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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.

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 99 m-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 18 F-2-fluoro-2-dexoyglucose positron emission tomography.

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.

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.

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.

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 (∼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.

This paper gives both general linear model (GLM) and support vector machine (SVM) analyses of an experiment concerned with tonality in music. The two forms of analysis are both contrasted and used to complement each other, and a new technique employing the GLM as a pre-processing step for the SVM is presented. The SVM is given the task of classifying the stimulus conditions (tonal or atonal) on the basis of the blood oxygen level-dependent signal of novel data, and the prediction performance is evaluated. In addition, a more detailed assessment of the SVM performance is given in a comparison of the similarity in the identification of voxels relevant to the classification of the SVM and a GLM. A high level of similarity between SVM weight and GLM t-maps demonstrate that the SVM is successfully identifying relevant voxels, and it is this that allows it to perform well in the classification task in spite of very noisy data and stimuli that involve higher-order cognitive functions and considerably inter-subject variation in neural response.

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.

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.

Previous studies in the auditory cortex of Mongolian gerbils on discrimination learning of the direction of frequency-modulated tones (FMs) revealed that long-term memory formation involves activation of the dopaminergic system, activity of the protein kinase mammalian target of rapamycin (mTOR), and protein synthesis. This led to the hypothesis that the dopaminergic system might modulate memory formation via regulation of mTOR, which is implicated in translational control. Here, we report that the D1/D5 dopamine receptor agonist SKF-38393 substantially improved gerbils’ FM discrimination learning when administered systemically or locally into the auditory cortex shortly before, shortly after, or 1 day before conditioning. Although acquisition performance during initial training was normal, the discrimination of FMs was enhanced during retraining performed hours or days after agonist injection compared with vehicle-injected controls. The D1/D5 receptor antagonist SCH-23390, the mTOR inhibitor rapamycin, and the protein synthesis blocker anisomycin suppressed this effect. By immunohistochemistry, D1 dopamine receptors were identified in the gerbil auditory cortex predominantly in the infragranular layers. Together, these findings suggest that in the gerbil auditory cortex dopaminergic inputs regulate mTOR-mediated, protein synthesis-dependent mechanisms, thus controlling for hours or days the consolidation of memory required for the discrimination of complex auditory stimuli.

Working memory (WM) tasks involve several interrelated processes during which past information must be transiently maintained, recalled, and compared with test items according to previously instructed rules. It is not clear whether the rule-specific comparisons of perceptual with memorized items are only performed in previously identified frontal and parietal WM areas or whether these areas orchestrate such comparisons by feedback to sensory cortex. We tested the latter hypothesis by focusing on auditory cortex (AC) areas with low-noise functional magnetic resonance imaging in a 2-back WM task involving frequency-modulated (FM) tones. The control condition was a 0-back task on the same stimuli. Analysis of the group data identified an area on right planum temporale equally activated by both tasks and an area on the left planum temporale specifically involved in the 2-back task. A region of interest analysis in each individual revealed that activation on the left planum temporale in the 2-back task positively correlated with the task performance of the subjects. This strongly suggests a prominent role of the AC in 2-back WM tasks. In conjunction with previous findings on FM processing, the left lateralized effect presumably reflects the complex sequential processing demand of the 2-back matching to sample task.

SummaryCategory 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 [1–3]. 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 [4–14]. For directional categorization of tone steps, as in melody recognition [15, 16], 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.

A central tenet in brain research is that early sensory cortex is modality specific, and, only in exceptional cases, such as deaf and blind subjects or professional musicians, is influenced by other modalities. Here we describe extensive cross-modal activation in the auditory cortex of two monkeys while they performed a demanding auditory categorization task: after a cue light was turned on, monkeys could initiate a tone sequence by touching a bar and then earn a reward by releasing the bar on occurrence of a falling frequency contour in the sequence. In their primary auditory cortex and posterior belt areas, we found many acoustically responsive neurons whose firing was synchronized to the cue light or to the touch or release of the bar. Of 315 multiunits, 45 exhibited cue light-related firing, 194 exhibited firing that was related to bar touch, and 268 exhibited firing that was related to bar release. Among 60 single units, we found one neuron with cue light-related firing, 21 with bar touch-related firing, and 36 with release-related firing. This firing disappeared at individual sites when the monkeys performed a visual detection task. Our findings corroborate and extend recent findings on cross-modal activation in the auditory cortex and suggests that the auditory cortex can be activated by visual and somatosensory stimulation and by movements. We speculate that the multimodal corepresentation in the auditory cortex has arisen from the intensive practice of the subjects with the behavioral procedure and that it facilitates the performance of audiomotor tasks in proficient subjects.

Summary: Purpose: After pilocarpine-induced epilepsy in rats, volumetric magnetic resonance imaging (MRI) reveals significant morphologic changes in functionally relevant structures of the brain. To relate structural changes to functional alteration, we studied the correlation of regional brain atrophy (e.g., of the hippocampus) with lesion-induced learning deficits in the Morris water maze. Methods: MRI experiments were performed on an MR scanner at 4.7 Tesla. For volumetric analysis, various cerebral structures were segmented in horizontal and coronal T2-weighted MR images. Before the MRI investigations, animals were trained for 10 days in a Morris water maze. Results: Volumetric MRI revealed a significant loss in hippocampal size in both the dorsal and ventral parts, correlated with an increase in ventricular size. Furthermore, significant losses were found in the relative size of thalamus, putamen, cortex, and the combined areas of perirhinal, entorhinal, and piriform cortices adjacent to the hippocampus. A significant correlation of learning performance in the Morris water maze with the relative hippocampal area and not with other areas tested was observed in pilocarpine-treated animals. Conclusions: The data provide a quantitative analysis of functionally relevant structural alterations in rats with chronic epilepsy. Water maze performance of pilocarpine-treated animals correlates with the degree of hippocampal but not with the degree of cortical damage, demonstrating the potential of this method for the investigation of cognitive impairments in relation to cerebral changes. In addition, the data point to an important role of even the residual hippocampus in memory formation. Ke yW ords: Temporal lobe epilepsy—Pilocarpine—MRI— Volumetry—Rat—Hippocampus—Learning—Water maze.

Animal and human studies suggest that directional categorization of frequency-modulated (FM) tones (rising vs. falling) is a function of the right auditory cortex (AC). To investigate this hemispheric specialization in more detail, we analyzed both the binaural and monaural representation of FM tones and the influence of contralateral white noise on the processing of FM tone direction. In two fMRI-experiments, FM tones with varied direction, center-frequencies, and duration were presented binaurally or monaurally without contralateral white noise (experiment 1) and with contralateral white noise (experiment 2) while the subjects had to perform the same directional categorization task. In experiment 1, contralateral FM tones led to strongest activation, binaural FM tones to intermediate, and ipsilateral FM tones to weakest activation in each AC. This is in accordance with binaural response properties of neurons in animal AC. In experiment 2, contralateral white noise had no significant effect on the activation of left AC by FM tones, whereas in right AC, it led to a significant increase in activation for ipsilateral FM tones. This result provides further support for the critical role of right AC for directional categorization of FM tones, which for ipsilateral input has to be processed in competition to the excitatory input of white noise via the direct contralateral pathway.

The weak field specificity and the heterogeneity of neuronal filters found in any given auditory cortex field does not substantiate the view that such fields are merely descriptive maps of sound features. But field mechanisms were previously shown to support behaviourally relevant classification of sounds. Here the prediction was tested in human auditory cortex (AC) that classification-tasks rather than the stimulus class per se determine which auditory cortex area is recruited. By presenting the same set of frequency-modulations we found that categorization of their pitch direction (rising versus falling) increased functional magnetic resonance imaging activation in right posterior AC compared with stimulus exposure and in contrast to left posterior AC dominance during categorization of their duration (short versus long). Thus, top-down influences appear to select not only auditory cortex areas but also the hemisphere for specific processing.

Comparison of brain imaging data requires the exact matching of data sets from different individuals. Warping methods, used to optimize matching of data sets, can exploit either local gray value distribution or identifiable reference points within the images to be compared. Gray value-based warping, which is more comfortable, cannot be used if gray values include functional information that should be compared between images. A major drawback in the use of point-based warping methods is the lack of methods for efficient and precise definition of reference points (landmarks) within comparable data sets. Here, we present a novel approach to automatically detect sufficient numbers of landmarks, which is based on 3D differential operators. In addition, we have developed a new distance-weighted warping method, which optimizes individual local weighting factors of displacement vectors. The quality of the methods was evaluated using a set of autoradiographs documenting the metabolic activity of gerbil brains after acoustic stimulation. The new warping method was compared with known methods of landmark-based warping, i.e., warping with radial basis functions and with distance-weighted methods. For the data sets presented in this study our new optimized warping method produced an increase in linear cross correlation of 4.44%, an increase in volume overlap index of 1.55%, and a decrease in the registration error of 36.2%. In addition, the detection of functional differences was improved after warping. Therefore, the new method is a powerful tool, which enhances the comparison of complex biological structures and the quantitative evaluation of functional imaging data.

The neural mechanisms and role of attention in the processing of visual form defined by luminance or motion cues were studied using magnetoencephalography. Subjects viewed bilateral stimuli composed of moving random dots and were instructed to covertly attend to either left or right hemifield stimuli in order to detect designated target stimuli that required a response. To generate form-from-motion (FFMo) stimuli, a subset of the dots could begin to move coherently to create the appearance of a simple form (e.g., square). In other blocks, to generate form-from-luminance (FFLu) stimuli that served as a control, a gray stimulus was presented superimposed on the randomly moving dots. Neuromagnetic responses were observed to both the FFLu and FFMo stimuli and localized to multiple visual cortical stages of analysis. Early activity in low-level visual cortical areas (striate/early extrastriate) did not differ for FFLu versus FFMo stimuli, nor as a function of spatial attention. Longer latency responses elicited by the FFLu stimuli were localized to the ventral-lateral occipital cortex (LO) and the inferior temporal cortex (IT). The FFMo stimuli also generated activity in the LO and IT, but only after first eliciting activity in the lateral occipital cortical region corresponding to MT/V5, resulting in a 50–60 msec delay in activity. All of these late responses (MT/V5, LO, and IT) were significantly modulated by spatial attention, being greatly attenuated for ignored FFLu and FFMo stimuli. These findings argue that processing of form in IT that is defined by motion requires a serial processing of information, first in the motion analysis pathway from V1 to MT/V5 and thereafter via the form analysis stream in the ventral visual pathway to IT.

Background Since the mesocortical dopaminergic system of rodents has several differences to that found in primate species, including humans, there is the need for more exhaustively studying causative relationships between activation/stimulation of the ventral tegmental area (VTA) and substantia nigra (SN) and behavior in monkeys. Objective To gain causative relationships between VTA/SN stimulation and behavior, we investigated whether monkeys perform audiovisual (AV) tasks using brain stimulation reward (BSR) as the reinforcer, and how reward intensity affects performance during self-stimulation. Methods Monkeys were required to touch a bar freely when self-stimulating or when instructed by an AV stimulus, to receive BSR. Results We were able to train monkeys to successfully perform the AV task for BSR within three days. Self-stimulation revealed an increase in the bar touch rate when using higher electrical currents, with no ceiling effects observed. During a training session the touch rate decreased, often before the monkeys had received 1000 deliveries of BSR, suggesting satiation. Conclusions When BSR is applied directly to the VTA/SN, it can motivate monkeys to perform detection tasks, exhibit operant actions, and may be used as a substitute for fluid or food rewards. Monkeys ceased self-stimulation during a training session by their own volition, in contrast to work on rodents. This may be an important safety aspect for consideration in the development of electrical stimulation procedures for patients with dysfunctions of the dopaminergic system; thus, satiation may avert additional compulsions to already existing compulsive behaviors in patients.

Auditory cortex has been shown to be a site of widespread neuronal learning processes even in the context of simple auditory conditioning behavior. In view of their presumed role in determining behavioral and motivational relevance of incoming information we investigated whether the dopaminergic and serotonergic systems are involved in auditory cortex learning. Using a chronic brain microdialysis technique over 4 days, samples from auditory cortex were obtained before, during, and after daily footshock avoidance training simultaneously from trained gerbils and passive control animals or pseudotrained animals. Because of detection limits of dopamine and serotonin in auditory cortex, the response profiles of extracellular homovanillic acid as the metabolite of the dopaminergic system and of 5-hydroxyindoleacetic acid as the metabolite of the serotonergic system were determined from consecutive dialysis samples each day. The response of the dopaminergic system appeared to reflect the initial formation of the behaviorally relevant association exclusively during the first training day, whereas the serotonergic response appeared to correlate with the stress level of animals.

Recent functional neuroimaging studies have emphasized the role of the different areas within the left superior temporal sulcus (STS) for the perception of various speech stimuli. We report here the results of three independent studies additionally demonstrating hemodynamic responses in the vicinity of the planum temporale (PT). In these studies we used consonant–vowel (CV) syllables, tones, white noise, and vowels as acoustic stimuli in the context of whole-head functional magnetic resonance imaging, applying a long TR to attenuate possible masking effects by the scanner noise. To summarize, we obtained the following results for the contrasts comparing hemodynamic responses obtained during the perception of CV syllables compared to tones or white noise: (i) stronger activation in the vicinity of the left PT with two distinct foci of activation, one in a lateral position and the other more medial in the vicinity of Heschl's sulcus; (ii) stronger activation in the vicinity of the right PT; and (iii) stronger bilateral activation within the mid-STS. Further contrasts revealed the following findings: (iv) stronger bilateral activation to CV syllables than to vowels in the medial PT, (v) stronger left-sided activation to CV syllables than to vowels in the mid-STS, and (vi) stronger activation to CV syllables with voiceless initial consonants than to CV syllables with voiced initial consonants in the left medial PT. The results are compatible with the hypothesis that the STS contains neurons specialized for speech perception. However, these results also emphasize the role of the PT in the analysis of phonetic features, namely the voice-onset-time. Yet this does not mean that the PT is solely specialized for phonetic analysis. We hypothesize rather that the PT contains neurons specialized for the analysis of rapidly changing cues as was suggested by P. Tallal et al. (1993, Ann. N. Y. Acad. Sci. 682: 27–47).

The spatial and temporal characteristics of the brain processes underlying memory retrieval were studied with both event-related potentials (ERP) and positron emission tomography (PET) techniques. Subjects studied lists of 20 words and then performed episodic (old/new judgment) or semantic (living/nonliving decision) retrieval tasks on multiple four-item test lists, each lasting 10 sec. The PET and ERP measurements at test were assessed in relation to both the task (episodic vs. semantic) and the item (old vs. new or living vs. nonliving). Episodic retrieval was associated with increased blood flow in the right frontal lobe (Brodmann Area 10) and a sustained, slowly developing positive ERP shift recorded from the right frontopolar scalp. Semantic retrieval was associated with increased blood flow in the left frontal (Area 45) and temporal (Area 21) lobes but no clear ERP concomitant. The two retrieval tasks also differed from each other in the ERPs to single items in an early (300-500 ms) time window. Item-related comparisons yielded convergent results mainly if the retrieved information was relevant to the given task (e.g., old/new items during episodic retrieval and living/nonliving items during semantic retrieval). Episodically retrieved old items were associated with increased blood flow in the left medial temporal lobe and a transient increase in the amplitude of the late positive component (500-700 ms) of the ERP. Semantically retrieved living items were associated with increased blood flow in the left frontal cortex and anterior cingulate and a transient late frontal slow wave (700-1,500 ms) in the ERPs. These results indicate that the brain regions engaged in memory retrieval are active in either a sustained or transient manner. They map task-related processes to sustained and item-related processes to transient neural activity. But they also suggest that task-related factors can transiently affect early stages of item processing.

It is well established that the tone-evoked response of neurons in auditory cortex can be attenuated if another tone is presented several hundred milliseconds before. The present study explores in detail a complementary phenomenon in which the tone-evoked response is enhanced by a preceding tone. Action potentials from multiunit groups and single units were recorded from primary and caudomedial auditory cortical fields in lightly anesthetized macaque monkeys. Stimuli were two suprathreshold tones of 100-ms duration, presented in succession. The frequency of the first tone and the stimulus onset asynchrony (SOA) between the two tones were varied systematically, whereas the second tone was fixed. Compared with presenting the second tone in isolation, the response to the second tone was enhanced significantly when it was preceded by the first tone. This was observed in 87 of 130 multiunit groups and in 29 of 69 single units with no obvious difference between different auditory fields. Response enhancement occurred for a wide range of SOA (110–329 ms) and for a wide range of frequencies of the first tone. Most of the first tones that enhanced the response to the second tone evoked responses themselves. The stimulus, which on average produced maximal enhancement, was a pair with a SOA of 120 ms and with a frequency separation of about one octave. The frequency/SOA combinations that induced response enhancement were mostly different from the ones that induced response attenuation. Results suggest that response enhancement, in addition to response attenuation, provides a basic neural mechanism involved in the cortical processing of the temporal structure of sounds.

This study examines the role of auditory cortex in the Mongolian gerbil in differential conditioning to pure tones and to linearly frequency-modulated (FM) tones by analyzing the effects of bilateral auditory cortex ablation. Learning behavior and performance were studied in a GO/NO-GO task aiming at avoidance of a mild foot shock by crossing a hurdle in a two-way shuttle box. Hurdle crossing as the conditioned response to the reinforced stimulus (CR+), as false alarm in response to the unreinforced stimulus (CR−), intertrial activity, and reaction times were monitored. The analysis revealed no effects of lesion on pure tone discrimination but impairment of FM tone discrimination. In the latter case lesion effects were dependent on timing of lesion relative to FM tone discrimination training. Lesions before training in naive animals led to a reduced CR+ rate and had no effect on CR− rate. Lesions in pretrained animals led to an increased CR− rate without effects on the CR+ rate. The results suggest that auditory cortex plays a more critical role in discrimination of FM tones than in discrimination of pure tones. The different lesion effects on FM tone discrimination before and after training are compatible with both the hypothesis of a purely sensory deficit in FM tone processing and the hypothesis of a differential involvement of auditory cortex in acquisition and retention, respectively.

In a previous functional magnetic resonance (fMRI) study, a subdivision of the human auditory cortex into four distinct territories was achieved. One territory (T1a) exhibited functional specialization in terms of a foreground-background decomposition task involving matching-to-sample monitoring on tone sequences. The present study more specifically determined whether memory-guided analysis of tone sequences is part of the T1a specialization. During the encoding periods, an arbitrary and unfamiliar four-tone-sequence (melody) played by one instrument was presented. The melody-instrument-combination was different in each period. During subsequent retrieval periods, learned and additional combinations were presented, and the tasks were either to detect the target melodies (experiment I) or the target instruments (experiment II). T1a showed larger activation during the melody retrieval. The results generally suggest that (1) activation of T1a during retrieval is determined less by the sound material than by the executed task, and (2) more specifically, that memory-guided sequential analysis in T1a is dominant over recognition of characteristic complex sounds.

It is commonly assumed that cortical activity in non-rapid eye movement sleep (NREMS) is spatially homogeneous on the mesoscopic scale. This is partly due to the limited observational scope of common metabolic or imaging methods in sleep. We used the recently developed technique of thallium-autometallography (TlAMG) to visualize mesoscopic patterns of activity in the sleeping cortex with single-cell resolution. We intravenously injected rats with the lipophilic chelate complex thallium diethyldithiocarbamate (TlDDC) during spontaneously occurring periods of NREMS and mapped the patterns of neuronal uptake of the potassium (K+) probe thallium (Tl+). Using this method, we show that cortical activity patterns are not spatially homogeneous during discrete 5-min episodes of NREMS in unrestrained rats—rather, they are complex and spatially diverse. Along with a relative predominance of infragranular layer activation, we find pronounced differences in metabolic activity of neighboring neuronal assemblies, an observation which lends support to the emerging paradigm that sleep is a distributed process with regulation on the local scale. Electronic supplementary material The online version of this article (doi:10.1007/s00429-014-0867-9) contains supplementary material, which is available to authorized users.

Brain activity was studied with fMRI and steady-state visual evoked potentials (SSVEPs) in separate sessions as subjects attended to letter sequences in either the right or left visual field. The two letter sequences were superimposed on small square backgrounds that flickered at 8.6 and 12.0 Hz, respectively, and elicited SSVEPs at the flicker frequencies. The amplitude of the frequency-coded SSVEP elicited by either of the flickering backgrounds was enlarged when attention was focused upon the letter sequence at the same location. Source analysis of the SSVEP waveforms localized the attentional modulation to ventral and lateral extrastriate visual cortex, which corresponded to zones of activation observed with fMRI.

A fundamental principle of brain organization is bilateral symmetry of structures and functions. For spatial sensory and motor information processing, this organization is generally plausible subserving orientation and coordination of a bilaterally symmetric body. However, breaking of the symmetry principle is often seen for functions that depend on convergent information processing and lateralized output control, e.g. left hemispheric dominance for the linguistic speech system. Conversely, a subtle splitting of functions into hemispheres may occur if peripheral information from symmetric sense organs is partly redundant, e.g. auditory pattern recognition, and therefore allows central conceptualizations of complex stimuli from different feature viewpoints, as demonstrated e.g. for hemispheric analysis of frequency modulations in auditory cortex (AC) of mammals including humans. Here we demonstrate that discrimination learning of rapidly but not of slowly amplitude modulated tones is non-uniformly distributed across both hemispheres: While unilateral ablation of left AC in gerbils leads to impairment of normal discrimination learning of rapid amplitude modulations, right side ablations lead to improvement over normal learning. These results point to a rivalry interaction between both ACs in the intact brain where the right side competes with and weakens learning capability maximally attainable by the dominant left side alone.

Disruption of neuronal networks in the Alzheimer-afflicted brain is increasingly recognized as a key correlate of cognitive and memory decline in Alzheimer patients. We hypothesized that functional synaptic disconnections within cortical columnar microcircuits by pathological β-amyloid accumulation, rather than cell death, initially causes the cognitive impairments. During development of cortical β-amyloidosis with still few plaques in the transgenic 5xFAD mouse model single cell resolution mapping of neuronal thallium uptake revealed that electrical activity of pyramidal cells breaks down throughout infragranular cortical layer V long before cell death occurs. Treatment of 5xFAD mice with the glutaminyl cyclase inhibitor, PQ 529, partially prevented the decline of pyramidal cell activity, indicating pyroglutamate-modified forms, potentially mixed oligomers of Aβ are contributing to neuronal impairment. Laminar investigation of cortical circuit dysfunction with current source density analysis identified an early loss of excitatory synaptic input in infragranular layers, linked to pathological recurrent activations in supragranular layers. This specific disruption of normal cross-laminar cortical processing coincided with a decline of contextual fear learning.

Neuronal damage shortly after onset or after brief episodes of cerebral ischemia has remained difficult to assess with clinical and preclinical imaging techniques as well as with microscopical methods. We here show, in rodent models of middle cerebral artery occlusion (MCAO), that neuronal damage in acute focal cerebral ischemia can be mapped with single-cell resolution using thallium autometallography (TlAMG), a histochemical technique for the detection of the K+-probe thallium (Tl+) in the brain. We intravenously injected rats and mice with thallium diethyldithiocarbamate (TlDDC), a lipophilic chelate complex that releases Tl+ after crossing the blood–brain barrier. We found, within the territories of the affected arteries, areas of markedly reduced neuronal Tl+ uptake in all animals at all time points studied ranging from 15 minutes to 24 hours after MCAO. In large lesions at early time points, areas with neuronal and astrocytic Tl+ uptake below thresholds of detection were surrounded by putative penumbral zones with preserved but diminished Tl+ uptake. At 24 hours, the areas of reduced Tl+uptake matched with areas delineated by established markers of neuronal damage. The results suggest the use of 201TlDDC for preclinical and clinical single-photon emission computed tomography (SPECT) imaging of hyperacute alterations in brain K+ metabolism and prediction of tissue viability in cerebral ischemia.

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.

The lateral habenula (LHb) is an epithalamic structure involved in signaling reward omission and aversive stimuli, and it inhibits dopaminergic neurons during motivated behavior. Less is known about LHb involvement in the acquisition and retrieval of avoidance learning. Our previous studies indicated that brief electrical stimulation of the LHb, time-locked to the avoidance of aversive footshock (presumably during the positive affective “relief” state that occurs when an aversive outcome is averted), inhibited the acquisition of avoidance learning. In the present study, we used the same paradigm to investigate different frequencies of LHb stimulation. The effect of 20 Hz vs. 50 Hz vs. 100 Hz stimulation was investigated during two phases, either during acquisition or retrieval in Mongolian gerbils. The results indicated that 50 Hz, but not 20 Hz, was sufficient to produce a long-term impairment in avoidance learning, and was somewhat more effective than 100 Hz in this regard. None of the stimulation parameters led to any effects on retrieval of avoidance learning, nor did they affect general motor activity. This suggests that, at frequencies in excess of the observed tonic firing rates of LHb neurons (>1–20 Hz), LHb stimulation may serve to interrupt the consolidation of new avoidance memories. However, these stimulation parameters are not capable of modifying avoidance memories that have already undergone extensive consolidation.

Learning from punishment is a powerful means for behavioral adaptation with high relevance for various mechanisms of self-protection. Several studies have explored the contribution of released dopamine (DA) or responses of DA neurons on reward seeking using rewards such as food, water, and sex. Phasic DA signals evoked by rewards or conditioned reward predictors are well documented, as are modulations of these signals by such parameters as reward magnitude, probability, and deviation of actually occurring from expected rewards. Less attention has been paid to DA neuron firing and DA release in response to aversive stimuli, and the prediction and avoidance of punishment. In this review, we first focus on DA changes in response to aversive stimuli as measured by microdialysis and voltammetry followed by the change in electrophysiological signatures by aversive stimuli and fearful events. We subsequently focus on the role of DA and effect of DA manipulations on signaled avoidance learning, which consists of learning the significance of a warning cue through Pavlovian associations and the execution of an instrumental avoidance response. We present a coherent framework utilizing the data on microdialysis, voltammetry, electrophysiological recording, electrical brain stimulation, and behavioral analysis. We end by outlining current gaps in the literature and proposing future directions aimed at incorporating technical and conceptual progress to understand the involvement of reward circuit on punishment based decisions.

Upon infection with the obligate intracellular parasite Toxoplasma gondii, fast replicating tachyzoites infect a broad spectrum of host cells including neurons. Under the pressure of the immune response, tachyzoites convert into slow-replicating bradyzoites, which persist as cysts in neurons. Currently, it is unclear whether T. gondii alters the functional activity of neurons, which may contribute to altered behaviour of T. gondii-infected mice and men. In the present study we demonstrate that upon oral infection with T. gondii cysts, chronically infected BALB/c mice lost over time their natural fear against cat urine which was paralleled by the persistence of the parasite in brain regions affecting behaviour and odor perception. Detailed immunohistochemistry showed that in infected neurons not only parasitic cysts but also the host cell cytoplasm and some axons stained positive for Toxoplasma antigen suggesting that parasitic proteins might directly interfere with neuronal function. In fact, in vitro live cell calcium (Ca(2+)) imaging studies revealed that tachyzoites actively manipulated Ca(2+) signalling upon glutamate stimulation leading either to hyper- or hypo-responsive neurons. Experiments with the endoplasmatic reticulum Ca(2+) uptake inhibitor thapsigargin indicate that tachyzoites deplete Ca(2+) stores in the endoplasmatic reticulum. Furthermore in vivo studies revealed that the activity-dependent uptake of the potassium analogue thallium was reduced in cyst harbouring neurons indicating their functional impairment. The percentage of non-functional neurons increased over time In conclusion, both bradyzoites and tachyzoites functionally silence infected neurons, which may significantly contribute to the altered behaviour of the host.

The temporal contingency of feedback during conversations is an essential requirement of a successful dialog. In the current study, we investigated the effects of delayed and omitted registering feedback on fMRI activation and compared both unexpected conditions to immediate feedback. In the majority of trials of an auditory task, participants received an immediate visual feedback which merely indicated that a button press was registered but not whether the response was correct or not. In a minority of trials, and thus unexpectedly, the feedback was omitted, or delayed by 500 ms. The results reveal a response hierarchy of activation strength in the dorsal striatum and the substantia nigra: the response to the delayed feedback was larger compared to immediate feedback and immediate feedback showed a larger activation compared to the omission of feedback. This suggests that brain regions typically involved in reward processing are also activated by non-rewarding, registering feedback. Furthermore, the comparison with immediate feedback revealed that both omitted and delayed feedback significantly modulated activity in a network of brain regions that reflects attentional demand and adjustments in cognitive and action control, i.e., the posterior medial frontal cortex (pMFC), right dorsolateral prefrontal cortex (dlPFC), bilateral anterior insula (aI), inferior frontal gyrus (Gfi), and inferior parietal lobe (Lpi). This finding emphasizes the importance of immediate feedback in human-computer interaction, as the effects of delayed feedback on brain activity in the described network seem to be similar to that of omitted feedback.

It is widely accepted that the perception of human voices is supported by neural structures located along the superior temporal sulci. However, there is an ongoing discussion to what extent the activations found in fMRI studies are evoked by the vocal features themselves or are the result of phonetic processing. To show that the temporal lobes are indeed engaged in voice processing, short utterances spoken by famous and unknown people were presented to healthy young participants whose task it was to identify the familiar speakers. In two event-related fMRI experiments, the temporal lobes were found to differentiate between familiar and unfamiliar voices such that named voices elicited higher BOLD signal intensities than unfamiliar voices. Yet, the temporal cortices did not only discriminate between familiar and unfamiliar voices. Experiment 2, which required overtly spoken responses and allowed to distinguish between four familiarity grades, revealed that there was a fine-grained differentiation between all of these familiarity levels with higher familiarity being associated with larger BOLD signal amplitudes. Finally, we observed a gradual response change such that the BOLD signal differences between unfamiliar and highly familiar voices increased with the distance of an area from the transverse temporal gyri, especially towards the anterior temporal cortex and the middle temporal gyri. Therefore, the results suggest that (the anterior and non-superior portions of) the temporal lobes participate in voice-specific processing independent from phonetic components also involved in spoken speech material.

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).

It is well established that auditory cortex is plastic on different time scales and that this plasticity is driven by the reinforcement that is used to motivate subjects to learn or to perform an auditory task. Motivated by these findings, we study in detail properties of neuronal firing in auditory cortex that is related to reward feedback. We recorded from the auditory cortex of two monkeys while they were performing an auditory categorization task. Monkeys listened to a sequence of tones and had to signal when the frequency of adjacent tones stepped in downward direction, irrespective of the tone frequency and step size. Correct identifications were rewarded with either a large or a small amount of water. The size of reward depended on the monkeys’ performance in the previous trial: it was large after a correct trial and small after an incorrect trial. The rewards served to maintain task performance. During task performance we found three successive periods of neuronal firing in auditory cortex that reflected (1) the reward expectancy for each trial, (2) the reward-size received, and (3) the mismatch between the expected and delivered reward. These results, together with control experiments suggest that auditory cortex receives reward feedback that could be used to adapt auditory cortex to task requirements. Additionally, the results presented here extend previous observations of non-auditory roles of auditory cortex and shows that auditory cortex is even more cognitively influenced than lately recognized.