Research reportPerformance of α7 nicotinic receptor null mutants is impaired in appetitive learning measured in a signaled nose poke task
Introduction
Nicotine binds with high affinity to neuronal nicotinic cholinergic receptors (nAChRs) throughout the brain and produces a wide range of behavioral responses including enhancement of learning and memory in a number of different animal species [23], [24], [25], [26], [40], [65]. Eleven nAChR subunits (α2–α7, α9, α10, and β2–β4) have been identified within the mammalian brain, with α4β2 and α7-type nAChRs being the most widely expressed subtypes of nAChRs [41].
While nAChRs are clearly required for nicotine to have its behavioral effects, the role of specific nAChR subtypes in regulating nicotine's behavioral effects as well as the roles of these receptors in regulating behavior in the absence of nicotine is not clear. The availability of null mutant mice that lack the expression of specific nAChRs allows the examination of the potential roles of the individual nAChR subtypes in behavioral processes including learning and memory. Examinations of nicotinic receptor subunit null mutants have demonstrated that β2-containing receptors are required for nicotine enhancement of avoidance learning [53], for normal responses to the discriminative stimulus and taste aversion properties of nicotine [62], and nicotine enhancement of contextual fear conditioning [67]. β2-containing nicotinic receptors also participate in mediating contextual learning when training conditions are more difficult [11], [67], passive avoidance learning [33] and some behavioral processes thought to measure executive function [27]. Thus, β2-containing receptors participate in the regulation of several forms of complex learning but less is known concerning the roles of other nAChRs in regulating behavior.
Behavioral studies of cognitive processes and attention also have been conducted using nicotinic antagonists to explore the role of nAChRs [3], [7], [28], [38], [39]. These studies using the nicotinic receptor antagonists dihydro-β-erythroidine (DHβE) and methyllycaconitine (MLA) have implicated β2- and α7-containing receptors in nicotine enhancement of cognition in some forms of learning [39] but these drugs may not be specific for either β2 or α7 subtypes, respectively [32], [48].
Recent studies have shown that α7 nAChRs participate in the mediation of sensitivity to the cognitive impairing effects of ethanol [67], but α7 null mutants are not impaired in contextual learning despite the high levels of expression of α7 in the hippocampus [52], [67]. In addition to its localization in brain regions regulating some types of memory, α7 receptors are unique among nAChRs in that they can function as homomers and have both presynaptic and postsynaptic localizations [44], [57], whereby they modulate the release of glutamate and play a role in synaptic transmission of dopamine, GABA, and glutamate [4], [17]. Additional interest in whether α7 nAChRs mediate behavioral processes also stems from the fact that human genetic studies have found an association of mutations in the α7 gene in families with schizophrenia [18]. Given that schizophrenics exhibit cognitive deficits, the potential role of α7 receptors remains an important issue [68].
Multiple other nAChRs are expressed as heteromers composed of α and β subunits in brain regions known to regulate cognitive processes such as prefrontal cortex, hippocampus, amygdala, and nucleus accumbens [16], [34], [43], [51], [66], [69], [70]. These other nAChRs have presynaptic localizations and function to modulate the release of several neurotransmitters known to be important for learning and memory processes including acetylcholine, dopamine, and norepinephrine ([4], see review [71]). Multiple nAChR subunits can also be expressed in the same neurons. For example, rat basal forebrain cholinergic neurons express α4, α7, and β2 mRNAs [5], mouse GABAergic interneurons in the dorsal hippocampus show immunoreactivity to antibodies to α3, α4, α5, and α7 in addition to β2 and β4 [20], and mouse striatal dopaminergic terminals express as many as four different functional nAChRs [59].
Given that many of the nAChRs may be involved in modulation of cognitive processes, the present study investigated the potential role of several nicotinic receptor subtypes in appetitive learning, measured in a signaled nose poke task. The signaled nose poke task, originally developed by Steinmetz et al. [64] as a barpressing task in rats to measure appetitive learning, was later modified by Logue et al. [42] for mice. Logue et al. [42] and Bowers and Wehner [8] used this task to provide measures of not only appetitive learning, but also behavioral impulsivity. Previous studies of smokers suggest that they exhibit increased impulsivity [21], [47] making this task useful to address whether any of the nAChRs are involved in regulation of appetitive learning as well as behavioral impulsivity.
While the present studies were being conducted, Young et al. [73] demonstrated a role of the α7 nAChR in regulation of sustained attention measured in a version of the 5-choice serial reaction-time (5-CSRT) task [12], another appetitive task affected by nicotine [7], [28], [29], [46], [73]. Whether other nicotinic receptor subtypes in addition to α7 nAChRs participate in the regulation of sustained attention was not determined.
Section snippets
Subjects
In the present study, wild-type and homozygous null mutant mice from each of the α5, α7, β2, β3, and β4 nAChR mouse lines were tested in the signaled nose poke task. A detailed description of the construction of each of these mutant mouse lines and genotyping reactions is available elsewhere [13], [50], [55], [58], [72]. Colonies of each mouse line were established and maintained by heterozygote breeding at the Institute for Behavioral Genetics at the University of Colorado (Boulder, CO). With
Performance of nicotinic null mutant lines on phases 1–3
nAChRs are present throughout the brain and are found in high concentrations in regions that may mediate learning and memory processes as well as reward processes [54]. While previous studies of other forms of learning suggested that α7 and β2-containing receptors would also be likely candidates for mediation of appetitive learning, it is possible that several nAChRs could be involved in the mediation of performance in the signaled nose poke task. Thus, the performances of wild types and
A role for α7 receptors in appetitive learning
These results demonstrate: (1) α7 nAChRs are involved in the regulation of appetitive learning and (2) receptors containing the α5, β2, β3, and β4 subunits do not mediate appetitive learning. Mutants lacking α7 expression showed impaired performance on phase 4 of the signaled nose poke task compared to their wild-type littermates. Since α7 mutants did not significantly differ from wild types, or from other mouse lines with various nicotinic receptor modifications, in phases 1–3, it appears that
Acknowledgements
This work was funded by CTRP grant (2RR-033), AA13018 to J.M.W. and a Conte Center grant to Dr. Robert Freedman (P50 MH068582). We thank Dr. Allan C. Collins for helpful discussions and for providing mice from the NIDA-supported nicotinic mutant colonies (DA15663) as well as Dr. Arthur Beaudet, Dr. Marina Picciotto, and Dr. Steven Heinemann for providing breeding pairs of null mutants to the breeding facility. We thank Estaban Loetz and Jill Miyamoto for assistance in breeding and genotyping
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