Classical conditioning and conditioning-specific reflex modification of rabbit heart rate as a function of unconditioned stimulus location.

Heart rate conditioning is used as an index of conditioned fear and is important for understanding disorders of anxiety and stress, including post traumatic stress disorder (PTSD). One important feature of PTSD is that patients generalize conditioned fear from danger signals to safety signals especially when the two signals have overlapping features. What has not been determined is whether generalization occurs between unconditioned stimuli with overlapping features. In the current experiment, heart rate conditioning and conditioning-specific reflex modification of rabbit heart rate were examined as a function of two different unconditioned stimulus locations. Heart rate conditioning occurred at identical terminal levels whether electrical stimulation was presented near the eye or on the back. Despite different heart rate response topographies to electrical stimulation at the two locations, conditioning-specific reflex modification was detected near the eye and on the back and appeared to generalize between the locations. Interestingly, only conditioning-specific reflex modification detected on the back persisted for a week after heart rate conditioning. This persistence may be a model for some features of post traumatic stress disorder. Overgeneralization of unconditioned responses to unconditioned stimuli similar to the trauma may also be an important aspect of PTSD modeled here.

Unpaired extinction: implications for treating post-traumatic stress disorder.

Extinction of fear is important for treating stress-related conditions particularly post-traumatic stress disorder (PTSD). Although traditional extinction presents the feared stimulus by itself, there is evidence from both clinical and basic research that repeatedly presenting the feared stimulus by itself does not prevent fear from returning. This renewal or relapse can be "thwarted" by unpaired extinction-presentations of the feared stimulus and the event producing the fear. However, no matter how effective standard unpaired extinction may be in the laboratory, repeated presentation of a traumatic event is untenable. To make an unpaired extinction procedure more clinically relevant, we classically conditioned the rabbit nictitating membrane response using electrical stimulation or air puff as the unconditioned stimulus and then during unpaired extinction reduced both the intensity of the unconditioned stimulus and the days of unpaired stimulus presentations. We found unpaired extinction reduced conditioned and exaggerated unconditioned responding (an animal analog of PTSD called conditioning-specific reflex modification) and could be accomplished with a weak unconditioned stimulus as long as extended presentations were used. Surprisingly, brief presentations of a weak unconditioned stimulus or extended presentations of a strong one made the exaggerated responses stronger. One implication is that brief treatment may not just be ineffectual; it may heighten the symptoms of PTSD. Another implication is that using strong stimuli may also heighten those symptoms.

Effects of extinction on classical conditioning and conditioning-specific reflex modification of rabbit heart rate.

Understanding the mechanisms of fear extinction has become increasingly important for treating a number of disorders, particularly post-traumatic stress disorder. Conditioning of rabbit heart rate (HR) is an established model for studying fear, yet little is known about procedures for extinguishing it other than repeated presentations of cue(s) associated with the fear-inducing event. The following study examined the effects of conditioned stimulus (CS) alone, unconditioned stimulus (US) alone, unpaired CS/US presentations, continued CS-US pairings, or no further stimulation on rabbit HR following HR conditioning. We have previously shown the rabbit HR response to the US can change as a function of learning when measured in the absence of the CS, a phenomenon referred to as conditioning-specific reflex modification (CRM). More specifically, the HR exhibits a deceleration in response to the US reminiscent of the conditioned bradycardia that develops to the CS. Consequently, the following study also examined the effects of extinction treatments on HR CRM. For HR conditioned responses (CRs), CS-alone and unpaired CS/US presentations were the most successful extinction treatments. For HR CRM, all conditions led to a reduction in CRM except for a subset of rabbits that maintained high levels following unpaired extinction, indicating a dissociation between extinction of HR CRs and CRM. The findings highlight the parameters of HR extinction, the transient nature of HR CRM, vagal involvement in both acquisition and extinction of HR CRM, and suggest that HR CRM cannot be fully explained as a CR that has generalized from the CS to the US.

Cholesterol enhances classical conditioning of the rabbit heart rate response.

The cholesterol-fed rabbit is a model of atherosclerosis and has been proposed as an animal model of Alzheimer's disease. Feeding rabbits cholesterol has been shown to increase the number of beta amyloid immunoreactive neurons in the cortex. Addition of copper to the drinking water of cholesterol-fed rabbits can increase this number still further and may lead to plaque-like structures. Classical conditioning of the nictitating membrane response in cholesterol-fed rabbits is retarded in the presence of these plaque-like structures but may be facilitated in their absence. In a factorial design, rabbits fed 2% cholesterol or a normal diet (0% cholesterol) for 8 weeks with or without copper added to the drinking water were given trace classical conditioning using a tone and periorbital electrodermal stimulation to study the effects of cholesterol and copper on classical conditioning of heart rate and the nictitating membrane response. Cholesterol-fed rabbits showed significant facilitation of heart rate conditioning and conditioning-specific modification of heart rate relative to normal diet controls. Consistent with previous research, cholesterol had minimal effects on classical conditioning of the nictitating membrane response when periorbital electrodermal stimulation was used as the unconditioned stimulus. Immunohistochemical analysis showed a significant increase in the number of beta amyloid positive neurons in the cortex, hippocampus and amygdala of the cholesterol-fed rabbits. Supplementation of drinking water with copper increased the number of beta amyloid positive neurons in the cortex of cholesterol-fed rabbits but did not produce plaque-like structures or have a significant effect on heart rate conditioning. The data provide additional support for our finding that, in the absence of plaques, dietary cholesterol may facilitate learning and memory.