Research report
Characteristics of changes in cholinergic function and impairment of learning and memory-related behavior induced by olfactory bulbectomy

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Abstract

Memory function after olfactory bulbectomy (OBX) was examined in two tasks, namely, step-through passive avoidance task and elevated plus-maze task. OBX mice showed a significant impairment of learning and memory-related behavior on the 7th and 14th day, as measured by passive avoidance task but not elevated plus maze task. The impairment of learning and memory-related behavior on the 14th day was improved by administration of the cholinesterase inhibitor physostigmine (0.1 mg/kg, i.p.), the non-selective muscarinic agonist oxotremorine (0.1 mg/kg, i.p.) or the selective muscarinic M1 agonist McN-A-343 (10 μg/mouse, i.c.v.). In contrast, administration of the nicotinic agonist lobeline (5–9.8 mg/kg, i.p.) or the selective muscarinic M2 antagonist methoctramine (2.25–18 μg/mouse, i.c.v.) has no effect on the impairment of learning and memory-related behavior induced by OBX. In addition, we have demonstrated that the intensity of choline acetyltransferase (ChAT) fluorescence is significantly decreased in the cortex, hippocampus and amygdala on the 14th day after OBX. These results suggest that the impairment of learning and memory-related behavior induced by OBX may be caused by degeneration of cholinergic neurons and muscarinic M1 receptors play an important role in the improvement process.

Introduction

It is well known that Alzheimer's disease (AD) patients show marked impairment of the olfactory system [6], [12], [23], [30]. A recent study has shown that olfaction is impaired in an early stage of AD [13]. The olfactory system is particularly rich in acetylcholine and other neurotransmitters and AD patients have been found to have a reduced activity of ChAT in the olfactory tubercle, indicating that cholinergic neurons may be degenerated in the olfactory system. Furthermore, an increased number of senile plaques containing amyloid β-protein (Aβ) and neurofibrillary tangles in the olfactory bulbs (OB) and anterior olfactory nuclei have been demonstrated in patients with AD [8]. These findings suggest that the olfactory system and AD may be relative to each other.

In animals, the olfactory bulbectomy (OBX) causes various abnormal behaviors, such as muricide [5], reduced sexual behavior [14], [15], increased exploratory behavior [24], impaired learning and memory [27], [31] and reduced rapid eye movement (REM) sleep [21], [22].

It is well known that cholinergic neurons in the brain play an important role in memory function. Several groups have reported that OBX induces a transient increase in choline acetyltransferase (ChAT) levels in the olfactory tubercle [4] and reduced binding of muscarinic receptors [7]. However, the cholinergic neuronal functions and the effect of cholinergic drugs on the impairment of learning and memory-related behavior after OBX remain unclear.

In the present study, memory function after OBX was examined in two tasks, namely, step-through passive avoidance task and elevated plus-maze task. We investigated the effects of cholinergic drugs on learning and memory-related behavior and cholinergic neuronal function after OBX.

Section snippets

Animals

Adult male ddY mice weighing 23–26 g were obtained from Nippon SLC (Hamamatsu, Japan). Animals were housed in cages with free access to food and water under the condition of constant temperature (23±1 °C) and humidity (55±5%) and a 12-h light/dark cycle (09:00–21:00 h). All experiments were performed according to the Guide for Care and Use of Laboratory Animals at Tohoku Pharmaceutical University.

Surgery

Mice anesthetized with pentobarbital Na (50 mg/kg, i.p.; Dainippon, Osaka, Japan) were placed in a

Influence of OBX on learning and memory-related behavior

The latency time was not significantly changed on the 1st day after OBX as compared with the sham mice (U=17.5, P=0.19). However, on days 7 (U=14, P<0.05) and 14 (U=9.0, P<0.01) after OBX, the latency time of the retention trial was gradually significantly decreased as compared to the sham mice (Fig. 1). Using the elevated plus-maze, the transfer latency time of the retention trial on days 7 (U=36, P=0.29) and 14 (U=23, P=0.16) after OBX was not significant compared with the sham mice (Table 1,

Discussion

Memory function after OBX was examined by two different tasks: elevated plus-maze performance and passive-avoidance behavior. In the present study using a passive-avoidance task, the learning and memory-related behavior was impaired on days 7 and 14 after OBX (Fig. 1). This finding is consistent with previously reported results measured by the eight-arm radial maze [9], the Morris water maze [20], the three-panel runway apparatus and the three-lever operant task [31]. However, the escape

References (31)

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