Disrupted cross-laminar cortical processing in ß amyloid pathology precedes cell death.

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 ß-amyloid accumulation, rather than cell death, initially causes the cognitive impairments. During development of cortical ß-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 Aß 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.

Resonance phenomena in the human auditory cortex: individual resonance frequencies of the cerebral cortex determine electrophysiological responses.

The brain can be considered a dynamical system which is able to oscillate at multiple frequencies. To study the brain's preferred oscillation frequencies, the resonance frequencies in the frequency response of the system can be assessed by stimulating the brain at various stimulation frequencies. Furthermore, the event-related potential (ERP) can be considered as the brain's impulse response. For linear dynamical systems, the frequency response should be equivalent to the frequency transform of the impulse response. The present study test whether this fundamental relation is also true for the frequency transform of the ERP and the frequency response of the brain. Results show that the spectral characteristics of both impulse and frequency response in the gamma frequency range are significantly correlated. Thus, we speculate that the resonance frequencies determine the frequency spectrum of the impulse response. This, in turn, implies that both measures are determined by the same, individually specific, neuronal generator mechanisms.

Spatial representation of frequency-modulated tones in gerbil auditory cortex revealed by epidural electrocorticography.

The present study investigated the topography of epidurally recorded middle latency components P1 and N1 evoked by spectrally dynamic stimuli (linearly frequency-modulated (FM) tones) with respect to the tonotopic structure of the right primary auditory cortex, field AI. Whereas the gross topography corresponded to the spectral content of the FM tones, specific tonotopic offsets were found between the potential distributions evoked by FM tones of different modulation direction (i.e. 'rising' vs. 'falling'). Potentials evoked by rising FM tones were located at tonotopic positions corresponding to higher frequencies compared with potentials evoked by falling FM tones. Data indicated that the magnitude of these offsets can be attributed to the local tonotopic resolution in AI and are not dependent on the modulation rate.

Categorical discrimination of direction in frequency-modulated tones by Mongolian gerbils.

Discrimination of the direction of linearly frequency-modulated tones (FMs) was investigated in adult Mongolian gerbils (Meriones unguiculatus) using a footshock motivated shuttle box avoidance go/no go procedure. Symmetric pairs of FMs with frequency linearly increasing with time (ascending FMs) and with frequency linearly decreasing with time (descending FMs) were used as conditioned stimuli, CS+ and CS-, respectively. Stimuli were presented in randomized order in daily sessions over a period of several months. After a number of sessions, the set of conditioned stimuli was changed with respect to frequency range, steepness of modulation and duration. In experiment 1, we observed that gerbils could discriminate between the ascending 2-4 kHz CS+ and the descending 4-2 kHz CS- after a training period of 10-15 days. In experiment 2, we used FM pairs of six other frequency ranges in successive sessions (6-13; 1-2; 13-25; 0.5-1; 3 6; 0.25 0.5 kHz). We found that in the final session the last FM pair (0.25-0.5 kHz) was discriminated already after 3-4 days. Experiment 3 showed that the animals were able to discriminate five of the FM pairs learned in the separate sessions of experiment 2 (i.e. 10 different stimuli) when they were given in randomized order during one training session. In experiment 4, novel FM pairs (not heard before) and familiar FM pairs (trained in experiments 1-3) were presented within one session. It was found that, except for FMs of very short duration and small frequency range, novel FMs were discriminated according to their modulation direction. These results show that Mongolian gerbils are able to discriminate FM tones by modulation direction and, after familiarization with a number of different FM pairs, transfer the ascending-descending concept to stimuli not heard before.

Right auditory cortex lesion in Mongolian gerbils impairs discrimination of rising and falling frequency-modulated tones.

Mongolian gerbils (Meriones unguiculatus) were trained in a shuttle box to discriminate the direction in frequency-modulated tones (FM). Whereas control animals easily acquired FM discrimination, animals with auditory cortex lesion on the right side showed considerable difficulties in learning this task. The discrimination performance of gerbils with left auditory cortex lesion, however, was not different from controls. This study, suggesting that the right auditory cortex plays a dominant role in FM discrimination learning in gerbils, describes a useful animal model for investigation of the basic mechanisms underlying hemispheric asymmetries in auditory perception.

Some functions of primary auditory cortex in learning and memory formation.

In the primary auditory field AI of gerbil auditory cortex, aversive tone conditioning paradigms reshaped frequency receptive fields of single units and also changed the spatial representation of tones in fluoro-2-deoxyglucose (FDG) experiments. As another aspect of learning-induced plasticity in gerbil AI, antibodies against the immediate early gene product c-Fos identified an unusual spatial pattern of neurons in terms of a "macrocolumn." The pattern resulted from repeated short exposure of the animals to a tone in a new environment. The search for transmitters that may mediate this gene activation is carried out by microdialysis through chronically implanted probes in auditory cortex. So far, dopamine transmission was found to reflect specific aspects of auditory learning in cortex. The results suggest that spectral features of sounds as well as aspects of learned behavioral meaning of the sounds may be represented in AI.

Phase de-synchronization effects auditory gating in the ventral striatum but not auditory cortex.

The underlying mechanisms and involved brain areas in sensory gating of repetitive auditory stimuli remain unclear. Especially, the influence of the auditory cortex and the role of temporal precision are under debate. Our first objective was to analyze gating dynamics of local field potentials in the primary auditory cortex and the ventral striatum in an animal experiment, particularly, assessing the influence of the cortex. The second aim was to follow the hypothesis that auditory gating results from phase de-synchronization of evoked potentials in response to the second auditory stimulus. Local field potentials were recorded simultaneously in the auditory cortex and ventral striatum of awake Mongolian gerbils (n=15) during stimulation with trains of frequency-modulated tones. Gating was analyzed by amplitude ratios of the auditory potentials evoked by the first two stimuli in a train, as well as by time-frequency analyses and between-area phase coupling. The strength of auditory gating in the striatum was found to exceed that in the primary auditory cortex by more than 50%. While total-signal-power was comparable between areas, energy in the striatum was primarily expressed in the non-phase-locked fraction. At the same time, energy in the auditory cortex remained phase-locked to the stimuli. Furthermore, we also observed a between-area phase unlocking during sound presentations. Phase de-synchronization appears to be the candidate mechanism behind attenuation of responses to identical repetitive stimuli in the ventral striatum. We conclude that a direct inhibitory response suppression by the auditory cortex plays a minor role in this process.

The combination of appetitive and aversive reinforcers and the nature of their interaction during auditory learning.

Learned changes in behavior can be elicited by either appetitive or aversive reinforcers. It is, however, not clear whether the two types of motivation, (approaching appetitive stimuli and avoiding aversive stimuli) drive learning in the same or different ways, nor is their interaction understood in situations where the two types are combined in a single experiment. To investigate this question we have developed a novel learning paradigm for Mongolian gerbils, which not only allows rewards and punishments to be presented in isolation or in combination with each other, but also can use these opposite reinforcers to drive the same learned behavior. Specifically, we studied learning of tone-conditioned hurdle crossing in a shuttle box driven by either an appetitive reinforcer (brain stimulation reward) or an aversive reinforcer (electrical footshock), or by a combination of both. Combination of the two reinforcers potentiated speed of acquisition, led to maximum possible performance, and delayed extinction as compared to either reinforcer alone. Additional experiments, using partial reinforcement protocols and experiments in which one of the reinforcers was omitted after the animals had been previously trained with the combination of both reinforcers, indicated that appetitive and aversive reinforcers operated together but acted in different ways: in this particular experimental context, punishment appeared to be more effective for initial acquisition and reward more effective to maintain a high level of conditioned responses (CRs). The results imply that learning mechanisms in problem solving were maximally effective when the initial punishment of mistakes was combined with the subsequent rewarding of correct performance.

Orderly cortical representation of vowels based on formant interaction.

Psychophysical experiments have shown that the discrimination of human vowels chiefly relies on the frequency relationship of the first two peaks F1 and F2 of the vowel's spectral envelope. It has not been possible, however, to relate the two-dimensional (F1, F2)-relationship to the known organization of frequency representation in auditory cortex. We demonstrate that certain spectral integration properties of neurons are topographically organized in primary auditory cortex in such a way that a transformed (F1,F2) relationship sufficient for vowel discrimination is realized.

Learning-induced dynamic receptive field changes in primary auditory cortex of the unanaesthetized Mongolian gerbil.

Learning-induced changes of the spectro-temporal characteristics of primary auditory cortex (AI) units were studied by response plane analysis of recordings from the AI in unanaesthetized Mongolian gerbils. Using response planes obtained prior to and after auditory discrimination training bins of significant change were identified and their spectro-temporal distribution was studied. Bins of significant changes were generally found to be distributed over the entire spectro-temporal receptive field but occurred most frequently within the first 100 ms of response in the spectral neighbourhood (1.5 octaves) of the frequency of the reinforced conditioned stimulus. Training-induced response decreases occurred early after 10 ms for reinforced conditioned tones and tones in the frequency neighbourhood. Response increases occurred so early only for non-reinforced tones in the neighbourhood of the reinforced frequency and occurred later (after 40 ms) for the reinforced tones. The results are discussed in the light of dynamic disinhibition.

Differential frequency conditioning enhances spectral contrast sensitivity of units in auditory cortex (field Al) of the alert Mongolian gerbil.

Differential aversive auditory conditioning in the awake Mongolian gerbil was performed during single- and multi-unit recording in field Al of the primary auditory cortex. Presentations of pure tone stimuli of a given frequency (reinforced conditioned stimulus; CS+) paired with electrocutaneous stimulation (unconditioned stimulus) were combined with several other non-reinforced tone stimuli (non-reinforced conditioned stimulus; CS-). Stimulus presentation during training and testing was optimized for constancy of the probability of occurrence of both the CS+ and the CS- stimulus. The paradigm led to a reorganization of both the spectral and temporal response characteristics of auditory cortical neurons with the following basic results. First, tone-evoked responses of Al neurons recorded after multiple acoustic stimulation under these conditions varied statistically around a mean value (stationarity). Conditioning produced a shift in mean values of evoked responses. The altered tone responses were also stationary (stability of the plastic effects). Second, the frequency-receptive fields (FRFs) of neurons were reorganized in a frequency-specific way such that the CS+ frequency became located in a local minimum of the FRF after training. This resulted from a training-induced increase in the responses to frequencies adjacent to the CS+ frequency in the FRF relative to the CS+ response. The effect can be interpreted as an enhancement of the 'spectral contrast' sensitivity of the unit in the CS+ neighbourhood. Third, apart from this frequency-specific plastic effect, responses to other frequencies also underwent changes during training. The non-frequency-specific changes were not generally predictable but the post-trial responses were stationary. Fourth, the analysis of the long-term behaviour of FRF reorganization revealed the stability of plastic effects under retention training and the gradual re-establishment of the pretrial FRF during extinction training. Fifth, not only the spectral characteristics but also the temporal structure of the tone-evoked responses could be affected by the training. In most cases the training-induced changes measured within the first tens of milliseconds of the response corresponded to the response changes obtained by integration over the total response period. There were some cases, however, in which the direction of the response change varied with time, indicating that excitatory and inhibitory influences on the temporal response pattern were differently affected by training.

Change in pattern of ongoing cortical activity with auditory category learning.

Humans are able to classify novel items correctly by category; some other animals have also been shown to do this. During category learning, humans group perceptual stimuli by abstracting qualities from similarity relationships of their physical properties. Forming categories is fundamental to cognition and can be independent of a 'memory store' of information about the items or a prototype. The neurophysiological mechanisms underlying the formation of categories are unknown. Using an animal model of category learning, in which frequency-modulated tones are distinguished into the categories of 'rising' and 'falling' modulation, we demonstrate here that the sorting of stimuli into these categories emerges as a sudden change in an animal's learning strategy. Electro-corticographical recording from the auditory cortex shows that the transition is accompanied by a change in the dynamics of cortical stimulus representation. We suggest that this dynamic change represents a mechanism underlying the recognition of the abstract quality (or qualities) that defines the categories.

Topographic analysis of epidural pure-tone-evoked potentials in gerbil auditory cortex.

This study investigated the tonotopic organization of pure-tone-evoked middle latency auditory evoked potentials (MAEPs) recorded at the auditory cortical surface in unanesthetized gerbils. Multielectrode array recording and multiple linear regression analysis of the MAEP demonstrated different degrees of tonotopic organization of early and late MAEP components. The early MAEP components P1 and N1 showed focal topography and clear dependence in location and size of cortical area covered on pure-tone frequency. The later components P2 and N2 showed a widespread topography which was largely unaffected in location and size of cortical area covered by pure-tone frequency. These results allow delimitation of the neural generators of the early and late MAEP components in terms of the spectral properties of functionally defined neural populations.

Field-specific responses in the auditory cortex of the unanaesthetized Mongolian gerbil to tones and slow frequency modulations.

Responses of multi-units in the auditory cortex (AC) of unanaesthetized Mongolian gerbils to pure tones and to linearly frequency modulated (FM) sounds were analysed. Three types of responses to pure tones could be clearly distinguished on the basis of spectral tuning properties, response latencies and overall temporal response pattern. In response to FM sweeps these three types discharged in a temporal pattern similar to tone responses. However, for all type-1 units the latencies of some phasic response components shifted systematically as a function of range and/or speed of modulation. Measurements of response latencies to FMs revealed that such responses were evoked whenever the modulation reached a particular instantaneous frequency (Fi). Effective Fi was: (1) independent of modulation range and speed, (2) always reached before the modulation arrived at a local maximum of the frequency response function (FRF) and consequently differed for downward and upward sweeps, and (3) was correlated with the steepest slope of that FRF maximum. The three different types of units were found in discrete and separate fields or regions of the AC. It is concluded that gross temporal response properties are one of the key features distinguishing auditory cortical regions in the Mongolian gerbil.

Bilateral ablation of auditory cortex in Mongolian gerbil affects discrimination of frequency modulated tones but not of pure tones.

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.

Early and late patterns of stimulus-related activity in auditory cortex of trained animals.

Epidural electrocorticograms over the right auditory cortex (field AI) were measured using implanted 18-channel (3 x 6) electrode arrays in four animals (Mongolian gerbil) trained to discriminate between a rising and a falling frequency modulated tone (frequency range 2-4 kHz). Using a previously introduced classification procedure, transient patterns of cortical activity suitable to discriminate between the rising and the falling modulation were identified. Early (locked to stimulus onset) and late (emerging at variable times poststimulus) patterns could be differentiated. Deletion of increasing numbers of randomly selected electrodes was used to determine a critical density of recording channels required to capture the discriminative power of the early and late patterns. Statistical analysis of the classification revealed a sigmoid dependence of the discriminative power from the number of remaining electrodes with an inflection point at 12 electrodes. The analysis of the minima of the classification statistic revealed that in the early patterns discriminative information was focal on regions corresponding to the tonotopic representation of the stimuli, whereas in late patterns this information seemed to be distributed nonfocally across larger cortical regions. This analysis supports the previous notion of the coexistence of topographically organized activity states related to the physical stimulus features and nontopographically organized states determined largely by intrinsic factors (Ohl et al. 2001).