Research ReportLesions to the nucleus basalis magnocellularis lower performance but do not block the retention of a previously acquired learning set
Introduction
The nucleus basalis magnocellularis (nBM; homologous to the nucleus basalis of Meynert in primates) provides the major source of cholinergic innervation to the prefrontal, frontal, and parietal cortices (Collerton, 1986, Mesulam et al., 1983). Scientists have been interested in the functional role of the nBM partly due to the degeneration of cells within this area in Alzheimer’s disease (AD; Coyle et al., 1983, Iraizoz et al., 1991, Jacobs and Butcher, 1986) and the positive correlation of cell damage in the nBM and the severity of dementia seen in AD (Jacobs and Butcher, 1986, Tohgi et al., 1996). Experimental damage to the nBM in rats has been found to significantly decrease cortical cholinergic markers using both non-selective excitotoxic lesions (Dubois et al., 1985, Evenden et al., 1989, Stoehr and Wenk, 1995, Roberts et al., 1992) and selective cholinergic lesions using 192 IgG-saporin (Bailey et al., 2003, Baxter et al., 1995). Experimental damage to the nBM has also been reported to impair various behaviors including conditional discrimination learning (Everitt et al., 1987), spatial learning (González et al., 2000, Hepler et al., 1985, Miyamoto et al., 1987), configural association learning (Butt and Bowman, 2002, Butt and Hodge, 1997), transfer learning (Butt et al., 2003), social learning (Berger-Sweeney et al., 2000, Vale-Martínez et al., 2002), and attention (Baxter et al., 1995, McGaughy et al., 1999, Muir et al., 1994, Voytko et al., 1994).
Lesions to the nBM have also been found to significantly impair the acquisition of olfactory discrimination learning set formation (ODLS; Bailey et al., 2003, Bailey and Thomas, 2001). Learning set formation was defined by Harlow (1949) as “learning how to learn efficiently in a situation an animal frequently encounters” (p. 51). Learning set has also been described as involving a “win-stay/lose-shift” hypothesis (Levine, 1965) to guide animal’s responses on subsequent trials and on new discrimination problems (Schrier and Thompson, 1984). The “win-stay/lose-shift” hypothesis implies that if an animal is reinforced with food (“wins”) on trial 1, it learns to “stay” with the object that is associated with that reward on trial 2 and succeeding trials. However, if the animal responds incorrectly on trial 1 (“lose”), acquiring learning set means that it will learn to “shift” to the other object on trial 2 to obtain reinforcement. Evidence of learning set is indicated best by above chance performance on trial 2 across a number of new problems (e.g., Harlow, 1949).
Acquisition of ODLS was found to be impaired following both nonselective quisqualic acid lesions (Bailey and Thomas, 2001) and selective 192 IgG-saporin (SAP) lesions (Bailey et al., 2003) to the nBM. However, it remained unclear if damage to the nBM would impair the retention of a previously established olfactory discrimination learning set. There are several reports of acquisition deficits following both non-selective excitotoxic lesions (e.g., Butt and Hodge, 1997, Everitt et al., 1987, González et al., 2000, Miyamoto et al., 1987) and selective cholinergic SAP lesions (e.g., Bailey et al., 2003, Butt and Bowman, 2002, Butt et al., 2002) to the nbM. Researchers have also reported impairment in the retention of previously learned material following nBM lesions. In particular, non-selective excitotoxic lesions to the nBM have been reported to impair the retention of conditional visual discrimination (Everitt et al., 1987), passive avoidance (Everitt et al., 1987, Flicker et al., 1983), and T-maze alteration (Salamone et al., 1984). Using selective cholinergic lesions with SAP, Berger-Sweeney et al. (2000) found that SAP lesions to the nBM significantly impaired the retention of socially cued food preference and they reported that cortical ChAT levels were correlated positively with the percentage of cued preference on the 24-h retention test. Additionally, Vale-Martínez et al. (2002) also using a socially cued food task, showed a significant deficit in immediate and 24 h retention in animals with SAP lesions to the nBM. However, others have reported no retention deficits following nBM lesions (see González et al., 2000, Nieto-Escámez et al., 2004). Additionally, the ability to perform well on a retention test following lesions to the nBM may be dependent on the extent of training prior to surgery. Vale-Martínez et al. (2002) reported that when given per-operative experience with the socially cued food task, lesions to the nBM significantly reduced performance from the pre-surgical level, but the lesioned animals were not significantly impaired when compared to control animals.
The reports of retention deficits following nonselective and selective lesions to the nBM led us to investigate the effects of lesions to the nBM on the retention of a previously learning ODLS. First we trained animals on ODLS using 40 unique olfactory discrimination problems. We then produced bilateral lesions to the nBM using either quisqualic acid (QUIS) or 192 IgG-saporin (SAP). Based on previous reports of the nBM playing an important role in retention of olfactory information (Berger-Sweeney et al., 2000, Vale-Martínez et al., 2002), we hypothesized that both QUIS and SAP lesions to the nBM would significantly impair retention of ODLS as demonstrated by chance performance on trial 2 using 20 new olfactory discrimination problems following surgical recovery. We also examined open field activity and working memory as measured by a delayed nonmatching-to-position task in order to assess whether deficits following nBM lesions were general or specific to the ODLS task. Based on previous research (Bailey et al., 2003, Bailey and Thomas, 2001) we did not expect to see any changes in behavior in the open field or changes in working memory following nBM lesions.
Section snippets
Acquisition of olfactory discrimination learning set (ODLS)
The overall performance across the original 40 olfactory unique learning set problems (each with five trials) can be seen in Fig. 1. A one-way repeated measures analysis of variance (ANOVA) showed a significant effect of Trial Number, F(4,100) = 171.5, p < 0.001 (see Fig. 1). Bonferroni t-tests (α = 0.005) showed significant increases in the percentage correct on each subsequent trial (all p-values < 0.005) except there was no such increase between Trial 3 and Trial 4, t(25) = 1.08, p > 0.05. Binomial
Discussion
Preoperatively, all animals performed significantly higher than expected by chance on trials 2–5 (see Fig. 1). The animals did not perform significantly higher than chance on trial 1 which suggested that they were not using the concept of odd when responding. Previous authors (Thomas, 1996, Thomas and Noble, 1988) have made clear arguments regarding the necessity for animals to show significantly better than expected by chance performance on trial 1 in order to make a claim regarding conceptual
Subjects and maintenance
Twenty-six male 80–90-day-old Long–Evans rats were purchased from Harlan (Indianapolis, IN) and were housed two per cage, in 42.5 cm (length) × 21.0 cm (width) × 21.0 cm (height) polycarbonate cages in a temperature controlled room. Rats were kept on a reverse light/dark (12:12) cycle and all testing was done during the dark phase. All rats were allowed a minimum 3-day adjustment period to the home condition following their arrival from shipment. Following the adjustment period, the animals were
Acknowledgments
The authors would like to thank Sandra Nauman, Sara Hapip, and Jennifer St. Germain for assistance in data collection and Dr. Roger K. Thomas for editorial comments regarding the manuscript.
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