Neural circuitry and plasticity mechanisms underlying delay eyeblink conditioning

Abstract

Pavlovian eyeblink conditioning has been used extensively as a model system for examining the neural mechanisms underlying associative learning. Delay eyeblink conditioning depends on the intermediate cerebellum ipsilateral to the conditioned eye. Evidence favors a two-site plasticity model within the cerebellum with long-term depression of parallel fiber synapses on Purkinje cells and long-term potentiation of mossy fiber synapses on neurons in the anterior interpositus nucleus. Conditioned stimulus and unconditioned stimulus inputs arise from the pontine nuclei and inferior olive, respectively, converging in the cerebellar cortex and deep nuclei. Projections from subcortical sensory nuclei to the pontine nuclei that are necessary for eyeblink conditioning are beginning to be identified, and recent studies indicate that there are dynamic interactions between sensory thalamic nuclei and the cerebellum during eyeblink conditioning. Cerebellar output is projected to the magnocellular red nucleus and then to the motor nuclei that generate the blink response(s). Tremendous progress has been made toward determining the neural mechanisms of delay eyeblink conditioning but there are still significant gaps in our understanding of the necessary neural circuitry and plasticity mechanisms underlying cerebellar learning.Eyeblink conditioning is an associative learning paradigm that was first developed for use in human participants in the 1920s (Cason 1922). It was initially valued as a method for studying learning and higher nervous system function without confounds associated with verbal reports, introspection, or prior experience with similar associations. The procedure involves presentation of a conditioned stimulus (CS), typically a tone or light, which is paired with an unconditioned stimulus (US) that reliably elicits eyelid closure, such as an air puff or brief electrical stimulation near the eye. Humans will often show a short-latency lowamplitude unconditioned (alpha) response to an auditory CS. After repeated CS-US trials, conditioned eyelid closure (conditioned response [CR]) occurs during the CS. Maximum eyelid closure for the CR typically occurs near the onset time of the US. Several shortcomings of the paradigm were later identified, most notably, the presence of alpha responses and voluntary responses among human participants who became explicitly aware of the stimulus contingency. These shortcomings and the need for an animal model for invasive neuroscience research led to the development of the rabbit eyeblink and nictitating membrane paradigms Schneiderman et al. 1962;Gormezano 1966). Rabbits tolerate restraint well, do not exhibit alpha responses, and precise measures of eyelid closure and nictitating membrane movement are obtained readily (Gormezano 1966). Most of the initial work on the neural mechanisms underlying eyeblink conditioning was conducted using rabbits, but the paradigm has been applied to frogs, turtles, mice, rats, ferrets, sheep, dogs, monkeys, and cats. A concern with using species other...

Relating Cerebellar Purkinje Cell Activity to the Timing and Amplitude of Conditioned Eyelid Responses

“…4B, 5B). This pattern of a decrease in activity preceded by an increase has been observed before in recordings from paralyzed animals (Hesslow and Ivarsson, 1994) and is generally consistent with the previously proposed role of PCs in response timing (Mauk and Donegan, 1997;Medina and Mauk, 2000), and a role for rebound excitation in the deep nucleus neurons in response expression (Freeman and Steinmetz, 2011). For all four ISIs the cross-correlation analyses revealed that eyelid PC activity was poorly related to subsequent eyelid acceleration but was about equally well related to subsequent eyelid position and velocity (Figs.…”

Central amygdala lesions inhibit pontine nuclei acoustic reactivity and retard delay eyeblink conditioning acquisition in adult rats

“…The acoustic CS signal is relayed through the medial thalamic nuclei, the cochlear nucleus, the nucleus of the lateral lemniscus, and finally to the PN, the last precerebellar nucleus that conveys acoustic signals to the cerebellum (Freeman & Steinmetz, 2011). Auditory cues were previously reported to be selectively relayed to the cerebellum through the LPN (Bao, Chen, & Thompson, 2000;Steinmetz et al, 1987), while other research found auditory-evoked responses throughout both the LPN and MPN (Cartford, Gohl, Singson, & Lavond, 1997).…”

“…For example, learning to fear specific stimuli or events depends on the amygdala (Duvarci & Pare, 2014;LeDoux, 2014), whereas simple forms of sensorimotor learning, such as eyeblink classical conditioning, depend on the cerebellum and brainstem (Christian & Thompson, 2003;Freeman & Steinmetz, 2011). In delay eyeblink conditioning (EBC), a light or tone conditioned stimulus (CS) is repeatedly paired with a mildly aversive corneal air puff or periorbital shock unconditioned stimulus (US).…”

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

“…Decades of research have established that the cerebellum is essential for the acquisition and retention of eyeblink conditioning (for review, see Freeman and Steinmetz 2011). The cerebellum receives conditioned stimulus (CS) information from the pontine nuclei via the middle cerebellar peduncle (MCP) (Steinmetz et al , 1987Steinmetz 1990), and unconditioned stimulus (US) information is transmitted to the cerebellum via climbing fiber projections from the inferior olive (McCormick et al 1985;Mauk et al 1986).…”