Neonatal nicotine exposure impairs nicotinic enhancement of central auditory processing and auditory learning in adult rats
ABSTRACT 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. In adult control rats, nicotine administered systemically (0.7 mg/kg, s.c.) enhanced the sensitivity to sound of neural responses recorded in primary auditory cortex. The effect was strongest in cortical layers 3 and 4, where there is a dense concentration of nicotinic acetylcholine receptors (nAChRs) that has been hypothesized to regulate thalamocortical inputs. In support of the hypothesis, microinjection into layer 4 of the nonspecific nAChR antagonist mecamylamine (10 microM) strongly reduced sound-evoked responses. In contrast to the effects of acute nicotine and mecamylamine in adult control animals, neither drug was as effective in adult animals that had been treated with 5 days of chronic nicotine exposure (CNE) shortly after birth. Neonatal CNE also impaired performance on an auditory-cued active avoidance task, while having little effect on basic auditory or motor functions. Thus, neonatal CNE impairs nicotinic regulation of cortical function, and auditory learning, in the adult. Our results provide evidence that developmental nicotine exposure is responsible for auditory-cognitive deficits in the offspring of women who smoke during pregnancy, and suggest a potential underlying mechanism, namely diminished function of cortical nAChRs.
- SourceAvailable from: Irakli Intskirveli
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- "There is abundant evidence that systemic administration of nicotine enhances sensory-evoked responses recorded within or near auditory, visual, or somatosensory cortex in animals and non-smoking humans (Guha and Pradhan, 1976; Bringmann, 1994; Harkrider and Champlin, 2001; Penschuck et al., 2002; Oldford and Castro-Alamancos, 2003; Metherate, 2004; Liang et al., 2006). Although nicotine can affect cortical sensory processing via nAChRs located subcortically throughout each sensory system (e.g., Morley and Happe, 2000), or by activating diffuse neuromodulatory systems that themselves regulate cortical responses (Lewandowski et al., 1993; Azam et al., 2002, 2003; Hasselmo and Sarter, 2011), the effects of systemic nicotine on sensory-evoked cortical responses are reduced by direct intracortical injection of nAChR antagonists (Parkinson et al., 1988; Liang et al., 2006; Kawai et al., 2007, 2011; Intskirveli and Metherate, 2012), indicating direct actions within the cortex or on thalamocortical afferent inputs. Effective nAChR antagonists include mecamylamine and dihydro-β-erythroidine (DHβE), but not methyllycaconitine (MLA), implying a role for α4β2 * but not α7 nAChRs. "
ABSTRACT: 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. Moreover, nicotinic agonists are being developed to treat a variety of disorders that involve attention-related or age-related cognitive dysfunction. Studies have shown that nicotine can enhance processing of attended stimuli and/or reduce processing of distracters; that is, nicotine enhances attentional filtering. To examine potential mechanisms within sensory cortex that may contribute to cognitive functions, here we describe nicotinic actions in primary auditory cortex, where well-characterized neural "filters"-frequency 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.Frontiers in Behavioral Neuroscience 07/2012; 6:44. DOI:10.3389/fnbeh.2012.00044 · 4.16 Impact Factor
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- "MAPK-mediated regulation of distinct thalamocortical and intracortical circuits. Previous studies have shown that systemic nicotine enhances sensory-evoked cortical responses measured by recording single units, evoked potentials, and LFPs in humans, cats, rats, and mice (Harkrider and Champlin 2001; Kawai et al. 2011; Liang et al. 2006; Metherate 2004; Oldford and Castro-Alamancos 2003; Parkinson et al. 1988). "
ABSTRACT: 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. Systemic nicotine enhanced characteristic frequency (CF) tone-evoked current-source density (CSD) profiles in A1, including the shortest-latency (presumed thalamocortical) current sink in layer 4 and longer-latency (presumed intracortical) sinks in layers 2-4, by increasing response amplitudes and decreasing response latencies. Microinjection of the MAPK kinase (MEK) inhibitor U0126 into the thalamus, targeting the auditory thalamocortical pathway, blocked the effect of nicotine on the initial (thalamocortical) CSD component but did not block enhancement of longer-latency (intracortical) responses. Conversely, microinjection of U0126 into supragranular layers of A1 blocked nicotine's effect on intracortical, but not thalamocortical, CSD components. Simultaneously with enhancement of CF-evoked responses, responses to spectrally distant (nonCF) stimuli were reduced, implying nicotinic "sharpening" of frequency receptive fields, an effect also blocked by MEK inhibition. Consistent with these physiological results, acoustic stimulation with nicotine produced immunolabel for activated MAPK in A1, primarily in layer 2/3 cell bodies. Immunolabel was blocked by intracortical microinjection of the nAChR antagonist dihydro-β-erythroidine, but not methyllycaconitine, implicating α4β2*, but not α7, nAChRs. Thus activation of MAPK in functionally distinct forebrain circuits--thalamocortical, local intracortical, and long-range intracortical--underlies nicotinic neuromodulation of A1.Journal of Neurophysiology 02/2012; 107(10):2782-93. DOI:10.1152/jn.01129.2011 · 3.04 Impact Factor
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- "Nicotinic enhancement of thalamocortical input is widely hypothesized to depend on presynaptic nAChRs (Gil et al., 1997; Clarke, 2004). This hypothesis is supported by a dense band of nicotine binding sites, presumably α4β2*-nAChRs, in layers 3/4 of primary sensory cortex in some species (rat: Clarke et al., 1984, 1985; London et al., 1985; cat: Prusky et al., 1987; Parkinson et al., 1988), and by suppression of sensory responses in the thalamocortical input layers by an intracortical injection of a nicotinic antagonist, mecamylamine (cat: Parkinson et al, 1988; rat: Liang et al., 2006). In this study, however, intracortical injections of nicotinic antagonists had little effect on the Input phase in either sex, suggesting the absence of presynaptic nAChRs in mouse A1. "
ABSTRACT: 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. At the youngest ages, systemic nicotine did not affect CSD profiles. However, beginning in early adolescence nicotine enhanced characteristic frequency (CF)-evoked responses in layers 2-4 by enhancing thalamocortical, early intracortical, and late intracortical response components. Nicotinic responsiveness developed rapidly and peaked over the course of adolescence, then declined thereafter. Generally, responsiveness in females developed more quickly, peaked earlier, and declined more abruptly and fully than in males. In contrast to the enhancement of CF-evoked responses, nicotine suppressed shorter-latency intracortical responses to spectrally distant (non-CF) stimuli while enhancing longer-latency responses. Intracortical infusion of nAChR antagonists showed that enhancement of CF-evoked intracortical processing involves α4β2*, but not α7, nAChRs, whereas both receptor subtypes regulate non-CF-evoked late intracortical responses. Notably, antagonist effects in females implied regulation by endogenous acetylcholine. Thus, nicotinic regulation of cortical processing varies with age and sex, with peak effects during adolescence that may contribute to the vulnerability of adolescents to smoking.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 10/2011; 31(40):14367-77. DOI:10.1523/JNEUROSCI.1705-11.2011 · 6.75 Impact Factor