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Eyeblink Conditioning in 12-Day-Old Rats Using Pontine Stimulation As the Conditioned Stimulus

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Eyeblink Conditioning in 12-Day-Old Rats Using Pontine Stimulation As the Conditioned Stimulus Eyeblink conditioning in 12-day-old rats using pontine stimulation as the conditioned stimulus Matthew M. Campolattaro and John H. Freeman* Department of Psychology, University of Iowa, E11 Seashore Hall, Iowa City, IA 52242 Edited by Richard F. Thompson, University of Southern California, Los Angeles, CA, and approved April 7, 2008 (received for review December 19, 2007) A fundamental issue in developmental science is whether ontoge- neurons might be fully capable of establishing learning-specific netic changes in memory are caused by the development of cellular plasticity in vivo during the first 2 postnatal weeks (12). plasticity mechanisms within the brain’s memory systems or mat- In vivo neurophysiological analyses of the ontogeny of eyeblink uration of sensory inputs to the memory systems. Here, we provide conditioning suggest that the PN receive weaker afferent input evidence that the development of eyeblink conditioning, a form of from sensory nuclei in younger rats (nonlearners), which results associative learning that depends on the cerebellum, is driven by in weaker mossy fiber input to the cerebellum (13). Stimulation the development of sensory inputs rather than the development of of the pontine mossy fibers may be able to overcome the neuronal plasticity mechanisms. We find that rats as young as 12 developmental limitations in eyeblink conditioning in younger days old show associative eyeblink conditioning when pontine rats by providing sufficient mossy fiber input to the cerebellum stimulation is used in place of an external (e.g., a tone) conditioned (14). The current study pushed the limits of this hypothesis by stimulus. Eyeblink-conditioned responses established with pontine examining whether PN stimulation could be an effective CS in stimulation in 12-day-old rats were reversibly abolished by an 12-day-old rats. Rats at this age have closed eyes and ear canals infusion of muscimol into the cerebellar interpositus nucleus. The and therefore cannot learn responses to visual and auditory findings suggest that cerebellar neurons are capable of supporting stimuli. The cerebellum is also immature at this age, with associative learning-specific plasticity in vivo in very immature ongoing neurogenesis in the external molecular layer and neu- animals if given sufficient afferent stimulation. ronal migration into the granule cell layer (15). However, Purkinje cells and deep nucleus neurons have synaptic inputs cerebellum ͉ eyelid conditioning ͉ learning ͉ memory that are sufficient for induction of long-term plasticity in vitro during the first 2–3 postnatal weeks (12). The main question in t seems reasonable to assume that the development of memory the current study was whether cerebellar learning could be Iis caused by the maturation of synaptic plasticity mechanisms induced in vivo in 12-day-old rats by direct stimulation of the within the memory systems of the brain. For example, the mossy fiber pathway as a CS paired with a peripheral US. development of declarative memory could be related to the development of long-term potentiation in the medial temporal Results lobe, and conditioning of discrete movements could be related In the first experiment, rat pups were given eyelid conditioning to the development of cerebellar long-term depression. On the by using a 300-ms train of 100-␮s current pulses at 200 Hz within other hand, it is possible that the cerebellum and hippocampus the PN as the CS, which was paired with a peripheral periorbital are capable of establishing learning-related synaptic plasticity in shock (10.0 ms, 4.0 mA) US on postnatal days 12 and 13. The young animals but simply do not receive sufficient sensory input pups were given three conditioning sessions per day with 100 during learning. We evaluated these possibilities by examining training trials in each session. An age-matched control group was the effects of electrically stimulating a sensory input pathway to given unpaired presentations of PN stimulation and the US the cerebellum on eyeblink conditioning in rats that are too during each conditioning session. The control group was neces- immature to show conditioning with external sensory stimuli. sary to show that blink responses in the group given paired Eyeblink conditioning, a type of associative learning, typically training were caused by the formation of a CS–US association involves the presentation of a conditioned stimulus (CS) that and not by nonassociative learning. The eyelids are normally does not produce a blink reflex before training (e.g., a tone or fused at this age in rats. It was, therefore, necessary to separate light) followed by an unconditioned stimulus (US) that reliably the eyelids surgically on postnatal day 11 to enable recording elicits the blink reflex. Repeated presentations of the CS and US eyelid electromyography (EMG) activity during lid closure. Rat result in the acquisition of a conditioned response (CR) that pups that were given paired presentations of PN stimulation, and precedes the onset of the US. Eyeblink conditioning emerges the US showed an increase in eyelid CRs across training and ontogenetically between postnatal days 17 and 24 in rats (1). significantly more eyelid responses than in the unpaired group Developmental changes in human eyeblink conditioning have during sessions 3–6 [Fig. 1A; F(5, 50) ϭ 4.60, P Ͻ 0.003]. The also been documented (2). increase in the percentage of eyelid CRs was, therefore, caused The cerebellar hemisphere that is ipsilateral to the condi- by acquisition of associative learning and cannot be attributed to tioned eye is essential for acquisition and retention of eyeblink sensitization. CRs in the group given paired training were conditioning in adult and infant animals (3, 4). Neurons within initiated during the CS and the maximum amplitude of the the pontine nuclei (PN) are part of the mossy fiber pathway that responses occurred before the onset of the US, as seen in adult sends CS information to the cerebellum (5–7). Cerebellar neu- rat eyelid EMG activity (Fig. 1B). Histological analysis indicated rons are thought to develop learning-specific changes in synaptic that the electrodes were consistently placed within or just dorsal efficacy to CS inputs, which underlies memory for the CS–US association (8). Using either cerebellar slices or cultured neurons from rodents, many sources of cerebellar synaptic plasticity have Author contributions: M.M.C. and J.H.F. designed research; M.M.C. performed research; been characterized that might play critical roles during in vivo M.M.C. analyzed data; and M.M.C. and J.H.F. wrote the paper. associative learning (9–12). Some of the in vitro studies of The authors declare no conflict of interest. cerebellar plasticity have used infant cerebellar cells to optimize This article is a PNAS Direct Submission. whole-cell or sharp electrode recordings. The findings of the in *To whom correspondence should be addressed. E-mail: [email protected]. vitro studies that used infant tissue suggest that cerebellar © 2008 by The National Academy of Sciences of the USA 8120–8123 ͉ PNAS ͉ June 10, 2008 ͉ vol. 105 ͉ no. 23 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0712006105 Downloaded by guest on October 1, 2021 Fig. 1. Associative eyelid conditioning in rats trained on postnatal days 12 and 13. (A) Mean CR percentage across six 100-trial training sessions for rat pups given paired or unpaired presentations of pontine stimulation as a CS and a peripheral US. Error bars indicate SEM. (B) Eyelid EMG activity for rat pups that were given paired (Upper) or unpaired (Lower) conditioning during test trials with only the CS from the last training session. Dashed lines indicate the onset time of the CS. (C) A digital image of a representative electrode placement (arrow) in the PN. (Magnification: ϫ2.5.) to the basilar PN (Fig. 1C). The findings of the first experiment cleus abolished eyelid CRs in adult and infant rats (17), a finding indicate that associative eyelid conditioning can be established in first demonstrated in adult rabbits (18). The rat pups were given rat pups as early as postnatal day 12, even though that is well five sessions in which the PN stimulation CS was paired with the before the age at which eyelid conditioning is observed with an US on postnatal days 12 and 13, as in the first experiment. They external CS such as a light or tone (postnatal day 20) (16). were then given an infusion of muscimol (0.5 ␮l, 5.0 nmol) into PN stimulation was clearly sufficient for establishing eyelid the interpositus nucleus ipsilateral to the conditioned eye. A conditioning in relatively young rat pups. It was possible, how- recovery session was administered the next day to confirm that ever, that PN stimulation supported learning through a noncer- the infusion did not produce any lasting effects on the production ebellar mechanism. That is, the eyelid CRs could have been of CRs. As in the first experiment, the pups given paired training generated through a different neural circuit than the neural showed an increase in eyelid CRs across training sessions [Fig. circuit that is needed for learning in older rats. The second 2A; F(6, 18) ϭ 8.05, P Ͻ 0.001]. Muscimol infusion into the experiment examined the effect of inactivating the cerebellum cerebellum produced a substantial decrease in the incidence of ipsilateral to the conditioned eye on the production of eyelid eyelid CRs (Fig. 2 A and B; P Ͻ 0.05). Complete recovery of CRs in rat pups given paired presentations of PN stimulation as eyelid CRs was seen after the muscimol infusion during the last NEUROSCIENCE the CS and a peripheral US. Previous studies found that mus- conditioning session (Fig. 2 A and B; P Ͻ 0.05). Analysis of cimol infusions into the ipsilateral cerebellar interpositus nu- fluorescently labeled muscimol indicated that it spread through- A B C 80 70 HVI 60 egatnecreP RC egatnecreP 50 40 30 20 DN 10 IN 0 1234567 100-Trial Session CS US Fig.
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