Arthur J. Nonneman

Sparing of function in rats with early prefrontal cortex lesions

Previous work has shown that medial frontal lesions in adult rats produce deficits on spatial reversals, delayed responses, and active avoidance, whereas more ventrolateral (orbital) lesions have little effect on these tasks. These findings were confirmed. However, when lesions were made at 2, 5 or 9 days of age, rats tested as adults showed dramatic sparing of function on all these tasks, whereas similar lesions inflicted at 35 or 40 days of age produced deficits on delayed responses and spatial reversals. Orbital frontal lesions failed to significantly alter behavior on any task at any age. The effects of the neonatal lesions are in striking contrast to the effects of juvenile or adult lesions, even though the infant lesions were considerably larger. Histological analysis revealed no retrograde degeneration in the dorsomedial thalamic nucleus of the rats operated in infancy unless the lesions were so large that the adjacent caudate-putamen was also damaged. The contrast between these results, and results obtained after similar lesions in adults may indicate the growth of sustaining collaterals after the infant lesions which might be involved in the observed behavioral sparing.

Toxin-induced models of neurological disorders

Animal Models and the Implications of Their Use (A.J. Nonneman, M.L. Woodruff). Strategies for Developing Animal Models of NeurotoxicantInduced Neurodegenerative Disorders (P.R. Solomon et al.). Experimental Paradigms of Motor Neuron Degeneration (M.J. Strong, R.M. Garruto). Hydroxydopamine Lesions of Nigrostriatal Neurons as an Animal Model of Parkinsons Disease (P.J. Reading, S.B. Dunnett). MPTPTreated Mice (E. Sundstrom et al.). Behavioral Effects of MPTP Administration in the Vervet Monkey (J.R. Taylor et al.). Intranigral Iron Infusion as a Model for Parkinsons Disease (G.W. Arendash et al.). Excitotoxic Lesions of the Neostriatum as an Animal Model of Huntingtons Disease (D.F. Emerich et al.). The Use of AF64A to Model Alzheimers Disease (T.J. Walsh, K.D. Opello). Perinatal Intake of Polychlorinated Biphenyl (L.M. Juarez de Ku, L.A. Meserve). Aluminum Exposure Produces Learning and Memory Deficits (R.A. Yokel). Trimethyltin Neurotoxicity in the Rat as an Analogous Model of Alzheimers Disease (M.L. Woodruff, R.H. Baisden). Index.

Effect of forebrain dopamine depletion on novelty-induced place preference behavior in rats

Novelty-induced place preference behavior of rats was studied in two experiments. In the first experiment, separate groups of animals were habituated to a distinct environment 30 min daily for either zero, one, two, four or eight days. On the day following the last habituation day, animals were allowed 15 min free access to both the habituated (familiar) and a distinct novel environment. The results revealed a significant novelty preference in the two-, four- and eight-day habituation groups. In these same animals, the rate of horizontal and vertical activity was lower in the novel environment relative to the familiar environment. The influence of forebrain dopamine (DA) projections on novelty preference behavior was studied in the second experiment. Animals were given an injection of 6-hydroxydopamine (6-OHDA) into the nucleus accumbens or were given sham surgery, and then they were given four habituation days to one environment. Novelty-induced place preference was blocked in the lesioned animals, as the amount of time spent in the novel and familiar environments was not significantly different. Lesioned animals also failed to show a difference in locomotor activity between the novel and familiar environments. Subsequent assay data revealed that the 6-OHDA lesion reduced DA levels in the nucleus accumbens, anterior striatum and olfactory tubercles by over 65% as compared to sham surgery. These results suggest that novelty preference behavior may be mediated by a central DA pathway similar to that involved in other types of reinforcing stimuli, such as food, water and drugs of abuse.

Perinatal glucocorticoids disrupt learning: A sexually dimorphic response

Glucocorticoid hormones administered during the perinatal period transiently inhibit postnatal granule cell neurogenesis, and thus interfere with normal hippocampal-dentate gyrus development. Chronic deficits on behavioral tests sensitive to hippocampal-dentate function result from such treatments. In the present study rats of both sexes received either a high dose (100 mg/kg) or low dose (1 mg/kg) of dexamethasone (a synthetic glucocorticoid) on postnatal day four. Control subjects received saline or nutritional deprivation intended to produce body and brain growth suppression comparable to that observed in low dose subjects. Behavioral tests sensitive to cerebellar (motor coordination) and hippocampal (place response acquisition and reversals) dysfunction were conducted in adulthood. Control and nutritional control subjects did not differ from each other on any behavioral measures. Motor coordination tests revealed no evidence of chronic dysfunction in dexamethasone treated or nutritionally deprived subjects. Spatial learning and reversal tests revealed a gender and dose-response effect for dexamethasone treatment. Low dose subjects were impaired relative to controls. High dose subjects exhibited significant learning impairments relative to low dose and saline or nutritional control subjects. Within the high dose group only, female subjects were more impaired than male subjects. These gender dependent effects may be related to enhanced glucocorticoid binding in the hippocampi of female versus male rats.

Disruption of neophobia, conditioned odor aversion, and conditioned taste aversion in rats with hippocampal lesions.

Previous studies have implicated the hippocampus in the acquisition of conditioned taste aversions. However, the effect of hippocampal (HPC) lesions on the acquisition of conditioned aversions to the distal olfactory cue has not been investigated. In this study rats with bilateral electrolytic hippocampal lesions were given access to an odor conditioned stimulus (CS) alone or a compound odor-taste CS, followed by an injection of LiCl or saline. The results indicated that HPC lesions attenuated the neophobic response to both CSs, and disrupted conditioned odor and taste aversions, relative to sham-operated controls. Furthermore, the disruption in conditioned odor aversions could not be attributed to attenuation of neophobia in lesioned subjects nor to prolonged neophobia in sham-operated controls. The results are consistent with pharmacological studies in suggesting that the hippocampus is involved in the formation of conditioned odor aversions.

Ontogeny of locomotor activity and grooming in the young rat: role of dopamine D1 and D2 receptors.

Locomotor activity and grooming were assessed in 11- and 17-day-old rat pups after treatment with selective dopamine (DA) D-1 and D-2 agonists (SKF 38393 and quinpirole, respectively) and antagonists (SCH 23390 and sulpiride, respectively). Quinpirole enhanced the locomotor activity of both the 11- and 17-day-olds, effects antagonized by either SCH 23390 or sulpiride. Drug-induced increases in grooming were apparent only after high doses (30.0 mg/kg i.p.) of SKF 38393 (11- and 17-day-olds) or when SKF 38393 (15.0 mg/kg i.p.) was given in conjunction with sulpiride (11-day-olds). In general, these results suggest that challenge with selective DA agonists and antagonists induces patterns of responding which are similar to those typically observed in adult rats. Moreover, these results indicate that rat pups, like adults, require a functioning DA D-1 receptor system for the expression of DA D-2-mediated activity.

Functional recovery after serial ablation of prefrontal cortex in the rat.

Abstract In two experiments, adult rats with 1-stage or 2-stage ablation of discrete subfields of the prefrontal cortex were compared on spatial delayed alternation, one way active avoidance, food hoarding, ingestive behavior, and postoperative body weight. Single stage removal of the ventrolateral (sulcal or orbital) cortex produced aphagia and adipsia for several days postoperatively and a chronic reduction in body weight. Serial removal of this same cortex produced a milder effect on postoperative food and water intake, and there was no chronic reduction of body weight. Ablation of dorsomedial cortex either in one or two stages did not significantly reduce food or water intake or body weight. In contrast, single stage removal of dorsomedial cortex produced dramatic impairment on spatial delayed alternation, active avoidance, and food hoarding; whereas ventrolateral lesions either in one or two stages did not significantly affect performance on these tasks. Animals with dorsomedial lesions produced in two stages were not significantly impaired on delayed alternation or active avoidance, but on food hoarding they were just as impaired as the animals with comparable lesions induced in a single stage. It is apparent that removal of either dorsomedial or ventrolateral prefrontal cortex in two stages causes an amelioration of the deficit that is obtained with single stage destruction of these areas on some tasks, but sparing of function is not an invariant consequence of serial destruction of rat prefrontal cortex.

Constraints on water maze spatial learning in rats: implications for behavioral studies of brain damage and recovery of function.

In an effort to develop spatial learning tasks not requiring food or water deprivation for use in studies of recovery of function after brain damage, T-maze spatial alternation learning was examined in intact rats using water maze swim-escape procedures. Consistent with previous studies, rewarded spatial alternation involving food or water deprivation was readily learned by intact rats. However, none of the groups of rats trained in the swim-escape tasks learned to alternate goal arm choices in the water maze at reliable rates. This was true regardless of whether non-correction or correction procedures were used, and regardless of intertrial delay intervals. Although average alternation rates over sessions did increase from chance levels, the majority of the rats did not reach criterion levels, even with as many as 38 consecutive days of testing. In contrast, a conditional spatial alternation task in the water maze, using a win-shift procedure, was readily learned. Surprisingly, a win-stay version of this conditional spatial task was not learned over 21 days of testing. These unexpected constraints on spatial learning and memory processes in rats cannot be attributed simply to failure of spatial information processing, nor to strict limitations on working memory in swim-escape tasks, since excellent spatial navigation abilities have been documented, and mastery of at least some working-memory tasks have now been demonstrated in swim-escape tasks.

Role of residual anterior neocortex in recovery from neonatal prefrontal lesions in the rat

Lesions of mediofrontal cortex in adult rats produce behavioral impairments on spatial alternation tasks as well as retrograde degeneration in the mediodorsal thalamic nucleus. The severity of the behavioral deficits and of the thalamic degeneration correlates positively with lesion size. In contrast, similar lesions in neonatal rats (10 days or younger) produce neither spatial alternation deficits nor thalamic degeneration, even after extensive lesions removing all of the mediofrontal cortex. This study examined the possibility that residual anterior cortex remaining intact after early mediofrontal lesions might be involved in the observed anatomical and behavioral sparing. The results show that the sparing of spatial alternation after neonatal frontal cortex lesions does not depend on functional substitution by intact regions of anterior cortex. Neonatal rats receiving extensive lesions including both the medial and orbital frontal cortex or the entire anterior neocortex remained unimpaired on this task. However, these same animals suffered severe retrograde degeneration in the mediodorsal thalamus. Therefore, although some form of neural plasticity cannot be entirely dismissed as the basis for the behavioral results, it seems more likely that behavioral rather than neural plasticity is involved. We suggest that rats deprived of frontal cortex from infancy are able to perform the spatial alternation task in a manner that differs from that used by most intact rats.

Hippocampal lesions impair rats' performance of a nonspatial matching-to-sample task

In the present study, we attempted to develop a nonspatial delayed match-to-sample task that would aid in assessing the role of the hippocampus in memory. It is difficult to compare directly the results of many past studies of hippocampal function because studies using different species often use very different tasks to assess the same theoretical constructs. Rodent studies typically have used spatial tasks, such as the radial arm maze, with or without delays, whereas primate studies typically have used match-to-sample (MTS) tasks. In the present study, we examined the performance of hippocampal-lesioned rats on nonspatial simultaneous matching-to-sample (SMTS) and delayed matching-to-sample (DMTS) in a cross maze. Postoperatively, the hippocampal-lesioned subjects were unable to reacquire the SMTS task they had learned preoperatively. The results suggest that this approach may provide a useful tool for probing the role of the hippocampus in memory, and that the configurai relationships between stimuli and events or the conditional nature of a learning/memory task may be especially important aspects for determining the impact of hippocampal damage.