Distinct Roles of Bulbar Muscarinic and Nicotinic Receptors in Olfactory Discrimination Learning

Abstract

The olfactory bulb (OB) and piriform cortex receive dense cholinergic projections from the basal forebrain. Cholinergic modulation within the piriform cortex has long been proposed to serve important functions in olfactory learning and memory. We here investigate how olfactory discrimination learning is regulated by cholinergic modulation of the OB inputs to the piriform cortex. We examined rats' performance on a two-alternative choice odor discrimination task following local, bilateral blockade of cholinergic nicotinic and/or muscarinic receptors in the OB. Results demonstrate that acquisition, but not recall, of novel discrimination problems is impaired following blockade of OB cholinergic receptors, although the relative contribution of muscarinic and nicotinic receptors depends on task difficulty. Blocking muscarinic receptors impairs learning for nearly all odor sets, whereas blocking nicotinic receptors only affects performance for perceptually similar odors. This pattern of behavioral effects is consistent with predictions from a model of cholinergic modulation in the OB and piriform cortex (de Almeida et al., 2013). Model simulations suggest that muscarinic and nicotinic receptors may serve complementary roles in regulating coherence and sparseness of the OB network output, which in turn differentially regulate the strength and overlap in cortical odor representations. Overall, our results suggest that muscarinic receptor blockade results in a bona fide learning impairment that may arise because cortical neurons are activated less often. Behavioral impairment following nicotinic receptor blockade may not be due to the inability of the cortex to learn, but rather arises because the cortex is unable to resolve highly overlapping input patterns.

Discrimination performance in aging is vulnerable to interference and dissociable from spatial memory

“…Cholinergic neurotransmission is critical to attention and memory (Hasselmo 2006), and can influence abilities to discriminate between similar stimuli in other sensory domains (Devore et al 2014). To determine whether increasing acetylcholine levels would alter spatial discrimination performance, rats received intraperitoneal injections of the acetylcholinesterase inhibitor donepezil (1 and 3 mg/kg) or vehicle prior to discrimination tests.…”

Internal Cholinergic Regulation of Learning and Recall in a Model of Olfactory Processing

“…The model implemented here is an extension of our previous work (de Almeida et al, 2013; Devore et al, 2014) in which we explored the relative contributions of ACh modulation in OB and PC. Here, in addition to OB and PC, we implemented a third network representing the HDB (Figure 1A).…”

“…In the OB, Ach has been shown to modulate principal cells and different classes of interneurons via both nicotinic and muscarinic receptors (Ravel et al, 1990; Castillo et al, 1999; Crespo et al, 2000; Pressler et al, 2007; D'souza and Vijayaraghavan, 2012; Ma and Luo, 2012; D'souza et al, 2013; Rothermel et al, 2014; Liu et al, 2015; Smith et al, 2015; Bendahmane et al, 2016). From these data, the net functional effect of ACh inputs to the OB can be constructed as enhancing mitral cell selectivity to odorants through increased inhibition and filtering of low amplitude inputs in concert with increased excitability in response to selective odorants; this idea is supported by behavioral and electrophysiological data (Elaagouby et al, 1991; Linster et al, 2001; Wilson et al, 2004; Mandairon et al, 2006; Devore et al, 2014). In the PC, ACh has been shown to have effects on principal cell and interneuron excitability and afterhyperpolarization, excitatory and inhibitory synaptic transmission as well as synaptic plasticity (Williams and Constanti, 1988; Tseng and Haberly, 1989; Hasselmo et al, 1992; Barkai and Hasselmo, 1994; Barkai et al, 1994; Hasselmo and Barkai, 1995; Hasselmo and Cekic, 1996; Patil et al, 1998; Patil and Hasselmo, 1999; Haberly, 2001).…”

“…Both OB and PC receive (presumably common) cholinergic inputs from the medial pre-optic area and particularly from the horizontal limb of the diagonal band of Broca (HDB) (Brashear et al, 1986; Záborszky et al, 1986) and electrical stimulation of axons coming out of the OB or principal cells in the PC results in firing rate modulation of neurons in the HDB (Linster and Hasselmo, 2000), suggesting the possible existence of a feedback loop between the HDB and olfactory structures. Our previous work has shown that concerted cholinergic modulation in OB and PC improve cortical learning and associative memory function (de Almeida et al, 2013; Devore et al, 2014), due to improved signal-to-noise ratio and synchronization in OB (which results in better cortical read-out) and increased excitability and plasticity in PC. Pyramidal cell networks trained using modulated inputs from the bulb exhibit more robust learning, with stronger neuronal activation and sparser cortical representations of odorants.…”

“…We and others have previously proposed that in computational models, cholinergic modulation in the OB can regulate odor representations and neural synchrony, thus changing odor inputs to the cortex (de Almeida et al, 2013; Li and Cleland, 2013; Devore et al, 2014). In piriform cortex, cholinergic modulation is thought to aid associative memory function by reducing interference between learned information and by increasing neural excitability and synaptic plasticity (Hasselmo et al, 1992; Patil et al, 1998; De Rosa and Hasselmo, 2000; De Rosa et al, 2001).…”