Research report
Unilateral hippocampal lesions in newborn and adult rats: effects on spatial memory and BDNF gene expression

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Abstract

Subcortical damage at birth often produces more severe deficits than similar lesions in an adult. In the present study, effects of unilateral electrolytic hippocampal ablations made on postnatal day 1 or in 3-month-old adult rats, were compared. Exploratory behavior and spatial navigation in the Morris water maze (MWM) were assessed 8 and 20 weeks after hippocampal damage. Rats with neonatal damage did not respond to novelty in the environment and did not learn to find the hidden platform in the MWM. Rats lesioned as adults did learn the water maze task, but slower than controls. We hypothesized that behavioral deficits observed in rats lesioned at birth, may be due, in part, to neurochemical dysfunction of the contralateral hippocampus. Specifically, cholinergic and GABAergic neurotransmission were assessed by measuring choline-acetyltransferase (ChAT) and GABAdecarboxylase (GAD) activity. In addition, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) mRNA levels were assayed in the remaining (contralateral) hippocampus. Of these molecules, only BDNF gene expression was significantly reduced (by 30%) at 8 and 20 weeks after neonatal and adult unilateral ablation. The similar reduction in BDNF mRNA in both treatment groups does not correspond with the lesion's differential effect on memory function. However, the more severe learning impairment after neonatal lesion may reflect increased dependence on trophins during development.

Introduction

Subcortical damage in the neonate often has more severe consequences than similar damage in the adult [16]. Unilateral hippocampal damage during the first 2 postnatal weeks causes longlasting impairment of T-maze alternation tasks [49], whereas similar lesions in adults do not [6]. Indeed, a unilateral neonatal lesion causes spatial memory deficits comparable with an adult bilateral lesion [49]. In the present study, behavioral effects of unilateral damage made at birth were further characterized. Specifically, exploration in an open field and navigation in the Morris water maze (MWM) were examined after unilateral hippocampal lesions.

Exploration is associated with the gathering of environmental information, and may be necessary to solve spatial problems 8, 40. This behavior is impaired in rats with bilateral lesions 4, 29. It is not known whether animals lesioned at birth exhibit a similar deficit. Indeed, following a unilateral lesion, one hippocampus may be sufficient to mediate exploration, but inadequate for a more demanding task, such as spatial learning in a water maze [43].

Given the severe spatial memory impairment of rats lesioned at birth [49], we hypothesize that, unilateral damage may be functionally `bilateral'. The lesions may result in deficits in neurochemical and physiological mechanisms related to learning, in the contralateral hippocampus. Initially, we studied the activities of biosynthetic enzymes for acetylcholine and GABA, the classical transmitters involved in hippocampal synaptic physiology as well as memory function in adult rats 14, 31, 32, 45. A second approach, was to test effects of the lesions on factors that play a role in the development and survival of hippocampal cells. Specifically, neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), were tested 20, 23. Trophic factor levels may change after brain injury as part of compensatory mechanisms 17, 24. In addition, these factors have been implicated in memory function 12, 11, 26, 36, 41. Thus, effects of unilateral lesions made at birth, or at 3 months of age on trophin gene expression, as well as choline-acetyltransferase (ChAT) and GABAdecarboxylase (GAD) activity in the contralateral hippocampus, were studied following assessment of performance in exploratory and water maze tasks.

Section snippets

Subjects

Pregnant albino Sprague–Dawley (several days before parturition) and 3-month-old adult male rats were obtained from Hilltop, and housed with food and water available ad libitum. Cages were checked daily for deliveries, and pups discovered at that time were considered to be born that day (postnatal day 1). At least four pups from at least two different litters were included in each experimental group.

Neonatal

Surgery was carried out on postnatal day 1 (P1). Rat pups were anesthetized by placing them on

Exploration

Exploratory behavior was observed in an open field 8 or 20 weeks postoperatively. In sessions 1 and 2, rats spent approximately equal amounts of time in the four zones. When a novel stimulus was added to zone two in sessions 3 and 4, control and adult lesioned rats spent significantly more time in zone two than in any other zone (Fig. 1a,b,c). In contrast, rats with neonatal lesions did not increase exploration in zone two (Fig. 1d,e).

To determine whether the impaired exploration of rats with

Discussion

Unilateral neonatal hippocampal lesion causes longlasting impairment of spatial memory function 6, 49. The present study confirms this observation. Exploratory behavior as well as spatial navigation in the water maze, were deficient as a result of unilateral hippocampal damage made at birth. In contrast, unilateral lesions made in adult rats did not impair exploration and attenuated water maze learning. BDNF gene expression, but not NGF mRNA, ChAT or GAD, was reduced in the contralateral

Acknowledgements

We thank Karim Nader, Ursula Staubli and Joe Scafidi for comments on the manuscript, Joe Wagner for statistical advice and Mian Hou for help with photography. This work was supported by NIH Grant 23315.

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