| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
REPORT
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas
Submitted 24 August 2004; accepted in final form 15 December 2004
 |
ABSTRACT |
|---|
|
|
|
INTRODUCTION |
|---|
|
). Long-term potentiation (LTP) is a putative cellular mechanism for aversive learning (LeDoux 2000). Repetitive stimulation of cortical and thalamic afferents, important in associative processing of emotional information (LeDoux 2000), induces long-term plasticity in the LA in vivo (Doyere et al. 2003) or in vitro (Chapman et al. 2003). The cortical afferents, which carry contextual, visual, or auditory information, also generate LTP in the basolateral amygdala (BLA) (Aroniadou-Anderjaska et al. 2001; Chapman et al. 2003). Little is known about LTP in another crucial part of the amygdala complex, the central amygdala (CeA), which is downstream from the sites of associativity in the LA and BLA and serves as a primary output nucleus for information processing (Davis 1986; LeDoux 2000).
The BLA and lateral amygdala (LA) project primarily to the capsular (CeAc) division of the rat CeA (Pitkanen 2000; Pitkanen et al. 1995; Savander et al. 1997), where they activate AMPA and N-methyl-D-aspartate (NMDA) receptors (Lopez de Armentia and Sah 2001; Sah et al. 2003). Inhibitory synaptic responses mediated through GABAA are also recorded in the CeA (Delaney and Sah 2001), and the majority of projection neurons are GABAergic (Swanson and Petrovich 1998). The two afferent pathways are thought to process different information, the LA-CeA, tone conditioned stimuli, and the BLA-CeA, contextual stimuli (LeDoux 2000). Other evidence suggests that the CeA itself may support fear learning (Killcross et al. 1997). A recent hypothesis posits that the LA input to the medial CeA via intercalated neurons is the main circuitry implicated in fear learning (Pare et al. 2004). The rat CeA is comprised of two primary cell types (Sah et al. 2003; Schiess et al. 1993), but there is no apparent correlation between electrophysiological and morphological characteristics (Sah et al. 2003). The purpose of this study was to compare synaptic plasticity in two pathways to the CeA, the BLA to CeA, and the LA to CeA.
|
|
METHODS |
|---|
|
). BLA/CeAc slices were more rostral (–2.5 to 3.0 mm from Bregma) than LA/CeAc slices (–3.0 to –3.5 mm) to reduce current spread from adjacent nuclei. Recording and stimulating electrode locations were carefully noted in each experiment. For LTP, fEPSP amplitudes (adjusted to 30% of maximal response) were recorded for 30 min (0.05 Hz) prior to high-frequency stimulation (HFS, 5 trains, 1-s duration at 100 Hz, 3-min intervals). Subsequent fEPSPs (0.05 Hz) were recorded for 1 h. Six consecutive traces were averaged, and the fEPSP slope was measured and plotted versus time; data were normalized to baseline responses analyzed with a two-tailed t-test or one-way ANOVA.
|
|
|
RESULTS |
|---|
|
). In PTX, HFS of the LA consistently generated LTP (150.7 ± 34.9% of baseline, P < 0.01, Fig. 1B, n = 12). In contrast, PTX had no significant effect on LTP in the BLA to CeAc pathway (PTX: 149.1 ± 18.7; control: 139.3 ± 14.3%, Fig. 1D, n = 10) but consistently induced BLA-CeA LTP in all slices tested. PTX also had no significant effect on fEPSP amplitude (control: 0.28 ± 0.02 mV; PTX: 0.32 ± 0.05 mV), duration (control: 11.9 ± 0.5 ms; PTX: 12.6 ± 1.1 ms), and latency (control: 2.4 ± 0.2 ms; PTX: 1.6 ± 0.5 ms). LTP pharmacology also differed in the LA and BLA to CeAc pathways (Fig. 2A). In the presence of the NMDA receptor antagonist, D-aminophosphonovaleric acid (APV, 50 µM), LTP could still be induced in the LA-CeAc pathway (before: 150.7 ± 34.9%, n = 12; after: 137.1 ± 12.2%, n = 6, P > 0.05, Fig. 2A); however, LTP was abolished in the CeAc when stimulating the BLA (109.8 ± 6.1% of baseline, n = 6, Fig. 2B).
|
|
|
|
DISCUSSION |
|---|
|
Inhibition in the LA-CeA pathway may reduce or restrain activity-dependent facilitation since LTP was induced only in its absence. Interposed between the LA and BLA and the CeA is a ribbon of intercalated cell masses (Millhouse 1986), which may serve as an inhibitory gate (Pare et al. 2003; Royer et al. 1999). Additionally, axon collaterals of GABAergic neurons within the CeA itself may generate feedback inhibition that could result in inhibition of the fEPSP (but see Pare et al. 2003; Royer et al. 1999). In contrast, in the BLA-CeAc pathway, inhibiting GABA transmission had little overall effect on LTP induction (Figs. 1D and 3A). This difference in PTX effect may be related to topography within the amygdala and physiology of the intervening intercalated cells (Pare et al. 2003; Royer et al. 1999). The intercalated cells have lateromedial correspondence between their position and input to the CeA and the afferent source within the LA/BLA complex (Pare et al. 2003; Royer et al. 1999). The more lateral intercalated cell clusters inhibit more medial clusters, which results in disinhibition (Royer et al. 1999) and would allow LTP induction in the BLA pathway. Disinhibition is less likely with LA stimulation, which would engage more laterally positioned intercalated cell masses and result in an inhibitory brake on afferent information. Intercalated neurons also possess a potassium current activated at subthreshold membrane potentials that is inactivated in response to suprathreshold depolarization, after which inactivation is slowly removed; the resultant effect is a self-sustaining state of heightened excitability after suprathreshold activity (Royer et al. 2000). This current would sustain inhibitory activity from the intercalated cells in the LA-CeA pathway and exert a persistent disinhibition of the medial intercalated neurons by the more lateral intercalated cells when the BLA pathway is activated, thus providing a physiological basis for different mechanisms underlying activity dependent plasticity in the LA and BLA pathways to the CeA. Additionally, the monosynaptic connections between the LA and BLA to the CeA suggest that these direct pathways may play a role in fear conditioning independent of the intercalated GABA-releasing cells (Pare et al. 2004).
In the absence of GABAergic inhibition, the mechanisms underlying LTP induction were pathway specific. At the LA-CeA synapse, LTP is independent of NMDARs and dependent on VGCCs. In contrast, LTP of BLA-CeAc pathway was dependent on NMDARs and L-type VGCCs. NMDAR- and VGCC-dependent LTP can be induced separately (Bauer et al. 2002; Morgan and Teyler 2001), depending on the induction protocol (Bauer et al. 2002; Weisskopf et al. 1999). At other amygdala synapses, LTP induction involves postsynaptic VGCCs (Weisskopf et al. 1999) or pre- or postsynaptic NMDARs (Humeau et al. 2003). In the BLA-CeA pathway, complete block of LTP by either NMDARs or VGCCs antagonists, however, suggests specific roles in the induction process involving interrelated mechanisms. For LTP induction, presynaptic and postsynaptic mechanisms at BLA-CeA synapses that require VGCC at one and NMDARs at the other synaptic site may be required. Alternatively, postsynaptic activation of both NMDARs and VGCCs may be necessary to achieve intracellular Ca2+ levels required for induction of BLA-CeA LTP. Conversely, in both pathways, LTP was associated with a decrease in PPRs, suggesting enhanced transmitter release plays a role in the expression of CeA LTP. Finally, this modulation of associative information by subsequent downstream CeA synapses may represent pathway specific integrative properties of the amygdala and provide distinct processing of tone or contextual information in cues related to anxiety and drug-taking.
|
|
GRANTS |
|---|
|
|
|
ACKNOWLEDGMENTS |
|---|
|
|
|
FOOTNOTES |
|---|
Address for reprint requests and other correspondence: P. Shinnick-Gallagher, Dept. of Pharmacology and Toxicology, Univ. of Texas Medical Branch, Galveston, TX 77555-1031 (E-mail: psgallag{at}utmb.edu)
|
|
REFERENCES |
|---|
|
Bauer EP, Schafe GE, and LeDoux JE. NMDA receptors and L-type voltage-gated calcium channels contribute to long-term potentiation and different components of fear memory formation in the lateral amygdala. J Neurosci 22: 5239–5249, 2002.
Chapman PF, Ramsey MF, and Krezel WKSG. Synaptic Plasticity in the amygdala: comparisons with hippocampus. Ann NY Acad Sci 985: 114–124, 2003.[CrossRef][Web of Science][Medline]
Davis M. Pharmacological and anatomical analysis of fear conditioning using the fear-potentiated startle paradigm. Behav Neurosci 100: 814–824, 1986.[CrossRef][Web of Science][Medline]
Delaney AJ and Sah P. Pathway-specific targeting of GABA(A) receptor subtypes to somatic and dendritic synapses in the central amygdala. J Neurophysiol 86: 717–723, 2001.
Doyere V, Schafe GE, Sigurdsson T, and LeDoux JE. Long-term potentiation in freely moving rats reveals asymmetries in thalamic and cortical inputs to the lateral amygdala. Eur J Neurosci 17: 2703–2715, 2003.[CrossRef][Web of Science][Medline]
Humeau Y, Shaban H, Bissiere S, and Luthi A. Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain. Nature 426: 841–845, 2003.[CrossRef][Medline]
Killcross S, Robbins TW, and Everitt BJ. Different types of fear-conditioned behaviour mediated by separate nuclei within amygdala. Nature 388: 377–380, 1997.[CrossRef][Medline]
LeDoux J. The amygdala and emotion: a view through fear. In: The Amygdala: A Functional Analysis, edited by Aggleton JP: Oxford: Oxford University Press, 2000, p. 289–310.
Lopez de Armentia M and Sah P. Excitatory projections to the central lateral nucleus of the amygdala in the rat. Soc Neurosci Abstr 31: 713.2, 2001.
Millhouse OE. The intercalated cells of the amygdala. J Comp Neurol 247: 246–271, 1986.[CrossRef][Web of Science][Medline]
Morgan SL and Teyler TJ. Electrical stimuli patterned after the theta-rhythm induce multiple forms of LTP. J Neurophysiol 86: 1289–1296, 2001.
Pare D, Quirk GJ, and LeDoux JE. New vistas on amygdala networks in conditioned fear. J Neurophysiol 92: 1–9, 2004.
Pare D, Royer S, Smith Y, and Lang EJ. Contextual inhibitory gating of impulse traffic in the intra-amygdaloid network. Ann NY Acad Sci 985: 78–91, 2003.[Web of Science][Medline]
Paxinos G and Watson C. The Rat Brain in Stereotaxic Coordinates. San Diego, CA: Academic Press, 1998.
Pitkanen A. Connectivity of the rat amygdaloid complex. In: The Amygdala: A Functional Analysis, edited by Aggleton JP: Oxford: Oxford University Press, 2000, p. 31–116.
Pitkanen A, Stefanacci L, Farb CR, Go GG, LeDoux JE, and Amaral DG. Intrinsic connections of the rat amygdaloid complex: projections originating in the lateral nucleus. J Comp Neurol 356: 288–310, 1995.[CrossRef][Web of Science][Medline]
Royer S, Martina M, and Pare D. An inhibitory interface gates impulse traffic between the input and output stations of the amygdala. J Neurosci 19: 10575–10583, 1999.
Royer S, Martina M, and Pare D. Bistable behavior of inhibitory neurons controlling impulse traffic through the amygdala: role of a slowly deinactivating K+ current. J Neurosci 20: 9034–9039, 2000.
Sah P, Faber ES, Lopez DA, and Power J. The amygdaloid complex: anatomy and physiology. Physiol Rev 83: 803–834, 2003.
Savander V, LeDoux JE, and Pitkanen A. Interamygdaloid projections of the basal and accessory basal nuclei of the rat amygdaloid complex. Neuroscience 76: 725–735, 1997.[CrossRef][Web of Science][Medline]
Schiess MC, Asprodini EK, Rainnie DG, and Shinnick-Gallagher P. The central nucleus of the rat amygdala: in vitro intracellular recordings. Brain Res 604: 283–297, 1993.[CrossRef][Web of Science][Medline]
See RE, Fuchs RA, Ledford CC, and McLaughlin J. Drug addiction, relapse, and the amygdala. Ann NY Acad Sci 985: 294–307, 2003.[Web of Science][Medline]
Swanson LW and Petrovich GD. What is the amygdala? Trends Neurosci 21: 323–331, 1998.[CrossRef][Web of Science][Medline]
Weisskopf MG, Bauer EP, and LeDoux JE. L-type voltage-gated calcium channels mediate NMDA-independent associative long-term potentiation at thalamic input synapses to the amygdala. J Neurosci 19: 10512–10519, 1999.
This article has been cited by other articles:
|
|
 |
|
  E. Knapska, K. Radwanska, T. Werka, and L. Kaczmarek Functional Internal Complexity of Amygdala: Focus on Gene Activity Mapping After Behavioral Training and Drugs of Abuse Physiol Rev, October 1, 2007; 87(4): 1113 - 1173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. de Armentia and P. Sah Bidirectional synaptic plasticity at nociceptive afferents in the rat central amygdala J. Physiol., June 15, 2007; 581(3): 961 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Fu, S. Pollandt, J. Liu, B. Krishnan, K. Genzer, L. Orozco-Cabal, J. P. Gallagher, and P. Shinnick-Gallagher Long-Term Potentiation (LTP) in the Central Amygdala (CeA) Is Enhanced After Prolonged Withdrawal From Chronic Cocaine and Requires CRF1 Receptors J Neurophysiol, January 1, 2007; 97(1): 937 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Barad Divide and conquer: An L-type voltage-gated calcium channel subtype finds a role in conditioned fear. Learn. Mem., September 1, 2006; 13(5): 560 - 561. [Full Text] [PDF]
|
|
|
|
|
|
D. Lebel, N. Sidhu, E. Barkai, and E. M. Quinlan Learning in the absence of experience-dependent regulation of NMDAR composition Learn. Mem., September 1, 2006; 13(5): 566 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Anglada-Figueroa and G. J. Quirk Lesions of the Basal Amygdala Block Expression of Conditioned Fear But Not Extinction J. Neurosci., October 19, 2005; 25(42): 9680 - 9685. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
TOP
ABSTRACT
INTRODUCTION
) and absence (
) of PTX.
