No 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.

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. Animals were then anesthetized, and tone-evoked local field potentials (LFPs) recorded in layer 4 of auditory cortex (ACx) before and after a test dose of nicotine (0.7mg/kg, s.c.) or saline. In "good" performers, nicotine enhanced LFP amplitude and decreased response threshold to characteristic frequency (CF) stimuli, yet had opposite effects (decreased amplitude, increased threshold) on responses to spectrally distant stimuli; i.e., cortical receptive fields became more selective for CF stimuli. In contrast, nicotine had little effect on LFP amplitude in "intermediate" or "poor" performing animals. Nicotine did, however, reduce LFP onset latency in all three groups, indicating that all received an effective dose of the drug. Our findings suggest that nicotinic regulation of cortical receptive fields may be a distinguishing feature of the best-performing animals, and may facilitate sensory-related learning by enhancing receptive field selectivity.

The cholinergic system has been implicated in learning and memory. The nucleus basalis (NB) provides acetylcholine (ACh) to the cerebral cortex. Pairing a tone with NB stimulation (NBstm) to alter cortical state induces both associative specific tuning plasticity in the primary auditory cortex (A1) and associative specific auditory behavioral memory. NB-induced memory has major features of natural memory that is induced by pairing a tone with motivational reinforcers, e.g., food or shock, suggesting that the cholinergic system may be a "final common pathway" whose activation promotes memory storage. Alternatively, NB-stimulation might itself be motivationally significant, either rewarding or punishing. To investigate these alternatives, adult male rats (n = 7) first formed a specific NB-induced memory (CS = 8.0 kHz, 2.0 s paired with NBstm, ISI = 1.8 s, 200 trials), validated by post-training (24 h) frequency generalization gradients (1-15 kHz) of respiration interruption that were specific to the CS frequency. Thereafter, they received the same level of NBstm that had induced memory, while confined to one quadrant of an arena, and later tested for place preference, i.e., avoidance or seeking of the quadrant of NBstm. This NBstm group exhibited neither preference for nor against the stimulated quadrant, compared to sham-operated subjects (n = 7). The findings indicate that specific associative memory can be induced by direct activation of the NB without detectable motivational effects of NB stimulation. These results are concordant with a memorypromoting role for the nucleus basalis that places it "downstream" of motivational systems, which activate it to initiate the storage of the current state of its cholinergic targets.

The primary auditory cortex is now known to be involved in learning and memory, as well as auditory perception. For example, spectral tuning often shifts toward or to the frequency of the conditioned stimulus during associative learning. As previous research has focused on tonal frequency, less is known about how learning might alter temporal parameters of response in the auditory cortex. This study addressed the effects of learning on the fidelity of temporal processing. Adult male rats were trained to avoid shock that was signaled by an 8.0 kHz tone. A novel control group received non-contingent tone and shock with shock probability decreasing over days to match the reduced number of shocks received by the avoidance group as they mastered the task. An untrained (naïve) group served as a baseline. Following training, neuronal responses to white noise and a broad spectrum of tones were determined across the primary auditory cortex in a terminal experiment with subjects under general anesthesia. Avoidance conditioning significantly improved the precision of spike timing: the coefficient of variation of 1st spike latency was significantly reduced in avoidance animals compared to controls and naïves, both for tones and for noise. Additionally, avoidance learning was accompanied by a reduction of the latency of peak response, by 2.0–2.5 ms relative to naïves and ~1.0 ms relative to controls. The shock-matched controls also exhibited significantly shorter peak latency of response than naïves, demonstrating the importance of this non-avoidance control. Plasticity of temporal processing showed no evidence of frequency-specificity and developed independently of the non-temporal parameters magnitude of response, frequency tuning and neural threshold, none of which were facilitated. The facilitation of temporal processing suggests that avoidance learning may increase synaptic strength either within the auditory cortex, in the subcortical auditory system, or both.