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In this study, the necessary conditions, including those related to behavior, for lasting modifications to occur in correlated activity ('functional plasticity') were examined in the behaving monkey. Previously, in-vitro studies of neuronal plasticity yielded important information about possible mechanisms of synaptic plasticity, but could not be used to test their functionality in the intact, behaving brain. In-vivo studies usually focused on analysis of the responsiveness of single cells, but did not examine interactions between pairs of neurons. In this study, we combined the two approaches. This was achieved by recording extracellularly and simultaneously the spike activity of several single cells in the auditory cortex of the behaving monkey. The efficacy of neuronal interactions was estimated by measuring the correlation between firing times of pairs of single neurons. Using acoustic stimuli, a version of cellular conditioning was applied when the monkey performed an auditory discrimination task and when it did not. We found that: (i) functional plasticity is a function of the change in correlation, and not of the correlation or covariance per se, and (ii) functional plasticity depends critically on behavior. During behavior, an increase in the correlation caused a short-lasting strengthening of the neuronal coupling efficacy, and a decrease caused a short-lasting weakening. These findings indicate that neuronal plasticity in the auditory cortex obeys a version of Hebb's associative rule under strong behavioral control, as predicted by Thorndike's "Law of Effect".

Units in the auditory cortex of cats respond to a large variety of stimuli: pure tones, AM- and FM-modulated signals, clicks, wideband noise, natural sounds, and more. However, no single family of sounds was found to be optimal (in the sense that oriented lines are optimal in the visual cortex). The search for optimal complex sounds is hard because of the high dimensionality of the space of interesting sounds. In an effort to overcome this problem, an automatic search procedure for finding efficient stimuli in high-dimensional sound spaces was developed. This procedure chooses the stimuli to be presented according to the responses to past stimuli, trying to increase the strength of the response. The results of applying this method to recordings of population activity in the primary auditory cortex of cats are described. The search was applied to single tones, two-tone stimuli, four-tone stimuli and to a two-dimensional subset of nine-tone stimuli, parametrized by the center frequency and the fixed difference between adjacent frequencies. The method was able to find efficient stimuli, and its performance improved with the dimension of the sound spaces. Efficient stimuli, found in different optimization runs using population activity recorded from the same electrode, often shared similar frequencies and pairs of frequencies, and tended to evoke similar levels of activity. This result indicates that a global analysis of the location of spectral peaks is performed at the level of the auditory cortex.

Population responses to multi-frequency sounds were recorded in primary auditory cortex of anesthetized cats. The sounds consisted of single-tone stimuli; two-tone stimuli; and nine-tone stimuli, with the tones evenly spaced on a linear frequency scale. The stimuli were presented through a sealed, calibrated sound delivery system. Single units, cluster activity (CA) and the short-time mean absolute value of the envelope of the neural signal (MABS) were recorded extracellularly from six microelectrodes simultaneously. The CA and MABS were interpreted as measures of the activity of large populations of neurons, in contrast with the single unit activity which is presumably recorded from single neurons. The responses of the MABS signal to simple stimuli were generally similar to those of the CA, but were more stable statistically. Thus, the MABS is better suited for studying the activity of populations of neurons. The responses to tones near the best frequency were strongly influenced by a second tone, even when the second tone was outside the single-tone response area. These influences could be both facilitatory and suppressory. They could not be predicted from the responses to single tones. The responses to the nine-tone stimuli could be explained qualitatively by the responses to the two-tone stimuli. It is concluded that the population responses in primary auditory cortex are shaped by the contributions of the individual frequencies appearing in the stimulus and by the interactions between pairs of frequencies. Interactions between stimulus components are therefore a necessary component of any attempt to explain the processing of complex sounds in the auditory cortex. They may play a role in a global representation of the stimulus spectrum in the primary auditory cortex. The presence of higher-order interactions cannot be excluded by the results presented here.

It has not been possible to analyze the cellular mechanisms underlying learning in behaving mammals because of the difficulties in recording intracellularly from awake animals. Therefore, in the present study of neuronal plasticity in behaving monkeys, the net effect of a single neuron on another neuron (the "functional connection") was evaluated by cross-correlating the times of firing of the two neurons. When two neurons were induced to fire together within a short time window, the functional connection between them was potentiated, and when simultaneous firing was prevented, the connection was depressed. These modifications were strongly dependent on the behavioral context of the stimuli that induced them. The results indicate that changes in the temporal contingency between neurons are often necessary, but not sufficient, for cortical plasticity in the adult monkey: behavioral relevance is required.

1. Neuronal mechanisms for decoding sound azimuth and angular movement were studied by recordings of several single units in parallel in the core areas of the auditory cortex of the macaque monkey. The activity of 180 units was recorded during the presentation of moving and static sound stimuli. Both the activity of single units and the interactions between neighboring neurons in response to each stimulus were analyzed. 2. Sixty-two percent of the units showed significant modulation of their firing rates as a function of the stimulus azimuth. Contralateral stimuli were preferred by the majority (approximately 60%) of these neurons. Thirty-five percent of the units showed mild but statistically significant modulation of their firing rates, which was specifically attributed to the angular movement of the sound source. 3. Eighty-nine percent of the "movement-sensitive" units were also "azimuth sensitive." The sound source's azimuth determined the pattern of the response components (on, sustained, off), whereas the source's movement affected only the magnitude of these components, typically the sustained component. Most neurons for which the sustained response to static sounds was greater for contralateral than ipsilateral stimuli preferred moving sounds that were moving into the contralateral hemifield. 4. Cross-correlation analysis was carried out for 245 neuron pairs. Cross-correlograms were computed for each pair under all stimulus conditions to allow comparison of the neuronal interactions under the various conditions. The shapes of some correlograms (after subtraction of direct stimulus effects) were dependent on specific stimulus conditions, suggesting that the effective connectivity between these neurons depended on the location and/or movement of the sound stimuli. Furthermore, joint peristimulus time (JPST) analysis indicated that modifications of connectivity may be temporally related to the stimulus and may occur over short periods of time. These results could not have been predicted from analysis of the independent single-unit responses to the stimuli. 5. The data suggest that both firing rates and correlated activity between adjacent neurons in the auditory cortex encode sound location and movement.

Simultaneous extracellular recordings from one electrode of 'local' groups of 3-6 neurons were obtained from the auditory cortex of unanesthetized, paralyzed cats. The activity and functional connectivity of local microenvironments were examined under various auditory stimuli. Single cell response patterns were examined using peri-stimulus (PST) histograms and functional connectivity among neighboring cells by the cross renewal density (CRD) histograms. Analysis of the PST histograms suggested that a high percentage of single cells demonstrated different response patterns to different stimuli. Analysis of the CRD histograms suggested, on the one hand, that only small numbers of neighboring cells behaved as if there were direct connections from one cell to another, and that these direct connections appeared to be excitatory. On the other hand, many cell pairs shared input from shared sources which lay outside the local groups. The majority of functional connections were altered by at least one of the stimuli delivered, thus demonstrating the system's plasticity. It is suggested that long-term gates at the synaptic level are responsible for this phenomenon.

Short term memory to tones (STMT) was investigated by recording single unit activity in the auditory cortex of a behaving monkey. The activity of each unit was studied in two behavioral conditions: a) During task performance, the monkey had to compare two tones separated by one second of silence (inter-stimulus interval). b) During a non-performing period; the monkey heard the two tones but did not respond behaviorally. It was noted that the firing rate of many units during the inter-stimulus interval (ISI) was dependent on the frequency of the first tone. Such dependency was observed even towards the end of the ISI, both during task performance trials (50% of the units) and during the non-performing period (32% of the units). The activity of these units could be the basis of STMT in both of these behavioral states. In 65% of all the units tested, the responses during the ISI were of a higher magnitude in the performance period than were the responses in the non-performance period. The activity of these units may be related either to general processes such as attention and expectation or to short-term memory processes. During task performance, the responses of 23% of the units to the second tone were dependent on whether its frequency was identical to that of the first tone. Such dependency was never observed during the non-performing period. These units may detect similarity or non similarity between two tones presented one second apart. Periodic patterns of firing were not found in the study, thus suggesting that the ISI responses were not generated by reverberatory activity in simple closed loops. On the basis of these results, several alternative mechanisms of STMT are suggested.

The spontaneous and acoustically driven activities of single units, pairs and triplets of units in the auditory cortex were analyzed. Data were obtained in two sets of experiments from nonbehaving awake cats and from a behaving monkey. The results of the two sets of experiments indicated that neighboring neurons usually fire independently. The weak correlations found between pairs of adjacent neurons were mostly indicative of a common input driving both units. In some cases, signs of synaptic interaction between the neurons were found. When triplets of units were considered, it was found that several independent inputs exist, even within a small group of adjacent neurons. When such small groups of neurons were studied in the behaving monkey, it was found that the temporal firing pattern of single neurons and the interactions between pairs of neurons were in some cases dependent on the behavioral state and on the sensorimotor association.