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PubMed2006

Lesions of the habenula produce stress- and dopamine-dependent alterations in prepulse inhibition and locomotion.

The habenula complex modulates the activity of dopamine and serotonin systems in the brain. An important question remains whether there is a link between habenula dysfunction and monoamine-related disorders, such as schizophrenia. In this study, we describe an interaction between habenula lesions and stress that produces long-lasting effects on behavior. Mice received control lesions or bilateral electrolytic lesions of the habenula and were tested for fear-potentiated startle and freezing measures of conditioned fear. They were also tested for prepulse inhibition (PPI) and locomotor activity in the presence or absence of a dopaminergic agonist (apomorphine) or an atypical antipsychotic with mixed dopamine/serotonin antagonist properties (clozapine). There were no detectable effects of habenula lesions on fear conditioning and no effects on PPI in the absence of stress. However, following conditioned fear stress, habenula-lesioned animals showed decreased PPI which normalized with clozapine. Lesioned animals also showed diminished activity at baseline, with hyperlocomotion following apomorphine. These data support the hypothesis that the habenula may be normally involved in stress-dependent regulation of monoamine systems.

Analysis of Variance↗
PubMed1999

Reciprocal changes in the firing probability of lateral and central medial amygdala neurons.

The amygdala is essential for classical fear conditioning. According to the current model of auditory fear conditioning, the lateral nucleus is the input station of the amygdala for conditioned auditory stimuli, whereas the central nucleus is the output station for conditioned fear responses. Yet, the lateral nucleus does not project to the central medial nucleus, where most brainstem projections of the amygdala originate. The available evidence suggests that the basal nuclei could transmit information from the lateral to the central medial nucleus. However, interposed between the basolateral complex and the central nucleus are clusters of GABAergic cells, the intercalated neurons, which receive inputs from the lateral and basal nuclei and contribute a massive projection to the central medial nucleus. Because it is impossible to predict the consequences of these connections, we correlated the spontaneous and auditory-evoked activity of multiple simultaneously recorded neurons of the lateral, basal, and central nuclei. The spontaneous activity of lateral and basolateral neurons was positively correlated to that of central lateral cells but negatively correlated to that of central medial neurons. In response to auditory stimuli, the firing probability of lateral and central medial neurons oscillated in phase opposition, initially being excited and inhibited, respectively. In light of previous anatomical findings, we propose that the lateral nucleus exerts two indirect actions on central medial neurons: an excitation via the basal nuclei and an inhibition via intercalated neurons.

Amygdala↗
PubMed2001

Effects of the phytoestrogen coumestrol on locomotor and fear-related behaviors in female mice.

Effects of the estrogenic plant isoflavonoid coumestrol (COUM) on locomotor activity and fear-related behaviors in both the absence and the presence of estradiol benzoate (EB) were examined in adult ovariectomized Swiss-Webster mice. In a running wheel paradigm conducted over 10 days, with treatment beginning 12 days prior to testing, daily subcutaneous (sc) injections of 10 microg of COUM did not influence locomotor activity, whereas even the low dose of EB supplied by sc Silastic implant (2.5 microg lasting 5 weeks) produced a significant increase in locomotor activity over animals receiving vehicle alone. In animals receiving both COUM and EB, locomotor activity was significantly diminished compared to the activity observed in animals receiving EB alone. The same animals were also tested in three behavioral paradigms having known activity and fear components (open field, dark/light transition, elevated plus-maze). COUM did not produce significant effects in these assays. However, in an associative fear learning paradigm (fear conditioning), COUM produced significantly less freezing ("fearfulness") in the conditioned fear task than with animals receiving vehicle or a low dose of EB, which did not differ from each other. Unlike EB, which has comparable affinities for estrogen receptor (ER) alpha and ER beta, COUM has a higher affinity for ER beta than for ER alpha. COUM might disrupt estrogen-enhanced locomotor activity by altering the dynamic by which EB acts on the brain through these two ER isoforms. The conditioned fear result suggests that COUM may produce additional effects through alternative pathways.

Animals↗
PubMed2006

Pharmacological treatments that facilitate extinction of fear: relevance to psychotherapy.

SUMMARY: A great deal is now known about the mechanisms of conditioned fear acquisition and expression. More recently, the mechanisms of inhibition of conditioned fear have become the subject of intensive study. The major model system for the study of fear inhibition in the laboratory is extinction, in which a previously fear conditioned organism is exposed repeatedly to the fear-eliciting cue in the absence of any aversive event and the fear conditioned response declines. It is well established that extinction is a form of new learning as opposed to forgetting or "unlearning" of conditioned fear, and it is hypothesized that extinction develops when sensory pathways conveying sensory information to the amygdala come to engage GABAergic interneurons through forms of experience-dependent plasticity such as long-term potentiation. Several laboratories currently are investigating methods of facilitating fear extinction in animals with the hope that such treatments might ultimately prove to be useful in facilitating exposure-based therapy for anxiety disorders in clinical populations. This review discusses the advances that have been made in this field and presents the findings of the first major clinical study to examine the therapeutic utility of a drug that facilitates extinction in animals. It is concluded that extinction is an excellent model system for the study of fear inhibition and an indispensable tool for the screening of putative pharmacotherapies for clinical use.

Excitatory Amino Acid Agonists↗
PubMed2004

Learning and memory performance in mice lacking the GAL-R1 subtype of galanin receptor.

The neuropeptide galanin induces performance deficits in a wide range of cognitive tasks in rodents. Three G-protein-coupled galanin receptor subtypes, designated GAL-R1, GAL-R2 and GAL-R3, have been cloned. The present study examined the role of GAL-R1 in cognition by testing mice with a null mutation in Galr1 on several different types of learning and memory tasks. Assessments of general health, neurological reflexes, sensory abilities and motor functions were conducted as control measures. Mutant mice were unimpaired in social transmission of food preference and the Morris water maze. In tests of fear conditioning, mutant mice were unimpaired in a delay version of cued fear conditioning. However, mice homozygous for the null mutation were impaired in a trace version of cued fear conditioning. Mutant mice were unimpaired in contextual fear conditioning, whether training was by the delay or trace protocol. General health, neurological reflexes, sensory abilities and motor functions did not differ across genotypes, indicating that the trace fear conditioning deficit was not an artifact of procedural disabilities. The findings of normal performance on several cognitive tasks and a selective deficit in trace cued fear conditioning in homozygous GAL-R1 mutant mice are discussed in terms of hypothesized roles of the GAL-R1 subtype. The generally normal phenotype of GAL-R1 null mutants supports the use of this line for identification of the receptor subtypes that mediate the cognitive deficits produced by exogenous galanin.

Animals↗
PubMed2006

Extracellular hippocampal acetylcholine level controls amygdala function and promotes adaptive conditioned emotional response.

Ample data indicate that tone and contextual fear conditioning differentially require the amygdala and the hippocampus. However, mechanisms subserving the adaptive selection among environmental stimuli (discrete tone vs context) of those that best predict an aversive event are still elusive. Because the hippocampal cholinergic neurotransmission is thought to play a critical role in the coordination between different memory systems leading to the selection of appropriate behavioral strategies, we hypothesized that this cholinergic signal may control the competing acquisition of amygdala-mediated tone and contextual conditioning. Using pavlovian fear conditioning in mice, we first show a higher level of hippocampal acetylcholine release and a specific pattern of extracellular signal-regulated kinase 1/2 (ERK1/2) activation within the lateral (LA) and basolateral (BLA) amygdala under conditions in which the context is a better predictor than a discrete tone stimulus. Second, we demonstrate that levels of hippocampal cholinergic neurotransmission are causally related to the patterns of ERK1/2 activation in amygdala nuclei and actually determine the selection among the context or the simple tone the stimulus that best predicts the aversive event. Specifically, decreasing the hippocampal cholinergic signal not only impaired contextual conditioning but also mimicked conditioning to the discrete tone, both in terms of the behavioral outcome and the LA/BLA ERK1/2 activation pattern. Conversely, increasing this cholinergic signal not only disrupted tone conditioning but also promoted contextual fear conditioning. Hence, these findings highlight that hippocampal cholinergic neurotransmission controls amygdala function, thereby leading to the selection of relevant emotional information.

Acetylcholine↗
PubMed2005

Fear conditioning-induced plasticity in auditory thalamus and cortex: To what extent is it expressed during slow-wave sleep?

After fear conditioning to a tone, rats received nonawakening presentations of the tone alone during slow-wave sleep (SWS) episodes. Multiunit activity was recorded in the medial part of the medial geniculate (MGm) and in the primary auditory cortex (ACx). Although tone-evoked responses were increased in MGm and ACx during the 3 conditioning sessions, group data failed to show any significant changes during SWS. Nonetheless, the few recordings (5/29) that exhibited the strongest conditioned responses during wakefulness expressed enhanced responding during SWS. Compared with previous data obtained in MGm during paradoxical sleep, associative plastic changes were less easily expressed during SWS. These results are discussed with regard to functional changes that occur in the thalamocortical system across vigilance states.

Action Potentials↗
PubMed2006

Hitting Ras where it counts: Ras antagonism in the basolateral amygdala inhibits long-term fear memory.

Several studies have implicated the Ras/mitogen-activated protein kinase (MAPK) pathway in Pavlovian fear conditioning. RasGRF1 knockout mice show significant deficits in acquisition of long-term fear memories and long-term potentaition (LTP) in the basolateral amygdala (BLA). MAPK kinase inhibition also impairs fear conditioning and amygdaloid LTP. However, there is no direct evidence to date for the involvement of Ras itself in fear conditioning. To address this issue, we examined the effects of intra-amygdala infusions of the selective Ras antagonist farnesylthiosalicylic acid (FTS) on the acquisition and expression of conditional freezing in rats. Micro-infusions of FTS into the BLA prior to contextual fear conditioning significantly impaired acquisition of long-term contextual fear memory in a dose-dependent manner. Post-training FTS infusions had no effect on acquisition of long-term fear memory. The effects of FTS on fear conditioning were specific for the BLA. Finally, intra-amygdala infusions of FTS inhibited MAPK activation in BLA. Collectively, these results provide further evidence for the involvement of amygdaloid Ras in the acquisition of long-term conditional fear memory.

Acoustic Stimulation↗
PubMed2005

Fear learning induces persistent facilitation of amygdala synaptic transmission.

In the maintenance phase of fear memory, synaptic transmission is potentiated and the stimulus requirements and signalling mechanisms are altered for long-term potentiation (LTP) in the cortico-lateral amygdala (LA) pathway. These findings link amygdala synaptic plasticity to the coding of fear memories. Behavioural experiments suggest that the amygdala serves to store long-term fear memories. Here we provide electrophysiological evidence showing that synaptic alterations in rats induced by fear conditioning are evident in vitro 10 days after fear conditioning. We show that synaptic transmission was facilitated and that high-frequency stimulation dependent LTP (HFS-LTP) of the cortico-lateral amygdala pathway remained attenuated 10 days following fear conditioning. Additionally, we found that the low-frequency stimulation dependent LTP (LFS-LTP) measured 24 h after fear conditioning was absent 10 days post-training. The persistent facilitation of synaptic transmission and occlusion of HFS-LTP suggests that, unlike hippocampal coding of contextual fear memory, the cortico-lateral amygdala synapse is involved in the storage of long-term fear memories. However, the absence of LFS-LTP 10 days following fear conditioning suggests that amygdala physiology 1 day following fear learning may reflect a dynamic state during memory stabilization that is inactive during the long-term storage of fear memory. Results from these experiments have significant implications regarding the locus of storage for maladaptive fear memories and the synaptic alterations induced by these memories.

Amygdala↗
PubMed2003

The amygdala, synaptic plasticity, and fear memory.

The nature and mechanisms of synaptic plasticity in the amygdala and the relation of amygdaloid plasticity to behavior are exciting new areas of study in neuroscience. These issues were at the heart of presentations by Paul Chapman, Michael Fanselow, Patricia Shinnick-Gallagher, and Michael Rogawski in a session entitled "Long-Term Plasticity in Amygdala Synaptic Transmission" that was held at the conference featured in this volume. In this chapter, I briefly summarize these talks and give my perspective on the presentations as the session chair. I argue that we must first understand the role of the amygdala in learning and memory in order to understand the contribution of amygdaloid synaptic plasticity to behavior. Although it is generally agreed that the amygdala is involved in several forms of emotional learning and memory such as pavlovian fear conditioning, a recent debate has emerged concerning the precise role of the amygdala in learning versus performing fear responses. I discuss data from my laboratory that unravel this issue. I argue that the basolateral complex of the amygdala (BLA) normally plays an essential role in associative processes in fear conditioning. Nonetheless, rats with BLA lesions acquire and express conditional fear under some conditions. A neuroanatomical model that accounts for these data is presented.

Amygdala↗
PubMed2003

Role of the amygdala in fear extinction measured with potentiated startle.

Although much is now known about the neural basis of excitatory fear conditioning, much less is known about the neural basis of inhibitory conditioning. One type of inhibitory conditioning is extinction, a process in which stimuli that elicit fear by virtue of previous associations with aversive stimuli such as shock (excitatory fear conditioning) are now presented in the absence of the aversive stimuli (extinction training). As a result, the ability of the conditioned stimulus to elicit fear gradually diminishes. Extinction is different from forgetting and does not reflect an erasure of the original fear memory. Instead, extinction is an active form of inhibitory learning that competes with excitatory fear conditioning. Infusions into the amygdala (a brain area essential for excitatory fear conditioning) of either NMDA receptor antagonists or inhibitors of the NMDA-receptor-linked mitogen-activated protein kinase cascade block extinction learning. Conversely, the NMDA receptor agonist D-cycloserine facilitates extinction after either systemic administration or intra-amygdala infusion. Because therapeutic interventions based on extinction procedures are commonly used to treat fear disorders, and because D-cycloserine is a widely available and safe compound, D-cycloserine or similar agents might be usefully combined with traditional extinction-based approaches in the treatment of clinical fear.

Amygdala↗
PubMed1993

The role of the amygdala and dorsal raphe nucleus in mediating the behavioral consequences of inescapable shock.

It has been argued that exposure to inescapable shock produces later behavioral changes such as poor shuttle box escape learning because it leads to the conditioning of intense fear, which later transfers to the shuttle box test situation and interferes with escape. Both fear, as assessed by freezing, and escape were measured in Sprague-Dawley rats 24 hr after exposure to inescapable shock. Lesions of the basolateral region and central nucleus of the amygdala eliminated the fear that transfers to the shuttle box after inescapable shock, as well as the fear conditioned in the shuttle box by the shuttle box shocks. However, the amygdala lesions did not reduce the escape learning deficit produced by inescapable shock. In contrast, dorsal raphe nucleus lesions did not reduce the fear that transfers to the shuttle box after inescapable shock, but eliminated the enhanced fear conditioning in the shuttle box as well as the escape deficit. The implications of these results for the role of fear and anxiety in mediating inescapable shock effects are discussed.

Amygdala↗
PubMed2002

Short-term memory resists the depressant effect of the nonimmobilizer 1-2-dichlorohexafluorocyclobutane (2N) more than long-term memory.

UNLABELLED: The nonimmobilizer 1,2-dichlorohexafluorocyclobutane (2N, also termed F6) does not suppress movement to noxious stimuli but does suppress learning of fear-potentiated startle. The mechanism whereby 2N suppresses this learning is unknown. Herein, we report the effect of 2N on suppression of two other forms of learning, fear conditioning to context and to tone. Because 2N does not cause sedation, we could study the effect of 2N on short-term memory (memory for fear conditioning measured during or immediately after training) as well as on long-term memory (measured 24 h after training). The EC(50) for suppression of long-term memory (the concentration decreasing memory by 50%) of fear conditioning to context was 2.00% plus/minus 0.01% (mean plus/minus SEM), and for fear conditioning to tone was 3.45% plus/minus 0.26%, (P < 0.05). The EC(50) for suppression of short-term memory of fear conditioning to context was 2.59% plus/minus 0.21% (P < 0.05, compared with long-term memory of context conditioning), whereas short-term memory of fear conditioning to tone was not suppressed by 3.5%, the largest concentration studied. Thus, short-term memory resists the depressant effect of 2N more than long-term memory, fear conditioning to tone is less vulnerable to the effect of 2N than fear conditioning to context, and 3.5% 2N does not preclude transmission of tone and shock signals to the site where tone-shock associations are formed. IMPLICATIONS: The nonimmobilizer 1,2-dichlorohexafluorocyclobutane has a greater depressant effect on long-term memory than short-term memory, suggesting that it impairs the processes responsible for the retention of memory more than for the formation of memory itself.

Animals↗
PubMed2003

NMDA currents and receptor protein are downregulated in the amygdala during maintenance of fear memory.

The amygdala plays a critical role in fear conditioning, a model of emotional learning and cue-induced anxiety. In the lateral amygdala, fear conditioning is associated with an enduring increase in synaptic strength mediated through AMPA receptors and with a reduction in paired-pulse facilitation, reflecting an increased probability of neurotransmitter release. Here we show that NMDA-mediated transmission in the thalamic-to-lateral amygdala pathway is not facilitated after fear conditioning, although probability of transmitter release is enhanced. Rather, the EC50 for NMDA receptor (NR)-mediated current is shifted threefold to fourfold to the right in fear-conditioned animals, suggesting a postsynaptic alteration in NMDA receptors in the maintenance phase of fear memory. Furthermore, the ability of nonselective and subunit-selective antagonists of NMDA receptors to block NMDA receptor-mediated EPSCs is reduced in lateral amygdala neurons from fear-conditioned animals, suggesting a reduction in NMDA receptors at thalamolateral amygdala synapses. In addition, Western blots show a reduction in phosphorylated-NR1, NR2A, and NR2B subunit protein expression in amygdalas from fear-conditioned animals. These data indicate that postsynaptic mechanisms are involved in synaptic plasticity in the thalamoamygdala pathway in fear conditioning and raise the possibility that: (1) downregulation of the NMDA receptor may protect against excitotoxicity of unchecked NMDA receptor recruitment during induction and consolidation of fear memories, (2) reduced NMDA current and protein may allow persistence of the "capacity to reactivate" amygdala pathways in NMDA receptor-dependent fear memories, or (3) a persistent long-term depression of NMDA transmission may occur after fear learning.

Amygdala↗
PubMed2006

Neurobiology of anxiety disorders and implications for treatment.

The neurobiology of the anxiety disorders, which include panic disorder, post-traumatic stress disorder (PTSD), and specific phobias, among others, has been clarified by advances in the field of classical or Pavlovian conditioning, and in our understanding of basic mechanisms of memory and learning. Fear conditioning occurs when a neutral conditioned stimulus (such as a tone) is paired with an aversive, or unconditioned stimulus (such as a footshock), and then in the absence of the unconditioned stimulus, causes a conditioned fear response. Preclinical studies have shown that the amygdala plays a key role in fear circuitry, and that abnormalities in amygdala pathways can affect the acquisition and expression of fear conditioning. Drugs such as glutamate N-methyl-D-aspartate (NMDA) antagonists, and blockers of voltage-gated calcium channels, in the amygdala, may block these effects. There is also preliminary evidence for the use of centrally acting beta-adrenergic antagonists, like propranolol, to inhibit consolidation of traumatic memories in PTSD. Finally, fear extinction, which entails new learning of fear inhibition, is central to the mechanism of effective anti-anxiety treatments. Several pharmacological manipulations, such as D-cycloserine, a partial NMDA agonist, have been found to facilitate extinction. Combining these medication approaches with psychotherapies that promote extinction, such as cognitive behavioral therapy (CBT), may offer patients with anxiety disorders a rapid and robust treatment with good durability of effect.

Amygdala↗
PubMed2006

Dorsal hippocampal contributions to unimodal contextual conditioning.

Although there is general consensus that the hippocampus is not critically involved in the acquisition of fear conditioned to an explicit conditioned stimulus (CS), the extent to which the hippocampus participates in contextual fear conditioning remains unclear. To further characterize the potential role of the hippocampus in contextual fear conditioning, the present experiments examined the effect of excitotoxic lesions of dorsal hippocampus on the acquisition of a novel contextual fear conditioning paradigm in which a unimodal (olfactory) cue served to disambiguate discrete "contexts" within a single behavioral training chamber. Selective lesions of dorsal hippocampus severely attenuated olfactory contextual conditioning without affecting conditioning to an explicit auditory or olfactory CS. Additional experiments indicate that these contextual conditioning deficits cannot be attributed to a lesion-induced decrement in olfactory perception, a preferential impairment of "weak" forms of conditioning, or hyperactivity. Thus, the hippocampus appears to contribute importantly to the acquisition of fear conditioned to explicitly nonspatial, unimodal, temporally, and spatially diffuse contextual stimuli.

Acoustic Stimulation↗
PubMed2006

Animal studies of amygdala function in fear and uncertainty: relevance to human research.

This article reviews research in both animals and humans on the considerable progress made in elucidating a brain circuitry of fear, particularly the importance of the amygdala in fear conditioning. While there is considerable agreement about the participation of the amygdala in fear in both animals and humans, there are several issues about the function of the amygdala raised by the human research that have not been addressed by or may be answered by animal research. Three of these are addressed in this article: (1) is the amygdala involved in or necessary for both fear learning and unconditioned fear? (2) Does the amygdala code for intensity of fear? (3) Is the amygdala preferentially involved in fear, or is it also activated when there are no overt fear or aversive stimuli, but where the situation can be described as uncertain? We present evidence indicating that the rodent amygdala is involved in some types of fear (conditioned fear), but not all types (unconditioned fear), and may therefore have significance for a differential neurobiology of certain anxiety disorders in humans. Further, similar to the human amygdala, the rodent amygdala responds to varying intensities of aversive stimulation. Finally, it is suggested that, similar to humans, the rodent amygdala is involved in the evaluation of uncertainty. We conclude that progress on elucidating the role of the amygdala in fear is facilitated by corroboration of findings from both animal and human research.

Amygdala↗
PubMed2001

Inhibition of amygdaloid dopamine D2 receptors impairs emotional learning measured with fear-potentiated startle.

Considerable advances have been made in understanding the neurocircuitry underlying the acquisition and expression of Pavlovian conditioned fear responses. Within the complex cellular and molecular processes mediating fearfulness, amygdaloid dopamine (DA), originating from cells in the ventral tegmental area (VTA) of the midbrain, is thought to contribute to fear-motivated responding. Considering that blockade of DA D(2) receptors is a common mechanism of action for antipsychotic agents, we hypothesized that inhibition of D(2) receptors in the amygdala may be involved in the antiparanoid effects of these drugs. To assess the role of amygdaloid DA D(2) receptors in aversive emotionality, the D(2) receptor antagonist raclopride was infused into the amygdala prior to Pavlovian fear conditioning. Potentiated startle was used as a behavioral indicator of fear and anxiety. Classical fear conditioning and acoustic startle testing were conducted in a single session allowing for the concomitant assessment of shock reactivity with startle enhancement. Depending on dose, the results found conditioned fear acquisition and retention to be impaired following administration of raclopride into the amygdala. Additionally, the learning deficit was dissociated from shock detection and from fear expression assessed with the shock sensitization of acoustic startle. These findings further refine the known neural mechanisms of amygdala-based emotional learning and memory and were interpreted to suggest that, along with D(1) receptors, D(2) receptors in the amygdala may mediate the formation and the retention of newly-acquired fear associations.

Amygdala↗