Alpha-2 nicotinic acetylcholine receptors regulate spectral integration in auditory cortex.

Introduction: In primary auditory cortex (A1), nicotinic acetylcholine receptors (nAChRs) containing α2 subunits are expressed in layer 5 Martinotti cells (MCs)-inhibitory interneurons that send a main axon to superficial layers to inhibit distal apical dendrites of pyramidal cells (PCs). MCs also contact interneurons in supragranular layers that, in turn, inhibit PCs. Thus, MCs may regulate PCs via inhibition and disinhibition, respectively, of distal and proximal apical dendrites.

Task-dependent effects of nicotine treatment on auditory performance in young-adult and elderly human nonsmokers.

Electrophysiological studies show that nicotine enhances neural responses to characteristic frequency stimuli. Previous behavioral studies partially corroborate these findings in young adults, showing that nicotine selectively enhances auditory processing in difficult listening conditions. The present work extended previous work to include both young and older adults and assessed the nicotine effect on sound frequency and intensity discrimination.

Nicotine Enhances Amplitude and Consistency of Timing of Responses to Acoustic Trains in A1.

Systemic nicotine enhances neural processing in primary auditory cortex (A1) as determined using tone-evoked, current-source density (CSD) measurements. For example, nicotine enhances the characteristic frequency (CF)-evoked current sink in layer 4 of A1, increasing amplitude and decreasing latency. However, since presenting auditory stimuli within a stream of stimuli increases the complexity of response dynamics, we sought to determine the effects of nicotine on CSD responses to trains of CF stimuli (one-second trains at 2-40 Hz; each train repeated 25 times).

Nicotine enhances auditory processing in healthy and normal-hearing young adult nonsmokers.

Rationale: Electrophysiological studies show that systemic nicotine narrows frequency receptive fields and increases gain in neural responses to characteristic frequency stimuli. We postulated that nicotine enhances related auditory processing in humans.

Objectives: The main hypothesis was that nicotine improves auditory performance.

Nicotine excites VIP interneurons to disinhibit pyramidal neurons in auditory cortex.

Nicotine activates nicotinic acetylcholine receptors and improves cognitive and sensory function, in part by its actions in cortical regions. Physiological studies show that nicotine amplifies stimulus-evoked responses in sensory cortex, potentially contributing to enhancement of sensory processing. However, the role of specific cell types and circuits in the nicotinic modulation of sensory cortex remains unclear.

Enhanced Sensory-Cognitive Processing by Activation of Nicotinic Acetylcholine Receptors.

Unlabelled: Activation of nicotinic acetylcholine receptors (nAChRs) enhances sensory-cognitive function in human subjects and animal models, yet the neural mechanisms are not fully understood. This review summarizes recent studies on nicotinic regulation of neural processing in the cerebral cortex that point to potential mechanisms underlying enhanced cognitive function. Studies from our laboratory focus on nicotinic regulation of auditory cortex and implications for auditory-cognitive processing, but relevant emerging insights from multiple brain regions are discussed.

Development of fluorescence imaging probes for nicotinic acetylcholine α4β2 receptors.

Nicotinic acetylcholine α4β2 receptors (nAChRs) are implicated in various neurodegenerative diseases and smoking addiction. Imaging of brain high-affinity α4β2 nAChRs at the cellular and subcellular levels would greatly enhance our understanding of their functional role. Since better resolution could be achieved with fluorescent probes, using our previously developed positron emission tomography (PET) imaging agent [F]nifrolidine, we report here design, synthesis and evaluation of two fluorescent probes, nifrodansyl and nifrofam for imaging α4β2 nAChRs.

Human brain imaging of nicotinic acetylcholine α4β2* receptors using [ F]Nifene: Selectivity, functional activity, toxicity, aging effects, gender effects, and extrathalamic pathways.

Nicotinic acetylcholinergic receptors (nAChR's) have been implicated in several brain disorders, including addiction, Parkinson's disease, Alzheimer's disease and schizophrenia. Here we report in vitro selectivity and functional properties, toxicity in rats, in vivo evaluation in humans, and comparison across species of [ F]Nifene, a fast acting PET imaging agent for α4β2* nAChRs. Nifene had subnanomolar affinities for hα2β2 (0.

Systemic Nicotine Increases Gain and Narrows Receptive Fields in A1 via Integrated Cortical and Subcortical Actions.

Nicotine enhances sensory and cognitive processing via actions at nicotinic acetylcholine receptors (nAChRs), yet the precise circuit- and systems-level mechanisms remain unclear. In sensory cortex, nicotinic modulation of receptive fields (RFs) provides a model to probe mechanisms by which nAChRs regulate cortical circuits. Here, we examine RF modulation in mouse primary auditory cortex (A1) using a novel electrophysiological approach: current-source density (CSD) analysis of responses to tone-in-notched-noise (TINN) acoustic stimuli.

Spectral breadth and laminar distribution of thalamocortical inputs to A1.

The GABAergic agonist muscimol is used to inactivate brain regions in order to reveal afferent inputs in isolation. However, muscimol's use in primary auditory cortex (A1) has been questioned on the grounds that it may unintentionally suppress thalamocortical inputs. We tested whether muscimol can preferentially suppress cortical, but not thalamocortical, circuits in urethane-anesthetized mice.

Synaptic interactions and inhibitory regulation in auditory cortex.

This Special Issue focuses on the auditory-evoked mismatch negativity (MMN), an electrophysiological index of change, and its reduction in schizophrenia. The following brief review is an attempt to complement the behavioral and clinical contributions to the Special Issue by providing basic information on synaptic interactions and processing in auditory cortex. A key observation in previous studies is that the MMN involves activation of cortical N-methyl-D-aspartate (NMDA) receptors.

Convergence of nicotine-induced and auditory-evoked neural activity activates ERK in auditory cortex.

Enhancement of sound-evoked responses in auditory cortex (ACx) following administration of systemic nicotine is known to depend on activation of extracellular-signaling regulated kinase (ERK), but the nature of this enhancement is not clear. Here, we show that systemic nicotine increases the density of cells immunolabeled for phosphorylated (activated) ERK (P-ERK) in mouse primary ACx (A1). Cortical injection of dihydro-β-erythroidine reduced nicotine-induced P-ERK immunolabel, suggesting a role for nicotinic acetylcholine receptors located in A1 and containing α4 and β2 subunits.

Tone-detection training enhances spectral integration mediated by intracortical pathways in primary auditory cortex.

Auditory-cued behavioral training can alter neural circuits in primary auditory cortex (A1), but the mechanisms and consequences of experience-dependent cortical plasticity are not fully understood. To address this issue, we trained adult rats to detect a 5 kHz target in order to receive a food reward. After 14 days training we identified three locations within A1: (i) the region representing the characteristic frequency (CF) 5 kHz, (ii) a nearby region with CF ∼10 kHz, and (iii) a more distant region with CF ∼20 kHz.

Nicotinic filtering of sensory processing in auditory cortex.

Although it has been known for decades that the drug nicotine can improve cognitive function, the nature of its effects and the underlying mechanisms are not well understood. Nicotine activates nicotinic acetylcholine (ACh) receptors (nAChRs) that normally are activated by endogenous ACh, presumably "hijacking" the cholinergic contribution to multiple cognitive functions, notably attention. Thus, studying nicotine's effects helps to better understand a commonly used drug as well as functions of nAChRs.

Nicotinic neuromodulation in auditory cortex requires MAPK activation in thalamocortical and intracortical circuits.

Activation of nicotinic acetylcholine receptors (nAChRs) by systemic nicotine enhances sensory-cognitive function and sensory-evoked cortical responses. Although nAChRs mediate fast neurotransmission at many synapses in the nervous system, nicotinic regulation of cortical processing is neuromodulatory. To explore potential mechanisms of nicotinic neuromodulation, we examined whether intracellular signal transduction involving mitogen-activated protein kinase (MAPK) contributes to regulation of tone-evoked responses in primary auditory cortex (A1) in the mouse.

Nicotinic acetylcholine receptors in rat forebrain that bind ¹⁸F-nifene: relating PET imaging, autoradiography, and behavior.

Nicotinic acetylcholine receptors (nAChRs) in the brain are important for cognitive function; however, their specific role in relevant brain regions remains unclear. In this study, we used the novel compound ¹⁸F-nifene to examine the distribution of nAChRs in the rat forebrain, and for individual animals related the results to behavioral performance on an auditory-cognitive task. We first show negligible binding of ¹⁸F-nifene in mice lacking the β2 nAChR subunit, consistent with previous findings that ¹⁸F-nifene binds to α4β2* nAChRs.

Null mutations in EphB receptors decrease sharpness of frequency tuning in primary auditory cortex.

Primary auditory cortex (A1) exhibits a tonotopic representation of characteristic frequency (CF). The receptive field properties of A1 neurons emerge from a combination of thalamic inputs and intracortical connections. However, the mechanisms that guide growth of these inputs during development and shape receptive field properties remain largely unknown.

Heightened nicotinic regulation of auditory cortex during adolescence.

Adolescent smoking is associated with auditory-cognitive deficits and structural alterations to auditory thalamocortical systems, suggesting that higher auditory function is vulnerable to nicotine exposure during adolescence. Although nicotinic acetylcholine receptors (nAChRs) regulate thalamocortical processing in adults, it is not known whether they regulate processing at earlier ages since their expression pattern changes throughout postnatal development. Here we investigate nicotinic regulation of tone-evoked current source density (CSD) profiles in mouse primary auditory cortex from just after hearing onset until adulthood.

Functional connectivity and cholinergic modulation in auditory cortex.

Although it is known that primary auditory cortex (A1) contributes to the processing and perception of sound, its precise functions and the underlying mechanisms are not well understood. Recent studies point to a remarkably broad spectral range of largely subthreshold inputs to individual neurons in A1--seemingly encompassing, in some cases, the entire audible spectrum--as evidence for potential, and potentially unique, cortical functions. We have proposed a general mechanism for spectral integration by which information converges on neurons in A1 via a combination of thalamocortical pathways and intracortical long-distance, "horizontal", pathways.

A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses.

Soluble amyloid beta oligomers (AbetaOs) interfere with synaptic function and bind with high affinity to synapses, but the mechanism underlying AbetaO synaptic targeting is not known. Here, we show that the accumulation of synthetic or native Alzheimer's disease (AD)-brain oligomers at synapses is regulated by synaptic activity. Electrical or chemical stimulation increased AbetaO synaptic localization and enhanced oligomer formation at synaptic terminals, whereas inhibition with TTX blocked AbetaO synaptic localization and reduced AbetaO synaptic load.

Nicotinic modulation of tone-evoked responses in auditory cortex reflects the strength of prior auditory learning.

Nicotinic acetylcholine receptors (nAChRs) contribute to sensory-cognitive function, as demonstrated by evidence that nAChR activation enhances, and nAChR blockade impairs, neural processing of sensory stimuli and sensory-cognitive behavior. To better understand the relationship between nAChR function and behavior, here we compare the strength of nAChR-mediated physiology in individual animals to their prior auditory behavioral performance. Adult rats were trained on an auditory-cued, active avoidance task over 4 days and classified as "good," "intermediate" or "poor" performers based on their initial rate of learning and eventual level of performance.

Nicotinic control of axon excitability regulates thalamocortical transmission.

The thalamocortical pathway, a bundle of myelinated axons that arises from thalamic relay neurons, carries sensory information to the neocortex. Because axon excitation is an obligatory step in the relay of information from the thalamus to the cortex, it represents a potential point of control. We now show that, in adult mice, the activation of nicotinic acetylcholine receptors (nAChRs) in the initial portion of the auditory thalamocortical pathway modulates thalamocortical transmission of information by regulating axon excitability.

Neonatal nicotine exposure impairs nicotinic enhancement of central auditory processing and auditory learning in adult rats.

Children of women who smoke cigarettes during pregnancy display cognitive deficits in the auditory-verbal domain. Clinical studies have implicated developmental exposure to nicotine, the main psychoactive ingredient of tobacco, as a probable cause of subsequent auditory deficits. To test for a causal link, we have developed an animal model to determine how neonatal nicotine exposure affects adult auditory function.

Spectral integration in auditory cortex: mechanisms and modulation.

Auditory cortex contributes to the processing and perception of spectrotemporally complex stimuli. However, the mechanisms by which this is accomplished are not well understood. In this review, we examine evidence that single cortical neurons receive input covering much of the audible spectrum.

Spectral integration in primary auditory cortex: laminar processing of afferent input, in vivo and in vitro.

Auditory cortex neurons integrate information over a broad range of sound frequencies, yet it is not known how such integration is accomplished at the cellular or systems levels. Whereas information about frequencies near a neuron's characteristic frequency is likely to be relayed to the neuron by lemniscal thalamocortical inputs from the ventral division of the medial geniculate nucleus, we recently proposed that information about frequencies spectrally distant from characteristic frequency is mainly relayed to the neuron via "horizontal" intracortical projections from neurons with spectrally-distant characteristic frequencies [J Neurophysiol 91 (2004) 2551]. Here we test this hypothesis by using current source density analysis to determine if characteristic frequency and spectrally-distant non-characteristic frequency stimuli preferentially activate thalamocortical and horizontal pathways, respectively, in rat auditory cortex.