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Nicotinic Filtering of Sensory Processing in Auditory Cortex UC Irvine UC Irvine Previously Published Works Title Nicotinic filtering of sensory processing in auditory cortex Permalink https://escholarship.org/uc/item/846470hj Journal Frontiers in Behavioral Neuroscience, 6 ISSN 1662-5153 Authors Metherate, Raju Intskirveli, Irakli Kawai, Hideki D Publication Date 2012-07-19 DOI 10.3389/fnbeh.2012.00044 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California REVIEW ARTICLE published: 19 July 2012 BEHAVIORAL NEUROSCIENCE doi: 10.3389/fnbeh.2012.00044 Nicotinic filtering of sensory processing in auditory cortex Raju Metherate 1*, Irakli Intskirveli 1 and Hideki D. Kawai 2 1 Department of Neurobiology and Behavior, Center for Hearing Research, University of California, Irvine, Irvine, CA, USA 2 Faculty of Engineering, Department of Bioinformatics, Soka University, Hachiouji, Tokyo, Japan Edited by: Although it has been known for decades that the drug nicotine can improve cognitive Anita Disney, Salk Institute for function, the nature of its effects and the underlying mechanisms are not well understood. Biological Studies, USA Nicotine activates nicotinic acetylcholine (ACh) receptors (nAChRs) that normally are Reviewed by: activated by endogenous ACh, presumably “hijacking” the cholinergic contribution to Jean-Marc Edeline, Université de Paris, France multiple cognitive functions, notably attention. Thus, studying nicotine’s effects helps to Alex Thiele, Newcastle University, better understand a commonly used drug as well as functions of nAChRs. Moreover, UK nicotinic agonists are being developed to treat a variety of disorders that involve *Correspondence: attention-related or age-related cognitive dysfunction. Studies have shown that nicotine Raju Metherate, Department of can enhance processing of attended stimuli and/or reduce processing of distracters; Neurobiology and Behavior, Center for Hearing Research, University of that is, nicotine enhances attentional filtering. To examine potential mechanisms within California, Irvine, 2205 McGaugh sensory cortex that may contribute to cognitive functions, here we describe nicotinic Hall, Irvine, CA 92697-4550, USA. actions in primary auditory cortex, where well-characterized neural “filters”—frequency e-mail: [email protected] receptive fields—can be exploited to examine nicotinic regulation of cortical processing. Using tone-evoked current-source density (CSD) profiles, we show that nicotine produces complex, layer-dependent effects on spectral and temporal processing that, broadly speaking, enhance responses to characteristic frequency (optimal) stimuli while simultaneously suppressing responses to spectrally distant stimuli. That is, nicotine appears to narrow receptive fields and enhances processing within the narrowed receptive field. Since basic cortical circuitry and nAChR distributions are similar across neocortex, these findings may generalize to neural processing in other sensory regions, and to non-sensory regions where afferent inputs are more difficult to manipulate experimentally. Similar effects across sensory and non-sensory cortical circuits could contribute to nicotinic enhancement of cognitive functions. Keywords: nicotine, acetylcholine, mouse, rat, attention INTRODUCTION: NICOTINIC ENHANCEMENT OF cognitive function. Moreover, there is intense interest in devel- COGNITIVE FUNCTION oping selective nicotinic agents that bind either to α7orα4β2∗ It has been known for decades that nicotine can enhance cog- nAChRs for therapeutic uses, e.g., for attention disorders in nitive function (Terry et al., 1996; Levin et al., 2006; Evans and adolescents and adults, cognitive decline in Alzheimer’s Disease Drobes, 2009; Sarter et al., 2009). In dozens of studies of ani- and other dementias, and other disorders such as schizophrenia mal and human behavior, performance on a variety of tasks (Levin et al., 2006; Taly et al., 2009). is improved by systemic administration of nicotine or agonists There is some uncertainty over which cognitive functions in specific for nicotinic acetylcholine (ACh) receptors (nAChR) sub- humans are enhanced by nicotine. Studies of smokers can be types, and impaired by nicotinic antagonists or disease-induced complicated by a common, though not universal, requirement loss of nAChRs. The α4β2∗ nAChR subtype that contains α4and that subjects abstain from smoking for some period of time prior β2 subunits (asterisk indicates presence of additional subunits) is to testing. “Pre-nicotine” measurements, therefore, may be more thought to be especially important for regulating cognitive func- accurately described as reflecting withdrawal from nicotine rather tion, but α7 nAChRs that contain only α7 subunits also may be than baseline measures, and nicotine’s effects likely reflect relief involved. Although it is not understood precisely which cognitive from withdrawal. However, a recent meta-analysis of 41 nico- functions are affected nor the underlying mechanisms, nicotine is tine studies on non-smokers or smokers who were not deprived presumed to “hijack” the endogenous cholinergic contribution to prior to testing indicates consistent enhancement of motor func- cognitive functions, especially attention, learning, and memory tion, attention, and memory (Heishman et al., 2010). The authors (Kassel, 1997; Levin and Simon, 1998; Dani and De Biasi, 2001; explicitly note that no studies were found that measured sensory Miwa et al., 2011). abilities, and also note that findings of cognitive improvement Studying nicotinic actions therefore is useful not only for sometimes were small in magnitude and contradicted by other understanding the effects of a commonly used drug, but also results. It is worth noting that analysesofnicotine’seffectson for understanding the role of endogenous ACh and nAChRs in human cognition can produce some ambiguity that is puzzling, Frontiers in Behavioral Neuroscience www.frontiersin.org July 2012 | Volume 6 | Article 44 | 1 Metherate et al. Nicotinic regulation of receptive fields especially given clear findings of nicotinic enhancement of cogni- absence of exogenous nicotine, implying that release of endoge- tive ability in animal studies (above). It has been suggested that nous ACh acts at nAChRs to maintain sensory responsiveness. task difficulty must be controlled carefully, since nicotinic effects Nicotinic enhancement of sensory responses is linked to may become more obvious as the task becomes more difficult (see enhancement of cognitive function. Nicotine and other nAChR below) (Evans and Drobes, 2009; St. Peters et al., 2011). agonists enhance performance on tasks that involve attention The abundance of research on nicotine’s cognitive effects is to behaviorally relevant stimuli (Warburton, 1992; Evans and matched by studies at the cellular level, with considerable infor- Drobes, 2009; Sarter et al., 2009), and while the demonstrated mation available on the molecular biology, cellular physiology, effects of nicotine in studies of attention likely involve non- and brain distribution of nAChRs (Jones et al., 1999; Leonard sensory regions (e.g., prefrontal cortex), effects of nicotine and Bertrand, 2001; Dani and Bertrand, 2007; Miwa et al., 2011). in sensory studies (referenced above) may reflect mechanisms While work remains to be done at every level, mechanistic links intended for attention-related enhancement of sensory responses. from the cellular to behavioral levels are especially unclear, and Consistent with this notion, behavioral discrimination of pure- information on how nAChRs function within specific cortical cir- tone stimuli is dramatically impaired in mice lacking β2∗ nAChRs cuits is needed to understand nicotinic functions in cognition. (Figure 1), whereas the same animals are not impaired in a task A better understanding of how nicotine’s cellular actions affect that involves similar behaviors but without sensory cues (Horst neural circuits also may provide insight into what kinds of cogni- et al., 2012). It is possible that attention to behaviorally rele- tive functions are enhanced, and better inform the use of nicotinic vant sensory cues depends on nAChR-mediated enhancement of agents as treatments. cue-evoked responses, and that similar effects result from the Sensory systems serve as useful models at the circuit/systems administration of exogenous nicotine. level because it is possible to activate neural circuits physiolog- In addition to increasing attention to relevant sensory stimuli, ically using sensory stimuli, thus enabling studies that integrate nicotine has been reported to reduce the effectiveness of irrel- information across levels from molecular to systems to behavior. evant distractors. Several authors have proposed that nicotine Recent work from our laboratory has focused on understanding improves “attentional narrowing” or stimulus filtering to help regulation of neural systems in rodent auditory cortex, for exam- focus attention on relevant stimuli (Figure 2). Friedman and col- ple examining the role of different neural circuits in establishing leagues (1974) observed faster habituation to an acoustic cue after sensory receptive fields (Kaur et al., 2004, 2005; Metherate, 2011). smoking, and suggested that nicotine enhances a “stimulus bar- Because thalamocortical and long-distance intracortical pathways rier” that suppresses distracting sensory cues (Friedman et al., may convey information about the center and edge, respectively, 1974). Similar hypotheses posit that
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