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Cholinergic effects on fear conditioning II: nicotinic and muscarinic modulations of atropine-induced disruption of the degraded contingency effect.

RATIONALE: In a companion study (Carnicella et al., 2005), we showed that the muscarinic antagonist atropine, when administered after extensive training during both conditioning and testing, affected neither cued nor contextual fear memories when both of them did not compete for the control of the overt behaviour. In contrast, atropine altered the degraded contingency effect (DCE), that is, the processes by which contextual fear memory competes with the cued one for the control of the conditioned response. Atropine-induced disruption of the DCE was fully reversed by the administration of the anticholinesterase inhibitor physostigmine, which suggests a direct cholinergic implication. OBJECTIVE: The present series of experiments was conducted in order to define more precisely the involvement of the cholinergic system in such an effect. METHODS: Oxotremorine (0.0, 0.0075, 0.015, or 0.03 mg/kg), pilocarpine (0.0, 0.3, 1, or 3 mg/kg), xanomeline (0.0, 2.5, 5.0, 10.0 or 20.0 mg/kg) and nicotine (0.0, 0.1, 0.2, or 0.4 mg/kg) were tested for reversal of the atropine-induced alteration of the DCE. RESULTS: Oxotremorine and pilocarpine did not reverse the atropine-induced alteration of the DCE. In contrast, xanomeline and nicotine reversed the effect of atropine on the DCE. CONCLUSION: The present series of experiments reveals complex pharmacological interactions within the cholinergic system when cued and contextual fear memories interact. Results are discussed in this connection and with regard to the relation between the properties of cholinergic agonists and their therapeutic values.

Animals↗

A visual pathway that mediates fear-conditioned enhancement of acoustic startle.

Eighty rats received 10 light-shock pairings on two successive days. Seventy-two h after the final training session, subjects received lesions directed at the primary visual areas (deep and superficial layers of the superior colliculus, dorsal lateral geniculate nucleus, pretectal nuclei, visual cortex and thalamic reticular nucleus) and at the nuclei of the lateral lemniscus and reticularis pontis caudalis, proposed components of a primary acoustic startle circuit in the rat. Control animals were sham operated. One day later, all animals were tested for startle by presenting noise bursts of 3 different intensities in the presence or absence of the light conditioned stimulus. Potentiated startle (the difference between light-noise vs noise-alone trials) was significantly attenuated or eliminated by lesions directed at the dorsal nucleus of the lateral geniculate, deep layers of the superior colliculus, visual cortex, and the posteroventral region of the nucleus of the lateral lemniscus. Lesions directed at pretectal nuclei, superficial layers of the superior colliculus, thalamic reticular nucleus, nucleus reticularis pontis caudalis or dorsal nucleus of the lateral lemniscus did not attenuate potentiated startle. The results suggest that the visual pathway that mediates potentiated startle goes from the retina to the dorsal lateral geniculate nucleus to visual cortex to deep layers of superior colliculus and down to the postero-ventral region of the lateral lemniscus where acoustic startle is modulated.

Acoustic Stimulation↗

Electrophysiological characteristics of amygdaloid central nucleus neurons during Pavlovian fear conditioning in the rabbit.

Recent evidence suggests that the amygdaloid central nucleus (ACE) may contribute importantly to cardiovascular adjustments in response to the presentation of conditioned emotional stimuli, possibly via direct ACE projections to cardiovascular regulatory nuclei in the medulla. The present experiment was conducted to obtain additional data relevant to this suggestion. Extracellular single-unit recordings were obtained from 85 histologically-verified ACE neurons during Pavlovian differentially conditioned heart-rate responding in rabbits. Conditioning involved pairing one tone (CS+), but not a second tone (CS-), with paraorbital shock. Those ACE neurons which project to the lower brainstem were identified by their antidromic responses to stimulation of a mesencephalic region through which descending ACE projections course. Under these conditions it was possible to classify ACE neurons as conforming to one of 6 general categories based on their spontaneous activity and conditioned response characteristics. In addition, it was determined that: (1) the electrophysiological characteristics of many ACE neurons were differentially altered in response to presentations of the CS+ versus the CS-; (2) the responses of many ACE neurons to presentations of the CS+ were correlated with the magnitudes of concomitant conditioned alterations in heart rate; and (3) the activity of antidromically-identified ACE neurons which project to the lower brainstem was decreased in response to presentations of each CS. These data provide additional support for the notion that the ACE contributes to cardiovascular regulation during the presentation of emotionally-arousing stimuli.

Action Potentials↗

Cortical activation during Pavlovian fear conditioning depends on heart rate response patterns: an MEG study.

In the present study, we examined stimulus-driven neuromagnetic activity in a delayed Pavlovian aversive conditioning paradigm using steady state visual evoked fields (SSVEF). Subjects showing an accelerative heart rate (HR) component to the CS+ during learning trials exhibited an increased activation in sensory and parietal cortex due to CS+ depiction in the extinction block. This was accompanied by a selective orientation response (OR) to the CS+ during extinction as indexed by HR deceleration. However, they did not show any differential cortical activation patterns during acquisition. In contrast, subjects not showing an accelerative HR component but rather unspecific HR changes during learning were characterized by greater activity in left orbito-frontal brain regions in the acquisition block but did not show differential SSVEF patterns during extinction. The results suggest that participants expressing different HR responses also differ in their stimulus-driven neuromagnetic response pattern to an aversively conditioned stimulus.

Adult↗

Fear-conditioned cues of impending pain facilitate attentional engagement.

AIMS OF STUDY: Selective attention to signals of impending pain allows the avoidance of bodily harm. In order to identify the attentional components involved in the selection of pain signals over competing demands, we used an emotional modification of an exogenous cueing task. METHODS: Fifty-two pain-free volunteers detected visual targets of which the location was correctly or incorrectly predicted by a spatial cue. Cues were emotionally modulated using differential classical conditioning. The conditioned cue (CS+) was sometimes followed by an electrocutaneous stimulus (UCS), thus becoming a pain signal, whereas the UCS never followed the other cue (CS-), referred to as safety signal. RESULTS: Analyses of response times showed that pain signals facilitated the directing of attention to their location in comparison to safety signals. In contrast, pain signals did not impair disengagement of attention from their location in comparison to safety signals. CONCLUSION: It is concluded that attention is more strongly engaged to a signal of impending pain compared with a cue signalling its absence. We explore why disengagement from the pain signal is not impaired compared to the safety signal. The findings are discussed in terms of the defensive importance of pain anticipation.

Adult↗

Disruption of reconsolidation but not consolidation of auditory fear conditioning by noradrenergic blockade in the amygdala.

Consolidation is a process through which labile memories are made persistent [Science 287 (2000) 248]; [Annu Rev Psychol 55 (2004) 51]. When retrieved, a consolidated memory is rendered labile again and undergoes reconsolidation [Learn Mem 7 (2000) 73]; [Trends Neurosci 26 (2003) 65]). Reconsolidation thus offers the opportunity to manipulate memory after it is formed, and may therefore provide a means of treating intrusive memories associated with post-traumatic stress disorder (PTSD). Reconsolidation is most usually studied using protein synthesis inhibitors, which is not practical in humans. However, the beta adrenergic receptor antagonist propranolol impairs consolidation of declarative memory in humans [Science 287 (2000) 248]; [Nature 371 (1994) 702] and consolidation and reconsolidation of inhibitory avoidance learning in rats [Brain Res 368 (1986) 125]; [J Neurosci 19 (1999) 6623]. Here, we show that systemic or intra-amygdala infused propranolol blocks reconsolidation but not consolidation. If the effects on reconsolidation are verified in humans, the results would suggest the possibility that propranolol after memory retrieval might be an effective way of treatment of intrusive memories in PTSD. That the systemic effects of propranolol on reconsolidation are achieved via an action in the amygdala is especially important in light of the fact that PTSD involves alterations in the amygdala [Arch Gen Psychiatry 53 (1996) 380].

Acoustic Stimulation↗

Unconditioned stimulus rehearsal and the retention and enhancement of differential "fear" conditioning: effects of trait and state anxiety.

In 2 experiments, the effect of anxiety on the cued-unconditioned stimulus (UCS) rehearsal phenomenon was investigated (T. Jones & G. C. L. Davey, 1990). In Experiment 1, postconditioning rehearsal of the unconditioned stimulus (UCS) resulted in an increase in conditioned response (CR) strength during extinction, but only in subjects with high levels of trait anxiety. An induced mood procedure was used in Experiment 2, and a postrehearsal increase in CR strength was found in subjects who had undergone induced somatic anxiety but not in subjects who had undergone induced worrying or who underwent a neutral induction procedure. In both experiments, the increase in CR strength following UCS rehearsal was associated with inflated ratings of the aversiveness of rehearsing the UCS. These results are discussed in terms of the ways in which anxiety might influence UCS rehearsal and facilitate physiological CRs to the conditioned stimulus.

Adolescent↗

Effect of tone-dependent fear conditioning on heart rate and behavior of C57BL/6N mice.

The effects of the temporal sequence of tone (conditioned stimulus [CS]) and footshock (unconditioned stimulus [US]) during training (acquisition) on tone-dependent retention were studied in mice. Freezing increased significantly as an associative behavioral response in mice subjected to CS paired with US or after unpaired by 30 s in the memory test performed 24 hr after training. In the home cage of freely moving mice implanted with an electrocardiogram transmitter, CS triggered a strong tachycardiac response in the memory test. Heart rate (HR) increased from about 580 bpm to more than 750 bpm, and HR variability decreased significantly. The inhibition of the HR increase by the nonspecific beta-adrenergic antagonist sotalol indicated the strong sympathetic contribution to the tachycardiac response. CS evoked a significant but minor HR increase in mice subjected to either CS or US only or CS and US unpaired by 60 s. Thus, HR and HR variability reflected associative learning.

Animals↗