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 establishedthat 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 activitydependent reorganization allowing for guided neuroplasticity.chondroitin sulfate proteoglycan | hyaluronidase | perineuronal net | intracortical microinjection | strategy change S tructural remodeling and stabilization of synaptic networks are key mechanisms underlying learning in the adult brain. During early life, high structural and functional plasticity is required for the experience-shaped development of basic neuronal circuits (1). With brain maturation, juvenile plasticity of so-called critical or sensitive periods is decreased and is accompanied by the appearance of the brain's extracellular matrix (ECM) and its specialized compact form named "perineuronal net" (PNN) enwrappping cell bodies and synaptic contacts (2, 3). Enzymatic degradation of the ECM in adult animals has been demonstrated to restore such forms of developmental (juvenile) plasticity with respect to topographical map plasticity in the visual cortex (4), fearresponse-mediating circuits in the amygdala (5), spinal cord injuries (6, 7), and song learning circuits of zebra finches (8). In addition, enzymatic ECM removal altered several forms of synaptic plasticity in vitro and in vivo (9-12). However, even though structural stability of networks acquired during developmental phases is essential for neuronal efficiency, mechanisms allowing synaptic remodeling are key events during learning and memory formation throughout life (13). We recently demonstrated that endogenous proteases moderately digesting specific components of the ECM are regulated in an activity-dependent manner (2, 14) and ECM removal modulates synaptic short-term plasticity by synaptic e...

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.

Dopaminergic neurotransmission in primary auditory cortex (AI) has been shown to be involved in learning and memory functions. Moreover, dopaminergic projections and D 1 /D 5 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 ( Our results show that D 1 /D 5 -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.

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Ketamine is a common anaesthetic agent used in research and more recently as medication in treatment of depression. It has known effects on inhibition of interneurons and cortical stimulus-locked responses, but the underlying functional network mechanisms are still elusive. r Analysing population activity across all layers within the auditory cortex, we found that doses of this anaesthetic induce a stronger activation and stimulus-locked response to pure-tone stimuli. r This cortical response is driven by gain enhancement of thalamocortical input processing selectively within granular layers due to an increased recurrent excitation. r Time-frequency analysis indicates a higher broadband magnitude response and prolonged phase coherence in granular layers, possibly pointing to disinhibition of this recurrent excitation. r These results further the understanding of ketamine's functional mechanisms, which will improve the ability to interpret physiological studies moving from anaesthetized to awake paradigms and may lead to the development of better ketamine-based depression treatments with lower side effects.

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.

Reward associations during auditory learning induce cortical plasticity in the primary auditory cortex. A prominent source of such influence is the ventral tegmental area (VTA), which conveys a dopaminergic teaching signal to the primary auditory cortex. Yet, it is unknown, how the VTA influences cortical frequency processing and spectral integration. Therefore, we investigated the temporal effects of direct optogenetic stimulation of the VTA onto spectral integration in the auditory cortex on a synaptic circuit level by current-source-density analysis in anesthetized Mongolian gerbils. While auditory lemniscal input predominantly terminates in the granular input layers III/IV, we found that VTA-mediated modulation of spectral processing is relayed by a different circuit, namely enhanced thalamic inputs to the infragranular layers Vb/VIa. Activation of this circuit yields a frequency-specific gain amplification of local sensory input and enhances corticocortical information transfer, especially in supragranular layers I/II. This effects persisted over more than 30 minutes after VTA stimulation. Altogether, we demonstrate that the VTA exhibits a long-lasting influence on sensory cortical processing via infragranular layers transcending the signaling of a mere reward-prediction error. We thereby demonstrate a cellular and circuit substrate for the influence of reinforcement-evaluating brain systems on sensory processing in the auditory cortex.

The primary auditory cortex (A1) is an essential, integrative node that encodes the behavioral relevance of acoustic stimuli, predictions, and auditory-guided decision-making. However, the realization of this integration with respect to the cortical microcircuitry is not well understood. Here, we characterize layer-specific, spatiotemporal synaptic population activity with chronic, laminar current source density analysis in Mongolian gerbils (Meriones unguiculatus) trained in an auditory decision-making Go/NoGo shuttle-box task. We demonstrate that not only sensory but also task-and choice-related information is represented in the mesoscopic neuronal population code of A1. Based on generalized linear-mixed effect models we found a layer-specific and multiplexed representation of the task rule, action selection, and the animal's behavioral options as accumulating evidence in preparation of correct choices. The findings expand our understanding of how individual layers contribute to the integrative circuit in the sensory cortex in order to code task-relevant information and guide sensorybased decision-making.