Search

For almost 75 years, classical eyeblink conditioning has been an invaluable tool for assessing associative learning processes across many species, thanks to its high translatability and well-defined neural circuitry. Our laboratory has adapted the paradigm to extensively detail associative changes in the rabbit reflexive eyeblink response (unconditioned response, UR), characterized by postconditioning increases in the frequency, size, and latency of the UR when the periorbital shock unconditioned stimulus (US) is presented alone, termed conditioning-specific reflex modification (CRM). Because the shape and timing of CRM closely resembles the conditioned eyeblink response (CR) to the tone conditioned stimulus (CS), we previously tested whether CRs and CRM share a common neural substrate, the interpositus nucleus of the cerebellum (IP), and found that IP inactivation during conditioning blocked the development of both CRs and the timing aspect of CRM. The goal of the current study was to examine whether extinction of CRs and CRM timing, accomplished simultaneously with unpaired CS/US extinction, also involves the IP. Results showed that muscimol inactivation of the IP during extinction blocked CR expression but not extinction of CRs or CRM timing, contrasting with the literature showing IP inactivation prevents CR extinction during CS-alone presentations. The continued presence of the US throughout the unpaired extinction procedure may have been sufficient to overcome IP blockade, promoting plasticity in the cerebellar cortex and/or extracerebellar components of the eyeblink conditioning pathway that can modulate extinction of CRs and CRM timing. Results therefore add support to the distributed plasticity view of cerebellar learning. (PsycINFO Database Record (c) 2019 APA, 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.

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.

The central nucleus (CE) of the amygdala has been gaining attention for its importance in the plasticity underlying conditioned emotional responding. Already known for its role in nictitating membrane response (NMR) reflex facilitation, the CE may also be involved in conditioning-specific reflex modification (CRM)--changes in the NMR to the unconditioned stimulus (US) when tested in the absence of the conditioned stimulus following classical conditioning. To examine the CE's role in acquisition and/or expression of CRM, the authors temporarily inactivated the CE of rabbits (Oryctolagus cuniculus) with muscimol during NMR conditioning and/or during US testing. Results show that CRM was abolished by inactivation during US testing but intact following inactivation during NMR conditioning, suggesting that the CE is involved in CRM expression. Also, inactivation during conditioning delayed the development of conditioned NMRs. These findings show that the CE may act as an output center for expression of emotional responding in one situation (CRM) but is involved in facilitating plasticity in another (NMR conditioning). The authors propose that analysis of CRM may be an important corollary to current models for the treatment of posttraumatic stress disorder.

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.

Robust classical conditioning modifies responding to the unconditioned stimulus (US) in the absence of the conditioned stimulus (CS), a phenomenon the researchers called conditioning-specific reflex modification. Unconditioned responses (URs) to periorbital stimulation varying in intensity and duration were assessed before and after 1, 3, or 6 days of paired, explicitly unpaired, or no presentations of tone and electrical stimulation. After 3 days of pairings, conditioned responding (CRs) reached 94%, and there was an increase in latency to the peak of URs. The peak latency increase was replicated in a second experiment where rabbits reached asymptotic conditioning during 6 days of pairings. There was also a conditioning-specific increase in the amplitude of URs. There were no UR changes as a function of low level of CRs following 1 day of pairings. Data suggest that there are learning-specific changes in pathways mediating the US/UR, as well as in those mediating the CS/CR.

Interest in classical conditioning is usually focused on anticipatory responses to a stimulus associated with a significant event, and it is assumed that responses to the event itself are reflexive, involuntary, and relatively invariant. However, there is compelling evidence that both the rabbit nictitating membrane response (NMR) and heart rate response (HR), well-known reflexive reactions to aversive events, can change quite dramatically as a function of learning when measured in the absence of the conditioned stimulus. In the case of NMR conditioning, a simple blink is transformed into a larger and more complex response. For HR conditioning, reflexive heart rate acceleration can actually change to heart rate deceleration. In both cases, the reflex comes to resemble the conditioned response and follows some of the same behavioral laws. This change in response to the aversive event itself or weaker forms of that event is called conditioning-specific reflex modification (CRM). CRM may force us to reevaluate the behavioral and neural consequences of classical conditioning and may have important consequences for the treatment of conditions such as 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.

Conditioning-specific reflex modification (CRM) occurs when classical conditioning modifies responding to an unconditioned stimulus in the absence of a conditioned stimulus. This form of reflex modification suggests that learning modifies the unconditioned reflex pathway. Rabbit (Oryctolagus cuniculus) nictitating membrane responses to 5 intensities and 3 durations of airpuff (AP) or periorbital electrical stimulation (ES) were monitored before and after conditioning. AP tests detected strong CRM after conditioning with ES and modest levels of CRM after conditioning with AP. After conditioning with AP, ES tests failed to detect CRM. After conditioning with a stronger AP, CRM was again detected by AP tests. CRM is a general phenomenon but is more readily detected after training with a relatively aversive stimulus; thus, it may be a function of level of arousal.

Robust classical conditioning modifies responding to the unconditioned stimulus (US) in the absence of the conditioned stimulus (CS), a phenomenon the researchers called conditioning-specific reflex modification. Unconditioned responses (URs) to periorbital stimulation varying in intensity and duration were assessed before and after 1, 3, or 6 days of paired, explicitly unpaired, or no presentations of tone and electrical stimulation. After 3 days of pairings, conditioned responding (CRs) reached 94%, and there was an increase in latency to the peak of URs. The peak latency increase was replicated in a second experiment where rabbits reached asymptotic conditioning during 6 days of pairings. There was also a conditioning-specific increase in the amplitude of URs. There were no UR changes as a function of low level of CRs following 1 day of pairings. Data suggest that there are learning-specific changes in pathways mediating the US/UR, as well as in those mediating the CS/CR.

Conditioned suppression of photokinesis by the marine mollusc Hermissenda was examined in 3 experiments. In each experiment, groups of animals received light (the conditioned stimulus, CS) that was paired with high-speed orbital rotation (the unconditioned stimulus, UCS), light and rotation explicitly unpaired, or no exposure to these stimuli. Twenty-four hours after training, all animals were tested for suppression of photokinesis in the presence of the light. To establish the effectiveness of our conditioning procedure, in Experiment 1 individual groups of animals received either 50, 100, or 150 CS-UCS pairings. Fifty pairings resulted in a marginal suppression of photokinesis, whereas 100 and 150 pairings produced strong suppression. In Experiment 2, the delay between CS onset and UCS onset was varied between 1 and 10 s. The 10-s interstimulus interval (ISI) did not support conditioning, whereas 1-s and 2-s ISIs were effective. As predicted by the current understanding of Hermissenda's neural network, in Experiment 3 it was found that CS-UCS pairings in which the CS preceded the onset of the UCS and terminated with the offset of the UCS evoked stronger conditioned suppression than either a CS that preceded the UCS and terminated with its onset or a CS that was paired in simultaneous compound with the UCS. This result indicates that CS-UCS contiguity as well as the forward ISI act additively to establish the CS-UCS association. In none of the 3 experiments were any differences observed between groups that were untreated and that received the CS and UCS unpaired. In total, these experiments suggest strong similarities in the temporal characteristics of associative learning in Hermissenda and vertebrate species.

Acquisition, extinction, and differential conditioning of the rabbit's nictitating membrane response to a tone conditioned stimulus were supported by electrical stimulation of the spinal trigeminal nucleus. Stimulation of the accessory abducens nucleus, the abducens nucleus, and the reticular formation at the level of the spinal trigeminal nucleus supported lower, transient levels of conditioning. The results are discussed in terms of stimulation of sensory inputs to the brainstem and cerebellum.