The ontogeny of fear-potentiated startle: Effects of earlier-acquired fear memories.

Research has shown that learned fear emerges in a response-specific sequence. For example, freezing is observed at a younger age than is potentiated startle (P. Hunt & B. A. Campbell, 1997). The present study shows that the age at which a specific learned fear response emerges is influenced by the animal's early experiences. Specifically, fear potentiation of startle emerges earlier in development if the rat is given prior fear conditioning to a different stimulus. Some constraints of this "facilitation" effect are determined in follow-up experiments. This facilitation effect may provide a novel way of testing the development of the neural circuits underlying learned fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Olfactory-mediated fear-potentiated startle.

Recently, R. Richardson, A. Vishney, and J. Lee (1999) reported that ambient odor cues that were previously paired with footshock potentiate the acoustic startle response in rats. The authors of the present study extend those findings by using a discrete 4-s amyl acetate odor paired with footshock to address several parametric issues that might be important for using odorants as conditioned stimuli (CSs) in this paradigm. Amyl acetate (5%) had no significant effect on startle in untrained rats but did potentiate startle in rats that received 1, 2, 5, or 10 odor-shock pairings. Fear-potentiated startle decreased but was still significant up to 40 days after conditioning and could be measured in test trials separated by as little as 30 s. The magnitude of potentiated startle decreased with decreasing concentrations of amyl acetate (5%-5 x 10-9%). The anxiolytic compound buspirone (10 mg/kg) significantly attenuated olfactory-mediated fear-potentiated startle. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Contingency awareness and fear inhibition in a human fear-potentiated startle paradigm.

Fear-potentiated startle is defined as an increase in the magnitude of the startle reflex in the presence of a stimulus that was previously paired with an aversive event. It has been proposed that a subject's awareness of the contingencies in the experiment may affect fear-potentiated startle. The authors adapted a conditional discrimination procedure (AX+/BX-), previously validated in animals, to a human fear-potentiated startle paradigm in 50 healthy volunteers. This paradigm allows for an assessment of fear-potentiated startle during threat conditions as well as inhibition of fear-potentiated startle during safety conditions. A response keypad was used to assess contingency awareness on a trial-by-trial basis. Both aware and unaware subjects showed fear-potentiated startle. However, awareness was related to stimulus discrimination and fear inhibition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of prior exposure to a lithium- and an amphetamine-paired flavor on the acoustic startle response in rats.

The experiments reported here evaluated the hypothesis that an amphetamine-paired flavor elicits conditioned fear-arousal, whereas a lithium-paired flavor elicits conditioned nausea-disgust by examining the effect of prior flavor exposure on an acoustic startle reaction (ASR). Exposure to a lithium-paired flavor by intraoral infusion, either immediately prior to a startle session (Experiment 1) or during a startle session (Experiments 2 and 3), resulted in a blunted ASR. In contrast, intraoral infusion of an amphetamine-paired flavor resulted in a potentiated ASR. The blunted ASR produced by exposure to a lithium-paired flavor dramatically reversed to a potentiated ASR when rats were pretreated with the antiemetic drug ondansetron prior to the saccharin-lithium pairing (Experiment 3). The findings shed light on a mechanism by which rewarding drugs produce conditioned taste avoidance in rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Neural systems involved in fear and anxiety measured with fear-potentiated startle.

A good deal is now known about the neural circuitry involved in how conditioned fear can augment a simple reflex (fear-potentiated startle). This involves visual or auditory as well as shock pathways that project via the thalamus and perirhinal or insular cortex to the basolateral amygdala (BLA). The BLA projects to the central (CeA) and medial (MeA) nuclei of the amygdala, which project indirectly to a particular part of the acoustic startle pathway in the brainstem. N-methyl-D-aspartate (NMDA) receptors, as well as various intracellular cascades in the amygdala, are critical for fear learning, which is then mediated by glutamate acting in the CeA. Less predictable stimuli, such as a long-duration bright light or a fearful context, activate the BLA, which projects to the bed nucleus of the stria terminalis (BNST), which projects to the startle pathway much as the CeA does. The anxiogenic peptide corticotropin-releasing hormone increases startle by acting directly in the BNST. CeA-mediated behaviors may represent stimulus-specific fear, whereas BNST-mediated behaviors are more akin to anxiety. NMDA receptors are also involved in extinction of conditioned fear, and both extinction in rats and exposure-based psychotherapy in humans are facilitated by an NMDA-partial agonist called D-cycloserine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of corticosterone in trace and delay conditioned fear-potentiated startle in rats.

Emotional events often lead to particularly strong memory formation. Corticosterone, the final product of hypothalamic-pituitary-adrenal (HPA)-axis activation, has been suggested to play a critical role in this effect. Although a great deal of work has implicated the amygdala as a necessary structure for the effects of corticosterone, other studies have suggested a critical role for the hippocampus in determining the involvement of corticosterone. The current experiments examined this question by disrupting corticosterone synthesis with administration of metyrapone (25 or 100 mg/kg) prior to training in either dorsal hippocampus-independent delay fear conditioning or dorsal hippocampus-dependent trace fear conditioning. Metyrapone administration 2 hrs prior to training significantly attenuated corticosterone secretion during training, but these effects were transient as corticosterone levels were similar to control subjects following the test session. As hypothesized, only trace fear conditioning was impaired. This suggests that only fear conditioning tasks that are dependent on the dorsal hippocampus require HPA-axis activation in order to be learned. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral expression of learned fear: Updating of early memories.

The expression of learned fear emerges in a response-specific sequence where freezing occurs before fear potentiated startle (FPS) to an odor conditioned stimulus (CS; Postnatal Day [PN] 16 vs. PN 23; e.g., Hunt, 1997; Richardson, Paxinos, & Lee, 2000). Studies have shown that learned fear is expressed in a manner appropriate to the animal's age at training and not its age at test (Richardson & Fan, 2002; Richardson et al., 2000). Specifically, animals trained with an odor CS at PN 16 exhibit avoidance but not FPS when tested at PN 23. The present study shows that subsequent training with a different CS can "update" an early memory, allowing it to be expressed in a manner appropriate to the animal's age at test. This updating effect appears to be modality specific, whereby the subsequent training must involve a CS of the same sensory modality as the original training. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Group II metabotropic glutamate receptors within the amygdala regulate fear as assessed with potentiated startle in rats.

The contribution to fear and fear learning of amygdala Group II metabotropic glutamate receptors was examined in rats. Pretest intra-amygdala infusions of the Group II receptor agonist LY354740 (0.3 or 1.0 μg/side) significantly disrupted fear-potentiated startle. The same rats were unimpaired when later tested without drug. The Group II receptor agonist (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (3.0 μg/side) mimicked the effect of LY354740, and coadministration of the Group II receptor antagonist LY341495 (0.3 μg/side) prevented it. Pretraining LY354740 (0.3 μg/side) infusions also blocked learning. The effects on learning and performance were significantly less pronounced in rats with misplaced cannulas. Thus, Group II metabotropic receptors within or very near the amygdala regulate fear and fear learning and are a potential target for anxiolytic compounds. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Centrally administered corticotropin-releasing hormone and peripheral injections of strychnine hydrochloride potentiate the acoustic startle response in preweanling rats.

Attempts to condition fear potentiation of startle (FPS) in rats younger than 23 days of age have not been successful, regardless of the type of aversively conditioned stimulus used (P. S. Hunt, R. Richardson, & B. A. Campbell, 1994; R. Richardson, G. Paxinos, & J. Lee, 2000; R. Richardson & A. Vishney, 2000). In the present study, the authors report that peripheral injections of strychnine hydrochloride, a glycine receptor antagonist, and intracerebroventricular infusions of corticotropin releasing hormone (CRH) both potentiated the acoustic startle response (ASR) in 16–18-day-old rats. Because strychnine and CRH have distinct sites of activation in the primary startle pathway, it can be concluded that this pathway is functional and modifiable in rats younger than 23 days of age. This finding suggests that the failure to observe conditioned FPS in preweanling rats is due to an immaturity of the secondary fear circuit responsible for enhancing the ASR during a fear state. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Experience increases the prepulse inhibition of the acoustic startle response in mice.

The authors have previously shown that inhibition of the acoustic startle response by a prepulse increases when it is repetitively elicited over days. The present experiments show in C3H and C57 mice that this change is caused by an increase in prepulse inhibition (PPI) and not by a decrease in prepulse facilitation. This PPI increase is only evoked if prepulses and startle stimuli are repeatedly given in a temporally paired ("contingent") order, proposing an associative learning process. (Only in C57 mice, PPI was additionally increased by adaptation in the same, but not in a different, context). As an underlying mechanism for this PPI increase by experience, the authors hypothesize Hebbian plasticity of an inhibitory synapse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Olfactory-Mediated Fear Conditioning in Mice: Simultaneous Measurements of Fear-Potentiated Startle and Freezing.

This study demonstrates that mice display olfactory-cued fear as measured with both freezing and fear-potentiated startle. Following a preconditioning test to measure any unconditioned responses to odor, mice received 5 pairings of a 10-s odor with a 0.25-s, 0.4-mA footshock. The next day, startle and freezing were measured in the presence and absence of the odor. Both fear measures increased after training with amyl acetate (Experiment 1) and acetophenone (Experiment 2). The enhancement of startle did not occur when the same number of odors and shocks were presented in an unpaired fashion (Experiment 3). Furthermore, mice were able to discriminate between an odor paired with shock and a nonreinforced odor (Experiment 4). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Alcohol selectively reduces anxiety but not fear: Startle response during unpredictable versus predictable threat.

Recent theory and empirical research have suggested that fear and anxiety are distinct processes with separable neurobiological substrates. Furthermore, a laboratory procedure has been developed to manipulate fear versus anxiety independently via administration of predictable or unpredictable electric shock, respectively. Benzodiazepines appear to selectively reduce anxiety but not fear in this procedure. The primary aim of this experiment was to determine if alcohol produced a similar selective reduction in anxiety. Intoxicated (target blood alcohol concentration of .08%) and nonintoxicated participants viewed a series of colored squares separated by variable intertrial intervals (ITIs) in 3 conditions. In the predictable shock condition, shocks were administered contingently during every square. In the unpredictable shock condition, shocks were administered noncontingently during both squares and ITIs. In the no-shock condition, no shocks were administered at any time. Alcohol significantly reduced startle potentiation during cues signaling unpredictable but not predictable shock, consistent with the thesis that alcohol selectively reduces anxiety but not fear. In addition, alcohol’s effect on startle potentiation during unpredictable shock was mediated by vigilance. This anxiolytic effect may clarify the nature of alcohol’s reinforcing effects in social and problem drinkers. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sexual orientation-related differences in prepulse inhibition of the human startle response.

Prepulse inhibition (PPI) refers to a reduction in the startle response to a strong sensory stimulus when this stimulus is preceded by a weaker stimulus--the prepulse. PPI reflects a nonlearned sensorimotor gating mechanism and also shows a robust gender difference, with women exhibiting lower PPI than men. The present study examined the eyeblink startle responses to acoustic stimuli of 59 healthy heterosexual and homosexual men and women. Homosexual women showed significantly masculinized PPI compared with heterosexual women, whereas no difference was observed in PPI between homosexual and heterosexual men. These data provide the first evidence for within-gender differences in basic sensorimotor gating mechanisms and implicate the known neural substrates of PPI in human sexual orientation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Age-related affective modulation of the startle eyeblink response: Older adults startle most when viewing positive pictures.

Previous studies reveal age by valence interactions in attention and memory, such that older adults focus relatively more on positive and relatively less on negative stimuli than younger adults. In the current study, eyeblink startle response was used to measure differences in emotional reactivity to images that were equally arousing to both age groups. Viewing positive and negative pictures from the International Affective Picture System had opposite effects on startle modulation for older and younger adults. Younger adults showed the typical startle blink pattern, with potentiated startle when viewing negative pictures compared to positive pictures. Older adults, on the other hand, showed the opposite pattern, with potentiated startle when viewing positive pictures compared to viewing negative and neutral pictures. Potential underlying mechanisms for this interaction are evaluated. This pattern suggests that, compared with younger adults, older adults are more likely to spontaneously suppress responses to negative stimuli and process positive stimuli more deeply. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Functional MRI of human amygdala activity during Pavlovian fear conditioning: Stimulus processing versus response expression.

Although laboratory animal studies have shown that the amygdala plays multiple roles in conditional fear, less is known about the human amygdala. Human subjects were trained in a Pavlovian fear conditioning paradigm during functional magnetic resonance imaging (fMRI). Brain activity maps correlated with reference waveforms representing the temporal pattern of visual conditional stimuli (CSs) and subject-derived autonomic responses were compared. Subjects receiving paired CS-shock presentations showed greater amygdala activity than subjects receiving unpaired CS-shock presentations when their brain activity was correlated with a waveform generated from their behavioral responses. Stimulus-based waveforms revealed learning differences in the visual cortex, but not in the amygdala. These data support the view that the amygdala is important for the expression of learned behavioral responses during Pavlovian fear conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pretraining Inactivation of the Caudal Pontine Reticular Nucleus Impairs the Acquisition of Conditioned Fear-Potentiated Startle to an Odor, but Not a Light.

Recent data from developing rats suggest that structures downstream from the amygdala are involved in the acquisition of conditioned fear-potentiated startle (FPS). The authors tested this idea in adult rats by temporarily inactivating the structure critical for FPS, the caudal pontine reticular nucleus (PnC), during fear conditioning. When the conditioned stimulus (CS) was an odor, rats displayed freezing, but not FPS, at test. This effect was not due to a decrease in footshock sensitivity. Further, no savings were evident on retraining. When the CS was a light, inactivation of the PnC had no effect on the acquisition of FPS. Thus, the PnC may be crucial for the acquisition of conditioned FPS to an odor, but not a light. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

In dubio pro defensio: Initial activation of conditioned fear is not cue specific.

This study explored the time course of conditioned fear response expression. Two neutral male facial expressions served as conditioned stimuli (CS) in a differential trace conditioning that involved either an aversive (n=14) or a nonaversive (n=12) unconditioned stimulus (UCS) in a between-subjects design. Skin conductance response (SCR) to the CSs and startle response magnitudes to acoustic probes presented at early (250 ms) or late (1,750 ms) probe times after CS onset were measured. As expected, conditioned SCR discrimination was observed in both aversive and nonaversive learning, whereas the conditioned potentiation of the startle response was only observed for the aversive UCS condition. Interestingly, conditioned startle discrimination was specific for the later probe time. In contrast, conditioned fear potentiation of the startle response at the early probe time was equally pronounced for CS+ and CS-. These findings suggest that fear-eliciting neural structures are rapidly activated in fear learning, whereas the expression of inhibitory conditioning requires more time, presumably reflecting the involvement of cortical top-down control processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differences in startle reactivity during the perception of angry and fearful faces.

Emotion researchers often categorize angry and fearful face stimuli as "negative" or "threatening". Perception of fear and anger, however, appears to be mediated by dissociable neural circuitries and often elicit distinguishable behavioral responses. The authors sought to elucidate whether viewing anger and fear expressions produce dissociable psychophysiological responses (i.e., the startle reflex). The results of two experiments using different facial stimulus sets (representing anger, fear, neutral, and happy) indicated that viewing anger was associated with a significantly heightened startle response (p     

Motor preparation and the effects of practice: Evidence from startle.

To examine sequential movement preparation, participants practiced unimanual movements that differed in amplitude and number of elements for 4 days in either a simple (Experiment 1) or choice (Experiment 2) reaction time (RT) paradigm. On Day 1 and 4, a startling stimulus was used to probe the preparation process. For simple RT, we found increased premotor RT for the two component movement during control trials on Day 1, which was minimized with practice. During startle trials, all movements were triggered at a short latency with similar consistency to control trials, suggesting full advance preparation of all movements. For choice RT, we also found increased premotor RT for control trials for the two component movement. As advance preparation could not occur, the startling stimulus did not trigger any of the movements. We hypothesized that complexity may relate to the neural commands needed to produce the movement, rather than a sequencing requirement. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Appetitively motivated instrumental learning in SynGAP heterozygous knockout mice.

The synaptic Ras/Rap-GTPase-activating protein (SynGAP) regulates specific intracellular events following N-methyl-d-aspartate receptor (NMDAR) activation. Here, the impact of SynGAP heterozygous knockout (SG+/?) on NMDAR-dependent functions was assessed using different positive reinforcement schedules in instrumental conditioning. The knockout did not affect the temporal control of operant responding under a fixed interval (FI) schedule, but led to a putative enhancement in response vigor and/or disinhibition. When examined on differential reinforcement of low rates of response (DRL) schedules, SG+/? mice showed increased responding under DRL-4s and DRL-8s, without impairing the response efficiency (total rewards/total lever presses) because both rewarded and nonrewarded presses were elevated. Motivation was unaffected as evaluated using a progressive ratio (PR) schedule. Yet, SG+/? mice persisted in responding during extinction at the end of PR training, although an equivalent phenotype was not evident in extinction learning following FI-20s training. This extinction phenotype is therefore schedule-specific and cannot be generalized to Pavlovian conditioning. In conclusion, constitutive SynGAP reduction increases vigor in the execution of learned operant behavior without compromising its temporal control, yielding effects readily distinguishable from NMDAR blockade. (PsycINFO Database Record (c) 2010 APA, all rights reserved)