 2014). Similarly increased locus coeruleus activity, and subsequent orexin receptor type 1 signalling can increase noradrenaline release which in turn activates beta-adrenoceptors in the amygdala, thereby enhancing plasticity in the amygdala (Sears et al., 2013; Tully & Bolshakov, 2010). The same primingchallenge mechanism would be predicted to increase noradrenaline release in other brain regions as well. Within the hippocampo-prefrontal cortical system there is some evidence that hints at such an effect. Plasticity in the hippocampo-prefrontal cortical pathway has been implicated in working memory and consolidation (Laroche, Davis, & Jay, 2000). LTP in the hippocampomedial prefrontal cortical pathway is modulated by dopaminergic and serotoninergic mechanisms and stress (Gurden, Takita, & Jay, 2000; Jay et al., 2004; Ohashi, Matsumoto, Togashi, Ueno, & Yoshioka, 2003; Rocher, Spedding, Munoz, & Jay, 2004). We found that LTP of hippocampo-prefrontal cortical synaptic transmission is also positively modulated by locus coeruleus mechanisms (Lim, Tan, Jay, & Dawe, 2010). Atypical antipsychotics can activate the locus coeruleus (Dawe et al., 2001; Nilsson et al., 2005; Ramirez & Wang, 1986; Souto et al., 1979), increase tyrosine hydroxylase expression in locus coeruleus and prefrontal cortex (Dawe et al., 2001; Verma, Rasmussen, & Dawe, 2006; Verma et al., 2007), release noradrenaline in the prefrontal cortex (Li, Perry, Wong, & Bymaster, 1998; Nutt, Lalies, Lione, & Hudson, 1997; Westerink, de Boer, de Vries, Kruse, & Long, 1998) and cause a beta-adrenoceptor antagonist sensitive induction of Fos-like immunoreactivity in the prefrontal cortex (Ohashi et al., 2000). Chronic treatment with the atypical antipsychotic, risperidone, produced b-adrenoceptor-dependent improvements in working memory (Lim, Verma, Nagarajah, & Dawe, 2007). Together these data suggest the hypothesis that priming of the locus coeruleus noradrenergic system could also influence hippocampoprefrontal cortical LTP and prefrontal cortical dependent working memory. Further studies are needed to investigate the possibility of implications of priming of the locus coeruleus noradrenergic system for synaptic plasticity and behavioural functions in other brain regions. Acknowledgments Current research in our laboratory is supported by a Ministry of Education, Singapore, Academic Research Fund Tier 1 Seed Fund for Basic Science Research (T1-BSRG 2014-03) and enabled by the behavioural neuroscience facilities provided by the NMRC NUHS Centre Grant—Neuroscience Phenotyping Core (NMRC/ CG/013/2013). Previous research related to the topic of this review was supported by the Biomedical Research Council of Singapore (BMRC 03/1/21/18/269, 06/1/21/19/458, 07/1/21/19/512 and 10/1/21/19/645) and the National Medical Research Council of Singapore (NMRC/1287/2011). The authors wish to thank Mr. Ho Woon Fei for excellent technical and administrative assistance. References Abraham, W. C., & Bear, M. F. (1996). Metaplasticity: The plasticity of synaptic plasticity. Trends in Neurosciences, 19, 126–130.

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