Effects of extinction treatments on the reduction of conditioned responding and conditioned hyperarousal in a rabbit model of posttraumatic stress disorder (PTSD).

Abstract

We have previously characterized a model of posttraumatic stress disorder (PTSD), based on classical conditioning of the rabbit nictitating membrane response (NMR), that focuses on 2 key PTSD-like features: conditioned responses to trauma-associated cues and hyperarousal. In addition to the development of conditioned NMRs (CRs) to a tone conditioned stimulus (CS) associated with a periorbital shock unconditioned stimulus (US), we have observed that rabbits also exhibit a conditioning-specific reflex modification (CRM) of the NMR that manifests as an exaggerated and more complex reflexive NMR to presentations of the US by itself, particularly to intensities that elicited little response prior to conditioning. Previous work has demonstrated that unpaired presentations of the CS and US are successful at extinguishing CRs and CRM simultaneously, even when a significantly weakened version of the US is utilized. In the current study, additional extinction treatments were tested, including continued pairings of the CS with a weakened US and exposure to the training context alone, and these treatments were contrasted with the effects of unpaired extinction with a weakened US and remaining in home cages with no further treatment. Results showed that continued pairings only slightly decreased CRs and CRM, while context exposure had no effect on CRs and marginal effects on reducing CRM. Unpaired extinction was still the most effective treatment for reducing both. Findings are discussed in terms of applications to cognitive–behavioral therapies for treatment of PTSD, such as incorporating mild, innately stressful stimuli into virtual reality therapy.

Grouping subjects based on conditioning criteria reveals differences in acquisition rates and in strength of conditioning-specific reflex modification

“…Data were analyzed from 145 rabbits that were classically conditioned using our standard NMR delay conditioning paradigm. The data came from 34 rabbits in a published study (Burhans et al, 2015) and from 111 rabbits in four unpublished studies collected over a period of several years. Subjects were male, New Zealand White rabbits ( Oryctolagus cuniculus ), supplied by Harlan (Indianapolis, IN, USA) or Charles River (Saint Constant, Quebec, Canada) weighing 2.0–2.2 kg and aged 69–77 days upon arrival.…”

“…Previous CRM experiments reported NMR conditioning data averaged across all rabbits receiving paired NMR conditioning (Burhans, Smith-Bell, & Schreurs, 2015; Schreurs et al, 1995, 2000). However, averaging group NMR conditioning data is known to mask behavioral phenomena and group averages may suggest that all subjects learn at the same rate in a monotonically increasing fashion (Gallistel, Fairhurst, & Balsam, 2004; Halverson, Hoffmann, Kim, Kish, & Mauk, 2016).…”

Inactivation of the interpositus nucleus blocks the acquisition of conditioned responses and timing changes in conditioning-specific reflex modification of the rabbit eyeblink response

“…For example, training rabbits to produce multiphasic CRs by conditioning with a tone paired with two sequential USs did not produce a multiphasic UR that paralleled the CR topography, and it was shown that CRs could be extinguished without CRM and vice versa if rabbits were given CS-alone or US-alone presentations, respectively (Schreurs et al, 2000). It was only when both treatments were combined using explicitly unpaired CS/US presentations that both CRs and CRM were extinguished simultaneously (Burhans, Smith-Bell, & Schreurs, 2015; Schreurs et al, 2000). In addition, CRs and CRM have been shown to differentially respond to systemic serotonergic, glutamatergic, and noradrenergic manipulations (Burhans, Smith-Bell, & Schreurs, 2013, 2017, 2018).…”

Delayed unpaired extinction as a treatment for hyperarousal of the rabbit nictitating membrane response and its implications for treating PTSD

“…In the rabbit model of PTSD, we have also shown that explicitly unpaired presentations of the CS and US effectively reduce CS responding and US hyperarousal (Buck et al, 2001, Schreurs et al, 2000). Because using the traumatic event as a means of treating PTSD is untenable, we since showed that extinguishing US hyperarousal as well as CRs using explicitly unpaired presentations of the CS and US can also be achieved when the intensity of the shock US is reduced eight-fold – an intensity that only elicits minimal responding (Burhans et al, 2015, Schreurs and Burhans, 2015).…”