Papers by Denise Manahan-Vaughan
Hippocampus, Jan 27, 2015
The noradrenergic system, driven by locus coeruleus (LC) activation, plays a key role in the regu... more The noradrenergic system, driven by locus coeruleus (LC) activation, plays a key role in the regulating and directing of changes in hippocampal synaptic efficacy. The LC releases noradrenalin in response to novel experience and LC activation leads to an enhancement of hippocampus-based learning, and facilitates synaptic plasticity in the form of long-term depression (LTD) and long-term potentiation (LTP) that occur in association with spatial learning. The predominant receptor for mediating these effects is the β-adrenoreceptor. Interestingly, the dependency of synaptic plasticity on this receptor is different in the hippocampal subfields whereby in the CA1 in vivo, LTP, but not LTD requires β-adrenoreceptor activation, whereas in the mossy fiber synapse LTP and LTD do not depend on this receptor. By contrast, synaptic plasticity that is facilitated by spatial learning is highly dependent on β-adrenoreceptor activation in both hippocampal subfields. Here, we explored whether LTP ind...
Neuropharmacology, 2013
Storage and processing of information at the synaptic level is enabled by the ability of synapses... more Storage and processing of information at the synaptic level is enabled by the ability of synapses to persistently alter their efficacy. This phenomenon, known as synaptic plasticity, is believed to underlie multiple forms of long-term memory in the mammalian brain. It has become apparent that the metabotropic glutamate (mGlu) receptor is critically required for both persistent forms of memory and persistent synaptic plasticity. Persistent forms of synaptic plasticity comprise long-term potentiation (LTP) and long-term depression (LTD) that last at least for 4 h but can be followed in vivo for days and weeks. These types of plasticity are believed to be analogous to forms of memory that persist for similar time-spans. The mGlu receptors are delineated into three distinct groups based on their G-protein coupling and agonist affinity and also exercise distinct roles in the way they regulate both long-term plasticity and long-term hippocampus-dependent memory. Here, the mGlu receptors will be reviewed both in general, and in the particular context of their role in persistent (>4 h) forms of hippocampusdependent synaptic plasticity and memory, as well as forms of synaptic plasticity that have been shown to be directly regulated by memory events.
Journal of Neuroscience, 2005
Intriguingly, the potential to exhibit LTP or LTD at many central synapses itself is powerfully m... more Intriguingly, the potential to exhibit LTP or LTD at many central synapses itself is powerfully modulated by previous synaptic activity. This higher-order form of plasticity has been termed metaplasticity. Here, we show that inhibitory autophosphorylation of Ca 2ϩ / calmodulin-dependent kinase II (CaMKII) is required for hippocampal metaplasticity at the lateral perforant path-dentate granule cell synapse. Brief 10 Hz priming, which does not affect basal synaptic transmission, caused a dramatic, pathway-specific and long-lasting (up to 18 h) reduction in subsequently evoked LTP at lateral perforant path synapses. In contrast, LTD was unaffected by priming. The induction of lateral perforant path metaplasticity required the activation of NMDA receptors during priming. In addition, metaplasticity was absent in knock-in mice expressing ␣CaMKII that cannot undergo inhibitory phosphorylation, indicating that inhibitory autophosphorylation of ␣CaMKII at threonines 305/306 is required for metaplasticity. Metaplasticity was not observed in the medial perforant pathway, consistent with the observation that CaMKII activity was not required for the induction of LTP at this synapse. Thus, modulation of ␣CaMKII activity via autophosphorylation at Thr305/Thr306 is a key mechanism for metaplasticity that may be of importance in the integration of temporally separated episodes of activity.
Hippocampus, 2008
In the hippocampus, synaptic depression of potentiated synapses in the form of depotentiation, or... more In the hippocampus, synaptic depression of potentiated synapses in the form of depotentiation, or of naive synapses in the form of long-term depression (LTD) is mediated by distinct molecular mechanisms. Activation of group 1 metabotropic glutamate receptors (mGluRs) is critically required for both hippocampal long-term potentiation (LTP) and LTD in vivo, but their involvement in depotentiation is unclear. In this study, we investigated whether this class of mGluRs contributes to depotentiation in freely moving rats. Male adult Wistar rats underwent chronic implantation of stimulating and recording electrodes in the perforant path and dentate gyrus granule cell layer, respectively, as well as an injection cannula in the ipsilateral cerebral ventricle. Robust LTP which endured for over 24 h, was induced by high frequency tetanization (HFT, 200 Hz). Depotentiation was induced with LFS (5 Hz, 600 pulses) given 5 min after the LTP-inducing tetanus was applied. The selective group 1 mGluR antagonists, (S)-4-carboxyphenylglycine and (R,S)-1-aminoindan-1,5-dicarboxylic acid significantly inhibited both depotentiation and LTP. Activation of group I mGluRs leads to changes in postsynaptic intracellular calcium levels. These findings suggest that activation of group I mGluRs mediate thresholds for depotentiation and for persistent LTP. Effects may be linked to the intensity and duration of the calcium signal elicited by LFS and HFT. V V C 2007 Wiley-Liss, Inc.
Hippocampus, 2013
In the intact mouse hippocampus patterned afferent stimulation does not lead to long-term depress... more In the intact mouse hippocampus patterned afferent stimulation does not lead to long-term depression (LTD) at Schaffer collateral (Sc)-CA1 synapses, but the same synapses express robust LTD (<24 h) if test-pulse or patterned afferent experience is coupled with novel spatial learning. This suggests that the failure of sole afferent stimulation to elicit LTD relates to the absence of neuromodulatory input related to increased arousal or novelty during learning. Locus coeruleus (LC) firing increases during novel experience, and in rats patterned stimulation of the LC together with test-pulse stimulation of Sc-CA1 synapses leads to robust LTD in vivo. This effect is mediated by beta-adrenergic receptors. Here, we explored if activation of beta-adrenergic receptors supports the expression of LTD in freely behaving mice. We also explored if beta-adrenergic receptors contribute to endogenous LTD that is expressed following spatial learning. Patterned stimulation of Sc-CA1 synapses at 3 Hz (200 pulses) resulted in short-term depression (STD). Pretreatment with isoproterenol, an agonist of beta-adrenergic receptors, resulted in robust LTD (<24 h). Test-pulse stimulation under control conditions elicited field potentials that were stable for the 24-h monitoring period. Coupling of test-pulses with a novel spatial object recognition task resulted in robust endogenous LTD (<24 h). Pretreatment with propranolol, a beta-adrenergic receptor antagonist, completely prevented endogenous LTD that was enabled by learning and prevented object recognition learning itself. These data indicate that the absence of LTD in freely behaving mice, under standard recording conditions, does not reflect an inability of mice to express LTD, rather it is due to the absence of a noradrenalin tonus. Our data also support that spatial object recognition requires beta-adrenergic receptor activation. Furthermore, LTD that is enabled by novel spatial learning critically depends on activation of beta-adrenergic receptors that are presumably activated by noradrenalin released by the LC in response to the novel experience.
Proceedings of the National Academy of Sciences, 1999
Homosynaptic long-term depression (LTD) consists of a persistent nonpathological decrease in syna... more Homosynaptic long-term depression (LTD) consists of a persistent nonpathological decrease in synaptic transmission, which is induced by low-frequency stimulation. In vivo, low-frequency stimulation (1 Hz, 900 pulses) induces LTD in Wistar but not Hooded Lister rats. In this study, we investigated the inf luence of behavioral learning and behavioral state on the expression of LTD in both rat strains. Recordings were taken from freely moving animals that had undergone chronic implantation of a recording electrode in the hippocampal CA1 region and a bipolar stimulating electrode in the ipsilateral Schaffer collateral-commissural pathway. Exposure of the rat strains to stress induced a significant elevation in serum corticosterone levels but did not facilitate LTD expression. However, LFS given during exploration of a novel environment resulted in LTD expression in Hooded Lister, and LTD enhancement in Wistar, rats. Reexposure to the same environment did not result in new expression of LTD. Behavioral comparison between the first and second environmental exposure confirmed that the animals had habituated to the novel environment. These observations strongly implicate an association between novelty acquisition and LTD.
PLoS ONE, 2012
We previously showed that the serum-and glucocorticoid-inducible kinase 3 (SGK3) increases the AM... more We previously showed that the serum-and glucocorticoid-inducible kinase 3 (SGK3) increases the AMPA-type glutamate receptor GluA1 protein in the plasma membrane. The activation of AMPA receptors by NMDA-type glutamate receptors eventually leads to postsynaptic neuronal plasticity. Here, we show that SGK3 mRNA is upregulated in the hippocampus of new-born wild type Wistar rats after NMDA receptor activation. We further demonstrate in the Xenopus oocyte expression system that delivery of GluA1 protein to the plasma membrane depends on the small GTPase RAB11. This RAB-dependent GluA1 trafficking requires phosphorylation and activation of phosphoinositol-3-phosphate-5-kinase (PIKfyve) and the generation of PI(3,5)P 2 . In line with this mechanism we could show PIKfyve mRNA expression in the hippocampus of wild type C57/BL6 mice and phosphorylation of PIKfyve by SGK3. Incubation of hippocampal slices with the PIKfyve inhibitor YM201636 revealed reduced CA1 basal synaptic activity. Furthermore, treatment of primary hippocampal neurons with YM201636 altered the GluA1 expression pattern towards reduced synaptic expression of GluA1. Our findings demonstrate for the first time an involvement of PIKfyve and PI(3,5)P 2 in NMDA receptor-triggered synaptic GluA1 trafficking. This new regulatory pathway of GluA1 may contribute to synaptic plasticity and memory.
PLoS ONE, 2008
Hippocampal synaptic plasticity and learning are strongly regulated by metabotropic glutamate rec... more Hippocampal synaptic plasticity and learning are strongly regulated by metabotropic glutamate receptors (mGluRs) and particularly by mGluR5. Here, we investigated the mechanisms underlying mGluR5-modulation of these phenomena. Prolonged pharmacological blockade of mGluR5 with MPEP produced a profound impairment of spatial memory. Effects were associated with 1) a reduction of mGluR1a-expression in the dentate gyrus; 2) impaired dentate gyrus LTP; 3) enhanced CA1-LTP and 4) suppressed theta (5-10 Hz) and gamma (30-100 Hz) oscillations in the dentate gyrus. Allosteric potentiation of mGluR1 after mGluR5 blockade significantly ameliorated dentate gyrus LTP, as well as suppression of gamma oscillatory activity. CA3-lesioning prevented MPEP effects on CA1-LTP, suggesting that plasticity levels in CA1 are driven by mGluR5-dependent synaptic and network activity in the dentate gyrus. These data support the hypothesis that prolonged mGluR5-inactivation causes altered hippocampal LTP levels and network activity, which is mediated in part by impaired mGluR1-expression in the dentate gyrus. The consequence is impairment of long-term learning.
Neuropharmacology, 1999
Slow-onset potentiation of synaptic transmission in the hippocampus in vitro and in vivo is induc... more Slow-onset potentiation of synaptic transmission in the hippocampus in vitro and in vivo is induced by application of the metabotropic glutamate receptor (mGluR) agonist, 1S,3R-amino cyclopentane 2,3-dicarboxylic acid (ACPD). This study investigated the cellular response in the CA1 region of freely moving rats to ACPD application. Drugs were applied via the lateral cerebral ventricle, and measurements were obtained from the CA1 region via permanently implanted electrodes. ACPD (20 nmol/5 ml) produced a dose-dependent slow-onset potentiation in the CA1 region which lasted over 4 h. Histological evaluation at either 4 h or 7 days following ACPD-injection indicated that slow-onset potentiation was associated with gradual but marked cell death in the CA1 region. Whereas 20 nmol ACPD produced significant CA1 neurotoxicity, concentrations which did not induce potentiation had little or no neurotoxic effect. Both the general mGluR antagonist R,S-a-methyl-carboxyphenylglycine (1 mmol/5 ml), and the group 1 mGluR antagonist (S)-4-carboxyphenylglycine (4CPG, 100 nmol/5 ml) significantly inhibited ACPD-induced neuropathology. In addition, 4CPG inhibited the expression of ACPD-mediated slow-onset potentiation. These results confirm previous findings that in the CA1 region in vivo, slow-onset potentiation is mediated group 1 mGluRs, and indicate that slow-onset potentiation may involve pathological processes.
Journal of Neuroscience Methods, 1998
The evaluation of neuronal cell survival after, for example, mechanical, hypoxic or drug-mediated... more The evaluation of neuronal cell survival after, for example, mechanical, hypoxic or drug-mediated injury requires the analysis of a high number of histological specimens. Since this is a time-consuming occupation, we have developed a semi-automated analysis routine for the determination of the distribution of live and dead cells. After digitalization of the histological preparations, 8-bit colour bitmaps were assessed using a compiled image-analysis programme of the software package Khoros. In the current study a detailed example of the application of this image-processing approach is described for the investigation of the cell survival after intraventricular application of N-methyl-D-aspartate (NMDA). The samples were prepared as fuchsin acid/toluidine blue stained hippocampal thin slices. The calculated areas of the live and dead cells were highly correlated with manual counts of live and dead cells in the 100 samples examined in this study. Twenty-four hours following NMDA-treatment animals (n = 5) were found to have significantly fewer live and more dead hippocampal cells than the saline-treated animals (n = 5), using either automated or manual examination techniques. The automated technique also revealed that NMDA treatment resulted in a reduction in the density of live cell distribution.
Frontiers in Integrative Neuroscience, 2013
Persistent synaptic plasticity has been subjected to intense study in the decades since it was fi... more Persistent synaptic plasticity has been subjected to intense study in the decades since it was first described. Occurring in the form of long-term potentiation (LTP) and long-term depression (LTD), it shares many cellular and molecular properties with hippocampus-dependent forms of persistent memory. Recent reports of both LTP and LTD occurring endogenously under specific learning conditions provide further support that these forms of synaptic plasticity may comprise the cellular correlates of memory. Most studies of synaptic plasticity are performed using in vitro or in vivo preparations where patterned electrical stimulation of afferent fibers is implemented to induce changes in synaptic strength. This strategy has proven very effective in inducing LTP, even under in vivo conditions. LTD in vivo has proven more elusive: although LTD occurs endogenously under specific learning conditions in both rats and mice, its induction has not been successfully demonstrated with afferent electrical stimulation alone. In this study we screened a large spectrum of protocols that are known to induce LTD either in hippocampal slices or in the intact rat hippocampus, to clarify if LTD can be induced by sole afferent stimulation in the mouse CA1 region in vivo. Low frequency stimulation at 1, 2, 3, 5, 7, or 10 Hz given in the range of 100 through 1800 pulses produced, at best, short-term depression (STD) that lasted for up to 60 min. Varying the administration pattern of the stimuli (e.g., 900 pulses given twice at 5 min intervals), or changing the stimulation intensity did not improve the persistency of synaptic depression. LTD that lasts for at least 24 h occurs under learning conditions in mice. We conclude that a coincidence of factors, such as afferent activity together with neuromodulatory inputs, play a decisive role in the enablement of LTD under more naturalistic (e.g., learning) conditions. Citation: Goh JJ and Manahan-Vaughan D (2013) Synaptic depression in the CA1 region of freely behaving mice is highly dependent on afferent stimulation parameters. Front. Integr. Neurosci. 7:1.
European Journal of Pharmacology, 1995
The effects of acute and repeated treatment with 1-(2-pyrimidinyl)piperazine (1-PP), a metabolite... more The effects of acute and repeated treatment with 1-(2-pyrimidinyl)piperazine (1-PP), a metabolite of the 5-HT1A receptor ligand azapirones, were investigated on hippocampal excitatory synaptic transmission. Recordings of the electrically evoked field population excitatory post-synaptic potentials (e.p.s.p.s.) were carried out in the stratum radiatum of the CA1 region of the dorsal hippocampus of alert rats. Acute i.p. administration of 1-PP transiently reduced the e.p.s.p. amplitude in a dose-dependent (0.25-1 mg/kg) manner. This effect was blocked by the 5-HT1A receptor antagonists spiroxatrine (1 mg/kg) and MDL 73005EF (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl methylaminoethyl]-8-azaspirol[4,5]decane-7,9-dione methyl sulphonate, 2 mg/kg). Intrahippocampal administration of 1-PP (5 microg) evoked a transient reduction of the e.p.s.p. amplitude which was similar to that obtained with 5-HT (10 microg). 1-PP (0.25 mg/kg per day) administered for 9 days produced a gradual reduction in the daily pre-injection baseline e.p.s.p. amplitude coupled with a decrease in the acute response to the drug. The chronic baseline reduction was transiently reversed by spiroxatrine and full recovery to pretreatment levels was observed 4 days after the last 1-PP dose. These findings indicate that the previously reported reduction in the e.p.s.p. produced by the azapirone group of 5-HT1A receptor ligands may be mediated in part by their metabolite 1-PP through activation of 5-HT1A receptors.
European Journal of Pharmacology, 1994
The effects of acute and repeated treatment with the 5-HTIA receptor ligand gepirone on hippocamp... more The effects of acute and repeated treatment with the 5-HTIA receptor ligand gepirone on hippocampal excitatory synaptic transmission were investigated. Recordings of the electrically evoked field population excitatory postsynaptic potentials (e.p.s.p.s) were made in the stratum radiatum of the CA1 region of the dorsal hippocampus of alert male Wistar rats. Acute injection of gepirone reduced the e.p.s.p, amplitude in a transient dose-dependent (0.5-10 mg/kg, i.p.) manner. This effect was blocked by the 5-HTxA receptor antagonist MDL 73005EF (8-[2-(2,3-dihydro-l,4-benzodioxin-2-yl methylaminoethys]-8-azaspiro[4,5]decane-7,9-dione methyl sulphonate, 2 mg/kg, i.p.). Gepirone (1 mg/kg per day, i.p.) administered for 7 days produced a gradual reduction in the daily pre-injection baseline e.p.s.p, amplitude coupled with a concomitant reduction of the acute response to the drug. The chronic baseline reduction was transiently reversed by the 5-HT1A receptor antagonist spiroxatrine and complete recovery to pretreatment levels was observed 48 h after the last gepirone dose. The data indicate that with repeated administration, a prolongation and enhancement of the 5-HTIA receptor-mediated reduction in the e.p.s.p, by gepirone occurs. This delayed effect may contribute to the slow onset of therapeutic action of gepirone.
Journal of Neurobiology, 1998
We investigated the expression of the extracellular matrix glycoprotein tenascin-C after inductio... more We investigated the expression of the extracellular matrix glycoprotein tenascin-C after induction of long-term potentiation (LTP) by high-frequency tetanization (HFT) in the rat dentate gyrus in vivo. Expression of tenascin-C was evaluated at the mRNA and protein levels by in situ hybridization and immunocytochemistry, respectively. Whereas no tenascin-C mRNA was detectable in control animals, an increase in tenascin-C mRNA levels was observed in the granule cell layer of the dentate gyrus 4 h after HFT. At 24 h after HFT, tenascin-C mRNA had returned to control levels. Expression of tenascin-C protein 4 h after HFT followed that of controls in that tenascin was detectable in the strata oriens and radiatum of CA1, in the molecular layer, and within a narrow area at the inner surface of the granule cell layer in the dentate gyrus. However, 24 h after HFT, additional patches of tenascin-C immunoreactivity were observed in the molecular layer of the dentate gyrus. No increase in tenascin mRNA or protein levels was detected in control animals that received no stimulation, low-frequency stimulation, or HFT in the presence of the N-methyl-D-aspartate receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid or the metabotropic glutamate receptor antagonist (R,S)-alpha-methyl-4-carboxyphenylglycine. These observations implicate a role for tenascin-C in N-methyl-D-aspartate and metabotropic glutamate receptor-dependent changes accompanying induction and/or maintenance of LTP.
Cerebral Cortex, 2013
Although synaptic plasticity is believed to comprise the cellular substrate for learning and memo... more Although synaptic plasticity is believed to comprise the cellular substrate for learning and memory, limited direct evidence exists that hippocampus-dependent learning actually triggers synaptic plasticity. It is likely, however, that long-term potentiation (LTP) works in concert with its counterpart, long-term depression (LTD) in the creation of spatial memory. It has been reported in rats that weak synaptic plasticity is facilitated into persistent plasticity if afferent stimulation is coupled with a novel spatial learning event. It is not known if this phenomenon also occurs in other species. We recorded from the hippocampal CA1 of freely behaving mice and observed that novel spatial learning triggers endogenous LTD. Specifically, we observed that LTD is enabled when test-pulse afferent stimulation is given during the learning of object constellations or during a spatial object recognition task. Intriguingly, LTP is significantly impaired by the same tasks, suggesting that LTD is the main cellular substrate for this type of learning. These data indicate that learning-facilitated plasticity is not exclusive to rats and that spatial learning leads to endogenous LTD in the hippocampus, suggesting an important role for this type of synaptic plasticity in the creation of hippocampusdependent memory.
Cerebral Cortex, 2014
Synaptic plasticity comprises a cellular mechanism through which the hippocampus most likely enab... more Synaptic plasticity comprises a cellular mechanism through which the hippocampus most likely enables memory formation. Neuromodulation, related to arousal, is a key aspect in information storage. The activation of locus coeruleus (LC) neurons by novel experience leads to noradrenaline release in the hippocampus at the level of the dentate gyrus (DG). We explored whether synaptic plasticity in the DG is influenced by activation of the LC via electrical stimulation. Coupling of test-pulses that evoked stable basal synaptic transmission in the DG with stimulation of the LC induced β-adrenoreceptor-dependent long-term depression (LTD) at perforant path-DG synapses in adult rats. Furthermore, persistent LTD (>24 h) induced by perforant path stimulation also required activation of β-adrenergic receptors: Whereas a β-adrenergic receptor antagonist (propranolol) prevented, an agonist (isoproterenol) strengthened the persistence of LTD for over 24 h. These findings support the hypothesis that persistent LTD in the DG is modulated by β-adrenergic receptors. Furthermore, LC activation potently facilitates DG LTD. This suggests in turn that synaptic plasticity in the DG is tightly regulated by activity in the noradrenergic system. This may reflect the role of the LC in selecting salient information for subsequent synaptic processing in the hippocampus.
Hippocampus, 2016
Long-term synaptic plasticity, represented by long-term depression (LTD) and long-term potentiati... more Long-term synaptic plasticity, represented by long-term depression (LTD) and long-term potentiation (LTP) comprise cellular processes that enable memory. Neuromodulators such as serotonin regulate hippocampal function, and the 5-HT4 -receptor contributes to processes underlying cognition. It was previously shown that in the CA1-region, 5-HT4 -receptors regulate the frequency-response relationship of synaptic plasticity: patterned afferent stimulation that has no effect on synaptic strength (i.e. a θm-frequency), will result in LTP or LTD, when given in the presence of a 5-HT4 -agonist, or antagonist, respectively. Here, we show that in the dentate gyrus (DG) and CA3 regions of freely behaving rats, pharmacological manipulations of 5-HT4 -receptors do not influence responses generated at θm-frequencies, but activation of 5-HT4 -receptors prevents persistent LTD in mossy fiber (mf)-CA3, or perforant path-DG synapses. Furthermore, the regulation by 5-HT4 -receptors of LTP is subfield-specific: 5-HT4 -receptor-activation prevents mf-CA3-LTP, but does not strongly affect DG-potentiation. These data suggest that 5-HT4 -receptor activation prioritises information encoding by means of LTP in the DG and CA1 regions, and suppresses persistent information storage in mf-CA3 synapses. Thus, 5-HT4 -receptors serve to shape information storage across the hippocampal circuitry and specify the nature of experience-dependent encoding. This article is protected by copyright. All rights reserved.
Frontiers in Behavioral Neuroscience, 2016
Dopamine contributes to the regulation of higher order information processing and executive contr... more Dopamine contributes to the regulation of higher order information processing and executive control. It is important for memory consolidation processes, and for the adaptation of learned responses based on experience. In line with this, under aversive learning conditions, application of dopamine receptor antagonists prior to extinction result in enhanced memory reinstatement. Here, we investigated the contribution of the dopaminergic system to extinction and memory reinstatement (renewal) of an appetitive spatial learning task in rodents. Rats were trained for 3 days in a T-maze (context "A") to associate a goal arm with a food reward, despite low reward probability (acquisition phase). On day 4, extinction learning (unrewarded) occurred, that was reinforced by a context change ("B"). On day 5, re-exposure to the (unrewarded) "A" context took place (renewal of context "A", followed by extinction of context "A"). In control animals, significant extinction occurred on day 4, that was followed by an initial memory reinstatement (renewal) on day 5, that was, in turn, succeeded by extinction of renewal. Intracerebral treatment with a D1/D5-receptor antagonist prior to the extinction trials, elicited a potent enhancement of extinction in context "B". By contrast, a D1/D5-agonist impaired renewal in context "A". Extinction in the "A" context on day 5 was unaffected by the D1/D5-ligands. Treatment with a D2-receptor antagonist prior to extinction had no overall effect on extinction in context "B" or renewal in context "A", although extinction of the renewal effect was impaired on day 5, compared to controls. Taken together, these data suggest that dopamine acting on the D1/D5-receptor modulates both acquisition and consolidation of context-dependent extinction. By contrast, the D2-receptor may contribute to context-independent aspects of this kind of extinction learning.
Cerebral cortex (New York, N.Y. : 1991), Jan 24, 2016
Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. ... more Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. It supports learning by increasing arousal and vigilance, whereby new experiences are "earmarked" for encoding. Within the hippocampus, experience-dependent information storage occurs by means of synaptic plasticity. Furthermore, novel spatial, contextual, or associative learning drives changes in synaptic strength, reflected by the strengthening of long-term potentiation (LTP) or long-term depression (LTD). NA acting on β-adrenergic receptors (β-AR) is a key determinant as to whether new experiences result in persistent hippocampal synaptic plasticity. This can even dictate the direction of change of synaptic strength.The different hippocampal subfields play different roles in encoding components of a spatial representation through LTP and LTD. Strikingly, the sensitivity of synaptic plasticity in these subfields to β-adrenergic control is very distinct (dentate gyrus > CA3...
Hippocampus, 2015
Brain-derived neurotrophic factor (BDNF) supports neuronal survival, growth and differentiation a... more Brain-derived neurotrophic factor (BDNF) supports neuronal survival, growth and differentiation and has been implicated in forms of hippocampus-dependent learning. In vitro, a specific role in hippocampal synaptic plasticity has been described, although not all experience-dependent forms of synaptic plasticity critically depend on BDNF. Synaptic plasticity is likely to enable long-term synaptic information storage and memory, and the induction of persistent (>24h) forms, such as long-term potentiation (LTP) and long-term depression (LTD) is tightly associated with learning specific aspects of a spatial representation. Whether BDNF is required for persistent (>24h) forms of LTP and LTD, and how it contributes to synaptic plasticity in the freely behaving rodent has never been explored. We examined LTP, LTD and related forms of learning in the CA1 region of freely dependent mice that have a partial knockdown of BDNF (BDNF(+/-) ). We show that whereas early-LTD (<90min) requires BDNF, short-term depression (<45min) does not. Furthermore, BDNF is required for LTP that is induced by mild, but not strong short afferent stimulation protocols. Object-place learning triggers LTD in the CA1 region of mice. We observed that object-place memory was impaired and the object-place exploration failed to induce LTD in BDNF(+/-) mice. Furthermore, spatial reference memory, that is believed to be enabled by LTP, was also impaired. Taken together, these data indicate that BDNF is required for specific, but not all, forms of hippocampal-dependent information storage and memory. Thus, very robust forms of synaptic plasticity may circumvent the need for BDNF, rather it may play a specific role in the optimization of weaker forms of plasticity. The finding that both learning-facilitated LTD and spatial reference memory are both impaired in BDNF(+/-) mice, suggests moreover, that it is critically required for the physiological encoding of hippocampus-dependent memory. This article is protected by copyright. All rights reserved.
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Papers by Denise Manahan-Vaughan