Scopolamine enhances generalization between odor representations in rat olfactory cortex.

Central cholinergic systems have been implicated in attention and memory, and degeneration of these systems may partially underlie aging/dementia-associated declines in cognitive ability (Olton and Wenk 1987; Fibiger 1991; Everitt and Robbins 1997). Cortical acetylcholine release is elevated during arousal and/or attention (Acquas et al. 1996), and lesions or pharmacological blockade of central cholinergic synapses impairs cognitive functions (Cheal 1981; Coyle et al. 1983). The olfactory system has been an especially useful model system for studying the role of acetylcholine in memory. Disruption of normal cholinergic function has been implicated in disruption of many forms of odor memory, including simple odor habituation (Hunter and Murray 1989; Paolini and McKenzie 1993), associative odor memory (Roman et al. 1993; Ravel et al. 1994; Ferreira et al. 1999; DeRosa and Hasselmo 2000; Winters et al. 2000; see also Wirth et al. 2000), and odor rule or set learning (Saar et al. 2001). The mechanisms of cholinergic modulation of olfactory memory, however, are unknown. The olfactory system primarily receives cholinergic input from the basal forebrain (Wenk et al. 1977; Shipley and Ennis 1996), although there is also a small population of intrinsic cholinergic neurons within the olfactory bulb and cortex (Phelps et al. 1992). The major source of acetylcholine (ACh) to the olfactory system is the horizontal limb of the diagonal band of Broca (HLDB), which also receives olfactory input. In fact, activity within the HLDB and ACh release are enhanced by olfactory system activation (Inglis and Fibiger 1995; Linster and Hasselmo 2000). In the olfactory bulb, the first central processor in the olfactory pathway, ACh modulates activity of both output neurons (mitral/tufted cells) and interneurons through both muscarinic and nicotinic receptors (Nickell and Shipley 1988; Ravel et al. 1990; Elaagouby et al. 1991; Castillo et al. 1999). In the piriform cortex, ACh modulates synaptic transmission between pyramidal neurons (association fibers; Hasselmo and Bower 1992; Rosin et al. 1999), modulates pyramidal cell excitability (Linster et al. 1999) and regulates adaptation of pyramidal cell firing to step depolarization (Barkai and Hasselmo 1994). In both the olfactory bulb (Elaagouby and Gervais 1992) and piriform cortex (Hasselmo and Barkai 1995; Saar et al. 2001), ACh also enhances some forms of neural plasticity. Modeling studies of piriform cortex indicate that ACh may function to reduce interference between different, stored patterns of odor-evoked activity, and therefore, reduce confusion between odorant memories (Hasselmo and Bower 1993; Linster and Hasselmo, 2001). Therefore, a reduction in cholinergic activity within the piriform cortex during odor exposure and learning should result in interference between cortical representations of different odors that could be expressed as a memory impairment. Neurons within the anterior piriform cortex (aPCX) display odor-receptive fields (Wilson 1998a, 2000b) similar to that reported for both olfactory receptor neurons (Sato et al. 1994; Duchamp-Viret et al. 1999; Malnic et al. 1999) and olfactory bulb mitral/tufted cells (Imamura et al. 1992; Yokoi et al. 1995). However, aPCX neurons are capable of a high degree of discrimination between odors within their receptive fields, a capability not expressed by mitral/tufted cells (Wilson 2000b). For example, habituation to one odor within the receptive field of an aPCX neuron does not generalize to responsiveness to other, highly similar odorants (e.g., varying by only two carbons in molecular length), whereas mitral/tufted cells show substantial generalization/cross-habituation between odors within their receptive fields (Wilson 2000a,b). This report examines whether the heightened specificity of responses within the aPCX may be related to the hypothesized (Hasselmo and Bower 1993; Linster and Hasselmo 2001) cholinergic reduction in interference between cortical odor representations mentioned above. The results indicate that the muscarinic ACh receptor antagonist scopolamine enhances cross-habituation (generalization) between odors by aPCX neurons in a simple odor memory test.