Diverse populations of intrinsic cholinergic interneurons in the mouse olfactory bulb

Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, MD 21250, USA.
Neuroscience (Impact Factor: 3.36). 04/2012; 213:161-78. DOI: 10.1016/j.neuroscience.2012.04.024
Source: PubMed


Cholinergic activities affect olfactory bulb (OB) information processing and associated learning and memory. However, the presence of intrinsic cholinergic interneurons in the OB remains controversial. As a result, morphological and functional properties of these cells are largely undetermined. We characterized cholinergic interneurons using transgenic mice that selectively mark choline acetyltransferase (ChAT)-expressing cells and immunolabeling. We found a significant number of intrinsic cholinergic interneurons in the OB. These interneurons reside primarily in the glomerular layer (GL) and external plexiform layer (EPL) and exhibit diverse distribution patterns of nerve processes, indicating functional heterogeneity. Further, we found these neurons express ChAT and vesicular acetylcholine transporter (VAChT), but do not immunoreact to glutamatergic, GABAergic or dopaminergic markers and are distinct from calretinin-expressing interneurons. Interestingly, the cholinergic population partially overlaps with the calbindin D28K-expressing interneuron population, revealing the neurotransmitter identity of this sub-population. Additionally, we quantitatively determined the density of VAChT labeled cholinergic nerve fibers in various layers of the OB, as well as the intensity of VAChT immunoreactivity within the GL, suggesting primary sites of cholinergic actions. Taken together, our results provide clear evidence showing the presence of a significant number of cholinergic interneurons and that these morphologically and distributionally diverse interneurons make up complex local cholinergic networks in the OB. Thus, our results suggest that olfactory information processing is modulated by dual cholinergic systems of local interneuron networks and centrifugal projections.

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    • "Cholinergic input to the OB is provided primarily by axons of neurons whose cell bodies reside in the HDB in the basal forebrain (Wenk et al., 1980; Senut et al., 1989). While a more recent study has demonstrated the presence of choline acetyltransferase (ChAT)expressing neurons within the OB itself (Krosnowski et al., 2012), "
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    ABSTRACT: The tractable, layered architecture of the olfactory bulb (OB), and its function as a relay between odor input and higher cortical processing, makes it an attractive model to study how sensory information is processed at a synaptic and circuit level. The OB is also the recipient of strong neuromodulatory inputs, chief among them being the central cholinergic system. Cholinergic axons from the basal forebrain modulate the activity of various cells and synapses within the OB, particularly the numerous dendrodendritic synapses, resulting in highly variable responses of OB neurons to odor input that is dependent upon the behavioral state of the animal. Behavioral, electrophysiological, anatomical, and computational studies examining the function of muscarinic and nicotinic cholinergic receptors expressed in the OB have provided valuable insights into the role of acetylcholine (ACh) in regulating its function. We here review various studies examining the modulation of OB function by cholinergic fibers and their target receptors, and provide putative models describing the role that cholinergic receptor activation might play in the encoding of odor information.
    Full-text · Article · Sep 2014 · Frontiers in Synaptic Neuroscience
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    • "Cholinergic fibers from the horizontal limb of the diagonal band of Broca project to all bulbar layers, with the heaviest density occurring in the GL and EPL (Ichikawa and Hirata, 1986; Záborszky et al., 1986; Matsutani and Yamamoto, 2008); the OB itself appears to be devoid of intrinsic cholinergic neurons (Godfrey et al., 1980; Le Jeune and Jourdan, 1991; Butcher et al., 1992; Ichikawa et al., 1997), although this view has been more recently challenged (Krosnowski et al., 2012). The M2 agonist oxotremorine (10 μM) increases from −10.8 ± 1.1 pA/pF (CTL) to −12.4 ± 1.1 pA/pF the amplitude of the current (n = 13; p < 0.01; t-test for paired data), an effect which is paralleled by a 4.5 ± 0.8 mV hyperpolarization in current-clamp conditions (n = 9; p < 0.001; t-test for paired data). "
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    ABSTRACT: Dopaminergic (DA) periglomerular (PG) neurons are critically placed at the entry of the bulbar circuitry, directly in contact with both the terminals of olfactory sensory neurons and the apical dendrites of projection neurons; they are autorhythmic and are the target of numerous terminals releasing a variety of neurotransmitters. Despite the centrality of their position, suggesting a critical role in the sensory processing, their properties -and consequently their function- remain elusive. The current mediated by inward rectifier potassium (Kir) channels in DA-PG cells was recorded by adopting the perforated-patch configuration in thin slices; IKir could be distinguished from the hyperpolarization-activated current (I h ) by showing full activation in <10 ms, no inactivation, suppression by Ba(2+) in a typical voltage-dependent manner (IC50 208 μM) and reversal potential nearly coincident with EK. Ba(2+) (2 mM) induces a large depolarization of DA-PG cells, paralleled by an increase of the input resistance, leading to a block of the spontaneous activity, but the Kir current is not an essential component of the pacemaker machinery. The Kir current is negatively modulated by intracellular cAMP, as shown by a decrease of its amplitude induced by forskolin or 8Br-cAMP. We have also tested the neuromodulatory effects of the activation of several metabotropic receptors known to be present on these cells, showing that the current can be modulated by a multiplicity of pathways, whose activation in some case increases the amplitude of the current, as can be observed with agonists of D2, muscarinic, and GABAA receptors, whereas in other cases has the opposite effect, as it can be observed with agonists of α1 noradrenergic, 5-HT and histamine receptors. These characteristics of the Kir currents provide the basis for an unexpected plasticity of DA-PG cell function, making them potentially capable to reconfigure the bulbar network to allow a better flexibility.
    Full-text · Article · Aug 2014 · Frontiers in Cellular Neuroscience
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    • "Previous in vitro work suggests exclusive extrinsic cholinergic modulation of M/T cell function, given that HDB cells are the only source of cholinergic input to the MOB (Mesulam et al., 1983; Fletcher and Chen, 2010). However, local intrinsic cholinergic activity has also been described (Phelps et al., 1992; Krosnowski et al., 2012). NDB modulation of M/T unit activities has been examined in a few studies (Inokuchi et al., 1987; Nickell and Shipley, 1988; Kunze et al., 1991), in which the effect on spontaneous activity was contradictory. "
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    ABSTRACT: Spontaneous activity is an important characteristic of the principal cells in the main olfactory bulb (MOB) for encoding odor information, which is modulated by the basal forebrain. Cholinergic activation has been reported to inhibit all major neuron types in the MOB. In this study, the effect of diagonal band (NDB) stimulation on mitral/tufted (M/T) cell spontaneous activity was examined in anesthetized mice. NDB stimulation increased spontaneous activity in 66 MOB neurons which lasted for 2-35 s before returning to the baseline level. The majority of the effected units showed a decrease of interspike intervals (ISI) at a range of 8-25 ms. Fifty-two percent of NDB stimulation responsive units showed intrinsic rhythmical bursting, which was enhanced temporarily by NDB stimulation, whereas the remaining non-rhythmic units were capable of synchronized bursting. The effect was attenuated by scopolamine in 21 of 27 units tested. Only four NDB units were inhibited by NDB stimulation, an inhibition that lasted less than 10 s. The NDB stimulation responsive neurons appeared to be M/T cells. Our findings demonstrate an NDB excitation effect on M/T neurons that mostly requires muscarinic receptor activation, and is likely due to non-selectivity of electrical stimulation. This suggests that cholinergic and a diverse group of non-cholinergic neurons in the basal forebrain co-ordinately modulate the dynamics of M/T cell spontaneous activity, which is fundamental for odor representation and attentional perception.
    Full-text · Article · Sep 2013 · Frontiers in Neural Circuits
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