Visual snake aversion in Octodon degus and C57BL/6 mice.

Phobia against spiders or snakes is common in humans, and similar phobia-like behaviors have been observed in non-human animals. Visual images of snakes elicit phobia in humans, but sensory modalities that cause snake aversion in non-human animals are not well examined. In this study, we examined visually induced snake aversion in two rodent species. Using a three-compartment experimental chamber, reactions to images of snakes were compared between the diurnal precocious rodent Octodon degus and nocturnal laboratory mice. The snakes whose images were presented do not live in the original habitats of degus or mice. Snake aversion was assessed by presenting snake vs. no-image, snake vs. flower, snake vs. degu, and snake vs. mouse images. The time spent in a compartment with the snake image and with the non-snake images were measured. Degus avoided images of snakes in every tests. In contrast, mice did not display snake aversion. Degus are diurnal animals, i.e., visual information is important for their survival. Since mice are nocturnal, visual information is less important for survival. Such behavioral differences in the two species may explain the difference in visually induced aversion to snakes. A principal component analysis of the stimulus images suggests that elementary cues, such as color, do not explain the differences in the species' aversion to snakes. Finally, snake aversion in degus suggests that aversion is innate, since the animals were born and raised in a laboratory.

Predictive cues for auditory stream formation in humans and monkeys.

Auditory perception is improved when stimuli are predictable, and this effect is evident in a modulation of the activity of neurons in the auditory cortex as shown previously. Human listeners can better predict the presence of duration deviants embedded in stimulus streams with fixed interonset interval (isochrony) and repeated duration pattern (regularity), and neurons in the auditory cortex of macaque monkeys have stronger sustained responses in the 60-140 ms post-stimulus time window under these conditions. Subsequently, the question has arisen whether isochrony or regularity in the sensory input contributed to the enhancement of the neuronal and behavioural responses. Therefore, we varied the two factors isochrony and regularity independently and measured the ability of human subjects to detect deviants embedded in these sequences as well as measuring the responses of neurons the primary auditory cortex of macaque monkeys during presentations of the sequences. The performance of humans in detecting deviants was significantly increased by regularity. Isochrony enhanced detection only in the presence of the regularity cue. In monkeys, regularity increased the sustained component of neuronal tone responses in auditory cortex while isochrony had no consistent effect. Although both regularity and isochrony can be considered as parameters that would make a sequence of sounds more predictable, our results from the human and monkey experiments converge in that regularity has a greater influence on behavioural performance and neuronal responses.

Neuronal activity in primate auditory cortex during the performance of audiovisual tasks.

This study aimed at a deeper understanding of which cognitive and motivational aspects of tasks affect auditory cortical activity. To this end we trained two macaque monkeys to perform two different tasks on the same audiovisual stimulus and to do this with two different sizes of water rewards. The monkeys had to touch a bar after a tone had been turned on together with an LED, and to hold the bar until either the tone (auditory task) or the LED (visual task) was turned off. In 399 multiunits recorded from core fields of auditory cortex we confirmed that during task engagement neurons responded to auditory and non-auditory stimuli that were task-relevant, such as light and water. We also confirmed that firing rates slowly increased or decreased for several seconds during various phases of the tasks. Responses to non-auditory stimuli and slow firing changes were observed during both the auditory and the visual task, with some differences between them. There was also a weak task-dependent modulation of the responses to auditory stimuli. In contrast to these cognitive aspects, motivational aspects of the tasks were not reflected in the firing, except during delivery of the water reward. In conclusion, the present study supports our previous proposal that there are two response types in the auditory cortex that represent the timing and the type of auditory and non-auditory elements of a auditory tasks as well the association between elements.

SPECT-imaging of activity-dependent changes in regional cerebral blood flow induced by electrical and optogenetic self-stimulation in mice.

Electrical and optogenetic methods for brain stimulation are widely used in rodents for manipulating behavior and analyzing functional connectivities in neuronal circuits. High-resolution in vivo imaging of the global, brain-wide, activation patterns induced by these stimulations has remained challenging, in particular in awake behaving mice. We here mapped brain activation patterns in awake, intracranially self-stimulating mice using a novel protocol for single-photon emission computed tomography (SPECT) imaging of regional cerebral blood flow (rCBF). Mice were implanted with either electrodes for electrical stimulation of the medial forebrain bundle (mfb-microstim) or with optical fibers for blue-light stimulation of channelrhodopsin-2 expressing neurons in the ventral tegmental area (vta-optostim). After training for self-stimulation by current or light application, respectively, mice were implanted with jugular vein catheters and intravenously injected with the flow tracer 99m-technetium hexamethylpropyleneamine oxime (99mTc-HMPAO) during seven to ten minutes of intracranial self-stimulation or ongoing behavior without stimulation. The 99mTc-brain distributions were mapped in anesthetized animals after stimulation using multipinhole SPECT. Upon self-stimulation rCBF strongly increased at the electrode tip in mfb-microstim mice. In vta-optostim mice peak activations were found outside the stimulation site. Partly overlapping brain-wide networks of activations and deactivations were found in both groups. When testing all self-stimulating mice against all controls highly significant activations were found in the rostromedial nucleus accumbens shell. SPECT-imaging of rCBF using intravenous tracer-injection during ongoing behavior is a new tool for imaging regional brain activation patterns in awake behaving rodents providing higher spatial and temporal resolutions than 18F-2-fluoro-2-dexoyglucose positron emission tomography.

Parahydrogen-induced polarization of carboxylic acids: a pilot study of valproic acid and related structures.

Parahydrogen-induced polarization (PHIP) is a promising new tool for medical applications of MR, including MRI. The PHIP technique can be used to transfer high non-Boltzmann polarization, derived from parahydrogen, to isotopes with a low natural abundance or low gyromagnetic ratio (e.g. (13)C), thus improving the signal-to-noise ratio by several orders of magnitude. A few molecules acting as metabolic sensors have already been hyperpolarized with PHIP, but the direct hyperpolarization of drugs used to treat neurological disorders has not been accomplished until now. Here, we report on the first successful hyperpolarization of valproate (valproic acid, VPA), an important and commonly used antiepileptic drug. Hyperpolarization was confirmed by detecting the corresponding signal patterns in the (1)H NMR spectrum. To identify the optimal experimental conditions for the conversion of an appropriate VPA precursor, structurally related molecules with different side chains were analyzed in different solvents using various catalytic systems. The presented results include hyperpolarized (13)C NMR spectra and proton images of related systems, confirming their applicability for MR studies. PHIP-based polarization enhancement may provide a new MR technique to monitor the spatial distribution of valproate in brain tissue and to analyze metabolic pathways after valproate administration.

Different synchronization rules in primary and nonprimary auditory cortex of monkeys.

Synchronized neuronal firing in cortex has been implicated in feature binding, attentional selection, and other cognitive processes. This study addressed the question whether different cortical fields are distinct by rules according to which neurons engage in synchronous firing. To this end, we simultaneously recorded the multiunit firing at several sites within the primary and the caudomedial auditory cortical field of anesthetized macaque monkeys, determined their responses to pure tones, and calculated the cross-correlation function of the spontaneous firing of pairs of units. In the primary field, the likelihood of synchronous firing of pairs of units increased with the similarity of their frequency tuning and their response latencies. In the caudomedial field, by contrast, the likelihood of synchronization was highest when pairs of units had an octave and other harmonic relationships and when units had different response latencies. The differences in synchrony of the two fields were not paralleled by differences in distributions of best frequency, bandwidth of tuning curves, and response latency. Our findings suggest that neuronal synchrony in different cortical fields may underlie the establishment of specific relationships between the sound features that are represented by the firing of the neurons and which follow the Gestalt laws of similarity in the primary field and good continuation in the caudomedial field.

Perforant pathway stimulation as a conditioned stimulus for active avoidance learning triggers BOLD responses in various target regions of the hippocampus: a combined fMRI and electrophysiological study.

Functional magnetic resonance imaging and electrophysiology were combined to monitor blood oxygen level dependent (BOLD) signals in the entire rat brain and neuronal activities in the dentate gyrus during electrical stimulation of the right perforant pathway. In naïve, medetomidine sedated animals, stimulation of the fiber bundle with 15 trains (i.e. 8 bursts of 20 pulses given with 10 ms intervals, one burst per second, pulse width 0.2 ms) generated significant BOLD responses in the right hippocampal formation and the left entorhinal cortex. The stimulation condition also caused changes in the synaptic efficacy of perforant pathway granular cell synapses that lasted for at least one day. Rerun of the same experiment one day later resulted in a significantly increased electrophysiological response in the dentate gyrus and an increase of the BOLD response in the entire hippocampal formation. Consequently, long-lasting changes in synaptic efficacy go along with changes in the generated BOLD response. Additional electrical stimulations of the perforant pathway in the awake animal between the two fMRI experiments caused in the second fMRI measurement an increased BOLD response in the hippocampal formation and an appearance of significant BOLD responses in target regions of the hippocampus, such as the septum, nucleus accumbens (NAcc), and anterior cingulate cortex/medial prefrontal cortex/motor cortex (ACC/mPFC/MC) regions. Consequently, the efficacy of signal processing in and propagation through the hippocampus can be monitored by variations of the BOLD response in target regions of the hippocampus. Using the electrical perforant pathway stimulations as conditioned stimulus for an active avoidance task (shuttle box) caused a further spreading of the BOLD response in the hippocampus formation, septum and ACC/mPFC/MC but not in the NAcc. In addition, the magnitude of the BOLD response in the trained animals was further increased in the right and left hippocampus and the ACC/mPFC/MC region but not in the septum. These results demonstrate that in addition to general stimulus parameter the behavioral relevance of the stimulus controls the quality of the generated BOLD response.

Altered neuronal activity patterns in the visual cortex of the adult rat after partial optic nerve crush--a single-cell resolution metabolic mapping study.

Thallium autometallography (TIAMG) is a novel method for high-resolution mapping of neuronal activity. With this method, we found that a general depression of neuronal activity occurs in response to optic nerve crush (ONC) within the first 2 weeks postinjury in the contralateral dorsal lateral geniculate nucleus (dLGN) as well as in the contralateral primary visual cortex (V1). Interestingly, the neuronal activity recovered thereafter in both brain regions and reached a plateau in the tenth week postinjury in layers IV and V of V1, monocular area (V1m). Several clusters of highly active neurons in V1m were found 6 weeks after ONC in layers IV and V on the side contralateral to the lesion. We reasoned that these clusters appeared due to a reorganization of the corticocolliucular projections. Employing a combination of biotinylated dextran amine retrograde tract tracing from the superior colliculus (SC) with TIAMG in the same animal, we indeed found that the clusters of neurons with high Tl(+) uptake in V1m are spatially in register with those neuronal subpopulations that project to the SC. These data suggest that extensive reorganization plasticity exists in the adult rat visual cortex following ONC.

Interaction between bottom-up and top-down effects during the processing of pitch intervals in sequences of spoken and sung syllables.

The processing of pitch intervals may be differentially influenced when musical or speech stimuli carry the pitch information. Most insights into the neural basis of pitch interval processing come from studies on music perception. However, music, in contrast to speech, contains a stable set of pitch intervals. To converge the investigation of pitch interval processing in music and speech, we used sequences of the same spoken or sung syllables. The pitch of these syllables varied either by semitone steps like in music or by smaller intervals. Participants had to differentiate the sequences according to their different sizes of pitch intervals or to the direction of the last frequency step in the sequence. The results depended strongly on the specific task demands. Whereas the interval-size task itself recruited more regions in right lateralized fronto-parietal brain network, stronger activity on semitone than on non-semitone sequences was found in the left hemisphere (mainly in frontal cortex) during this task. These effects were also influenced by the speech mode (spoken or sung syllables). Our findings suggest that the processing of pitch intervals in sequences of syllables depends on an interaction between bottom-up (speech mode, pitch interval) and top-down effects (task).

The use of thallium diethyldithiocarbamate for mapping CNS potassium metabolism and neuronal activity: Tl+ -redistribution, Tl+ -kinetics and Tl+ -equilibrium distribution.

The potassium (K(+)) analogue thallium (Tl(+)) can be used as a tracer for mapping neuronal activity. However, because of the poor blood-brain barrier (BBB) K(+) -permeability, only minute amounts of Tl(+) enter the brain after systemic injection of Tl(+) -salts like thallium acetate (TlAc). We have recently shown that it is possible to overcome this limitation by injecting animals with the lipophilic chelate complex thallium diethyldithiocarbamate (TlDDC), that crosses the BBB and releases Tl(+) prior to neuronal or glial uptake. TlDDC can thus be used for mapping CNS K(+) metabolism and neuronal activity. Here, we analyze Tl(+) -kinetics in the rodent brain both experimentally and using simple mathematical models. We systemically injected animals either with TlAc or with TlDDC. Using an autometallographic method we mapped the brain Tl(+) -distribution at various time points after injection. We show that the patterns and kinetics of Tl(+) -redistribution in the brain are essentially the same irrespective of whether animals have been injected with TlAc or TlDDC. Data from modeling and experiments indicate that transmembrane Tl(+) -fluxes in cells within the CNS in vivo equilibrate at similar rates as K(+) -fluxes in vitro. This equilibration is much faster than and largely independent of the equilibration of Tl(+) -fluxes across the BBB. The study provides further proof-of-concept for the use of TlDDC for mapping neuronal activity and CNS K(+) -metabolism. A theoretical guideline is given for the use of K(+) -analogues for imaging neuronal activity with general implications for the use of metal ions in neuroimaging.

Dopamine modulates memory consolidation of discrimination learning in the auditory cortex.

In Mongolian gerbils, the auditory cortex is critical for discriminating rising vs. falling frequency-modulated tones. Based on our previous studies, we hypothesized that dopaminergic inputs to the auditory cortex during and shortly after acquisition of the discrimination strategy control long-term memory formation. To test this hypothesis, we studied frequency-modulated tone discrimination learning of gerbils in a shuttle box GO/NO-GO procedure following differential treatments. (i) Pre-exposure of gerbils to the frequency-modulated tones at 1 day before the first discrimination training session severely impaired the accuracy of the discrimination acquired in that session during the initial trials of a second training session, performed 1 day later. (ii) Local injection of the D1/D5 dopamine receptor antagonist SCH-23390 into the auditory cortex after task acquisition caused a discrimination deficit of similar extent and time course as with pre-exposure. This effect was dependent on the dose and time point of injection. (iii) Injection of the D1/D5 dopamine receptor agonist SKF-38393 into the auditory cortex after retraining caused a further discrimination improvement at the beginning of subsequent sessions. All three treatments, which supposedly interfered with dopamine signalling during conditioning and/or retraining, had a substantial impact on the dynamics of the discrimination performance particularly at the beginning of subsequent training sessions. These findings suggest that auditory-cortical dopamine activity after acquisition of a discrimination of complex sounds and after retrieval of weak frequency-modulated tone discrimination memory further improves memory consolidation, i.e. the correct association of two sounds with their respective GO/NO-GO meaning, in support of future memory recall.

Differential neuromodulation of acquisition and retrieval of avoidance learning by the lateral habenula and ventral tegmental area.

Several studies suggest an opponent functional relationship between the lateral habenula (LHb) and the ventral tegmental area (VTA). Previous work has linked LHb activation to the inhibition of dopaminergic neurons during loss of reward, as well as to deficits in escape and avoidance learning. We hypothesized that a dopamine signal might underlie the negative reinforcement of avoidance responses and that LHb activation could block this signal and thereby cause avoidance deficits. To test this idea, we implanted stimulating electrodes in either the VTA or LHb of gerbils engaged in two-way active avoidance learning, a task that shows learning-associated dopamine changes and that is acquired faster following LHb lesions. We delivered brief electrical brain stimulation whenever the animal performed a correct response, i.e., when the successful avoidance of foot shock was hypothesized to trigger an intrinsic reward signal. During the acquisition phase, VTA stimulation improved avoidance performance, while LHb stimulation impaired it. VTA stimulation appeared to improve both acquisition and asymptotic performance of the avoidance response, as VTA-stimulated animals reached above-normal performance but reverted to normal responding when stimulation was discontinued. The effects of LHb stimulation during avoidance acquisition were long lasting and persisted even after stimulation was discontinued. However, when given after successful acquisition of avoidance behavior, LHb stimulation had no effect, indicating that LHb stimulation specifically impaired avoidance acquisition without affecting memory retrieval or motivation or ability to perform the avoidance response. These results demonstrate opponent roles of LHb and VTA during acquisition but not during retrieval of avoidance learning.

Global versus local processing of frequency-modulated tones in gerbils: an animal model of lateralized auditory cortex functions.

Hemispheric asymmetries of speech and music processing might arise from more basic specializations of left and right auditory cortex (AC). It is not clear, however, whether such asymmetries are unique to humans, i.e., consequences of speech and music, or whether comparable lateralized AC functions exist in nonhuman animals, as evolutionary precursors. Here, we investigated the cortical lateralization of perception of linearly frequency-modulated (FM) tones in gerbils, a rodent species with human-like low-frequency hearing. Using a footshock-reinforced shuttle-box avoidance go/no-go procedure in a total of 178 gerbils, we found that (i) the discrimination of direction of continuous FM (rising versus falling sweeps, 250-ms duration) was impaired by right but not left AC lesions; (ii) the discrimination of direction of segmented FM (50-ms segments, 50-ms silent gaps, total duration 250 ms) was impaired by bilateral but not unilateral AC lesions; (iii) the discrimination of gap durations (10-30 ms) in segmented FM was impaired by left but not right AC lesions. AC lesions before and after training resulted in similar effects. Together, these experiments suggest that right and left AC, even in rodents, use different strategies in analyzing FM stimuli. Thus, the right AC, by using global cues, determines the direction of continuous and segmented FM but cannot discriminate gap durations. The left AC, by using local cues, discriminates gap durations and determines FM direction only when additional segmental information is available.

Imaging of Functional Brain Circuits during Acquisition and Memory Retrieval in an Aversive Feedback Learning Task: Single Photon Emission Computed Tomography of Regional Cerebral Blood Flow in Freely Behaving Rats.

Active avoidance learning is a complex form of aversive feedback learning that in humans and other animals is essential for actively coping with unpleasant, aversive, or dangerous situations. Since the functional circuits involved in two-way avoidance (TWA) learning have not yet been entirely identified, the aim of this study was to obtain an overall picture of the brain circuits that are involved in active avoidance learning. In order to obtain a longitudinal assessment of activation patterns in the brain of freely behaving rats during different stages of learning, we applied single-photon emission computed tomography (SPECT). We were able to identify distinct prefrontal cortical, sensory, and limbic circuits that were specifically recruited during the acquisition and retrieval phases of the two-way avoidance learning task.

The BOLD response in the rat hippocampus depends rather on local processing of signals than on the input or output activity. A combined functional MRI and electrophysiological study.

Functional magnetic resonance imaging (fMRI) of the human brain is widely used in neuroscience, but the exact relationship between measured fMRI response and the underlying changes in neuronal activity is still elusive. To obtain further information about the specific roles of synaptic (input) and spiking activity (output) for the generation of fMRI-related signals, we used an approach that combines electrophysiological and MRI measurements in the anatomically and physiologically well defined rat hippocampus. Direct electrical stimulation of the perforant pathway enabled us to control synchronized input activity to the dentate gyrus, whereas recorded population spikes from the granular cell layer indicated the dentate output activity. The perforant pathway was first stimulated with 15 identical pulse trains (10 Hz for 8 s), and evoked blood oxygenation level-dependent (BOLD) responses and population spikes were measured for each individual stimulus train. Spatial and magnitude aspects of the elicited BOLD responses differentially changed in the dentate gyrus and hippocampus from early to late stimulus trains together with population spike latencies in the dentate indicating delayed inhibitory network processing. Furthermore, the same number of stimuli presented in different patterns within trains (i.e., bursts of 10 stimuli at 50, 100, or 200 Hz) clearly altered the BOLD responses. Similarly, variations in the BOLD response also occurred when different stimulus patterns were chosen that caused the same number of population spikes. The results indicate that neuronal network activity including inhibitory interneurons rather than exclusively the input or spiking activity of the principal neurons determine a BOLD response to repetitive stimuli.

Auditory cortical activity after intracortical microstimulation and its role for sensory processing and learning.

Several studies have shown that animals can learn to make specific use of intracortical microstimulation (ICMS) of sensory cortex within behavioral tasks. Here, we investigate how the focal, artificial activation by ICMS leads to a meaningful, behaviorally interpretable signal. In natural learning, this involves large-scale activity patterns in widespread brain-networks. We therefore trained gerbils to discriminate closely neighboring ICMS sites within primary auditory cortex producing evoked responses largely overlapping in space. In parallel, during training, we recorded electrocorticograms (ECoGs) at high spatial resolution. Applying a multivariate classification procedure, we identified late spatial patterns that emerged with discrimination learning from the ongoing poststimulus ECoG. These patterns contained information about the preceding conditioned stimulus, and were associated with a subsequent correct behavioral response by the animal. Thereby, relevant pattern information was mainly carried by neuron populations outside the range of the lateral spatial spread of ICMS-evoked cortical activation (approximately 1.2 mm). This demonstrates that the stimulated cortical area not only encoded information about the stimulation sites by its focal, stimulus-driven activation, but also provided meaningful signals in its ongoing activity related to the interpretation of ICMS learned by the animal. This involved the stimulated area as a whole, and apparently required large-scale integration in the brain. However, ICMS locally interfered with the ongoing cortical dynamics by suppressing pattern formation near the stimulation sites. The interaction between ICMS and ongoing cortical activity has several implications for the design of ICMS protocols and cortical neuroprostheses, since the meaningful interpretation of ICMS depends on this interaction.

The current functional state of local neuronal circuits controls the magnitude of a BOLD response to incoming stimuli.

The purpose of this study was to determine how the history-dependent activation state of neuronal networks controls fMRI signals to incoming stimuli. Simultaneous electrophysiological and blood oxygen level-dependent (BOLD) responses were monitored during stimulation of the perforant pathway with low, high, and again low intensity but, otherwise identical pulse trains. Under three different anesthetics (alpha-chloralose, medetomidine, isoflurane) consecutive low intensity stimulation trains, set just below the threshold for population spike generation to single pulses, yielded a stable BOLD response, although at different magnitudes. The first high intensity train increased the BOLD response under all anesthetics and generated population spikes, with varying amplitudes and latencies (alpha-chloralose, metedomidine) or in a regular pattern (isoflurane). Concurrent to the second high intensity train, the BOLD response became minimal, then slowly increasing with subsequent trains (alpha-chloralose, metedomidine), or immediately rising to a stable level (isoflurane). Second train population spikes became regularized, but at low amplitudes and long latencies that were slowly reversed across trains (alpha-chloralose, medetomidine); while under isoflurane, amplitude and latencies became stabilized with the second train. In comparison to initial stimulation, the final low intensity stimulation trains failed to produce BOLD responses (alpha-chloralose, medetomidine), or left the response unchanged (isoflurane), only reaching stable potentiation of population spikes when under isoflurane. Therefore, the fate of BOLD responses depends on whether a new stable functional state of the intrinsic network can be reached after high intensity stimulation.

High-resolution mapping of neuronal activity using the lipophilic thallium chelate complex TlDDC: protocol and validation of the method.

In neurons the rate of K(+)-uptake increases with increasing activity. K(+)-analogues like the heavy metal ion thallium (Tl(+)) can be used, therefore, as tracers for imaging neuronal activity. However, when water-soluble Tl(+)-salts are injected systemically only minute amounts of the tracer enter the brain and the Tl(+)-uptake patterns are influenced by regional differences in blood-brain barrier (BBB) K(+)-permeability. We here show that the BBB-related limitations in using Tl(+) for imaging neuronal activity are no longer present when the lipophilic Tl(+) chelate complex thallium diethyldithiocarbamate (TlDDC) is applied. We systemically injected rodents with TlDDC and mapped the Tl(+)-distribution in the brain using an autometallographic (AMG) technique, a histochemical method for detecting heavy metals. We find that Tl(+)-doses for optimum AMG staining could be substantially reduced, and regional differences attributable to differences in BBB K(+)-permeability were no longer detectable, indicating that TlDDC crosses the BBB. At the cellular level, however, the Tl(+)-distribution was essentially the same as after injection of water-soluble Tl(+)-salts, indicating Tl(+)-release from TlDDC prior to neuronal or glial uptake. Upon sensory stimulation or intracortical microstimulation neuronal Tl(+)-uptake increased after TlDDC injection, upon muscimol treatment neuronal Tl(+)-uptake decreased. We present a protocol for mapping neuronal activity with cellular resolution, which is based on intravenous TlDDC injections during ongoing activity in unrestrained behaving animals and short stimulation times of 5 min.

Dual time scales for categorical decision making in auditory cortex.

Category formation allows us to group perceptual objects into meaningful classes and is fundamental to cognition. Categories can be derived from similarity relationships of object features by using prototypes or multiple exemplars, or from abstract relationships of features and rules . A variety of brain areas have been implicated in categorization processes, but mechanistic insights on the single-cell and local-network level are still rare and limited to the matching of individual objects to categories . For directional categorization of tone steps, as in melody recognition , abstract relationships between sequential events (higher or lower in frequency) have to be formed. To explore the neuronal mechanisms of this categorical identification of step direction, we trained monkeys for more than two years on a contour-discrimination task with multiple tone sequences. In the auditory cortex of these highly trained monkeys, we identified two interrelated types of neuronal firing: Increased phasic responses to tones categorically represented the reward-predicting downward frequency steps and not upward steps; subsequently, slow modulations of tonic firing predicted the behavioral decisions of the monkeys, including errors. Our results on neuronal mechanisms of categorical stimulus identification and of decision making attribute a cognitive role to auditory cortex, in addition to its role in signal processing.