The most pronounced differences between genotypes were observed during the memory retention test, during which ��4?/? male mice showed a significant reduction in the use of the spatial strategy, indicating deficits in spatial memory retention. The medial habenula receives inputs from the septal nuclei, which during are themselves targeted by afferents from the hippocampus involved in spatial learning (Bannerman et al., 2003; Moser, Moser, & Andersen, 1993; Paylor, Zhao, Libbey, Westphal, & Crawley, 2001; Richmond et al., 1999). The habenular complex has been hypothesized to integrate spatial memories with outcome incentive value and thereby contribute to the selection of appropriate coping strategies in stressful situations (for review, see Lecourtier & Kelly, 2007).
Accordingly, lesions of the habenular complex resulted in marked spatial memory impairment during acquisition and retrieval in the Morris water maze, a spatial memory task that is more anxiogenic and stressful than the Barnes maze (Harrison, Hosseini, & McDonald, 2009; Lecourtier et al., 2004). Although ��4-containing nAChRs are expressed in the hippocampus and medial habenula (Dineley-Miller & Patrick, 1992; Gahring, Persiyanov, & Rogers, 2004; Picciotto et al., 2000), the genetic ablation of the ��4 nAChR subunit induced only limited deficits in spatial memory retention and did not affect general performance in the Barnes maze. Furthermore, ��4?/? mice tended to exhibit decreased anxiety-like behavior in the light�Cdark box compared with ��4+/+ mice, suggesting that the observed small deficit in spatial memory retention in ��4?/? may not be anxiety related, although being in a brightly lit, open space in the Barnes maze is considered anxiogenic for mice.
In agreement Cilengitide with previously published findings (Wehner et al., 2004), contextual learning was similar in both ��4?/? and ��4+/+ mice as measured by freezing during the contextual fear conditioning test and retest of memory retention. Furthermore, both ��4?/? and ��4+/+ mice acquired the cued fear conditioning task and showed significant increases in freezing in response to the cue previously associated with footshocks. Interestingly, however, ��4?/? male but not ��4?/? female mice exhibited reduced freezing during the cue-induced fear conditioning test, indicating memory deficits in this task. In contrast, previously published findings reported no deficits in cue-induced fear conditioning in ��4?/? mice (Wehner et al., 2004). During memory retention tests, both ��4?/? male and female mice exhibited reduced freezing indicating memory deficits in cue-induced fear conditioning.