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Treatment for PTSD (Post-traumatic stress disorder) is rarely available immediately after trauma and often delayed for weeks or months after an event. In a rabbit eyeblink conditioning model of PTSD, we have previously shown that presentations of a tone conditioned stimulus (CS) and shock unconditioned stimulus (US) in an explicitly unpaired manner known as unpaired extinction is effective in reducing CS responding and US hyperarousal even if shock intensity is reduced eight-fold and elicits only minimal responding. Here we determined if delayed delivery of unpaired extinction would still be effective in extinguishing hyperarousal. Rabbits were tested for sensitivity to shock before CS-US pairings and after six days of unpaired extinction presented a day, a week or a month after CS-US pairings. Hyperarousal was extinguished a day and a week after conditioning but not after a month suggesting a significant delay in "treatment" can make hyperarousal persist. We next assessed if this persistence of hyperarousal was associative by comparing rabbits given CS-US pairings to those given explicitly unpaired CS and US presentations, measuring hyperarousal a day and a month later, followed by unpaired extinction and hyperarousal assessment. After four weeks, there was an increase in responding for all rabbits but only rabbits receiving CS-US pairings showed a significant increase in associatively-mediated hyperarousal. Importantly, both paired and unpaired groups showed increased levels of responding after unpaired extinction suggesting treatment delayed for too long may no longer be effective and could cause generalized hyperarousal., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Averaging behavioral data such as the nictitating membrane response (NMR) across subjects can conceal important individual and group differences. Analyses were conducted of NMR data from rabbits that were grouped based on the point during NMR conditioning when subjects produced 8 conditioned responses (CR) in a set of 10 trials. This resulted in five groups (Early Day 1, Late Day 1, Early Day 2, Late Day 2, Early Day 3) in which group differences in CR acquisition rates were found. Percent (%) CRs were not found to increase monotonically and between-session differences in % CR were found. Conditioning-specific reflex modification (CRM) of the NMR is a type of enhanced reflexive responding of the NMR that is detected when the unconditioned stimulus (US) is presented in the absence of the conditioned stimulus (CS) following paired classical conditioning. CRM occurred in some subjects in all five groups. Subjects from both the group that was fastest and the group that was slowest to reach the learning criterion had unconditioned response (UR) topographies following NMR conditioning that strongly resembled the CR-UR response sequence elicited during NMR conditioning. This finding was most pronounced when the US duration used to assess CRM was equivalent to that used during NMR conditioning, further evidence to support the hypothesis that CRM is a CR that has generalized from the CS to the US. While grouping data based on conditioning criteria did not facilitate identifying individuals more predisposed to exhibiting CRM, strong CRM only occurred in the groups that reached the conditioning criterion the fastest., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Rats are responsive to shock from an early age, but eyeblink conditioning to a tone-conditioned stimulus (conditional stimulus; CS) paired with a shock-unconditioned stimulus (US) does not emerge until postnatal Day 20 (P20). More generalized postural responses such as conditioned freezing can occur at P16. Using the same periorbital shock as both the CS and US in a US-US conditioning paradigm previously shown to be effective in adult animals, we found that shock-shock pairings with a 200-ms trace interval resulted in eyeblink conditioning in younger animals than previously thought. Some rat pups showed conditioned eyeblink responses as early as P12, and by P18, conditioned responses were fully developed in all animals. Unpaired control subjects confirmed that responding in paired subjects was associative. Although many stimuli can act as a CS in adults, the advantage of using US-US pairings is that responses to the first US ensure young rat pups are capable of detecting the stimulus-something that may not be true when auditory or visual stimuli are used early in the development of altricial animals. The US-US pairing paradigm could be used to study the ontogeny and neural substrates of learning and memory before other sensory systems mature, and evaluate learning and memory in animal models of early developmental disorders., ((PsycINFO Database Record (c) 2013 APA, all rights reserved).)

Incubation of fear has been used to account for the delayed manifestation of symptoms of fear and anxiety including the delayed onset of Post Traumatic Stress Disorder (PTSD). We have shown the utility of classical conditioning-specific modification of the rabbit nictitating membrane response (NMR) as a model of PTSD. This modification includes an exaggeration in the size and a change in the timing of the unconditioned NMR after several days of classical conditioning. To assess the effects of incubation on conditioning-specific modification, we measured changes in responding as a function of the time between classical conditioning and NMR testing. After just one day of classical conditioning resulting in modest levels of learning, increases in response size were an inverted-U shaped function of days of incubation with little if any change occurring one and ten days after training but significant change occurring after six days. The incubation effect persisted for a week. An unpaired control group showed no change in the size of the response confirming the incubation effect was associative. The results bear a striking resemblance to symptoms of PTSD that do not always occur immediately after trauma and become exacerbated over time and then persist. They point to a window when incubation can exacerbate symptoms and speak to the vulnerability of re-experiencing trauma too soon. This could be a serious problem for military or emergency personnel recalled to combat or a disaster site without sufficient time to deal with the effects of their initial experiences., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

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., ((PsycINFO Database Record (c) 2011 APA, all rights reserved).)

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., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

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.

Modifying dietary cholesterol may improve learning and memory but very high cholesterol can cause pathophysiology and death. Rabbits fed 2% cholesterol for 8, 10 or 12 weeks with 0.12 ppm copper added to distilled water and rabbits fed a normal diet without copper added to distilled water (0 weeks) were given a difficult trace classical conditioning task and an easy delay conditioning task pairing tone with corneal air puff. The majority of cholesterol-fed rabbits survived the deleterious effects of the diet but survival was an inverse function of the diet duration. Compared to controls, the level of classical conditioning and conditioning-specific reflex modification were an inverted "U"-shaped function of diet duration. Highest levels of responding occurred in rabbits on cholesterol for 10 weeks and trace conditioning was negatively correlated with the number of hippocampal beta-amyloid-positive neurons. Rabbits on the diet for 12 weeks responded at levels comparable to controls. The data provide support for the idea that dietary cholesterol may facilitate learning and memory but there is an eventual trade off with pathophysiological consequences of the diet.

Studies have shown that modifying dietary cholesterol may improve learning and that serum cholesterol levels can be positively correlated with cognitive performance. Rabbits fed a 0, 0.5, 1 or 2% cholesterol diet for eight weeks and 0.12 ppm copper added to their drinking water received trace and then delay classical conditioning pairing tone with corneal air puff during which movement of the nictitating membrane (NM) across the eye was monitored. We found that the level of classical conditioning and conditioning-specific reflex modification (CRM) as well as the number of beta amyloid-labeled neurons in the cortex and hippocampus were a function of the concentration of cholesterol in the diet. The data provide support for the idea that dietary cholesterol may facilitate learning and memory.

Conditioning-specific reflex modification (CRM) describes changes in rabbit (Oryctolagus cuniculus) nictitating membrane responses (NMR) to an unconditioned stimulus (US) when the US is tested by itself after pairings of tone and electrodermal stimulation. Although CRM has been replicated, it is unclear whether it occurs in response systems other than that of the NMR. The authors report that CRM of rabbit heart rate (HR) can occur following HR conditioning. A US that elicits HR acceleration before conditioning can elicit HR deceleration after conditioning. The rabbits' electrocardiograms showed both HR conditioning and HR CRM were correlated with an increased PQ interval--an index of parasympathetic function mediated by the vagus. The data suggest conditioned HR deceleration can generalize from conditioned stimulus to US as a function of conditioning., (Copyright (c) 2006 APA, all rights reserved.)

Conditioning-specific reflex modification (CRM) of the rabbit's nictitating membrane response (NMR) involves changes in responding to an unconditioned stimulus (US) when the US is tested in the absence of the conditioned stimulus. Previous experiments have shown that CRM is a function of the type and intensity of the aversive US used during classical conditioning. As a result, it has been suggested that CRM may be mediated, at least in part, by the aversiveness of the US. Here, we show that by using a moderately intense electrical pulse to the skin as a US, CRM of the rabbit NMR is accompanied by an increase in heart rate. The largest changes in heart rate occur at US intensities that produce the strongest levels of CRM. The heart rate data show that there may be an increased emotional/arousal component to the US that is correlated with CRM and support the use of CRM as a potential model for posttraumatic stress disorder.

Cholesterol plays an important role in synapse formation, receptor function, and synaptic plasticity, and animal studies show that modifying cholesterol may improve learning and memory. Other data show that feeding animals cholesterol can induce beta amyloid accumulation. Rabbits (Oryctolagus cuniculus) fed 2% cholesterol for 8 weeks were given trace conditioning of the nictitating membrane response using a 100-ms tone, a 700-ms trace, and periorbital electrical stimulation or airpuff. Rabbits fed cholesterol showed significant facilitation of trace conditioning to airpuff and conditioning-specific reflex modification to periorbital electrical stimulation and airpuff. The cholesterol-fed rabbits had beta amyloid accumulation in the cortex, but little in the hippocampus. The data suggest cholesterol had facilitative effects that outweighed potential amnesic effects of cortical beta amyloid., ((c) 2003 APA)