Matthias Deliano

Enhanced cognitive flexibility in reversal learning induced by removal of the extracellular matrix in auditory cortex

Significance The brain’s extracellular matrix (ECM) mediates structural stability by enwrapping synaptic contacts fundamental for long-term memory storage. Whether the ECM in the adult brain might thereby govern learning-related plasticity, lifelong memory reformation, and higher cognitive functions is largely unknown. Here, we enzymatically degraded the ECM in the auditory cortex of adult Mongolian gerbils during a reversal learning task. Such local weakening of the structurally rigid ECM specifically accelerated strategy changes required for reversal learning. It neither affected general sensory learning nor erased already established, learned memory traces. Thus, ECM modulation might promote the cognitive flexibility that can build on learned behaviors, and has further implications to develop new tools for guided neuroplasticity with therapeutic potential. During brain maturation, the occurrence of the extracellular matrix (ECM) terminates juvenile plasticity by mediating structural stability. Interestingly, enzymatic removal of the ECM restores juvenile forms of plasticity, as for instance demonstrated by topographical reconnectivity in sensory pathways. However, to which degree the mature ECM is a compromise between stability and flexibility in the adult brain impacting synaptic plasticity as a fundamental basis for learning, lifelong memory formation, and higher cognitive functions is largely unknown. In this study, we removed the ECM in the auditory cortex of adult Mongolian gerbils during specific phases of cortex-dependent auditory relearning, which was induced by the contingency reversal of a frequency-modulated tone discrimination, a task requiring high behavioral flexibility. We found that ECM removal promoted a significant increase in relearning performance, without erasing already established—that is, learned—capacities when continuing discrimination training. The cognitive flexibility required for reversal learning of previously acquired behavioral habits, commonly understood to mainly rely on frontostriatal circuits, was enhanced by promoting synaptic plasticity via ECM removal within the sensory cortex. Our findings further suggest experimental modulation of the cortical ECM as a tool to open short-term windows of enhanced activity-dependent reorganization allowing for guided neuroplasticity.

Stimulus duration influences perceived simultaneity in audiovisual temporal-order judgment.

The temporal integration of stimuli in different sensory modalities plays a crucial role in multisensory processing. Previous studies using temporal-order judgments to determine the point of subjective simultaneity (PSS) with multisensory stimulation yielded conflicting results on modality-specific delays. While it is known that the relative stimulus intensities of stimuli from different sensory modalities affect their perceived temporal order, we have hypothesized that some of these discrepancies might be explained by a previously overlooked confounding factor, namely the duration of the stimulus. We therefore studied the influence of both factors on the PSS in a spatial-audiovisual temporal-order task. In addition to confirming previous results on the role of stimulus intensity, we report that varying the temporal duration of an audiovisual stimulus pair also affects the perceived temporal order of the auditory and visual stimulus components. Although individual PSS values varied from negative to positive values across participants, we found a systematic shift of PSS values in all participants toward a common attractor value with increasing stimulus duration. This resulted in a stabilization of PSS values with increasing stimulus duration, indicative of a mechanism that compensates individual imbalances between sensory modalities, which might arise from attentional biases toward one modality at short stimulus durations.

Dopamine-Modulated Recurrent Corticoefferent Feedback in Primary Sensory Cortex Promotes Detection of Behaviorally Relevant Stimuli

Dopaminergic neurotransmission in primary auditory cortex (AI) has been shown to be involved in learning and memory functions. Moreover, dopaminergic projections and D1/D5 receptor distributions display a layer-dependent organization, suggesting specific functions in the cortical circuitry. However, the circuit effects of dopaminergic neurotransmission in sensory cortex and their possible roles in perception, learning, and memory are largely unknown. Here, we investigated layer-specific circuit effects of dopaminergic neuromodulation using current source density (CSD) analysis in AI of Mongolian gerbils. Pharmacological stimulation of D1/D5 receptors increased auditory-evoked synaptic currents in infragranular layers, prolonging local thalamocortical input via positive feedback between infragranular output and granular input. Subsequently, dopamine promoted sustained cortical activation by prolonged recruitment of long-range corticocortical networks. A detailed circuit analysis combining layer-specific intracortical microstimulation (ICMS), CSD analysis, and pharmacological cortical silencing revealed that cross-laminar feedback enhanced by dopamine relied on a positive, fast-acting recurrent corticoefferent loop, most likely relayed via local thalamic circuits. Behavioral signal detection analysis further showed that activation of corticoefferent output by infragranular ICMS, which mimicked auditory activation under dopaminergic influence, was most effective in eliciting a behaviorally detectable signal. Our results show that D1/D5-mediated dopaminergic modulation in sensory cortex regulates positive recurrent corticoefferent feedback, which enhances states of high, persistent activity in sensory cortex evoked by behaviorally relevant stimuli. In boosting horizontal network interactions, this potentially promotes the readout of task-related information from cortical synapses and improves behavioral stimulus detection.

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 (∼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.

Pathological gamma oscillations, impaired dopamine release, synapse loss and reduced dynamic range of unitary glutamatergic synaptic transmission in the striatum of hypokinetic Q175 Huntington mice

Huntingtons disease (HD) is a severe genetically inherited neurodegenerative disorder. Patients present with three principal phenotypes of motor symptoms: choreatic, hypokinetic-rigid and mixed. The Q175 mouse model of disease offers an opportunity to investigate the cellular basis of the hypokinetic-rigid form of HD. At the age of 1 year homozygote Q175 mice exhibited the following signs of hypokinesia: Reduced frequency of spontaneous movements on a precision balance at daytime (-55%), increased total time spent without movement in an open field (+42%), failures in the execution of unconditioned avoidance reactions (+32%), reduced ability for conditioned avoidance (-96%) and increased reaction times (+65%) in a shuttle box. Local field potential recordings revealed low-frequency gamma oscillations in the striatum as a characteristic feature of HD mice at rest. There was no significant loss of DARPP-32 immunolabeled striatal projection neurons (SPNs) although the level of DARPP-32 immunoreactivity was lower in HD. As a potential cause of hypokinesia, HD mice revealed a strong reduction in striatal KCl-induced dopamine release, accompanied by a decrease in the number of tyrosine hydroxylase-(TH)- and VMAT2-positive synaptic varicosities. The presynaptic TH fluorescence level was also reduced. Patch-clamp experiments were performed in slices from 1-year-old mice to record unitary EPSCs (uEPSCs) of presumed cortical origin in the absence of G-protein-mediated modulation. In HD mice, the maximal amplitudes of uEPSCs amounted to 69% of the WT level which matches the loss of VGluT1+/SYP+ synaptic terminals in immunostained sections. These results identify impairment of cortico-striatal synaptic transmission and dopamine release as a potential basis of hypokinesia in HD.

Dynamics of cortical theta activity correlates with stages of auditory avoidance strategy formation in a shuttle-box.

By comparing behavioral performance and cortical theta activity (4-8 Hz) on a trial by trial basis we examined how the different behavioral stages of tone-induced avoidance learning in the shuttle-box may be distinguishable by theta power as a potential correlate of changing strategies of information processing. Electrocorticograms with pronounced theta content were recorded across the cortical surface of gerbils during avoidance learning and analyzed in each trial in conjunction with reaction times and unconditioned and conditioned responses. The focus of theta analysis in this paradigm with a 5-s delay between tone and foot-shock onsets was on the 14-s periods after hurdle crossing where feedback information from a trial is available. The strongest theta activity occurred in stage 1 of initial tone conditioning which was sharply reduced to a minimum during stage 2 of optimization of unconditioned escape responses from the foot shock. A few initial successful avoidance responses gave rise to a reversal of the decline of theta activity that later reached a second maximum. A systematic increase of theta activity during this stage 3 of avoidance conditioning was found for the occasional trials with unconditioned responses and not for the increasing number of conditioned responses suggesting that error processing is a major correlate of this new increase of theta power. After the second maximum the theta power slowly declined together with a further improvement of behavioral performance indicating that stage 4 of retrieval of the consolidated avoidance response was reached. The results suggest that behind a previously reported general trend of decreasing theta power with increasing performance in this paradigm there is a hidden microstructure of theta activity across trials which separates stages of avoidance conditioning and is partially mirrored by known changes of prefrontal dopamine release.

Segregation of task-relevant conditioned stimuli from background stimuli by associative learning

In the real world, task-relevant, conditioned stimuli are often embedded in a varying background, from which they have to be segregated. Besides sensory mechanisms, associative learning assumingly plays an important role for the segregation of the conditioned from the background stimuli, especially if conditioned and background stimuli are spectro-temporally structured, and psychophysically similar. We therefore investigated the influence of spectro-temporally structured background tones on associative learning of conditioned tones depending on the complexity of the behavioral task and the psychophysical similarity between conditioned and background tones. Frequency-modulated tone sweeps were used as conditioned stimuli, and persisting frequency-modulated tones as background. In a shuttle-box, Mongolian gerbils were subjected to a simple detection task, or to a more complex discrimination task. In contrast to detection learning, introduction or change of background tones affected discrimination performance both during learning and at the stage of retrieval, especially when conditioned and background tones were spectro-temporally similar. The change from a familiar to a new background tone at the stage of retrieval caused a prefrontal dopamine increase and lead to relearning of task-relevant associations. We conclude that conditioned stimuli and background stimuli are processed concomitantly, which might provide contextual information, but requires additional cognitive processing.

Theta activity attenuation correlates with avoidance learning progress in gerbils.

Changes of cortical activity were examined with electrocorticograms sampled from gerbils during learning. Animals were subjected to tone-conditioned avoidance training in a shuttle-box. Electrocorticograms were recorded from an electrode placed over medial prefrontal cortex. Temporal patterns of theta activity were analyzed across 180 successive trials. With the start of conditioning strong theta activity occurred in each trial in the phase immediately after hurdle crossing. With reliable occurrence of conditioned responses, that is at the stage of retrieval of the avoidance response, the theta activity became reduced. A negative correlation exists between the theta power and the development of learning progress. Theta reduction thus could reflect decreasing demands on information processing in the course of avoidance success monitoring across trials.

Electrocortical components of anticipation and consumption in a monetary incentive delay task

In order to improve our understanding of the components that reflect functionally important processes during reward anticipation and consumption, we used principle components analyses (PCA) to separate and quantify averaged ERP data obtained from each stage of a modified monetary incentive delay (MID) task. Although a small number of recent ERP studies have reported that reward and loss cues potentiate ERPs during anticipation, action preparation, and consummatory stages of reward processing, these findings are inconsistent due to temporal and spatial overlap between the relevant electrophysiological components. Our results show three components following cue presentation are sensitive to incentive cues (N1, P3a, P3b). In contrast to previous research, reward-related enhancement occurred only in the P3b, with earlier components more sensitive to break-even and loss cues. During feedback anticipation, we observed a lateralized centroparietal negativity that was sensitive to response hand but not cue type. We also show that use of PCA on ERPs reflecting reward consumption successfully separates the reward positivity from the independently modulated feedback-P3. Last, we observe for the first time a new reward consumption component: a late negativity distributed over the left frontal pole. This component appears to be sensitive to response hand, especially in the context of monetary gain. These results illustrate that the time course and sensitivities of electrophysiological activity that follows incentive cues do not follow a simple heuristic in which reward incentive cues produce enhanced activity at all stages and substages.

Improving Accuracy and Temporal Resolution of Learning Curve Estimation for within- and across-Session Analysis.

Estimation of learning curves is ubiquitously based on proportions of correct responses within moving trial windows. Thereby, it is tacitly assumed that learning performance is constant within the moving windows, which, however, is often not the case. In the present study we demonstrate that violations of this assumption lead to systematic errors in the analysis of learning curves, and we explored the dependency of these errors on window size, different statistical models, and learning phase. To reduce these errors in the analysis of single-subject data as well as on the population level, we propose adequate statistical methods for the estimation of learning curves and the construction of confidence intervals, trial by trial. Applied to data from an avoidance learning experiment with rodents, these methods revealed performance changes occurring at multiple time scales within and across training sessions which were otherwise obscured in the conventional analysis. Our work shows that the proper assessment of the behavioral dynamics of learning at high temporal resolution can shed new light on specific learning processes, and, thus, allows to refine existing learning concepts. It further disambiguates the interpretation of neurophysiological signal changes recorded during training in relation to learning.