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Item Mice Lacking M1 and M3 Muscarinic Acetylcholine Receptors Have Impaired Odor Discrimination and Learning(Frontiers, 2017-02-02) Chan, Wilson; Singh, Sanmeet; Keshav, Taj; Dewan, Ramita; Eberly, Christian; Maurer, Robert; Nunez-Parra, Alexia; Araneda, Ricardo C.The cholinergic system has extensive projections to the olfactory bulb (OB) where it produces a state-dependent regulation of sensory gating. Previous work has shown a prominent role of muscarinic acetylcholine (ACh) receptors (mAChRs) in regulating the excitability of OB neurons, in particular the M1 receptor. Here, we examined the contribution of M1 and M3 mAChR subtypes to olfactory processing using mice with a genetic deletion of these receptors, the M1-/- and the M1/M3-/- knockout (KO) mice. Genetic ablation of the M1 and M3 mAChRs resulted in a significant deficit in odor discrimination of closely related molecules, including stereoisomers. However, the discrimination of dissimilar molecules, social odors (e.g., urine) and novel object recognition was not affected. In addition the KO mice showed impaired learning in an associative odor-learning task, learning to discriminate odors at a slower rate, indicating that both short and long-term memory is disrupted by mAChR dysfunction. Interestingly, the KO mice exhibited decreased olfactory neurogenesis at younger ages, a deficit that was not maintained in older animals. In older animals, the olfactory deficit could be restored by increasing the number of new born neurons integrated into the OB after exposing them to an olfactory enriched environment, suggesting that muscarinic modulation and adult neurogenesis could be two different mechanism used by the olfactory system to improve olfactory processing.Item Hyperpolarization-Activated Currents and Subthreshold Resonance in Granule Cells of the Olfactory Bulb(Society for Neuroscience, 2016-10-27) Hu, Ruilong; Ferguson, Katie A.; Whiteus, Christina B.; Meijer, Dimphna H.; Araneda, Ricardo C.An important contribution to neural circuit oscillatory dynamics is the ongoing activation and inactivation of hyperpolarization-activated currents (/h). Network synchrony dynamics play an important role in the initial processing of odor signals by the main olfactory bulb (MOB) and accessory olfactory bulb (AOB). In the mouse olfactory bulb, we show that /h is present in granule cells (GCs), the most prominent inhibitory neuron in the olfactory bulb, and that /h underlies subthreshold resonance in GCs. In accord with the properties of /h, the currents exhibited sensitivity to changes in extracellular K+ concentration and ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidin chloride), a blocker of /h. ZD7288 also caused GCs to hyperpolarize and increase their input resistance, suggesting that /h is active at rest in GCs. The inclusion of cAMP in the intracellular solution shifted the activation of /h to less negative potentials in the MOB, but not in the AOB, suggesting that channels with different subunit composition mediate /h in these regions. Furthermore, we show that mature GCs exhibit /h-dependent subthreshold resonance in the theta frequency range (4–12 Hz). Another inhibitory subtype in the MOB, the periglomerular cells, exhibited /h-dependent subthreshold resonance in the delta range (1–4 Hz), while principal neurons, the mitral cells, do not exhibit /h-dependent subthreshold resonance. Importantly, /h size, as well as the strength and frequency of resonance in GCs, exhibited a postnatal developmental progression, suggesting that this development of /h in GCs may differentially contribute to their integration of sensory input and contribution to oscillatory circuit dynamics.