Dopaminergic modulation of spontaneous inhibitory network activity in the lateral amygdala
Introduction
The amygdala, a group of interconnected nuclei in the temporal lobe, plays a central role for attributing and adjusting emotional valence to sensory inputs (Le Doux, 2000, Davis, 2000). In particular, there is compelling evidence that during classical fear conditioning, information about the conditioned (CS) and unconditioned (US) stimuli are converging at the level of the lateral nucleus of the amygdala (LA; Sah et al., 2003). In the LA, induction of associative synaptic plasticity by converging CS and US inputs is thought to underlie, at least in part, the acquisition and storage of fear learning (Maren, 2001, Rosenkranz and Grace, 2002a, Goosens et al., 2003). The activity of LA projection neurons and the induction of synaptic plasticity in the LA are strongly regulated by local inhibitory interneurons (Li et al., 1996, Lang and Paré, 1997, Bissière et al., 2003). Consistent with these physiological findings, behavioral experiments indicate that the acquisition and expression of different measures of conditioned and unconditioned fear are under the control of GABAergic inhibition (Davis, 2000). Converging evidence indicates that neuromodulators, such as dopamine (DA), affect amygdala-dependent fear learning by targeting inhibitory circuits in the basolateral amygdala. DA is released in the amygdala upon stress (Inglis and Moggadham, 1999), and intra-amygdala injection of DA receptor antagonists prevents the acquisition of conditioned fear (Lamont and Kokkinidis, 1998, Guarracci et al., 1999, Guarracci et al., 2000, Greba and Kokkinidis, 2001, Greba et al., 2001). The effects of locally released DA on inhibitory circuits in the LA appear to be complex. In vivo and in vitro electrophysiological experiments indicate that DA suppresses inhibition triggered by stimulation of excitatory afferents from the medial prefrontal cortex (mPFC) or from the thalamus thereby facilitating the induction of synaptic plasticity (Rosenkranz and Grace, 2001, Rosenkranz and Grace, 2002b, Bissière et al., 2003). Conversely, recordings from anaesthetized rats have demonstrated that DA receptor activation increases the firing rate of putative interneurons (Rosenkranz and Grace, 1999).
DA receptors are generally grouped into two subfamilies, the D1-like and the D2-like receptors (Missale et al., 1998). Both receptor subfamilies seem to be involved in regulating amygdala-dependent fear learning (Guarracci et al., 1999, Guarracci et al., 2000) and are expressed in the basolateral amygdala (Boyson et al., 1986, Meador-Woodruff et al., 1991). Whereas the attenuation of inhibition triggered by stimulation of mPFC afferents has been shown to involve activation of D1-like receptors (Rosenkranz and Grace, 2002a, Rosenkranz and Grace, 2002b), suppression of feedforward inhibition upon stimulation of thalamic afferents is mediated by D2-like receptor activation (Bissière et al., 2003). In contrast, the mechanism underlying the DA-induced increase in interneuron firing rate is poorly understood. The present study was designed to investigate the impact of DA receptor activation on spontaneous inhibitory network activity in vitro, and to elucidate the underlying signaling mechanisms.
Section snippets
Slice preparation
Standard procedures were used to prepare 350 μm thick coronal slices from 3 to 4 week old male C57BL/6J mice following a protocol approved by the Veterinary Department of the Canton of Basel-Stadt. Briefly, the brain was dissected in ice-cold artificial cerebrospinal fluid (ACSF), mounted on an agar block and sliced with a vibratome at 4 °C. Slices were maintained for 45 min at 35 °C in an interface chamber containing ACSF equilibrated with 95% O2/5% CO2 and containing (in mM): 124 NaCl, 2.7
DA increases spontaneous inhibitory network activity
To address the effect of DA on spontaneous inhibitory network activity in the LA we have obtained whole-cell voltage-clamp recordings from LA projection neurons that were located in the dorsal subdivision of the LA. Spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded at −70 mV using a CsCl-based filling solution. sIPSCs were pharmacologically isolated by application of the AMPA/kainate receptor antagonist CNQX (20 μM) and the NMDA receptor antagonist CPP (10 μM). As previously
Discussion
Consistent with in vivo studies showing an increase in the spontaneous firing rate of putative interneurons upon systemic administration of DA receptor agonists (Rosenkranz and Grace, 1999), the present study demonstrates that spontaneous inhibitory network activity is strongly increased by DA. This effect involved the activation of somatodendritic DA receptors on LA interneurons since DA application did not affect mIPSC frequency, and directly depolarized interneurons in the LA. Indeed,
Acknowledgements
We thank all members of the Lüthi lab for helpful discussions and comments on the manuscript. This work was supported by the Swiss National Science Foundation, the Borderline Personality Disorder Research Foundation, and the Novartis Research Foundation.
References (43)
- et al.
Dopamine receptor-interacting proteins: the Ca2+ connection in dopamine signaling
Trends in Pharmacological Sciences
(2003) - et al.
Evidence that dopaminergic axons provide a dense innervation of specific neuronal subpopulations in the rat basolateral amygdala
Brain Research
(1999) - et al.
Spontaneous activity of the perirhinal cortex in behaving cats
Neuroscience
(1999) - et al.
Prolonged fear responses in mice lacking dopamine D1 receptor
Brain Research
(2001) - et al.
G protein antagonists
Trends in Pharmacological Sciences
(1999) - et al.
Auditory-evoked spike firing in the lateral amygdala and Pavlovian fear conditioning: mnemonic code or fear bias?
Neuron
(2003) - et al.
Inhibition of amygdaloid dopamine D2 receptors impairs emotional learning measured with fear-potentiated startle
Brain Research
(2001) - et al.
G-protein-independent signaling by G-protein-coupled receptors
Trends in Neurosciences
(2000) - et al.
Infusion of the dopamine D1 receptor antagonist SCH 23390 into the amygdala blocks fear expression in a potentiated startle paradigm
Brain Research
(1998) - et al.
A network of electrically coupled interneurons drives synchronized inhibition in neocortex
Nature Neuroscience
(2000)
Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition
Nature Neuroscience
Quantitative autoradiographic localization of the D1 and D2 subtypes of dopamine receptors in rat brain
The Journal of Neuroscience
The role of the amygdala in conditioned and unconditioned fear and anxiety
Dopamine D1 receptor-dependent trafficking of striatal NMDA receptors to the postsynaptic membrane
The Journal of Neuroscience
Dopamine D1-dependent trafficking of striatal N-methyl-d-aspartate glutamate receptors requires fyn protein tyrosine kinase but not DARPP-32
Molecular Pharmacology
A network of fast-spiking cells in the neocortex connected by electrical synapses
Nature
Two networks of electrically coupled inhibitory neurons in neocortex
Nature
Amygdaloid D1 dopamine receptor involvement in Pavlovian fear conditioning
Brain Research
The effects of intraamygdaloid infusions of a D2 dopamine receptor antagonist on Pavlovian fear conditioning
Behavioral Neuroscience
Peripheral and intraamygdalar administration of the dopamine D1 receptor antagonist SCH23390 blocks fear-potentiated startle but not shock reactivity or the shock sensitization of acoustic startle
Behavioral Neuroscience
G-protein-independent signaling mediated by metabotropic glutamate receptors
Nature Neuroscience
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These authors contributed equally to this work.