Biology subjects

Malmierca, M. S.

Publications and source records attributed to Malmierca, M. S..

3 recordsLinked to original sources

bioRxiv2019

Dopamine gates prediction error forwarding in the cortices of the inferior colliculus

The predictive processing framework describes perception as a hierarchical predictive model of sensation. Higher-level neural structures constrain the processing at lower-level structures by suppressing synaptic activity induced by predictable sensory input. But when predictions fail, deviant input is forwarded bottom-up as prediction error to update the perceptual model. The earliest prediction error signals identified in the auditory pathway emerge from the nonlemniscal inferior colliculus (IC). The drive that these feedback signals exert on the perceptual model depends on their expected precision, which determines the postsynaptic gain applied in prediction error forwarding. Expected precision is theoretically encoded by the neuromodulatory (e.g., dopaminergic) systems. To test this empirically, we recorded extracellular responses from the rat nonlemniscal IC to oddball and cascade sequences before, during and after the microiontophoretic application of dopamine or eticlopride (a D2-like receptor antagonist). Hence, we studied dopaminergic modulation on the subcortical processing of unpredictable and predictable auditory changes. Results demonstrate that dopamine reduces the net neuronal responsiveness exclusively to unexpected input, without significantly altering the processing of expected auditory events at population level. We propose that, in natural conditions, dopaminergic projections from the thalamic subparafascicular nucleus to the nonlemniscal IC could serve as a precision-weighting mechanism mediated by D2-like receptors. Thereby, the levels of dopamine release in the nonlemniscal IC could modulate the early bottom-up flow of prediction error signals in the auditory system by encoding their expected precision.

neuroscience↗

bioRxiv2019

Prediction errors explain mismatch signals of neurons in the medial prefrontal cortex

The mismatch negativity (MMN) is a key biomarker of automatic deviance detection thought to emerge from two cortical sources. First, the auditory cortex (AC) encodes spectral regularities and reports frequency-specific deviances. Then, more abstract representations in the prefrontal cortex (PFC) allow to detect contextual changes of potential behavioral relevance. However, the precise location and time asynchronies between neuronal correlates underlying this fronto-temporal network remain unclear and elusive. Our study presented auditory oddball paradigms along with no-repetition controls to record mismatch responses in neuronal spiking activity and local field potentials at the rat medial PFC. Whereas mismatch responses in the auditory system are mainly induced by stimulus-dependent effects, we found that auditory responsiveness in the PFC was driven by unpredictability, yielding context-dependent, comparatively delayed, more robust and longer-lasting mismatch responses mostly comprised of prediction error signaling activity. This characteristically different composition discarded that mismatch responses in the PFC could be simply inherited or amplified downstream from the auditory system. Conversely, it is more plausible for the PFC to exert top-down influences on the AC, since the PFC exhibited flexible and potent predictive processing, capable of suppressing redundant input more efficiently than the AC. Remarkably, the time course of the mismatch responses we observed in the spiking activity and local field potentials of the AC and the PFC combined coincided with the time course of the large-scale MMN-like signals reported in the rat brain, thereby linking the microscopic, mesoscopic and macroscopic levels of automatic deviance detection.

neuroscience↗

bioRxiv2019

The effect of NMDA-R antagonist, MK-801, on Neuronal Mismatch along the Auditory Thalamocortical System

Efficient sensory processing requires that the brain is able to maximize its response to unexpected stimuli, while suppressing responsivity to expected events. Mismatch negativity (MMN) is an auditory event-related potential that occurs when a regular pattern is interrupted by an event that violates the expected properties of the pattern. MMN has been found to be reduced in individuals with schizophrenia in over 100 separate studies, an effect believed to be underpinned by glutamate N-methyl-D-aspartate receptor (NMDA-R) dysfunction, as it is observed that NMDA-R antagonists also reduce MMN in healthy volunteers. The aim of the current study is to examine this effect in rodents. Using single unit recording in specific auditory areas using methods not readily utilized in humans, we have previously demonstrated that neuronal indices of rodent mismatch responses recorded from thalamic and cortical areas of the brain can be decomposed into a relatively simple repetition suppression and a more sophisticated prediction error process. In the current study, we aimed to test how the NMDA-R antagonist, MK-801, affected both of these processes along the rat auditory thalamocortical pathway. We found that MK-801 had the opposite effect than expected, and enhanced thalamic repetition suppression and cortical prediction error. These single unit data correlate with the recordings of local field responses. Together with previous data, this study suggests that our understanding of the contribution of NMDA-R system to MMN generation is far from complete, and also has potential implications for future research in schizophrenia.\n\nSignificance StatementIn this study, we demonstrate that an NMDA-R antagonist, MK-801, differentially affects single neuron responses to auditory stimuli along the thalamocortical axis by increasing the response magnitude of unexpected events in the auditory cortex and intensifying the adaptation of responses to expected events in the thalamus. Thus, we provide evidence that NMDA-R antagonists alter the balance between prediction-error and repetition suppression processes that underlie the generation of mismatch responses in the brain, and these effects are differentially expressed at different levels of auditory processing. As effects of MK-801 were in the opposite direction to our expectations, it demonstrates that our understanding of role of NMDA-R in synaptic plasticity and the neural processes underpinning MMN generation are far from complete.

neuroscience↗