Recovery of functional and structural age-related changes in the rat primary auditory cortex with operant training

Cognitive decline is a virtually universal aspect of the aging process. However, its neurophysiological basis remains poorly understood. We describe here more than 20 age-related cortical processing deficits in the primary auditory cortex of aging versus young rats that appear to be strongly contributed to by altered cortical inhibition. Consistent with these changes, we recorded in old rats a decrease in parvalbumin-labeled inhibitory cortical neurons. Furthermore, old rats were slower to master a simple behavior, with learning progressions marked by more false-positive responses. We then examined the effect of intensive auditory training on the primary auditory cortex in these aged rats by using an oddball discrimination task. Following training, we found a nearly complete reversal of the majority of previously observed functional and structural cortical impairments. These findings suggest that age-related cognitive decline is a tightly regulated plastic process, and demonstrate that most of these age-related changes are, by their fundamental nature, reversible.     

Disruption of primary auditory cortex by synchronous auditory inputs during a critical period

In the primary auditory cortex (AI), the development of tone frequency selectivity and tonotopic organization is influenced by patterns of neural activity. Introduction of synchronous inputs into the auditory pathway achieved by exposing rat pups to pulsed white noise at a moderate intensity during P9-P28 resulted in a disrupted tonotopicity and degraded frequency-response selectivity for neurons in the adult AI. The latter was manifested by broader-than-normal tuning curves, multipeaks, and discontinuous, tone-evoked responses within AI-receptive fields. These effects correlated with the severe impairment of normal, developmental sharpening, and refinement of receptive fields and tonotopicity. In addition, paradoxically weaker than normal temporal correlations between the discharges of nearby AI neurons were recorded in exposed rats. In contrast, noise exposure of rats older than P30 did not cause significant change of auditory cortical maps. Thus, patterned auditory inputs appear to play a crucial role in shaping neuronal processing/decoding circuits in the primary auditory cortex during a critical period.     

Neural correlates of instrumental learning in primary auditory cortex

In instrumental learning, Thorndike's law of effect states that stimulus-response relations are strengthened if they occur prior to positive reinforcement and weakened if they occur prior to negative reinforcement. In this study, we demonstrate that neural correlates of Thorndike's law may be observed in the primary auditory cortex, A1. Adult owl monkeys learned to discriminate tones higher than a standard frequency. Responses recorded from implanted microelectrodes initially exhibited broad spectral selectivity over a four-to-five octave range. With training, frequency discrimination thresholds changed from close to one octave to about 1/12 octave. Physiological recordings during the week in which the monkey came under behavioral control signaled by a drop in measured threshold had stronger responses to all frequencies. During the same week, A1 neural responses to target stimuli increased relative to standard and nontarget stimuli. This emergent difference in responsiveness persisted throughout the subsequent weeks of behavioral training. These data suggest that behavioral responses to stimuli modulate responsiveness in primary cortical areas.     

Neural deficits in children with dyslexia ameliorated by behavioral remediation: evidence from functional MRI

Developmental dyslexia, characterized by unexplained difficulty in reading, is associated with behavioral deficits in phonological processing. Functional neuroimaging studies have shown a deficit in the neural mechanisms underlying phonological processing in children and adults with dyslexia. The present study examined whether behavioral remediation ameliorates these dysfunctional neural mechanisms in children with dyslexia. Functional MRI was performed on 20 children with dyslexia (8-12 years old) during phonological processing before and after a remediation program focused on auditory processing and oral language training. Behaviorally, training improved oral language and reading performance. Physiologically, children with dyslexia showed increased activity in multiple brain areas. Increases occurred in left temporo-parietal cortex and left inferior frontal gyrus, bringing brain activation in these regions closer to that seen in normal-reading children. Increased activity was observed also in right-hemisphere frontal and temporal regions and in the anterior cingulate gyrus. Children with dyslexia showed a correlation between the magnitude of increased activation in left temporo-parietal cortex and improvement in oral language ability. These results suggest that a partial remediation of language-processing deficits, resulting in improved reading, ameliorates disrupted function in brain regions associated with phonological processing and produces additional compensatory activation in other brain regions.     

Enduring effects of early structured noise exposure on temporal modulation in the primary auditory cortex

Studies have shown that acoustic experiences significantly contribute to the functional shaping of the structural organization and signal processing capacities of the mammalian auditory system during postnatal development. Here, we show how an early epoch of exposure to structured noise influences temporal processing in the rat primary auditory cortex documented immediately after exposure and again in adulthood. Pups were continuously exposed to broadband-pulsed noise across the critical period for auditory system development. Immediately after cessation of exposure at postnatal day ≈35 (P35) or ≈55 days later (i.e., P90) in other rats, the temporal modulation-transfer functions of cortical neurons were documented. We found that pulsed noise exposure at a low modulation rate significantly decreased cortical responses to repetitive stimuli presented across a range of higher modulation rates. The highest temporal rate at which temporal modulation-transfer function was at half of its maximum was reduced when compared with naïve rats. Low-rate pulsed noise exposure also decreased cortical response synchronization at higher stimulus rates, as shown by vector strength and Rayleigh statistic measures. These postexposure changes endured into adulthood. These findings bear significant implications for the role of early sound experiences as contributors to the ontogeny of human auditory and language-related abilities and impairments.     

Electrophysiological Response to Ethanol in P and NP Rats

Event-related potentials (ERPs) have been successfully used in human subjects to evaluate alcoholics as well as those at risk for the future development of alcoholism. In the present study, two lines of rats, those with a preference for ethanol consumption (P) and those not preferring (NP) to drink ethanol were studied using ERP-producing stimuli. Rats were implanted with electrodes in the frontal cortex and dorsal hippocampus (DHPC). A passive auditory "oddball" paradigm was used to record ERP responses following saline and two doses (0.5, 1.0 g/kg) of ethanol. P and NP rats differed under the saline condition in that P rats had smaller N1-like ERP components and larger P2 waves in both cortex and hippocampus. P and NP rats were also found to differ in response to ethanol administration. NP rats evidenced dose-dependent reductions in ERP component amplitudes such as the N1 recorded from cortical sites. P rats did not have such reductions in N1 amplitudes and in fact, displayed increased N1 amplitudes in hippocampal sites. These studies provide further electrophysiological evidence that rats with a genetically influenced preference for ethanol consumption differ from nonpreferring rats at baseline and have a less intense depressant or more stimulating response to ethanol challenge.     

Spatial processing in the auditory cortex of the macaque monkey

The patterns of cortico-cortical and cortico-thalamic connections of auditory cortical areas in the rhesus monkey have led to the hypothesis that acoustic information is processed in series and in parallel in the primate auditory cortex. Recent physiological experiments in the behaving monkey indicate that the response properties of neurons in different cortical areas are both functionally distinct from each other, which is indicative of parallel processing, and functionally similar to each other, which is indicative of serial processing. Thus, auditory cortical processing may be similar to the serial and parallel "what" and "where" processing by the primate visual cortex. If "where" information is serially processed in the primate auditory cortex, neurons in cortical areas along this pathway should have progressively better spatial tuning properties. This prediction is supported by recent experiments that have shown that neurons in the caudomedial field have better spatial tuning properties than neurons in the primary auditory cortex. Neurons in the caudomedial field are also better than primary auditory cortex neurons at predicting the sound localization ability across different stimulus frequencies and bandwidths in both azimuth and elevation. These data support the hypothesis that the primate auditory cortex processes acoustic information in a serial and parallel manner and suggest that this may be a general cortical mechanism for sensory perception.     

Modulation of early sensory processing in human auditory cortex during auditory selective attention.

Neuromagnetic fields were recorded from human subjects as they listened selectively to sequences of rapidly presented tones in one ear while ignoring tones of a different pitch in the opposite ear. Tones in the attended ear evoked larger magnetic brain responses than did unattended tones in the latency ranges 20-50 msec and 80-130 msec poststimulus. Source localization techniques in conjunction with magnetic resonance imaging placed the neural generators of these early attention-sensitive brain responses in auditory cortex on the supratemporal plane. These data demonstrate that focused auditory attention in humans can selectively modulate sensory processing in auditory cortex beginning as early as 20 msec poststimulus, thereby providing strong evidence for an "early selection" mechanism of auditory attention that can regulate auditory input at or before the initial stages of cortical analysis.     

Interplay between spontaneous and induced brain activity during human non-rapid eye movement sleep

Humans are less responsive to the surrounding environment during sleep. However, the extent to which the human brain responds to external stimuli during sleep is uncertain. We used simultaneous EEG and functional MRI to characterize brain responses to tones during wakefulness and non-rapid eye movement (NREM) sleep. Sounds during wakefulness elicited responses in the thalamus and primary auditory cortex. These responses persisted in NREM sleep, except throughout spindles, during which they became less consistent. When sounds induced a K complex, activity in the auditory cortex was enhanced and responses in distant frontal areas were elicited, similar to the stereotypical pattern associated with slow oscillations. These data show that sound processing during NREM sleep is constrained by fundamental brain oscillatory modes (slow oscillations and spindles), which result in a complex interplay between spontaneous and induced brain activity. The distortion of sensory information at the thalamic level, especially during spindles, functionally isolates the cortex from the environment and might provide unique conditions favorable for off-line memory processing.     

Changing meaning causes coupling changes within higher levels of the cortical hierarchy

Processing of speech and nonspeech sounds occurs bilaterally within primary auditory cortex and surrounding regions of the superior temporal gyrus; however, the manner in which these regions interact during speech and nonspeech processing is not well understood. Here, we investigate the underlying neuronal architecture of the auditory system with magnetoencephalography and a mismatch paradigm. We used a spoken word as a repeating “standard” and periodically introduced 3 “oddball” stimuli that differed in the frequency spectrum of the word's vowel. The closest deviant was perceived as the same vowel as the standard, whereas the other 2 deviants were perceived as belonging to different vowel categories. The neuronal responses to these vowel stimuli were compared with responses elicited by perceptually matched tone stimuli under the same paradigm. For both speech and tones, deviant stimuli induced coupling changes within the same bilateral temporal lobe system. However, vowel oddball effects increased coupling within the left posterior superior temporal gyrus, whereas perceptually equivalent nonspeech oddball effects increased coupling within the right primary auditory cortex. Thus, we show a dissociation in neuronal interactions, occurring at both different hierarchal levels of the auditory system (superior temporal versus primary auditory cortex) and in different hemispheres (left versus right). This hierarchical specificity depends on whether auditory stimuli are embedded in a perceptual context (i.e., a word). Furthermore, our lateralization results suggest left hemisphere specificity for the processing of phonological stimuli, regardless of their elemental (i.e., spectrotemporal) characteristics.     

Impaired monosynaptic potentiation in in vitro hippocampal slices from aged, memory-deficient rats.

Neurophysiological experiments were conducted in vitro on 400 mu thick transverse hippocampal slices from aged and young rats. These slices exhibit neurophysiological responses similar to those of intact hippocampus. The aged rats have previously been found to exhibit impaired retention. Synaptic responses of the Schaffer collateral system were not found to be different between aged and young slices when elicited by very low frequency (0.3 Hz) electrical stimulation. However, the aged slices exhibited marked deficits in frequency and posttetanic potentiation in response to repetitive stimulation (15 Hz). This deficit was interpreted as resulting from an increased tendency to synaptic depression, rather than from impaired potentiation processes. The possibility of a relationship of these physiological deficits in hippocampal synaptic plasticity to the deficits in behavioral plasticity found in these aged animals is considered.     

Ethanol Withdrawal Increases Sensory Responsiveness of Single Somatosensory Cortical Neurons in the Awake, Behaving Rat

This study investigated the effects of ethanol withdrawal on sensory responses of single neurons recorded in the somatosensory (SI) cortex of awake, behaving, ethanol-dependent rats. Eleven rats were fed an ethanol-containing liquid diet for 90-120 days, while 11 weight-matched controls were pair-fed an equivalent sucrose containing diet to equalize caloric intake. Single SI cortical neurons in the chronically treated rats were recorded continuously over several hours after withdrawal from ethanol, and after reintoxication induced by intraperitoneal injection of 10% (v/v) ethanol solution. Intoxication and withdrawal related changes in sensory responsiveness of these neurons were quantitatively measured by stimulating through electrodes chronically implanted under the skin of the forepaw. Sensory response histograms constructed from these stimuli showed a characteristic pattern, typically consisting of two early excitatory peaks (E1a and E1b), followed by an inhibition (I1), and in some neurons, a late excitatory response (E2). As withdrawal advanced, the sensory response histograms exhibited marked increases in the magnitudes of the E1a, I1, and E2 responses, coupled with a reduced spontaneous discharge rate. These changes are similar to, but quantitatively greater than, those which have previously been observed in normal and control rats during "immobile arousal" behaviors, which can be evoked when an experimenter holds the animals still, producing an immobile "aversive arousal." In withdrawing animals this same "holding" manipulation tended to markedly exacerbate and accelerate behavioral and neurophysiological signs of withdrawal. By contrast, the same manipulations had little effect when carried out during light intoxication or early stages of withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation

A number of in vitro studies have shown that activation of muscarinic receptors by cholinergic agonists stimulates the nonamyloidogenic, alpha-secretase-processing pathway of amyloid precursor protein (APP). To determine whether increased cholinergic neurotransmission can modify the APP processing in vivo, we administered a muscarinic receptor agonist (RS86) to normal or aged rats and rats with severe basal forebrain cholinergic deficits (induced by 192 IgG-saporin). The levels of the cell-associated APP in neocortex, hippocampus, and striatum, as well as the secreted form of APP (APPs) in cerebrospinal fluid, were examined by Western blots. Additionally, we investigated the association between the altered APP levels and behavioral deficits caused by cholinergic lesions. We found that treatment with muscarinic receptor agonist resulted in decreased APP levels in neocortex and hippocampus and increased levels of APPs in cerebrospinal fluid. Regulation of APP processing by the muscarinic agonist treatment occurred not only in normal rats, but also in aged and cholinergic denervated rats that model this aspect of Alzheimer's disease. Interestingly, we found that elevation of APP in neocortex correlated with the cognitive deficits in water-maze testing of rats with cholinergic dysfunction. These data indicate that increased cholinergic neurotransmission can enhance nonamyloidogenic APP processing in intact and lesioned rats and that APP may be involved in cognitive performance.     

Comparison of the impact of melatonin on chronic ethanol-induced learning and memory impairment between young and aged rats

Chronic alcohol exposure causes functional and structural changes in nervous system which have all been associated with learning and memory impairments. Furthermore, alcohol consumption has been shown to alter the pattern of neural cell adhesion molecules (NCAM) which are involved in memory processes. In the current work, we investigated the effects of melatonin on learning and memory deficits induced by alcohol exposure in young and aged rats. A group of young rats (3 months old) were administered ethanol for 45 days and half of them were co-treated with melatonin. Similar treatments were performed in the aged (19 months old) rats. Morris water maze test and passive avoidance task were used to assess cognitive performance. Lipid peroxidation (LPO) and glutathione (GSH) levels were determined to characterize the level of oxidative stress in the hippocampus and cortex. NCAM levels were determined by Western blotting in the hippocampal homogenates. There was a significant elevation in LPO levels and a reduction in GSH levels in aged and alcohol-exposed rats. Furthermore, both young and aged rats displayed some cognitive impairment when given with alcohol for 45 days. Co-administration of melatonin with ethanol significantly reduced LPO and elevated GSH levels while improving the learning and memory deficits induced by ethanol; the aged rats exhibited a greater response to melatonin supplementation. Moreover, melatonin modulated NCAM expression in hippocampus. Present findings indicate that exposure to ethanol induces learning and memory deficits probably by generating reactive oxygen species and downregulating NCAM 180 in hippocampus of aged rats. Melatonin improves learning and memory deficits and the behavioral responses of rats to melatonin supplementation are age dependent.     

Ethanol-induced loss-of-righting response during ethanol withdrawal in male and female rats: associations with alterations in Arc labeling

Background: There is increasing evidence for relevant sex differences in responses to ethanol. Several investigations have found differences in expression and recovery from ethanol withdrawal (EW) in people and across various animal models. We have found that female rats recover more quickly than male rats and show differential responses to various behavioral assessments and pharmacological challenges during withdrawal. The purpose of this study was to determine whether sex differences in EW behaviors extend to the hypnotic effects of acute ethanol administration. Methods: We used a repeated measures design to assess duration and latency for loss‐of‐righting reflex following an acute injection of ethanol (4.2 g/kg; 20% w/v) to pair‐fed control or ethanol‐withdrawn animals at 1 and 3 days EW in male, female, and ovariectomized female (OVX) rats. We determined protein levels of the activity‐regulated cytoskeletal protein (Arc), used as a marker for synaptic activity in glutamatergic synapses, in the motor cortex and prefrontal cortex across these same treatment conditions. Results: Ethanol‐withdrawn animals had a reduced ethanol‐induced sleep time compared to controls at 1 day EW. Sleep time remained shortened at 3 days EW for males and OVX, but not females. Arc protein levels in motor cortex and preoptic nuclei significantly increased at 1 day EW across all sex conditions, suggestive of an association with the reduced ethanol‐induced sleep times during EW. Arc levels increased further for males and OVX, but not females, at the 3 days EW time point. Conclusions: These findings add further support to sex differences in effects of and responses to ethanol. They suggest that the more rapid recovery from EW for females than males also includes expression of tolerance to the hypnotic effects of ethanol. These sex differences may involve some differential neuroadaptations in glutamatergic signaling.     

Specialization of primary auditory cortex processing by sound exposure in the "critical period"

Environmental acoustic exposure to a complex tone sequence within the critical period in infant rats resulted in the emergence of large-scale, selective changes that radically altered primary auditory cortex (A1) organization. In the sound exposure-revised A1, responses were segregated into two explicit zones representing spectrally and temporally separated lower and higher frequency tone sequence progressions. Cortical neurons between these two A1 zones were poorly driven by sound stimuli. Stimulus sequence-specific ("combination-selective") responses emerged in the A1 of exposed rats. These selective representational changes induced in the critical period persisted into adulthood. These results show that the temporal order and pace of early, repetitive postnatal auditory inputs strongly affect the emergent and enduring functional organization of A1.     

Task reward structure shapes rapid receptive field plasticity in auditory cortex

As sensory stimuli and behavioral demands change, the attentive brain quickly identifies task-relevant stimuli and associates them with appropriate motor responses. The effects of attention on sensory processing vary across task paradigms, suggesting that the brain may use multiple strategies and mechanisms to highlight attended stimuli and link them to motor action. To better understand factors that contribute to these variable effects, we studied sensory representations in primary auditory cortex (A1) during two instrumental tasks that shared the same auditory discrimination but required different behavioral responses, either approach or avoidance. In the approach task, ferrets were rewarded for licking a spout when they heard a target tone amid a sequence of reference noise sounds. In the avoidance task, they were punished unless they inhibited licking to the target. To explore how these changes in task reward structure influenced attention-driven rapid plasticity in A1, we measured changes in sensory neural responses during behavior. Responses to the target changed selectively during both tasks but did so with opposite sign. Despite the differences in sign, both effects were consistent with a general neural coding strategy that maximizes discriminability between sound classes. The dependence of the direction of plasticity on task suggests that representations in A1 change not only to sharpen representations of task-relevant stimuli but also to amplify responses to stimuli that signal aversive outcomes and lead to behavioral inhibition. Thus, top-down control of sensory processing can be shaped by task reward structure in addition to the required sensory discrimination.     

Suppression of cortical representation through backward conditioning

Temporal stimulus reinforcement sequences have been shown to determine the directions of synaptic plasticity and behavioral learning. Here, we examined whether they also control the direction of cortical reorganization. Pairing ventral tegmental area stimulation with a sound in a backward conditioning paradigm specifically reduced representations of the paired sound in the primary auditory cortex (AI). This temporal sequence-dependent bidirectional cortical plasticity modulated by dopamine release hypothetically serves to prevent the over-representation of frequently occurring stimuli resulting from their random pairing with unrelated rewards.     

The effects of priming on frontal-temporal communication

Repeated exposure to a stimulus facilitates its processing. This is reflected in faster and more accurate identification, reduced perceptual identification thresholds, and more efficient classifications for repeated compared with novel items. Here, we test a hypothesis that this experience-based behavioral facilitation is a result of enhanced communication between distinct cortical regions, which reduces local processing demands. A magnetoencephalographic investigation revealed that repeated object classification led to decreased neural responses in the prefrontal cortex and temporal cortex. Critically, this decrease in absolute activity was accompanied by greater neural synchrony (a measure of functional connectivity) between these regions with repetition. Additionally, the onset of the enhanced interregional synchrony predicted the degree of behavioral facilitation. These findings suggest that object repetition results in enhanced interactions between brain regions, which facilitates performance and reduces processing demands on the regions involved.     

Neural encoding of auditory discrimination in ventral premotor cortex

Monkeys have the capacity to accurately discriminate the difference between two acoustic flutter stimuli. In this task, monkeys must compare information about the second stimulus to the memory trace of the first stimulus, and must postpone the decision report until a sensory cue triggers the beginning of the decision motor report. The neuronal processes associated with the different components of this task have been investigated in the primary auditory cortex (A1); but, A1 seems exclusively associated with the sensory and not with the working memory and decision components of this task. Here, we show that ventral premotor cortex (VPC) neurons reflect in their activities the current and remembered acoustic stimulus, their comparison, and the result of the animal''s decision report. These results provide evidence that the neural dynamics of VPC is involved in the processing steps that link sensation and decision-making during auditory discrimination.