Mark E. Stanton

Deficient cerebellar long-term depression and impaired motor learning in mGluR1 mutant mice

mGluR1 mutant mice are viable but show characteristic cerebellar symptoms such as ataxic gait and intention tremor. The anatomy of the cerebellum is not overtly disturbed. Excitatory synaptic transmission from parallel fibers (PFs) to Purkinje cells and that from climbing fibers (CFs) to Purkinje cells appear to be functional, and voltage-gated Ca2+ channels of Purkinje cells are normal. Both PF and CF synapses display normal short-term synaptic plasticity to paired stimuli. By marked contrast, long-term depression (LTD) is clearly deficient and conditioned eyeblink response is impaired. We conclude that mGluR1 is required for the induction of LTD and that the ataxic behavior and impaired eyeblink conditioning of the mGluR1 mutant mice are primarily due to deficient LTD.

Fimbria-fornix transections disrupt the ontogeny of delayed alternation but not position discrimination in the rat

In Experiment 1, Long-Evans rat pups received fimbria-fornix transections or sham surgery on Postnatal Day 10 (PND10) and were then trained on PND23 to perform either a discrete-trials delayed alternation (DA) or a simple position discrimination (PD) task in a T maze. Rat pups in both surgical conditions learned the PD task within five 12-trial blocks of training. However, only sham-operated pups learned the DA task. In Experiment 2, performance of DA emerged between PND19 and PND27 in sham-operated pups but failed entirely to develop in pups with early lesions. In Experiment 3, fornix-transected pups that were given extended DA training (132 trials) on PND23-PND24 showed some improvement in performance but remained impaired in relation to sham-operated controls. These findings implicate the limbic system in the postnatal development of DA but not PD and suggest that dual-process theories of memory may be relevant to the psychobiology of cognitive development.

Medial prefrontal cortex lesions and spatial delayed alternation in the developing rat: Recovery of sparing?

In Experiment 1, Long-Evans rat pups received medial prefrontal cortex (PFC) aspirations or sham surgery on Postnatal Day 10 (PND10) and were then trained on PND23 to perform one of two T-maze tasks: discrete-trials delayed alternation (DA) or simple position discrimination. Early PFC damage produced a selective failure to learn the DA task. In Experiment 2, pups given the same lesion or sham surgery were trained on DA on PND19, PND27, or PND33. In relation to sham-operated controls, pups with PFC damage were impaired on PND19, somewhat impaired on PND27, and entirely unimpaired when tested on PND33. In Experiment 3, pups given larger lesions of the frontal cortex on PND10 were impaired on DA when tested on PND23 but not when tested on PND33. These findings indicate that early PFC lesions result in a memory deficit around the time of weaning, which then recovers over the next 10-14 days of development. Moreover, the early deficit is selective for a late developing cognitive process (or processes) that is involved in acquisition of DA.

Early cerebellar lesions impair eyeblink conditioning in developing rats : differential effects of unilateral lesions on postnatal day 10 or 20

Experiment 1 demonstrated that the ipsilateral cerebellar hemisphere is essential for the acquisition of eyeblink conditioning in infant rats and that cerebellar lesions given on Postnatal Day 10 (PND10) produced deficits in eyeblink conditioning when given to either hemisphere. For both hemispheres, lesions that were restricted to the cerebellar cortex produced less severe deficits than lesions that included the deep nuclei. Experiment 2 showed that the age at which the cerebellar lesions occurred determined whether damage to the contralateral cerebellar hemisphere impaired conditioning. Lesions of either the ipsilateral or contralateral hemisphere that included the deep nuclei disrupted eyeblink conditioning when given on PND10. In contrast, when lesions were given on PND20, ipsilateral lesions that included the deep nuclei abolished conditioning, while the same lesion given to the contralateral hemisphere had no effect.

DEVELOPMENT OF CHOLINERGIC NEURONS IN RAT BRAIN REGIONS: DOSE-DEPENDENT EFFECTS OF PROPYLTHIOURACIL-INDUCED HYPOTHYROIDISM

The effects of hypothyroidism on development of cholinergic system in brain regions (prefrontal cortex and hippocampus) were evaluated by measuring choline acetyltransferase (ChAT) activity and hemicholinium-3 binding to the high-affinity choline transporter. Various degrees of thyroid deficiency were produced by perinatal exposure to propylthiouracil (PTU) in drinking water ranging from 5 ppm (mg/l) to 25 ppm beginning at gestational day 18 until postnatal day 21. ChAT, a marker for cholinergic nerve terminals, was reduced by PTU in a dose-dependent manner. Concomitant with the enzyme deficits, hemicholinium-3 binding was elevated, suggesting an increase in neuronal impulse activity. Although similar changes were seen in both brain regions examined, the magnitude and duration of these changes were more definitive in the prefrontal cortex. Nonetheless, these neurochemical alterations appeared to be recoverable when the rats returned to a euthyroid state, and no further changes were observed as the animals reached adulthood. In comparison, data reported in a succeeding article indicate that deficits in cognitive function were first seen in weanling hypothyroid rats, but that the behavioral impairments lasted well into adulthood when thyroid status and cholinergic parameters in the brain appeared to have recovered to normal. These results suggest that alterations of cholinergic system caused by perinatal hypothyroidism are associated with neurobehavioral deficits at weaning, and these developmental deviations may cause permanent impairment of cognitive function despite recovery from the hormonal imbalance at adult ages.

Ontogeny of eyeblink conditioning using a visual conditional stimulus.

The developmental emergence of associative learning in rodents is determined by interactions among sensory, motor, and associative systems that are engaged in a particular experimental preparation (Carter & Stanton, 1996; Hunt & Campbell, 1997; Rudy, 1992). In fear conditioning, chemosensory, auditory, and visual cues emerge successively as effective conditional stimuli (CS) during postnatal ontogeny. In the present study, we begin to examine the generality of this principle of sensory system development for eyeblink conditioning, a form of associative learning that develops substantially later than conditioned fear (Carter & Stanton, 1996). We asked whether the developmental emergence of eyeblink conditioning to a visual CS occurs at an age that is the same or different from conditioning to an auditory CS. In Experiment 1, rat pups were trained on postnatal Day 17 or 24 with experimental parameters (and design) that were identical to our previous studies of eyeblink conditioning except that presentation of a light rather than a tone served as the CS. The outcome was also identical: no eyeblink conditioning on Day 17 and strong conditioning on Day 24. In Experiment 2, conditioning to tone versus light was directly compared by means of a discrimination learning design on postnatal Days 19, 21, 23, and 31. There was no evidence for differential development of auditory versus visual eyeblink conditioning. The difference between this outcome and previous ones involving conditioned fear (Hunt & Campbell, 1997; Rudy, 1992) suggests that principles concerning sensory maturation and learning may be different for early- versus late-developing associative systems.

Behavioral Development Following Daily Episodes of Mother-Infant Separation in the Rat

Use of dermal or inhalation routes of maternal exposure during the postnatal period in rodent developmental neurotoxicity evaluations would be most practical if dams could be separated from their pups during the exposure period. However, this procedure raises questions concerning the effects of mother-infant separation itself on neurotoxicity endpoints. In the present study, Sprague-Dawley rat pups were either maternally deprived in warm incubators for 6 hr each day (7:00 AM-1:00 PM) or left with their dams (control), from Postnatal Day 4-20 (PND4-20), and were tested on a range of endpoints commonly used in developmental neurotoxicology. These included motor activity (PND13, 17, 19, 21, 29, 60), olfactory learning (PND18) and retention (PND25), T-maze delayed alternation (PND23, 24), acoustic startle response (PND23, 62), and auditory thresholds (PND62). None of the behavioral measures were affected by daily separation. Apparently, interrupting the mother-infant interaction for 6 hr/day has little or no effect by itself on behavioral development, as assessed by these measures.