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PubMed2000

Median raphe nucleus mediates forming long-term but not short-term contextual fear conditioning in rats.

The brain serotonin is involved in mediation of emotional behaviour including anxiety and related fear conditioning. It is known that the median raphe nucleus (MRN) is the origin of a serotonergic pathway and mainly innervates septo-hippocampal formation which plays an important role in emotional cognition. However, its regulatory role in different types of fear conditioning is still unclear. In the present study, the animals underwent ibotenic acid or sham lesions of the median raphe nucleus and the effects of MRN lesions on immediate and delayed fear conditioning to multiple contextual cues were studied. Freezing behaviour served as a measure of contextual fear. Sham-lesioned animals showed reliable conditional freezing when observed immediately following foot-shock (1.0 mA) for 3-min test and 48 h after the shock for 12-min test. Rats with MRN lesions displayed robust freezing behaviour immediately after the shock, even though they showed a marked deficit in freezing 48 h following the shock. These findings indicate that the MRN-serotonergic septo-hippocampal pathway is involved in the regulation of anxiety related to fear conditioning triggered by contextual cues, suggesting that short-term contextual fear is independent on the MRN while long-term contextual fear depends on the MRN.

Animals↗
PubMed2004

New vistas on amygdala networks in conditioned fear.

It is currently believed that the acquisition of classically conditioned fear involves potentiation of conditioned thalamic inputs in the lateral amygdala (LA). In turn, LA cells would excite more neurons in the central nucleus (CE) that, via their projections to the brain stem and hypothalamus, evoke fear responses. However, LA neurons do not directly contact brain stem-projecting CE neurons. This is problematic because CE projections to the periaqueductal gray and pontine reticular formation are believed to generate conditioned freezing and fear-potentiated startle, respectively. Moreover, like LA, CE may receive direct thalamic inputs communicating information about the conditioned and unconditioned stimuli. Finally, recent evidence suggests that the CE itself may be a critical site of plasticity. This review attempts to reconcile the current model with these observations. We suggest that potentiated LA outputs disinhibit CE projection neurons via GABAergic intercalated neurons, thereby permitting associative plasticity in CE. Thus plasticity in both LA and CE would be necessary for acquisition of conditioned fear. This revised model also accounts for inhibition of conditioned fear after extinction.

Amygdala↗
PubMed1996

The NMDA antagonist MK-801 blocks the extinction of Pavlovian fear conditioning.

Five groups of rats were given Pavlovian fear conditioning. Four groups were then given extinction training. Prior to extinction these groups received an injection of either the noncompetitive NMDA antagonist MK-801 (0.025, 0.05, or 0.1 mg/kg) or saline. The 5th group received saline but no extinction. During testing, the extinction groups given saline or 0.025 mg/kg of MK-801 showed reduced fear, but the groups that had received the higher doses exhibited as much conditioned fear as the saline group, which had not received extinction. This study showed that MK-801 blocked extinction in a dose-dependent manner. The design of the study ruled out the possibility that the effect was due to state-dependency or to MK-801 interfering with the processing of the conditioned stimulus.

Animals↗
PubMed2004

Selective serotonin reuptake inhibitor reduces conditioned fear through its effect in the amygdala.

Selective serotonin reuptake inhibitors are first-line treatment for most anxiety disorders, but their mechanism of anxiolytic action has not been clarified. Selective serotonin reuptake inhibitors are anxiolytic in conditioned fear stress (re-exposure to an environment paired previously with inescapable electric footshocks). To clarify the brain regions where selective serotonin reuptake inhibitors act, we examined the effect of microinjection of the selective serotonin reuptake inhibitor, citalopram, into the amygdala, medial prefrontal cortex and mediodorsal nucleus of the thalamus on freezing behavior, an index of fear, induced by conditioned fear stress. Bilateral injection of citalopram into the amygdala before testing reduced freezing significantly, while bilateral injection into the medial prefrontal cortex or mediodorsal nucleus of the thalamus did not. These results suggest that the anxiolytic effect of a selective serotonin reuptake inhibitor in conditioned fear is mediated by its effect in the amygdala, and support the hypothesis of serotonin function in anxiety by which facilitation of serotonin neurotransmission decreases anxiety.

Amygdala↗
PubMed2001

Fear conditioning in inbred mouse strains: an analysis of the time course of memory.

Three mouse strains were examined for short- and long-term memory for Pavlovian fear conditioning measured 1 hr and 24 hr after conditioning. Both DBA/2J and CBA/J mice exhibit reduced long-term memory for contextual fear conditioning compared with C57BL/6J mice. In cued fear conditioning, however, DBA/2J mice show reduced short- and long-term memory compared with C57BL/6J mice, whereas CBA/J mice exhibit reductions only in short-term memory. These results underscore the importance of examining the time course of memory retention, and they suggest that inbred mouse strains may provide a diversity of phenotypes. The results also suggest that the processes of short- and long-term memory storage as well as contextual and cued fear conditioning are dissociable and are mediated by genetically distinct neurobiological mechanisms.

Animals↗
PubMed2000

The amygdala modulates memory consolidation of fear-motivated inhibitory avoidance learning but not classical fear conditioning.

Although the lateral and basal nuclei of the amygdala are believed to be essential for the acquisition of Pavlovian fear conditioning, studies using post-training manipulations of the amygdala in the inhibitory avoidance learning paradigm have recently called this view into question. We used the GABA(A) agonist muscimol to functionally inactivate these nuclei immediately after single-trial Pavlovian fear conditioning or single-trial inhibitory avoidance learning. Immediate post-training infusions of muscimol had no effect on Pavlovian conditioning but produced a dose-dependent effect on inhibitory avoidance. However, pre-training infusions dose-dependently disrupted Pavlovian conditioning. These findings indicate that the amygdala plays an essential role in the acquisition of Pavlovian fear conditioning and contributes to the modulation of memory consolidation of inhibitory avoidance but not of Pavlovian fear conditioning.

Acoustic Stimulation↗
PubMed2006

Alcohol exposure during adolescence impairs auditory fear conditioning in adult Long-Evans rats.

Few studies have examined long-term effects of ethanol on auditory fear conditioning, and fewer still have examined whether adolescence represents a unique period of vulnerability. We investigated the impact of ethanol consumption during adolescence and adulthood on fear conditioning, following an extended abstinence period. Male and female Long-Evans rats (N = 80) consumed 10% ethanol or water (control) in a limited-access drinking paradigm (1 h) between postnatal (P) days 28-45 (adolescent) and P80-97 (adult). After the abstinence period (30 days), ethanol and control groups were assessed on the auditory fear-conditioning task. Alcohol consumption impaired tone conditioning in the male and female adolescent group. There were no persisting effects of adult dosing. In addition, adolescent rats consumed more ethanol than adults. These data provide evidence that ethanol consumption during adolescence produces enduring effects on auditory fear conditioning. The age-specific effect of ethanol may be attributable to an interplay of higher ethanol intake and the unique neurobiological characteristics of adolescents.

Acoustic Stimulation↗
PubMed2006

A robust automated method to analyze rodent motion during fear conditioning.

A central question in the study of LTP has been to determine what role it plays in memory formation and storage. One valuable form of learning for addressing this issue is associative fear conditioning. In this paradigm an animal learns to associate a tone and shock, such that subsequent presentation of a tone evokes a fear response (freezing behavior). Recent studies indicate that overlapping cellular processes underlie fear conditioning and LTP. The fear response has generally been scored manually which is both labor-intensive and subject to potential artifacts such as inconsistent or biased results. Here we describe a simple automated method that provides unbiased and rapid analysis of animal motion. We show that measured motion, in units termed significant motion pixels (SMPs), is both linear and robust over a wide range of animal speeds and detection thresholds and scores freezing in a quantitatively similar manner to trained human observers. By comparing the frequency distribution of motion during baseline periods and to the response to fox urine (which causes unconditioned fear), we suggest that freezing and non-freezing are distinct behaviors. Finally, we show how this algorithm can be applied to a fear conditioning paradigm yielding information on long and short-term associative memory as well as habituation. This automated analysis of fear conditioning will permit a more rapid and accurate assessment of the role of LTP in memory.

Algorithms↗
PubMed2006

Hemispheric differences in protein kinase C betaII levels in the rat amygdala: baseline asymmetry and lateralized changes associated with cue and context in a classical fear conditioning paradigm.

The amygdala is critically important for fear learning, and specific kinases have been implicated as contributors to the mechanisms that underlie learning. We examined levels of protein kinase C betaII (PKC betaII) in the left and right lateral and basolateral nuclei (LA/BLA) of the amygdala from animals that were classically fear conditioned with tones as cues and footshocks. Groups consisted of animals that received neither tones nor shocks, paired tones and shocks, or unpaired tones and shocks. At 1 h after conditioning, some animals from each group were used for biochemical measurements of PKC betaII levels and other animals were given probe trials to assess freezing behavior to cue and context. The levels of PKC betaII were greater in the left hemisphere in animals receiving neither tones nor shocks and animals receiving paired tones and shocks. PKC betaII levels were greater in the right hemisphere of animals receiving randomly presented tones and shocks. Freezing times to cue were long (>80% of probe trial time) in both the paired tone/shock and randomly unpaired tone/shock groups. Freezing times to context were long in the unpaired tone/shock group, but not the paired tone/shock group. Correlational analyses showed that freezing times to context, but not cue, precisely predicted the right/left relation of PKC betaII levels in the LA/BLA: the greater the time spent freezing to context, the greater the increase in right hemisphere PKC betaII levels. We conclude that fear conditioning causes hemisphere and input specific increases in PKC betaII in the rat LA/BLA.

Acoustic Stimulation↗
PubMed1996

Effect of the selective CCKB receptor antagonist LY288513 on conditioned fear stress in rats.

In order to investigate the involvement of cholecystokinin (CCK) in the regulation of anxiety, the effect of the selective non-peptide CCKB receptor antagonist LY288513 ((4S, 5R)-N-(4-bromophenyl)-3-oxo-4,5-diphenyl-1-1-pyrazolidinecarboxamide+ ++) on freezing behavior induced by conditioned fear stress was examined using a time-sampling procedure. Rats were individually subjected to 5 min of inescapable electric footshock in a shock chamber. Twenty-four hours after the footshock, the rats were again placed in the shock chamber and observed for 5 min without shocks: this procedure is termed conditioned fear stress. Subcutaneous administration of LY288513 30 min before footshock (0.3 mg/kg) and 30 min before conditioned fear stress (0.03 mg/kg) reduced conditioned freezing. This indicates that LY288513 blocked both the acquisition and expression of conditioned fear. The relatively selective non-peptide CCKA receptor antagonist, lorglumide (D, L-4-(3,4-dichlorobenzoylamino)-5-(diphentylamino)-5-oxo-pent anoic acid), blocked the expression of conditioned fear, though only at a high dose (1.0 mg/kg). The peripheral non-peptide CCKA/B receptor antagonist, loxiglumide (D, L-4-(3,4-dichlorobenzoylamino)-5- (N-3-methoxypropyl-pentylamino)-5-oxo-pentanoic acid), failed to do so. These results suggest that brain CCKB receptors are involved in the regulation of anxiety.

Animals↗
PubMed2005

Nicotine enhances both foreground and background contextual fear conditioning.

The present study examined if nicotine enhances contextual fear conditioning when the training context is either a background stimulus or a foreground stimulus. In the background conditioning experiment, mice were trained using two auditory conditioned stimulus (CS; 30 s, 85 dB white noise)-footshock unconditioned stimulus (US; 2 s, 0.57 mA) pairings and tested 24 h later. In the foreground conditioning experiment, mice were trained with two presentations of a footshock US (2 s, 0.57 mA) and tested 24 h later. Mice received 0.09 mg/kg nicotine before training and testing. For both the foreground and background conditioning experiments, nicotine enhanced contextual conditioning. No enhancement of the auditory CS-US association was seen. These results demonstrate that nicotine enhances contextual fear conditioning regardless of whether the context is a background stimulus or a foreground stimulus during conditioning.

Acoustic Stimulation↗
PubMed2006

Inactivation of the ventromedial prefrontal cortex reduces expression of conditioned fear and impairs subsequent recall of extinction.

Anxiety disorders are thought to reflect deficits in the regulation of fear expression. Evidence from rodent studies implicates the ventromedial prefrontal cortex (vmPFC) in the regulation of conditioned fear. Lesions of the vmPFC have had differing effects on the acquisition and expression of conditioned fear, as well as on recall of extinction. The use of permanent lesions, however, makes it difficult to assess the phase of training in which the vmPFC is acting and can trigger recruitment of other structures, thereby masking lesion deficits. To overcome these problems, we temporarily inactivated the vmPFC of rats with tetrodotoxin (10 ng in a 0.5-microl midline infusion) at one of four time points: prior to conditioning, prior to extinction, immediately after extinction or prior to recall of extinction. Consistent with lesion findings, inactivation of the vmPFC prior to acquisition had no effect but inactivation prior to extinction led to impaired recall of extinction the following day. In contrast to lesion findings, inactivation of the vmPFC decreased freezing at all time points, suggesting that some component of the vmPFC facilitates the expression of conditioned fear. These findings suggest that inactivation of the vmPFC can have opposite effects depending on the phase of training. The vmPFC appears to be involved both in stimulating the expression of conditioned fear and in serving as a site of extinction-related plasticity that inhibits fear during recall of extinction.

Analysis of Variance↗
PubMed2004

Understanding contextual fear conditioning: insights from a two-process model.

Contextual fear conditioning is an important behavioral paradigm for studying the neurobiology of learning and memory and the mnemonic function of the hippocampus. We suggest that research in this domain can profit by a better theoretical understanding of the processes that contribute to this phenomenon. To facilitate this understanding, we describe a theory which assumes that physical elements of a conditioning context represented in the brain as either (a) a set of independent features or (b) features bound into a conjunctive representation by the hippocampus which supports pattern completion. Conditioning produced by shocking a rat in a particular context, in principle, can be produced by strengthening connections between the feature representations and/or the conjunctive representation and basolateral region of the amygdala. We illustrate how this theory clarifies some of the complexities associated with the existing literature and how it can be used to guide future empirical work. We also argue that the mechanisms (conjunctive representations and pattern completion) that mediate the contribution the hippocampus makes to contextual fear conditioning are the same ones that enable the hippocampus to support declarative memory in humans.

Amygdala↗
PubMed2000

Differential expression of EGR-1 mRNA in the amygdala following diazepam in contextual fear conditioning.

The amygdaloid complex is thought to be a major site of action of anxiolytic benzodiazepine agonists. To investigate whether activity in the amygdaloid complex is altered with anxiolytic effects of diazepam, mRNA expression of the immediate-early gene EGR-1 was examined in the amygdala following blockade of fear conditioning by diazepam. It was previously shown that mRNA expression of EGR-1 (also called, NGFI-A, Zif 268, Krox 24) increases in the lateral nucleus of the amygdala (LA) shortly following contextual fear conditioning. It was therefore hypothesized that diazepam would block both contextual fear and the concomitant increase in EGR-1 mRNA expression in the LA induced by fear conditioning. Rats administered systemic diazepam before fear conditioning displayed both anxiolytic effects during the post-shock period and amnesic effects during a retention test 24 h later. Diazepam blocked the fear-conditioning-induced increase in EGR-1 expression in the LA. In addition, diazepam significantly increased EGR-1 mRNA expression in the central nucleus of the amygdala (CeA) in a dose-dependent manner. The results reveal differential regulation of EGR-1 by diazepam in the central and lateral nuclei of the amygdala suggesting that these two amygdala nuclei act in a reciprocal manner during the anxiolytic and amnesic action of the benzodiazepine agonist.

Amygdala↗
PubMed2003

Single neurons in CA1 hippocampus encode trace interval duration during trace heart rate (fear) conditioning in rabbit.

This study sought to determine whether CA1 hippocampal neurons encode the duration of the trace interval during trace fear conditioning. Single neurons were recorded extracellularly in the CA1 of rabbits during and after a single trace fear classical conditioning session. Trace fear conditioning trials consisted of an auditory conditioned stimulus (CS; 3 sec) and a fear-producing shock unconditioned stimulus (US; 0.5 sec) separated by a silent trace interval. One group of rabbits was trained using a 10 sec trace interval (n = 5), and another group was trained using a 20 sec trace interval (n = 4). These groups were compared with pseudoconditioning control rabbits (n = 5 and n = 4, respectively) that received unpaired CSs and USs. One day after trace and pseudo fear conditioning rabbits received a CS-alone retention session in which no USs were presented. The trace conditioned groups showed larger bradycardiac-fear responses on CS-alone trials compared with the pseudoconditioning groups. A significant percentage of CA1 neurons from the 10 and 20 sec trace groups (24 and 28%, respectively) showed maximal firing on CS-alone retention trials timed to 10 sec (+/-1.5 sec) and 20 sec (+/-2.0 sec) after CS offset, respectively. These latencies were similar to the duration of the trace interval used on previous CS-trace-US trials. Timed CA1 firing was not seen in pseudoconditioning control animals, suggesting that a subset of CA1 neurons encoded the trace interval duration. The percentage of neurons encoding trace duration was largest when rabbits exhibited significant fear responses to the CS, suggesting that trace encoding was related to the strength of the CS and US association.

Acoustic Stimulation↗
PubMed1986

Effects of zolpidem, a new imidazopyridine hypnotic, on the acquisition of conditioned fear in mice. Comparison with triazolam and CL 218,872.

Benzodiazepines and other compounds which act at benzodiazepine binding sites have been shown previously to attenuate the acquisition of conditioned fear in rodents when administered before the acquisition session, an effect which may parallel the disruption of human memory produced by anxiolytics and sedatives. Such an action is usually, but not invariably, produced by doses which have direct behavioural depressant effects. The present study was carried out to extend previous work by investigating the effects of the hypnotic benzodiazepine triazolam and the nonbenzodiazepines zolpidem and CL 218,872 on the acquisition of learned fear in mice. All these drugs reduced locomotor activity shortly after injection. They also produced disruptions of the acquisition of learned fear. Triazolam exerted behavioural effects similar to those found previously with other benzodiazepines, the does which disrupted the acquisition of conditioned fear being similar to, or lower than, the doses which depressed locomotion. In contrast, the results indicated that zolpidem was more potent at reducing locomotion than at interfering with fear conditioning, a result which may reflect the preferential sedative action of zolpidem.

Animals↗
PubMed2000

Amygdala, hippocampus and discriminative fear conditioning to context.

Various measures of fear have been shown to condition to a fearful context with different acquisition rates (Antoniadis EA, McDonald RJ. Fear conditioning to context expressed by multiple measures of fear in the rat, Behav Brain Res 1999;101(1):1-14). Freezing, locomotion, urination and preference are 'fast' measures of fear in that they discriminatively condition to context after a single training session, while ultrasonic vocalizations and defecation are 'slow' measures of fear given that they condition following three training sessions. In the present experiment we sought to assess the contribution of the amygdala and the hippocampus in this form of learning. Existing views differ on the degree of involvement of each memory structure. This discord probably emerges from the common use of non-discriminative paradigms and the assessment of a single measure of fear. With the use of a discriminative paradigm and the assessment of multiple measures of fear, results indicate that the amygdala is a memory structure that selectively mediates the conditioning of heart rate, and the hippocampus selectively mediates the conditioning of defecation and body temperature. The conditioning of preference, locomotion, freezing and ultrasonic vocalizations, necessitate the participation of both memory structures while the conditioning of urination does not seem to require the participation of either the hippocampus or the amygdala. The proposed view ascribes an equal role in fear conditioning to both the amygdala and the hippocampus.

Amygdala↗
PubMed1986

Excitatory strength of expressive faces: effects of happy and fear expressions and context on the extinction of a conditioned fear response.

In a recent study, Orr and Lanzetta (1984) showed that the excitatory properties of fear facial expressions previously described (Lanzetta & Orr, 1981; Orr & Lanzetta, 1980) do not depend on associative mechanisms; even in the absence of reinforcement, fear faces intensify the emotional reaction to a previously conditioned stimulus and disrupt extinction of an acquired fear response. In conjunction with the findings on acquisition, the failure to obtain extinction suggests that fear faces have some of the functional properties of "prepared" (fear-relevant) stimuli. In the present study we compared the magnitude of conditioned fear responses to happy and fear faces when a potent danger signal, the shock electrodes, are attached or unattached. If fear faces are functionally analogous to prepared stimuli, then, even in the absence of veridical support for an expectation of shock, they should retain excitatory strength, whereas happy faces should not. The results are consistent with this view of fear expressions. In the absence of reinforcement, and with shock electrodes removed, conditioned fear responses and basal levels of arousal were of greater magnitude for the fear-face condition than for the happy-face condition.

Arousal↗