The neural pathways that convey conditioned stimulus (CS) information to the cerebellum during eyeblink conditioning have not been fully delineated. It is well established that pontine mossy fiber inputs to the cerebellum convey CS-related stimulation for different sensory modalities (e.g., auditory, visual, tactile). Less is known about the sources of sensory input to the pons that are important for eyeblink conditioning. The first experiment of the current study was designed to determine whether electrical stimulation of the medial auditory thalamic nuclei is a sufficient CS for establishing eyeblink conditioning in rats. The second experiment used anterograde and retrograde tract tracing techniques to assess neuroanatomical connections between the medial auditory thalamus and pontine nuclei. Stimulation of the medial auditory thalamus was a very effective CS for eyeblink conditioning in rats, and the medial auditory thalamus has direct ipsilateral projections to the pontine nuclei. The results suggest that the medial auditory thalamic nuclei and their projections to the pontine nuclei are components of the auditory CS pathway in eyeblink conditioning.A primary emphasis in neurobiological analyses of Pavlovian eyeblink conditioning has been on identifying the anatomical sites and cellular mechanisms of memory storage (Christian and Thompson 2003;Thompson 2005). Less emphasis has been placed on identifying the neural pathways that conduct stimulation from conditioned stimuli to the sites of memory induction and retention. The cerebellum is the anatomical site of memory storage in Pavlovian eyeblink (eyelid and nictitating membrane movement) conditioning (Christian and Thompson 2003;Thompson 2005;Ohyama et al. 2006). Cerebellar function may be influenced by processes occurring within its sensory input pathways, interactions among components of the input pathways, and sources of feedback to the input pathways (Clark et al. 1997;Bao et al. 2000;Medina et al. 2002). A full characterization of the sensory input pathways to the cerebellum necessary for motor learning is, therefore, critical for developing a comprehensive understanding of cerebellar function. Identification of sensory input pathways to the cerebellum is also critical for elucidating the mechanisms underlying the ontogeny of motor learning (Freeman et al. 2005).Several key components of the conditioned stimulus (CS) pathway in eyeblink conditioning have been identified using lesion, inactivation, unit recording, stimulation, and tract tracing techniques (Steinmetz et al. 1986(Steinmetz et al. , 1987(Steinmetz et al. , 1989Lewis et al. 1987;Knowlton and Thompson 1988;Steinmetz 1990;Steinmetz and Sengelaub 1992;Gould et al. 1993;Tracy et al. 1998;Hesslow et al. 1999;Bao et al. 2000;Freeman and Rabinak 2004;Freeman et al. 2005). The pontine mossy fiber projection to the cerebellum is necessary for eyeblink conditioning with CSs of different modalities and stimulation of the pontine nuclei or the middle cerebellar peduncle is sufficient for eyeblink condit...

Pontine neuronal activation during auditory stimuli increases ontogenetically between postnatal days (P) P17 and P24 in rats. Pontine neurons are an essential component of the conditioned stimulus (CS) pathway for eyeblink conditioning, providing mossy fiber input to the cerebellum. Here we examined whether the developmental limitation in pontine responsiveness to a CS in P17 rats could be overcome by direct stimulation of the CS pathway. Eyeblink conditioning was established in infant rats on P17-P18 and P24-P25 using pontine stimulation as a CS. There were no significant age-related differences in the rate or level of conditioning. Eyeblink conditioned responses established with the stimulation CS were abolished by inactivation of the ipsilateral cerebellar nuclei and overlying cortex in both age groups. The findings suggest that developmental changes in the CS pathway play an important role in the ontogeny of eyeblink conditioning.Eyeblink classical conditioning has been used as a model system for examining developmental changes in the neural mechanisms underlying motor learning . It is well established that eyeblink conditioning in adult mammals depends on cerebellar interactions with its afferent and efferent brainstem nuclei (Mauk and Donegan 1997;Christian and Thompson 2003). The cerebellum receives input stimulation from an auditory conditioned stimulus (CS) through the pontine mossy fiber projection (Steinmetz et al. , 1987(Steinmetz et al. , 1989Steinmetz 1990;Steinmetz and Sengelaub 1992;Tracy et al. 1998). Input stimulation from an air puff or face shock unconditioned stimulus (US) reaches the cerebellum through the climbing fiber projection from the inferior olive (McCormick et al. 1985;Mauk et al. 1986;Steinmetz et al. 1989). The convergence of mossy and climbing fiber activation of cerebellar neurons is thought to result in changes in synaptic efficacy that constitute the substrate of learning and drive the production of the eyeblink conditioned response (CR). Cerebellar output produces inhibitory feedback to the inferior olive and excitatory feedback to the pons (Sears and Steinmetz 1991;Clark et al. 1997;Kim et al. 1998;Bao et al. 2000;Medina et al. 2002). The feedback connections are thought to be important for acquisition and maintenance of CRs (Medina et al. 2002).Eyeblink conditioning emerges ontogenetically between postnatal days (P) P17 and P24 in rats (Stanton et al. 1992). Neurophysiological, neuropharmacological, and neuroanatomical analyses of the ontogeny of eyeblink conditioning in rats indicate that the developmental emergence of eyeblink conditioning is due to developmental changes in the CS and US pathways . The most substantial developmental change in the US pathway is an increase in the magnitude of cerebellar inhibitory feedback to the inferior olive (Nicholson and Freeman Jr. 2003a,b). The developmental change in inhibitory feedback is due to an increase in inhibitory synapses within the inferior olive (Nicholson and Freeman Jr. 2003a). Developmental addition of inhibitory syn...

A fundamental issue in developmental science is whether ontogenetic changes in memory are caused by the development of cellular plasticity mechanisms within the brain's memory systems or maturation of sensory inputs to the memory systems. Here, we provide evidence that the development of eyeblink conditioning, a form of associative learning that depends on the cerebellum, is driven by the development of sensory inputs rather than the development of neuronal plasticity mechanisms. We find that rats as young as 12 days old show associative eyeblink conditioning when pontine stimulation is used in place of an external (e.g., a tone) conditioned stimulus. Eyeblink-conditioned responses established with pontine stimulation in 12-day-old rats were reversibly abolished by an infusion of muscimol into the cerebellar interpositus nucleus. The findings suggest that cerebellar neurons are capable of supporting associative learning-specific plasticity in vivo in very immature animals if given sufficient afferent stimulation.cerebellum ͉ eyelid conditioning ͉ learning ͉ memory I t seems reasonable to assume that the development of memory is caused by the maturation of synaptic plasticity mechanisms within the memory systems of the brain. For example, the development of declarative memory could be related to the development of long-term potentiation in the medial temporal lobe, and conditioning of discrete movements could be related to the development of cerebellar long-term depression. On the other hand, it is possible that the cerebellum and hippocampus are capable of establishing learning-related synaptic plasticity in young animals but simply do not receive sufficient sensory input during learning. We evaluated these possibilities by examining the effects of electrically stimulating a sensory input pathway to the cerebellum on eyeblink conditioning in rats that are too immature to show conditioning with external sensory stimuli.Eyeblink conditioning, a type of associative learning, typically involves the presentation of a conditioned stimulus (CS) that does not produce a blink reflex before training (e.g., a tone or light) followed by an unconditioned stimulus (US) that reliably elicits the blink reflex. Repeated presentations of the CS and US result in the acquisition of a conditioned response (CR) that precedes the onset of the US. Eyeblink conditioning emerges ontogenetically between postnatal days 17 and 24 in rats (1). Developmental changes in human eyeblink conditioning have also been documented (2).The cerebellar hemisphere that is ipsilateral to the conditioned eye is essential for acquisition and retention of eyeblink conditioning in adult and infant animals (3, 4). Neurons within the pontine nuclei (PN) are part of the mossy fiber pathway that sends CS information to the cerebellum (5-7). Cerebellar neurons are thought to develop learning-specific changes in synaptic efficacy to CS inputs, which underlies memory for the CS-US association (8). Using either cerebellar slices or cultured neurons from rodents, many ...

Eyeblink conditioning using a conditioned stimulus (CS) from one sensory modality (e.g., an auditory CS) is greatly enhanced when the subject is previously trained with a CS from a different sensory modality (e.g., a visual CS). The enhanced acquisition to the second modality CS results from cross modal savings. The current study was designed to examine the role of the cerebellum in establishing cross modal savings in eyeblink conditioning with rats. In the first experiment rats were given paired or unpaired presentations with a CS (tone or light) and an unconditioned stimulus (US). All rats were then given paired training with a different modality CS. Only rats given paired training showed cross modal savings to the second modality CS. Experiment 2 showed that cerebellar inactivation during initial acquisition to the first modality CS completely prevented savings when training was switched to the second modality CS. Experiment 3 showed that cerebellar inactivation during initial cross modal training also prevented savings to the second modality stimulus. These results indicate that the cerebellum plays an essential role in establishing cross modal savings of eyeblink conditioning.Keywords associative learning; classical conditioning; eyelid conditioning; interpositus nucleus; cerebellar cortex In a typical eyeblink conditioning experiment, a brief conditioned stimulus (CS), such as a tone or a light, is paired with an unconditioned stimulus (US). Before training, the US elicits an unconditioned eyeblink response (eyelid closure or nictitating membrane (NM) movement). After a sufficient number of CS-US pairings, conditioned eyeblink responses (CRs) occur to presentations of the CS and precede the onset of the US (Gormezano, Schneiderman, Deaux, & Fuentes, 1962;. The brain areas necessary for acquiring delay eyeblink conditioning are located within the cerebellum and its interconnected brainstem nuclei (Christian & Thompson, 2003). In the cerebellum, the anterior cerebellar interpositus nucleus (IPN) and cerebellar cortex (CCTX) are known to be necessary for acquisition, retention and timing of conditioned eyeblink responses (Attwell, Cooke, & Yeo, 2002;Attwell, Ivarsson, Millar, & Yeo, 2002;Attwell, Rahman, & Yeo, 2001;Bao, Chen, Kim, & Thompson, 2002;Clark & Lavond, 1993;Freeman, Halverson, & Poremba, 2005;Krupa & Thompson, 1997;Krupa, Thompson, & Thompson, 1993;McCormick, Clark, Lavond, & Thompson, 1982;Ohyama, Nores, Medina, Riusech, & Mauk, 2006;Perrett, Ruiz, & Mauk, 1993). CS and US inputs are relayed to the cerebellum from separate brainstem nuclei. CS information is sent to the cerebellum via pontine mossy fiber projections (Hesslow, Svensson, & Ivarsson, 1999; Correspondence concerning this article should be addressed to John H Freeman, Department of Psychology, University of Iowa, E11 Seashore Hall, Iowa City, IA 52242, E-mail: E-mail: john-freeman@uiowa.edu, Phone: (319) 335-0565. NIH Public Access Author ManuscriptBehav Neurosci. Author manuscript; available in PMC 2010 April 1. Steinmetz...

The role of the perirhinal cortex in inhibitory eyeblink conditioning was examined. In Experiment 1, rats were given lesions of the perirhinal cortex or control surgery and subsequently trained with a feature-negative discrimination procedure followed by summation and retardation tests for conditioned inhibition. Perirhinal cortex lesions impaired, but did not prevent acquisition of feature-negative discrimination. Results from the summation test showed that rats with perirhinal cortex lesions could not generalize feature-negative discrimination to a new stimulus. There were no group differences during the retardation test. Experiment 2 showed that lesions of the perirhinal cortex did not impair simple excitatory conditioning. Experiment 3 showed that perirhinal cortex lesions had no effect on acquisition of a simple tone-light discrimination. The results suggest that the perirhinal cortex plays a role in eyeblink conditioning when using discrimination procedures involving overlapping stimuli.