Developmental Changes in the Neural Mechanisms of Eyeblink Conditioning

Freeman, John H.; Nicholson, Daniel A.

doi:10.1177/1534582304265865

Cited by 26 publications

(24 citation statements)

References 68 publications

(98 reference statements)

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“…There are fewer inhibitory synapses in the inferior olive in P17 rats relative to P24 rats, and, as a result of this relative lack of inhibition, learning-related Purkinje cell activity associated with inferior olive input is temporarily suppressed immediately following the US during CR trials in P24s but undergoes no CR-related modification in P17s (Nicholson and Freeman 2003a). It is therefore possible that learning-related plasticity established in P17s using MCP stimulation as a CS was unable to be expressed as well as in P24s following a 24-h retention interval due to partial dysregulation of cerebellar activity resulting from insufficient feedback from the cerebellum to the inferior olive (cf., Freeman and Nicholson 2004). This hypothesis could be tested by replicating the current procedures while simultaneously blocking inhibitory input to the inferior olive during all phases of training.…”

Section: Discussionmentioning

confidence: 99%

“…Development of the CS and US pathways between P17 and 24 contributes to the ontogenetic emergence of eyeblink conditioning (Freeman and Nicholson 2004;Freeman 2010). Eyeblink conditioning increases substantially between P17 and P24 when standard peripheral stimuli (e.g., tones, lights) are used as CSs (Stanton et al 1992(Stanton et al , 1998Paczkowski et al 1999).…”

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Extinction, reacquisition, and rapid forgetting of eyeblink conditioning in developing rats

Brown

Freeman

2014

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Eyeblink conditioning is a well-established model for studying the developmental neurobiology of associative learning and memory. However, age differences in extinction and subsequent reacquisition have yet to be studied using this model. The present study examined extinction and reacquisition of eyeblink conditioning in developing rats. In Experiment 1, post-natal day (P) 17 and 24 rats were trained to a criterion of 80% conditioned responses (CRs) using stimulation of the middle cerebellar peduncle (MCP) as a conditioned stimulus (CS). Stimulation CS-alone extinction training commenced 24 h later, followed by reacquisition training after the fourth extinction session. Contrary to expected results, rats trained starting on P17 showed significantly fewer CRs to stimulation CS-alone presentations relative to P24s, including fewer CRs as early as the first block of extinction session 1. Furthermore, the P17 group was slower to reacquire following extinction. Experiment 2 was run to determine the extent to which the low CR percentage observed in P17s early in extinction reflected rapid forgetting versus rapid extinction. Twenty-four hours after reaching criterion, subjects were trained in a session split into 50 stimulation CS-unconditioned stimulus paired trials followed immediately by 50 stimulation CS-alone trials. With this "immediate" extinction protocol, CR percentages during the first block of stimulation CSalone presentations were equivalent to terminal acquisition levels at both ages but extinction was more rapid in the P17 group. These findings indicate that forgetting is observed in P17 relative to P24 rats 24 h following acquisition. The forgetting in P17 rats has important implications for the neurobiological mechanisms of memory in the developing cerebellum.

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Section: Discussionmentioning

confidence: 99%

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Extinction, reacquisition, and rapid forgetting of eyeblink conditioning in developing rats

Brown

Freeman

2014

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“…There is an enormous body of empirical research on the behavioral and neurobiological mechanisms of eyeblink conditioning gathered over the past 60 years in both humans [54] and animals models [55]. Much is known concerning the development of eyeblink conditioning in rodents [47,50] and humans [21,18], and about the neural mechanisms underlying this development [13]. There is an expanding literature about how disorders of development affect eyeblink conditioning in both animal models [5,15,16,48] and humans [19,24,30,33]---including human autism [40,41].…”

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Discrimination learning and reversal of the conditioned eyeblink reflex in a rodent model of autism

Stanton

Peloso

Brown

et al. 2007

Behavioural Brain Research

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Offspring of rats exposed to valproic acid (VPA) on Gestational Day (GD) 12 have been advocated as a rodent model of autism because they show neuron loss in brainstem nuclei and the cerebellum resembling that seen in human autistic cases [20,37]. Studies of autistic children have reported alterations in acquisition of classical eyeblink conditioning [40] and in reversal of instrumental discrimination learning [9]. Acquisition of discriminative eyeblink conditioning depends on known brainstem-cerebellar circuitry whereas reversal depends on interactions of this circuitry with the hippocampus and prefrontal cortex. In order to explore behavioral parallels of the VPA rodent model with human autism, the present study exposed pregnant Long-Evans rats to 600 mg/kg VPA on GD12 [cf. 37] and tested their offspring from PND26-31 on discriminative eyeblink conditioning and reversal. VPA rats showed faster eyeblink conditioning, consistent with studies in autistic children [40]. This suggests that previously reported parallels between human autism and the VPA rodent model with respect to injury to brainstem-cerebellar circuitry [37] are accompanied by behavioral parallels when a conditioning task engaging this circuitry is used. VPA rats also showed impaired reversal learning, but this likely reflected "carry-over" of enhanced conditioning during acquisition rather than a reversal learning deficit like that seen in human autism. Further studies of eyeblink conditioning in human autism and in various animal models may help to identify the etiology of this developmental disorder. KeywordsEyeblink Conditioning; Gestational Valproate Exposure; Discrimination Reversal; Cerebellum; Hippocampus; Development The purpose of this article is to use a developmental rodent model of eyeblink conditioning to gather evidence bearing on the hypothesis that early gestational injury to the brainstem plays a role in the etiology of autism [3,37,39]. Evidence for this hypothesis arises from a disparate set of findings that show remarkable convergence [39]. The first clues came from reports of an association between autism and early gestational exposure to thalidomide and misoprostol [27]. Knowledge concerning the teratology of thalidomide permits inferences concerning the timing of thalidomide exposure based on the presence of craniofacial defects (ear anomolies). When thalidomide cases involving exposure specifically between 20-24 days post-conception were considered, autism occurred at a staggering rate (~30%, [39]). It was subsequently

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“…With sufficient CS-US pairings, the CS comes to elicit a learned or "conditioned" response (CR), similar to the UR but timed to occur prior to the onset of the US. The classically conditioned eyeblink response has been extensively studied and validated in humans (normal and clinical populations), rabbits, rats, and normal and genetically modified mice (Woodruff-Pak & Steinmetz, 2000a, 2000b, but, to our knowl edge, there are no published reports of eyeblink conditioning in sheep. Eyeblink conditioning is ideally suited for comparative behav ioral studies in animal models of developmental disorders.…”

Section: Introductionmentioning

confidence: 99%

“…For acquisition of trace conditioning and other higher-order procedural variants, the hippocampus and related forebrain structures are additionally required (Ivkovich & Stanton, 2001;McGlinchey-Berroth, Carrillo, Gabrieli, Brawn, & Disterhoft, 1997;Solomon, Vander Schaaf, Thompson, & Weisz, 1986;Weiss, Bouwmeester, Power, & Disterhoft, 1999). The developmental emergence of eyeblink conditioning has been characterized in rodents and humans (Claflin, Stanton, Herbert, Greer, & Eckerman, 2002;Freeman, Carter, & Stanton, 1995;Freeman, Barone, & Stanton, 1995;Ivkovich, Paczkowski, & Stanton, 2000, Freeman, Spencer, Skelton, & Stanton, 1993Stanton, Freeman, & Skelton, 1992), including characterization of correlated developmental changes in structure and function of identified eyeblink conditioning neural circuits (Freeman & Muckler, 2003;Freeman & Nicholson, 2000a, 2000b, suggesting that eyeblink conditioning may be a useful tool as an early indicator of prenatal brain damage in translational research.Developmental alcohol-induced structural damage to the cerebellum and correlated deficits in acquisition of eyeblink conditioning were first demonstrated in rats following binge-like exposure to alcohol during the "brain growth spurt" of the early postnatal period (Green, 2004;Green, Johnson, Goodlett, & Steinmetz, 2002;Green, Rogers, Goodlett, & Steinmetz, 2000;Green, Tran, Steinmetz, & Goodlett, 2002;Stanton & Goodlett, 1998;Tran, Stanton, & Goodlett, 2007 , 1997). Taken together, these findings suggest that cerebellar damage and deficits in cerebellar-dependent learning may be a common phenotype of the fetal alcohol spectrum disorder (FASD) that results from heavy prenatal alcohol exposure (Riley & McGee, 2005).…”

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Eyeblink classical conditioning in the preweanling lamb.

Johnson¹,

Stanton²,

Goodlett³

et al. 2008

Behavioral Neuroscience

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Classical conditioning of eyeblink responses has been one of the most important models for studying the neurobiology of learning, with many comparative, ontogenetic, and clinical applications. The current study reports the development of procedures to conduct eyeblink conditioning in preweanling lambs and demonstrates successful conditioning using these procedures. These methods will permit application of eyeblink conditioning procedures in the analysis of functional correlates of cerebellar damage in a sheep model of fetal alcohol spectrum disorders, which has significant advantages over more common laboratory rodent models. Because sheep have been widely used for studies of pathogenesis and mechanisms of injury with many different prenatal or perinatal physiological insults, eyeblink conditioning can provide a wellstudied method to assess postnatal behavioral outcomes, which heretofore have not typically been pursued with ovine models of developmental insults. Keywords delay conditioning; associative learning in lamb; ovine model; cerebellum Eyeblink classical conditioning involves exposing subjects to series of discrete trials in which a neutral (e.g., auditory) condi tioned stimulus (CS) is consistently presented prior to the onset of an unconditioned stimulus (US), such as an airpuff directed at the cornea. Initially, the CS does not evoke a behavioral response whereas the US reliably elicits a reflexive eyeblink, the "uncon ditioned" response (UR). With sufficient CS-US pairings, the CS comes to elicit a learned or "conditioned" response (CR), similar to the UR but timed to occur prior to the onset of the US. The classically conditioned eyeblink response has been extensively studied and validated in humans (normal and clinical populations), rabbits, rats, and normal and genetically modified mice (Woodruff-Pak & Steinmetz, 2000a, 2000b, but, to our knowl edge, there are no published reports of eyeblink conditioning in sheep. Eyeblink conditioning is ideally suited for comparative behav ioral studies in animal models of developmental disorders. A key advantage is that the neural circuitry involved in learning and performance has been identified in multiple species. Cerebellar and brainstem circuitry is necessary and sufficient for learning the CS-US association with delay conditioning, and sites of learning-related functional and structural neuroplasticity mediating the conditioned eyeblink response have been identified (Christian & Thompson, 2003;Kleim et al., 2002;Lavond, Kim, & Thompson, 1993;Medina, Nores, Ohyama, & Mauk, 2000;Steinmetz, 1996;Thompson, 1986;Thompson & Kim, 1996). For acquisition of trace conditioning and other higher-order procedural variants, the hippocampus and related forebrain structures are additionally required (Ivkovich & Stanton, 2001;McGlinchey-Berroth, Carrillo, Gabrieli, Brawn, & Disterhoft, 1997;Solomon, Vander Schaaf, Thompson, & Weisz, 1986;Weiss, Bouwmeester, Power, & Disterhoft, 1999). The developmental emergence of eyeblink conditioning has been characterized in ...

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Developmental Changes in the Neural Mechanisms of Eyeblink Conditioning

Cited by 26 publications

References 68 publications

Extinction, reacquisition, and rapid forgetting of eyeblink conditioning in developing rats

Extinction, reacquisition, and rapid forgetting of eyeblink conditioning in developing rats

Discrimination learning and reversal of the conditioned eyeblink reflex in a rodent model of autism

Eyeblink classical conditioning in the preweanling lamb.

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