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Stimulation of the nucleus raphe medialis modifies basal synaptic transmission at the dentate gyrus, but not long-term potentiation or its reinforcement by stimulation of the basolateral amygdala
Neuroscience Letters 464 (2009) 179–183
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Stimulation of the nucleus raphe medialis modifies basal synaptic transmission at the dentate gyrus, but not long-term potentiation or its reinforcement by stimulation of the basolateral amygdala Jorge A. Bergado a , Thomas Scherf b , William Almaguer-Melian a , Sabine Frey b , Jeffrey López b , Julietta U. Frey b,∗ a b
Centro Internacional de Restauración Neurológica (CIREN), La Habana, Cuba Leibniz Institute für Neurobiologie, Magdeburg, Germany
a r t i c l e
i n f o
Article history: Received 16 May 2009 Received in revised form 12 August 2009 Accepted 14 August 2009 Keywords: Nucleus raphe medialis Hippocampal long-term potentiation LTP reinforcement Basolateral amygdala Freely moving rats
a b s t r a c t Affective factors importantly interact with behavior and memory. Physiological mechanisms that underlie such interactions are objects of intensive studies. This involves the direct investigation of its relevance to understand learning and memory formation as well as the search for possibilities to treat memory disorders. The prolonged maintenance of long-term potentiation (LTP) – a cellular model for memory formation – is characterized by neuromodulatory, associative requirements. During the last years, we have delineated a neural system that may be responsible for affective–cognitive interactions at the cellular level. The stimulation of the basolateral amygdala (BLA), within an effective, associative time window, reinforces a normally transient, protein synthesis-independent early-LTP (less than 4–6 h) into a longlasting, protein synthesis-dependent late-LTP in the dentate gyrus (DG) in freely moving rats (Frey et al., 2001 [12]). LTP reinforcement by stimulation of the BLA was mediated by cholinergic projection of the medial septum to the DG, and the noradrenergic projection from the locus coeruleus (Bergado et al., 2007 [2]). We were now interested to investigate a possible interaction of the nucleus raphe medialis (NRM) with DG-LTP. Although, NRM stimulation resulted in a depressing effect on basal synaptic transmission, we did not observe any interactions with early-LTP or with the BLA-DG LTP-reinforcement system. © 2009 Elsevier Ireland Ltd. All rights reserved.
Synaptic plasticity can modify the activity of neuronal circuits, adjusting behavior to new conditions, and allowing animals to face the unpredictable environment with a minimally predetermined neuronal subset. Such basic neuronal processes may underlie learning and memory. Bliss and Colleagues [3] first described in 1973 that a brief high-frequency stimulation of hippocampal afferents can lead to a prolonged increase of synaptic efficacy, named longterm potentiation (LTP). LTP is considered as a cellular mechanism for learning and memory [35]. Similarly to memory formation, LTP is characterized by an early phase depending on post-translational protein modifications (E-LTP) and a late phase that depends on protein synthesis (L-LTP) [1,16,30]. It has been shown that L-LTP is dependent on ‘late-associative’ interactions of glutamatergic as well as neuromodulatory systems within a specific time window around LTP induction [13–15,17,18]. E-LTP in the dentate gyrus (DG) in the freely moving rat can also be modulated, i.e. reinforced
∗ Corresponding author at: Dept. Neurophysiology, Leibniz-Institute for Neurobiology, Brenneckestrasse 6, 39118 Magdeburg, Germany. Tel.: +49 391 6263 422; fax: +49 391 6263 421. E-mail address: [email protected] (J.U. Frey). 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.08.034
into L-LTP by the emotional/motivational status of the individual or by direct stimulation of neuromodulatory brain systems within an effective time window [12,13,45]. During the last years we have identified for LTP in the DG in intact freely moving rats a specific reinforcement system [2,13]. The medial septum and the locus coeruleus are probably not the only components of the BLA reinforcement system. We have recently obtained evidence that the nucleus accumbens shell, or core, differentially influences LTP induction at the perforant pathway (PP)-DG in anaesthetized rats [33]. Here, we were interested to study the possible effects of the nucleus raphe on PP-DG-LTP. The nucleus raphe is a brain stem group of neurons that provides serotonergic innervation to widespread regions of the brain, including the DG that receives projections from the ventral portion of the raphe: the nucleus raphe medialis (NRM) [10]. Serotonergic control by the raphe participates in several important processes, including general functions like the control of sleep-wake cycle [48] and very specific ones like respiratory control [8]. Evidence point to a relationship between serotonergic dysfunction and negative mood states [21,51] as anxiety [34] in animals and humans [5,31]. Theta electroencephalographic activity in the hippocampus, a pattern that has been related with memory [7,29,38,40], and LTP [23,24,36,39]
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shows also a relationship with serotonergic innervation from the raphe [26,49,50]. The amygdala projects to midbrain aminergic nuclei including the noradrenergic locus coeruleus, and the serotonergic raphe nuclei [6]. Reciprocally, the NRM projects to the central amygdaloidal nucleus [20], and the BLA [19]. Thus, the question arises whether the raphe is involved in the reinforcement of plasticity at the DG by the BLA. A relationship between serotonin, the raphe and LTP has been documented, though the effects are different depending on the brain area. Serotonin induced L-LTP in the amygdala [22], but inhibited the induction of NMDA receptor-dependent LTP in the rat primary visual cortex [9,25]. On the other hand, the outcomes may also depend from environmental constraints: a 5-HT1A serotoninreceptor antagonists blocked PP-DG LTP induced in novel, but not familiar, environments [43]. The main objective of this investigation was to assess whether the NRM can influence LTP or the reinforcement of LTP by stimulation of the BLA. To that purpose male Wistar rats weighing 250–300 g (8 weeks old) at the beginning of the study were used. After surgery the animals were housed individually in plastic translucent cages with free access to food and water and controlled room conditions (12 h light: dark cycle, temperature and humidity) during the entire experiments. Ethical approval was sought prior to the studies according to the German requirements for the use of experimental animals. For surgery, rats were anaesthetized with Nembutal (40 mg/kg, i.p.) and mounted in a stereotactic frame (David Kopf, Saint Louis, USA). The preparation included the implantation of one stainless steel monopolar recording electrode in the DG (0.125 mm diameter, coordinates: anteroposterior AP = −4.0 mm, mediolateral ML = 2.3 mm from bregma and dorsoventral DV approximately 2.5 mm from the dural surface, with lambda and bregma at the same level). A bipolar stainless steel electrode was placed in the medial perforant path (AP = −7.5 mm, ML = 4.1 mm from bregma, DV = −3.0 mm from the dural surface). The position in the DV axis of the electrodes in the DG and the PP was adjusted under observation of the evoked potentials to optimize its location. Additional bipolar electrodes were placed into the BLA (AP = −3.5 mm, ML = 5.0 mm from bregma, DV = −7.6 mm from the dural surface) and the NRM (AP = −7.7 mm, ML = 2.1 mm from bregma, DV = −7.5 mm from dura tilted 17.5◦ to the vertical). In a number of animals a guide cannula (stainless steel tubes 0.5 mm external diameter) were implanted into the NRM. All implants were placed at the right hemisphere. Three miniscrews were attached to the skull to serve as ground, indifferent electrode and mechanical fixation, respectively. Electrodes were then connected to flexible rubber female sockets and fixed to the skull with dental cement. A week after surgery the animals were tested and habituated to the recording chamber for no less than 4 h. An input–output (I/O) relation was obtained stimulating the PP with increasing currents (100–800 A) to determine the stimulus intensity to be used in each animal (40% maximal population spike). Each record consisted of 5 averaged waveforms evoked by square pulses (0.1 ms) delivered at 0.1 Hz (Isolated Pulse Stimulator, A-M System, USA) to the PP. Signals were filtered between 1 and 5000 Hz using a Biolelectric Amplifier, fed to a CED1401 Plus A/D converter (CED, Cambridge, UK), and processed by a special software (PWIN, Institute for Neurobiology, Magdeburg, Germany). The amplitude of the population spike (PSA) was measured in mV (from the first positive peak to the subsequent negative peak, see Fig. 1A). The PSA was averaged in the last six baseline recordings to determine pre-tetanus baseline value. The PSA of the post-tetanus recordings for each animal was compared to these values and expressed in percent changes. We used the PSA as a measure of LTP instead of the field excitatory post-synaptic potential (fEPSP), because working in freely moving animals and the use of a single
recording electrode makes it difficult to obtain stable recordings of both the fEPSP and the PSA, especially if the recording electrode was located in the hilus, i.e. far away from EPSP-generation. On the other hand, the PSA represents the discharge of action potentials by the post-synaptic population, which is functionally the most relevant resulting outcome of synaptic function, although we are aware that it is not the optimal measurement to evaluate synaptic plasticity events. The experiments were performed on the following day, after the determination of the stimulation intensities. In general, a baseline was obtained (12 recordings with 5 min interval) followed by the induction of LTP by a weak tetanus (WTET, 3 trains of 15 impulses at 200 Hz, 0.1 ms duration) to the PP. The time course of LTP was followed up for 8 h with recordings every 15 min. A further recording was made 24 h after tetanization. Fig. 1A shows relevant aspects of the preparation, the recording and histological control of the location of the implants. The histological examination showed that the electrode aimed to the NRM was placed outside the target in 3 animals, and in one animal for BLA. The results of these rats 4 were discarded, and not considered in the final analysis of the data. The pattern of WTET employed was able to induce a potentiation at the PP-DG synapses that decays to baseline within the next hours (Fig. 1B, LTP-group) corresponding to the temporal pattern of an E-LTP [12,45]. Tetanization of the BLA (400 A) 15 min after LTP induction resulted in a prolongation of the potentiation (Fig. 1B, LTP + BLA group). Both groups differed significantly (repeated measures ANOVA, F1, 18 = 6.3099) from each other. These control experiments confirmed previous results showing that the stimulation of the BLA reinforces E-LTP into L-LTP [12]. To study whether the stimulation of the NRM can influence LTP induction or its duration, WTET was applied to the NRM at a constant 400 A intensity 15 min before or after LTP induction. The results are shown in Fig. 1C (groups LTP + NRM, and NRM + LTP, respectively) and showed no influence of NRM stimulation with that pattern on the level, or time course of the DG-potentiation (repeated measures ANOVA, F2, 21 = 0.4801). Previous studies on the influence of NRM and serotonin on LTP showed inconsistent results, with a little or no effect on LTP induction [4,28,37,42,46,47]. A recent study, in which also later LTP time points were included, showed that 5-HT1A serotonin-receptor antagonist blocked LTP induction in a novel environment, but not in a familiar one [43] a condition that corresponds to our results, considering that the animals in our study have been adapted to the recording condition over several hours. Under our experimental conditions the tetanic stimulation of the NRM did not affect LTP induction or the rate of decay of LTP, irrespective when NRM stimulation occurred, i.e. before or after WTET to PP-DG. To establish the possible effects of NRM stimulation on basal PP-DG transmission the NRM was stimulated without induction of LTP in separate groups of animals. The stimulation of the NRM in the absence of tetanization to the PP induced a slowly developing and long-lasting depression of synaptic basal transmission at the DG as shown in Fig. 1D. The effect seemed to be not being frequency-dependent as similar results were obtained after high- (200 Hz) or low- (45 impulses at 1 Hz) frequency stimulation of the NRM (NRM + HFS and NRM + LFS groups, respectively). Both groups significantly differed from the non-stimulated group (repeated measures ANOVA, F2, 21 = 10.6823) but not between each other (post hoc test, Tukey HSD). A comparable depression of PPDG synaptic transmission was reported previously for the PP-DG synapses [42], the CA1 [27,28] and the amygdala [41] when serotonin agonists were applied. Our results show that these effects can be even long-lasting, suggesting the occurrence of plastic functional re-arrangements, mimicking in that respect a long-term depression. Furthermore, this particular depression could also be responsible and thus prevent a possible reinforcement of E-LTP.
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Fig. 1. (A) Coronal sections/schemas illustrate the location of the recording electrode at the dentate gyrus (DG) and stimulating electrodes at the perforant pathway (PP) and the basolateral amygdala (BLA). The analog traces show an example of recordings made before (baseline, filled line) and 1 h after the induction of E-LTP (dotted line) (calibration bar: 5 mV:5 ms). The microphotograph represents the region of the NRM and the trace of an electrode pointing to the NRM, enclosed by a dotted ellipse. (B) Time course of LTP induced by a weak tetanus (WTET, see text) pattern to the PP (open circles, n = 10), compared with a group of animals in which the BLA was stimulated with a high-frequency stimulation (HFS) 15 min after E-LTP induction in the PP-DG (filled squares, n = 10; significant differences between groups, F value from ANOVA is given). (C) Time course of E-LTP induced by a WTET to PP (open circles, n = 10) and its combination with stimulation (HFS) of the NRM 15 min before (HFS-NRM + WTET, filled squares, n = 7) or 15 min after (WTET + HFS-NRM, triangles, n = 7) E-LTP induction in the DG; no significant differences among groups (ANOVA). (D) Baseline recordings of DG evoked potentials after PP control stimulation (baseline, open circles, n = 9) and the effect of NRM stimulation with low- (NRM-LFS, filled squares, n = 7) or high- (HFS, triangles, n = 8) frequency. The ANOVA confirmed a significant effect of NRM stimulation and the Tukey post hoc test demonstrated that baseline (a) differed significantly from both NRM stimulated groups (b, p < 0.05). (E) The inactivation of NRM by lidocaine had no effect on the time course of E-LTP when both groups were compared (ANOVA; control E-LTP, open circles, n = 10; WTET in the DG + lidocaine-NRM, filled squares, n = 9). (F) Inactivation of the NRM (WTET + BLA + lidocaine-NRM, filled squares, n = 8) did not affect E-LTP reinforcement by stimulation of the BLA (WTET + BLA, open circles, n = 10; ANOVA, no significant differences). In all graphs means ± SEM are provided.
Serotonergic receptors of the 5-HT1A type are the most abundant and distribute on the projection neurons at the DG (the granule cells) as well as on inhibitory interneurons [11] that participate on feed-forward, and feed-back inhibitory circuits [32]. Such effects have been explained based on a hyperpolarizing action of serotonin mediated by a K+ current activated via 5-HT1A-receptors [44]. Thus, the outcome may be different depending on the neuronal population targeting the raphe actions on the DG. A main effect on principal neurons, should hyperpolarize them, and reduce their excitability. A dominant effect on the interneurons, should reduce GABA-mediated inhibition of the principal neurons and lead to an increased excitability and a reduced paired pulses inhibition. To assess whether NRM modifies excitability of the DG neurons we
have evaluated I/O curves under stimulation of the NRM. The costimulation of the PP (with increasing intensities) and the NRM (constant intensity at 400 A) does not modify the I/O relationships compared with the I/O values obtained using PP stimulation alone in the same animals (n = 6), for both the PSA and the fEPSP (data not shown). Stimulation of the PP with paired pulses at 20 ms interstimulus interval led to a depression of the second evoked potential which is not significantly modified by co-stimulation of the NRM (data not shown). Therefore, these results make an inhibitory feedforward or feed-back mechanisms induced by NRM stimulation under our experimental conditions unlikely and favors the direct hyperpolarizing effect of the principal granular cells by 5-HT1Areceptors.
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Finally, we have tested whether the inactivation of the NRM influenced LTP or the reinforcement of E-LTP by the BLA. Inactivation of NRM was achieved by the topical injection of lidocaine (lidocaine hydrochloride 2%, Hexal, Holzkirchen, BRD). The injection cannulas were made of stainless steel tubes (0.3 mm external diameter) cut to protrude 1 mm from the tip of the guide cannula. The injector was carefully introduced into the implanted guide cannula, and a volume of 1 l was injected using a Hamilton microsyringe (CR-700-20, Hamilton Co., Reno, USA) within 2 min (approximately 0.05 l every 5 s) and left in place for 1 min to prevent retrograde flow. The local injection of lidocaine into the NRM 10 min after WTET to the PP did not modify LTP (Fig. 1E, repeated measures ANOVA, F1, 17 = 0.0089) and showed no influence on LTP reinforcement by BLA stimulation (Fig. 1F, repeated measures ANOVA, F1, 16 = 0.8538). 5-HT1A-receptors in the hippocampus are linked to inhibition of adenyl cyclase [10] a key member of a kinase-regulatory cascade involved in L-LTP [15]. This would predict an inhibitory action of serotonin that could be involved in the depression observed after NRM stimulation under baseline conditions. Apparently, the induction of LTP, and more importantly, the reinforcing effect of the BLA, are strong enough to overcome any inhibitory effects of serotonin released after NRM stimulation. Conversely, inactivating the NRM did not add any improvements in the efficacy to the reinforcing mechanisms of BLA stimulation and its LTP reinforcement in the DG. Taken together, our data show that the stimulation of the NRM, before or after LTP induction at the PP-DG synapses had no influence on the level and duration of E-LTP. The stimulation of the NRM did not mimic or interfered with the effect of the BLA, i.e. to reinforce E-LTP into L-LTP in the DG. The NRM, therefore, does not appear to participate in E-LTP reinforcement in the DG by itself or in cooperative action with the BLA. However, NRM did have a depressing influence on synaptic basal transmission in the DG, which apparently depends neither on a change in excitability of the dentate granules, nor on a modification in the local retroactive inhibition circuits but on a direct action on target cells. Acknowledgements JAB was granted by the German Service for Academic Exchange (DAAD). The skilled technical support from Silvia Vieweg, Sabine Opitz and Jeanette Maiwald is gratefully acknowledged. References [1] W.C. Abraham, S. Otani, Maintenance of long-term potentiation in the dentate gyrus requires proteins synthesized shortly after tetanization in the anaesthetized rat, J. Physiol. 407 (1988) 50. [2] J.A. Bergado, S. Frey, J. López, W. Almaguer-Melian, J.U. Frey, Cholinergic afferents to the locus coeruleus and noradrenergic afferents to the medial septum mediate LTP-reinforcement in the dentate gyrus by stimulation of the amygdala, Neurobiol. Learn. Mem. 88 (2007) 331–341. [3] T.V. Bliss, A.R. Gardner-Medwin, Long-lasting potentiation of synaptic transmission in the dentate area of the unanaesthetized rabbit following stimulation of the perforant path, J. Physiol. (Lond.) 232 (1973) 357–374. [4] T.V. Bliss, G.V. Goddard, M. Riives, Reduction of long-term potentiation in the dentate gyrus of the rat following selective depletion of monoamines, J. Physiol. (Lond.) 334 (1983) 475–491. [5] M. Boldrini, M.D. Underwood, A. Martini, A.M. Romoli, M. Rossi, J.J. Mann, V. Arango, Brainstem raphe nucleus changes in suicide victims, Psychiatr. Danub. 18 (Suppl. 1) (2006) 120. [6] H. Braak, E. Braak, D. Yilmazer, J. Bohl, Functional anatomy of human hippocampal formation and related structures, J. Child Neurol. 11 (1996) 265–275. [7] G. Buzsáki, Theta rhythm of navigation: link between path integration and landmark navigation, episodic and semantic memory, Hippocampus 15 (2005) 827–840. [8] Y. Cao, K. Matsuyama, Y. Fujito, M. Aoki, Involvement of medullary GABAergic and serotonergic raphe neurons in respiratory control: electrophysiological and immunohistochemical studies in rats, Neurosci. Res. 56 (2006) 322–331.
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Stimulation of the nucleus raphe medialis modifies basal synaptic transmission at the dentate gyrus, but not long-term potentiation or its reinforcement by stimulation of the basolateral amygdala Jorge A. Bergado a , Thomas Scherf b , William Almaguer-Melian a , Sabine Frey b , Jeffrey López b , Julietta U. Frey b,∗ a b
Centro Internacional de Restauración Neurológica (CIREN), La Habana, Cuba Leibniz Institute für Neurobiologie, Magdeburg, Germany
a r t i c l e
i n f o
Article history: Received 16 May 2009 Received in revised form 12 August 2009 Accepted 14 August 2009 Keywords: Nucleus raphe medialis Hippocampal long-term potentiation LTP reinforcement Basolateral amygdala Freely moving rats
a b s t r a c t Affective factors importantly interact with behavior and memory. Physiological mechanisms that underlie such interactions are objects of intensive studies. This involves the direct investigation of its relevance to understand learning and memory formation as well as the search for possibilities to treat memory disorders. The prolonged maintenance of long-term potentiation (LTP) – a cellular model for memory formation – is characterized by neuromodulatory, associative requirements. During the last years, we have delineated a neural system that may be responsible for affective–cognitive interactions at the cellular level. The stimulation of the basolateral amygdala (BLA), within an effective, associative time window, reinforces a normally transient, protein synthesis-independent early-LTP (less than 4–6 h) into a longlasting, protein synthesis-dependent late-LTP in the dentate gyrus (DG) in freely moving rats (Frey et al., 2001 [12]). LTP reinforcement by stimulation of the BLA was mediated by cholinergic projection of the medial septum to the DG, and the noradrenergic projection from the locus coeruleus (Bergado et al., 2007 [2]). We were now interested to investigate a possible interaction of the nucleus raphe medialis (NRM) with DG-LTP. Although, NRM stimulation resulted in a depressing effect on basal synaptic transmission, we did not observe any interactions with early-LTP or with the BLA-DG LTP-reinforcement system. © 2009 Elsevier Ireland Ltd. All rights reserved.
Synaptic plasticity can modify the activity of neuronal circuits, adjusting behavior to new conditions, and allowing animals to face the unpredictable environment with a minimally predetermined neuronal subset. Such basic neuronal processes may underlie learning and memory. Bliss and Colleagues [3] first described in 1973 that a brief high-frequency stimulation of hippocampal afferents can lead to a prolonged increase of synaptic efficacy, named longterm potentiation (LTP). LTP is considered as a cellular mechanism for learning and memory [35]. Similarly to memory formation, LTP is characterized by an early phase depending on post-translational protein modifications (E-LTP) and a late phase that depends on protein synthesis (L-LTP) [1,16,30]. It has been shown that L-LTP is dependent on ‘late-associative’ interactions of glutamatergic as well as neuromodulatory systems within a specific time window around LTP induction [13–15,17,18]. E-LTP in the dentate gyrus (DG) in the freely moving rat can also be modulated, i.e. reinforced
∗ Corresponding author at: Dept. Neurophysiology, Leibniz-Institute for Neurobiology, Brenneckestrasse 6, 39118 Magdeburg, Germany. Tel.: +49 391 6263 422; fax: +49 391 6263 421. E-mail address: [email protected] (J.U. Frey). 0304-3940/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2009.08.034
into L-LTP by the emotional/motivational status of the individual or by direct stimulation of neuromodulatory brain systems within an effective time window [12,13,45]. During the last years we have identified for LTP in the DG in intact freely moving rats a specific reinforcement system [2,13]. The medial septum and the locus coeruleus are probably not the only components of the BLA reinforcement system. We have recently obtained evidence that the nucleus accumbens shell, or core, differentially influences LTP induction at the perforant pathway (PP)-DG in anaesthetized rats [33]. Here, we were interested to study the possible effects of the nucleus raphe on PP-DG-LTP. The nucleus raphe is a brain stem group of neurons that provides serotonergic innervation to widespread regions of the brain, including the DG that receives projections from the ventral portion of the raphe: the nucleus raphe medialis (NRM) [10]. Serotonergic control by the raphe participates in several important processes, including general functions like the control of sleep-wake cycle [48] and very specific ones like respiratory control [8]. Evidence point to a relationship between serotonergic dysfunction and negative mood states [21,51] as anxiety [34] in animals and humans [5,31]. Theta electroencephalographic activity in the hippocampus, a pattern that has been related with memory [7,29,38,40], and LTP [23,24,36,39]
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shows also a relationship with serotonergic innervation from the raphe [26,49,50]. The amygdala projects to midbrain aminergic nuclei including the noradrenergic locus coeruleus, and the serotonergic raphe nuclei [6]. Reciprocally, the NRM projects to the central amygdaloidal nucleus [20], and the BLA [19]. Thus, the question arises whether the raphe is involved in the reinforcement of plasticity at the DG by the BLA. A relationship between serotonin, the raphe and LTP has been documented, though the effects are different depending on the brain area. Serotonin induced L-LTP in the amygdala [22], but inhibited the induction of NMDA receptor-dependent LTP in the rat primary visual cortex [9,25]. On the other hand, the outcomes may also depend from environmental constraints: a 5-HT1A serotoninreceptor antagonists blocked PP-DG LTP induced in novel, but not familiar, environments [43]. The main objective of this investigation was to assess whether the NRM can influence LTP or the reinforcement of LTP by stimulation of the BLA. To that purpose male Wistar rats weighing 250–300 g (8 weeks old) at the beginning of the study were used. After surgery the animals were housed individually in plastic translucent cages with free access to food and water and controlled room conditions (12 h light: dark cycle, temperature and humidity) during the entire experiments. Ethical approval was sought prior to the studies according to the German requirements for the use of experimental animals. For surgery, rats were anaesthetized with Nembutal (40 mg/kg, i.p.) and mounted in a stereotactic frame (David Kopf, Saint Louis, USA). The preparation included the implantation of one stainless steel monopolar recording electrode in the DG (0.125 mm diameter, coordinates: anteroposterior AP = −4.0 mm, mediolateral ML = 2.3 mm from bregma and dorsoventral DV approximately 2.5 mm from the dural surface, with lambda and bregma at the same level). A bipolar stainless steel electrode was placed in the medial perforant path (AP = −7.5 mm, ML = 4.1 mm from bregma, DV = −3.0 mm from the dural surface). The position in the DV axis of the electrodes in the DG and the PP was adjusted under observation of the evoked potentials to optimize its location. Additional bipolar electrodes were placed into the BLA (AP = −3.5 mm, ML = 5.0 mm from bregma, DV = −7.6 mm from the dural surface) and the NRM (AP = −7.7 mm, ML = 2.1 mm from bregma, DV = −7.5 mm from dura tilted 17.5◦ to the vertical). In a number of animals a guide cannula (stainless steel tubes 0.5 mm external diameter) were implanted into the NRM. All implants were placed at the right hemisphere. Three miniscrews were attached to the skull to serve as ground, indifferent electrode and mechanical fixation, respectively. Electrodes were then connected to flexible rubber female sockets and fixed to the skull with dental cement. A week after surgery the animals were tested and habituated to the recording chamber for no less than 4 h. An input–output (I/O) relation was obtained stimulating the PP with increasing currents (100–800 A) to determine the stimulus intensity to be used in each animal (40% maximal population spike). Each record consisted of 5 averaged waveforms evoked by square pulses (0.1 ms) delivered at 0.1 Hz (Isolated Pulse Stimulator, A-M System, USA) to the PP. Signals were filtered between 1 and 5000 Hz using a Biolelectric Amplifier, fed to a CED1401 Plus A/D converter (CED, Cambridge, UK), and processed by a special software (PWIN, Institute for Neurobiology, Magdeburg, Germany). The amplitude of the population spike (PSA) was measured in mV (from the first positive peak to the subsequent negative peak, see Fig. 1A). The PSA was averaged in the last six baseline recordings to determine pre-tetanus baseline value. The PSA of the post-tetanus recordings for each animal was compared to these values and expressed in percent changes. We used the PSA as a measure of LTP instead of the field excitatory post-synaptic potential (fEPSP), because working in freely moving animals and the use of a single
recording electrode makes it difficult to obtain stable recordings of both the fEPSP and the PSA, especially if the recording electrode was located in the hilus, i.e. far away from EPSP-generation. On the other hand, the PSA represents the discharge of action potentials by the post-synaptic population, which is functionally the most relevant resulting outcome of synaptic function, although we are aware that it is not the optimal measurement to evaluate synaptic plasticity events. The experiments were performed on the following day, after the determination of the stimulation intensities. In general, a baseline was obtained (12 recordings with 5 min interval) followed by the induction of LTP by a weak tetanus (WTET, 3 trains of 15 impulses at 200 Hz, 0.1 ms duration) to the PP. The time course of LTP was followed up for 8 h with recordings every 15 min. A further recording was made 24 h after tetanization. Fig. 1A shows relevant aspects of the preparation, the recording and histological control of the location of the implants. The histological examination showed that the electrode aimed to the NRM was placed outside the target in 3 animals, and in one animal for BLA. The results of these rats 4 were discarded, and not considered in the final analysis of the data. The pattern of WTET employed was able to induce a potentiation at the PP-DG synapses that decays to baseline within the next hours (Fig. 1B, LTP-group) corresponding to the temporal pattern of an E-LTP [12,45]. Tetanization of the BLA (400 A) 15 min after LTP induction resulted in a prolongation of the potentiation (Fig. 1B, LTP + BLA group). Both groups differed significantly (repeated measures ANOVA, F1, 18 = 6.3099) from each other. These control experiments confirmed previous results showing that the stimulation of the BLA reinforces E-LTP into L-LTP [12]. To study whether the stimulation of the NRM can influence LTP induction or its duration, WTET was applied to the NRM at a constant 400 A intensity 15 min before or after LTP induction. The results are shown in Fig. 1C (groups LTP + NRM, and NRM + LTP, respectively) and showed no influence of NRM stimulation with that pattern on the level, or time course of the DG-potentiation (repeated measures ANOVA, F2, 21 = 0.4801). Previous studies on the influence of NRM and serotonin on LTP showed inconsistent results, with a little or no effect on LTP induction [4,28,37,42,46,47]. A recent study, in which also later LTP time points were included, showed that 5-HT1A serotonin-receptor antagonist blocked LTP induction in a novel environment, but not in a familiar one [43] a condition that corresponds to our results, considering that the animals in our study have been adapted to the recording condition over several hours. Under our experimental conditions the tetanic stimulation of the NRM did not affect LTP induction or the rate of decay of LTP, irrespective when NRM stimulation occurred, i.e. before or after WTET to PP-DG. To establish the possible effects of NRM stimulation on basal PP-DG transmission the NRM was stimulated without induction of LTP in separate groups of animals. The stimulation of the NRM in the absence of tetanization to the PP induced a slowly developing and long-lasting depression of synaptic basal transmission at the DG as shown in Fig. 1D. The effect seemed to be not being frequency-dependent as similar results were obtained after high- (200 Hz) or low- (45 impulses at 1 Hz) frequency stimulation of the NRM (NRM + HFS and NRM + LFS groups, respectively). Both groups significantly differed from the non-stimulated group (repeated measures ANOVA, F2, 21 = 10.6823) but not between each other (post hoc test, Tukey HSD). A comparable depression of PPDG synaptic transmission was reported previously for the PP-DG synapses [42], the CA1 [27,28] and the amygdala [41] when serotonin agonists were applied. Our results show that these effects can be even long-lasting, suggesting the occurrence of plastic functional re-arrangements, mimicking in that respect a long-term depression. Furthermore, this particular depression could also be responsible and thus prevent a possible reinforcement of E-LTP.
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Fig. 1. (A) Coronal sections/schemas illustrate the location of the recording electrode at the dentate gyrus (DG) and stimulating electrodes at the perforant pathway (PP) and the basolateral amygdala (BLA). The analog traces show an example of recordings made before (baseline, filled line) and 1 h after the induction of E-LTP (dotted line) (calibration bar: 5 mV:5 ms). The microphotograph represents the region of the NRM and the trace of an electrode pointing to the NRM, enclosed by a dotted ellipse. (B) Time course of LTP induced by a weak tetanus (WTET, see text) pattern to the PP (open circles, n = 10), compared with a group of animals in which the BLA was stimulated with a high-frequency stimulation (HFS) 15 min after E-LTP induction in the PP-DG (filled squares, n = 10; significant differences between groups, F value from ANOVA is given). (C) Time course of E-LTP induced by a WTET to PP (open circles, n = 10) and its combination with stimulation (HFS) of the NRM 15 min before (HFS-NRM + WTET, filled squares, n = 7) or 15 min after (WTET + HFS-NRM, triangles, n = 7) E-LTP induction in the DG; no significant differences among groups (ANOVA). (D) Baseline recordings of DG evoked potentials after PP control stimulation (baseline, open circles, n = 9) and the effect of NRM stimulation with low- (NRM-LFS, filled squares, n = 7) or high- (HFS, triangles, n = 8) frequency. The ANOVA confirmed a significant effect of NRM stimulation and the Tukey post hoc test demonstrated that baseline (a) differed significantly from both NRM stimulated groups (b, p < 0.05). (E) The inactivation of NRM by lidocaine had no effect on the time course of E-LTP when both groups were compared (ANOVA; control E-LTP, open circles, n = 10; WTET in the DG + lidocaine-NRM, filled squares, n = 9). (F) Inactivation of the NRM (WTET + BLA + lidocaine-NRM, filled squares, n = 8) did not affect E-LTP reinforcement by stimulation of the BLA (WTET + BLA, open circles, n = 10; ANOVA, no significant differences). In all graphs means ± SEM are provided.
Serotonergic receptors of the 5-HT1A type are the most abundant and distribute on the projection neurons at the DG (the granule cells) as well as on inhibitory interneurons [11] that participate on feed-forward, and feed-back inhibitory circuits [32]. Such effects have been explained based on a hyperpolarizing action of serotonin mediated by a K+ current activated via 5-HT1A-receptors [44]. Thus, the outcome may be different depending on the neuronal population targeting the raphe actions on the DG. A main effect on principal neurons, should hyperpolarize them, and reduce their excitability. A dominant effect on the interneurons, should reduce GABA-mediated inhibition of the principal neurons and lead to an increased excitability and a reduced paired pulses inhibition. To assess whether NRM modifies excitability of the DG neurons we
have evaluated I/O curves under stimulation of the NRM. The costimulation of the PP (with increasing intensities) and the NRM (constant intensity at 400 A) does not modify the I/O relationships compared with the I/O values obtained using PP stimulation alone in the same animals (n = 6), for both the PSA and the fEPSP (data not shown). Stimulation of the PP with paired pulses at 20 ms interstimulus interval led to a depression of the second evoked potential which is not significantly modified by co-stimulation of the NRM (data not shown). Therefore, these results make an inhibitory feedforward or feed-back mechanisms induced by NRM stimulation under our experimental conditions unlikely and favors the direct hyperpolarizing effect of the principal granular cells by 5-HT1Areceptors.
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Finally, we have tested whether the inactivation of the NRM influenced LTP or the reinforcement of E-LTP by the BLA. Inactivation of NRM was achieved by the topical injection of lidocaine (lidocaine hydrochloride 2%, Hexal, Holzkirchen, BRD). The injection cannulas were made of stainless steel tubes (0.3 mm external diameter) cut to protrude 1 mm from the tip of the guide cannula. The injector was carefully introduced into the implanted guide cannula, and a volume of 1 l was injected using a Hamilton microsyringe (CR-700-20, Hamilton Co., Reno, USA) within 2 min (approximately 0.05 l every 5 s) and left in place for 1 min to prevent retrograde flow. The local injection of lidocaine into the NRM 10 min after WTET to the PP did not modify LTP (Fig. 1E, repeated measures ANOVA, F1, 17 = 0.0089) and showed no influence on LTP reinforcement by BLA stimulation (Fig. 1F, repeated measures ANOVA, F1, 16 = 0.8538). 5-HT1A-receptors in the hippocampus are linked to inhibition of adenyl cyclase [10] a key member of a kinase-regulatory cascade involved in L-LTP [15]. This would predict an inhibitory action of serotonin that could be involved in the depression observed after NRM stimulation under baseline conditions. Apparently, the induction of LTP, and more importantly, the reinforcing effect of the BLA, are strong enough to overcome any inhibitory effects of serotonin released after NRM stimulation. Conversely, inactivating the NRM did not add any improvements in the efficacy to the reinforcing mechanisms of BLA stimulation and its LTP reinforcement in the DG. Taken together, our data show that the stimulation of the NRM, before or after LTP induction at the PP-DG synapses had no influence on the level and duration of E-LTP. The stimulation of the NRM did not mimic or interfered with the effect of the BLA, i.e. to reinforce E-LTP into L-LTP in the DG. The NRM, therefore, does not appear to participate in E-LTP reinforcement in the DG by itself or in cooperative action with the BLA. However, NRM did have a depressing influence on synaptic basal transmission in the DG, which apparently depends neither on a change in excitability of the dentate granules, nor on a modification in the local retroactive inhibition circuits but on a direct action on target cells. Acknowledgements JAB was granted by the German Service for Academic Exchange (DAAD). The skilled technical support from Silvia Vieweg, Sabine Opitz and Jeanette Maiwald is gratefully acknowledged. References [1] W.C. Abraham, S. Otani, Maintenance of long-term potentiation in the dentate gyrus requires proteins synthesized shortly after tetanization in the anaesthetized rat, J. Physiol. 407 (1988) 50. [2] J.A. Bergado, S. Frey, J. López, W. Almaguer-Melian, J.U. Frey, Cholinergic afferents to the locus coeruleus and noradrenergic afferents to the medial septum mediate LTP-reinforcement in the dentate gyrus by stimulation of the amygdala, Neurobiol. Learn. Mem. 88 (2007) 331–341. [3] T.V. Bliss, A.R. Gardner-Medwin, Long-lasting potentiation of synaptic transmission in the dentate area of the unanaesthetized rabbit following stimulation of the perforant path, J. Physiol. (Lond.) 232 (1973) 357–374. [4] T.V. Bliss, G.V. Goddard, M. Riives, Reduction of long-term potentiation in the dentate gyrus of the rat following selective depletion of monoamines, J. Physiol. (Lond.) 334 (1983) 475–491. [5] M. Boldrini, M.D. Underwood, A. Martini, A.M. Romoli, M. Rossi, J.J. Mann, V. Arango, Brainstem raphe nucleus changes in suicide victims, Psychiatr. Danub. 18 (Suppl. 1) (2006) 120. [6] H. Braak, E. Braak, D. Yilmazer, J. Bohl, Functional anatomy of human hippocampal formation and related structures, J. Child Neurol. 11 (1996) 265–275. [7] G. Buzsáki, Theta rhythm of navigation: link between path integration and landmark navigation, episodic and semantic memory, Hippocampus 15 (2005) 827–840. [8] Y. Cao, K. Matsuyama, Y. Fujito, M. Aoki, Involvement of medullary GABAergic and serotonergic raphe neurons in respiratory control: electrophysiological and immunohistochemical studies in rats, Neurosci. Res. 56 (2006) 322–331.
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