Research ReportOrexin receptor activity in the basal forebrain alters performance on an olfactory discrimination task
Introduction
The basal forebrain including the nucleus basalis magnocellularis (nBM), the medial septal area (MSA), and the nuclei of the diagonal band (nDB) play a significant role in learning and memory and attention. The nBM (in primates, nucleus basalis of Meynert) is a subnuclei of the basal forebrain providing the majority of acetylcholine (ACh) to the frontal, prefrontal, and parietal cortex (Divac, 1975; Hartgraves et al., 1982, Mesulam et al., 1983). Progressive cholinergic deinnervation of the cortex following nBM degeneration comprises a major neuropathological symptom of the senile dementias, including Alzheimer׳s disease (AD; Mesulam, 2004, Muir, 1997). Such degeneration is correlated with the degree of cognitive impairment in AD (Perry et al., 1978), suggesting that cholinergic transmission contributes to cognitive functioning.
In rodents, cortical ACh release increases with cognitive demand (Himmelheber et al., 2000, Himmelheber et al., 2001). Lesions depriving the cortex of basal forebrain cholinergic input disturb executive functions including attention and cognitive flexibility. Immunotoxic lesions specific to cholinergic neurons of the nBM impair attentional performance, as measured by the five-choice serial reaction time task (5-CSRTT), while largely sparing other cognitive functions such as spatial working memory (Dalley et al., 2004, Harati et al., 2008, Lehmann et al., 2003). Cholinergic activation appears to be particularly important under task conditions elevating attentional demand (Burk et al., 2008, Harati et al., 2008, McGaughy et al., 2002). Similarly, aspects of cognitive flexibility including learning set acquisition and reversal are disrupted by cholinergic lesions of the nBM (Bailey and Lee, 2007, Bailey et al., 2003). Rats performing an operant serial reversal learning task following cholinergic nBM lesion require more training and commit more errors before successfully completing a reversal than do control animals (Cabrera et al., 2006). Such deficits are primarily restricted to the first reversal, as subsequent reversal performance is generally no different from control animals. Collectively, these deficits suggest a critical role for the nBM in cognition, particularly when task difficulty is increased.
Despite evidence suggesting nBM and basal forebrain involvement in cognition, less is known about potential afferent modulators of basal forebrain activity that may mediate cognitive functioning. One candidate is the orexins (also termed hypocretins), a family of hypothalamic neuropeptides that serve as homeostatic regulators of arousal, motivated behavior, and attention (Fadel and Burk, 2010). Released from discrete neuronal populations in the lateral and perifornical hypothalamus, the peptides orexin A (OxA; hypocretin-1) and orexin B (OxB; hypocretin-2) project to distributed cortical and subcortical regions, including the basal forebrain (España et al., 2005, Fadel and Burk, 2010, Fadel et al., 2005, Peyron et al., 1998). In vitro evidence suggests that OxA in particular may play a role in functions mediated by the basal forebrain, as cholinergic neurons of the basal forebrain are excited by OxA (Arrigoni et al., 2010, Eggermann et al., 2001, Hoang et al., 2004, Wu et al., 2004). Consistent with a more prominent role for OxA in cognition-related nBM activity, intra-nBM OxA is generally more efficacious than OxB in stimulating ACh release in the cortex (Dong et al., 2006, Fadel et al., 2005). Systemic or intra-nBM blockade of the orexin 1 receptor (OxR1), to which OxA binds with 10 to 100 fold higher affinity than OxB (Ammoun et al., 2003), impairs attentional performance on a sustained attention task (Boschen et al., 2009). Rats receiving intra-nBM OxR1 performed less accurately and had fewer hits than saline infused control animals. Similarly, intra-nBM antagonism or lesion of orexinergic cell bodies decreases arousal to natural reinforcers (Frederick-Duus et al., 2007). Thus, the appropriate application of salience and attentional resources to motivationally-relevant environmental cues (reinforcers or cues that predict primary reinforcers) may be mediated in part by OxA acting in the nBM. These experiments suggest that OxA acting in the basal forebrain can regulate aspects of cognitive functioning, likely through the stimulation of cortical ACh release.
Although the basal forebrain is known to be involved in cognitive flexibility and OxA can modulate basal forebrain cholinergic transmission and attentional function, the particular role of basal forebrain OxA in cognitive flexibility is unknown. The present study examined performance of rats on a task known to be sensitive to nBM manipulation, olfactory discrimination acquisition and reversal, following intra-basal manipulation of OxA activity. We predicted that intra-basal OxA administration would facilitate flexible responding during acquisition and reversal of the olfactory discrimination task, while selective antagonism of OxR1 with SB-334867 would impair such responding.
Section snippets
Behavioral results
Performance on both acquisition and reversal of the olfactory discrimination problem was analyzed by examining the trials to criteria and the number of errors. There were no differences between the two groups of control animals on trials to criteria (F (1,16)=.40, p >.05) or errors to criteria (F (1,16)=1.1, p>.05) and thus, they were combined to create one control group for all additional analyses. A two-way mixed analysis of variance (ANOVA; day x drug) indicted an overall significant
Discussion
The data generated in the present study support the hypothesis that orexinergic activity in the basal forebrain regulates cognitive flexibility as measured using an olfactory-discrimination reversal learning task. On this task, control animals required more trials to criterion and made more errors following reversal of the previously acquired olfactory-discrimination rule, consistent with a report using a similar olfactory reversal task (Bailey et al., 2003). In contrast, intra-basal forebrain
Subjects and maintenance
Thirty-seven male 60–70-day-old Sprague Dawley rats were purchased from Charles River (Raleigh, NC) and were housed two per cage, in 42.5 cm (length) x 21.0 cm (width) x 21.0 cm (height) polycarbonate cages in a temperature controlled room. Rats were kept on a 12/12-hour light/dark cycle (lights on at 9AM). All animals were allowed a minimum 10-day adjustment period to the animal colony following their arrival from shipment, were given ad lib access to food, and were handled daily. Prior to
Acknowledgments
The authors would like to thank Jennifer Marsh for assistance on data collection and histology.
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Current address: Department of Psychology and Brain Research Centre, University of British Columbia, Canada.