Cortical glutamatergic projection neuron types contribute to distinct functional subnetworks

The cellular basis of cerebral cortex functional architecture remains not well understood. A major challenge is to monitor and decipher neural network dynamics across broad cortical areas yet with projection neuron (PN)-type resolution in real time during behavior. Combining genetic targeting and wide-field imaging, we monitored activity dynamics of subcortical-projecting (PTFezf2) and intratelencephalic-projecting (ITPlxnD1) types across dorsal cortex of mice during different brain states and behaviors. ITPlxnD1 and PTFezf2 neurons showed distinct activation patterns during wakeful resting, spontaneous movements, and upon sensory stimulation. Distinct ITPlxnD1 and PTFezf2 subnetworks were dynamically tuned to different sensorimotor components of a naturalistic feeding behavior, and optogenetic inhibition of subnetwork nodes disrupted specific components of this behavior. Lastly, ITPlxnD1 and PTFezf2 projection patterns are consistent with their subnetwork activation patterns. Our results show that, in addition to the concept of columnar organization, dynamic areal and PN type-specific subnetworks are a key feature of cortical functional architecture linking microcircuit components with global brain networks

Pyramidal cell types drive functionally distinct cortical activity patterns during decision-making

Understanding how cortical circuits generate complex behavior requires investigating the cell types that comprise them. Functional differences across pyramidal neuron (PyN) types have been observed within cortical areas, but it is not known whether these local differences extend throughout the cortex, nor whether additional differences emerge when larger-scale dynamics are considered. We used genetic and retrograde labeling to target pyramidal tract, intratelencephalic and corticostriatal projection neurons and measured their cortex-wide activity. Each PyN type drove unique neural dynamics, both at the local and cortex-wide scales. Cortical activity and optogenetic inactivation during an auditory decision task revealed distinct functional roles. All PyNs in parietal cortex were recruited during perception of the auditory stimulus, but, surprisingly, pyramidal tract neurons had the largest causal role. In frontal cortex, all PyNs were required for accurate choices but showed distinct choice tuning. Our results reveal that rich, cell-type-specific cortical dynamics shape perceptual decisions

The relation of sensory adaptation and stimulus perception in the rat whisker-system

Zusammenfassung Die Abnahme neuronaler Antworten bei wiederholter Präsentation eines sensorischen Stimulus ist eine weit verbreitete Eigenschaft, sowohl im peripheren als auch im zentralen Nervensystem. Diese sensorische Adaptation tritt in nahezu allen sensorischen Modalitäten auf und wird durch eine Vielzahl verschiedener Mechanismen, z.B. biophysikalische Effekte sensorischer Rezeptoren, inhibitorische Rückopplungen, intrinsische Zellmechanmismen oder Depression von Projektionssynapsen bedingt. Zahlreiche psychophysikalische Studien haben außerdem gezeigt das Adaptation einen signifikanten Einfluß auf die sensorische Wahrnehmung hat. Die anhaltende Präsentation eines sensorischen Stimulus reduziert hierbei die Wahrnehmung eines anschließend präsentierten Teststimulus, während die Unterschiede zwischen verschiedenen Stimuli verstärkt werden. Der genaue Zusammenhang zwischen neurophysiologischer und perzeptueller Adaptation ist jedoch weitgehend unbekannt. Das Ziel der vorliegenden Studie ist die Herstellung einer direkten Verbindung zwischen der Adaptation kortikaler Neuronen und der daraus resultierenden sensorischen Wahrnehmung. Hierzu wurde eine Kombination von elektrophysiologischen Ableitungen, optogenetischer neuronaler Stimulation und Verhaltensversuchen in dem somatosensorischen System der Ratte eingesetzt. In Kapitel 1 gebe ich eine Einführung über sensorische Adaptation und bespreche verschiedene Nachweise für seine physiologischen Ursachen, funktionellen Auswirkungen und Bedeutung für Stimuluswahrnehmung. Der erste Teil dieses Kapitels konzentriert sich auf generelle Adaptation die in einer Vielzahl verschiedener neuronaler Netzwerke auftritt. Der zweite Teil behandelt die Bedeutung von stimulus-spezifischer Adaptation (SSA), die einen Spezialfall darstellt und vor Allem im sensorischen Cortex auftritt. Der letzte Teil bietet eine Übersicht über die verschiedenen experimentalen Ansätze und Ziele der Arbeit. Kapitel 2 behandelt die Hauptergebnisse meiner Arbeit und liegt in Form eines wissenschaftlichen Aufsatzes vor, der in dem wissenschaftlichen Magazin Nature Neuroscience veröffentlich wurde. Im Rahmen dieser Studie habe ich ein neuartiges Verhaltensparadigma zur psychophysikalischen Prüfung einzelner Schnurrhaarstimulationen genutzt und zusätzlich die Aktivität einzelner Neurone im Barrelfeld der Ratte aufgezeichnet. Durch den Einsatz verschiedener theoretischer Modelle konnte ich das Verhalten trainierter Ratten auf Basis der stimulus-induzierten Aktivität kortikaler Neurone zutreffend beschreiben. Um einen kausalen Zusammenhang zwischen kortikaler Adaptation und Stimuluswahrnehmung herzustellen, induzierte ich die kortikale Expression des Blaulicht sensitiven Ionenkanals Channelrhodopsin-2. Im Gegensatz zur Stimulation einzelner Schnurrhaare, die frequenzabhängige Adaption auslöst, erzeugte die direkte Stimulation kortikaler Neurone adaptationsfreie, lichtinduzierte Antworten. Der direkte Vergleich der Verhaltensperformance mit Schnurrhaar- oder Lichtstimulation zeigte, dass die Umgehung der kortikalen Adaptation die interhemisphärische Diskrimierung von Stimulusfrequenzen stark verbessert aber gleichzeitig die Wahrnehmung von Intensitätsveränderungen einschränkt. Dies zeigt, dass die Adaptation kortikaler Neurone von kritischer Bedeutung für die Sinneswahrnehmung ist und die Wahrnehmung konstanter Reize reduziert um die perzeptuelle Intensität abweichender Stimuli zu verstärken. Kapitel 3 beinhaltet die zweite Studie die ich während meines Doktorats durchgeführt habe und zurzeit zur Begutachtung bei dem wissenschaftlichen Magazin Cerebral Cortex vorliegt. Im Rahmen dieser Studie erweiterte ich unser Verhaltensparadigma durch eine Kombination verschiedener Stimulationsmerkmale und studierte so die perzeptuelle Bedeutung von SSA. Ich konnte zeigen, dass die gezielte Veränderung verschieden Stimulationsmerkmale, wie die Richtung einer Schnurhaar-Auslenkung oder Stimulation eines benachbarten Schnurrhaares, die Wahrnehmung eines abweichenden sensorischen Stimulus deutlich steigert. Änderungen der gleichen Merkmale induzierten außerdem einen Anstieg im Antwortverhalten einzelner Neurone im cortikalen Barrelfeld. Die Analyse der neuronalen Antworten in verschiedenen cortikalen Tiefen ergab, dass die Antworten auf abweichende Stimuli in spezifischen Schichten des Cortex verstärkt werden. Dies legt nahe, dass die stimulus- spezifische Detektion abweichender sensorischer Reize ein Merkmal intracorticaler Informationsverarbeitung ist. In Kapitel 4 diskutiere ich wie die verschiedenen Ergebnisse meiner Arbeit das bestehende Wissen über sensorische Adaptation erweitern und ihre Bedeutung für das Verständnis cortikaler sensorischer Verarbeitung. Abstract The attenuation of neuronal responses to repeated sensory stimulation is an omnipresent feature in both the peripheral and central nervous system. Such sensory adaptation occurs in virtually all sensory modalities and is caused by a variety of different mechanisms, including biophysical effects on sensory receptors, inhibitory feedback loops, intrinsic cellular mechanisms and short-term depression of projection synapses. Numerous psychophysical studies also showed that adaptation has a significant influence on sensory perception. Here, prolonged presentation of an adaptor stimulus reduces the perception of a subsequently presented test stimulus while markedly increasing the discriminability between different stimuli. However, the precise relation between these neurophysiological and behavioral results is widely unknown. The main objective of this thesis is to establish a direct relation between adaptation of cortical neurons and stimulus perception. To achieve this goal, I applied a combination of electrophysiological recordings, optogenetic neural stimulation and animal behavior in the rat whisker-system. In chapter 1, I will provide an introduction to sensory adaptation and review the evidence for its physiological origins, functional implications for stimulus processing and importance for sensory perception. The first part of chapter 1 will focus on general adaptation that is widely observed in a variety of different neuronal circuits. The second part will focus on stimulus- specific adaptation (SSA), a special case of adaptation that mainly occurs in sensory cortex. The last part gives an overview of the experimental approaches and specific aims of the thesis. Chapter 2 contains the main results of my project and is presented in the form of a research article that has been published in the scientific journal Nature Neuroscience. In this study, I used a novel behavioral paradigm for psychophysical testing of single-whisker stimuli and recorded the activity of sensory neurons in the rat barrel cortex. Using different theoretical models, I could closely describe the behavioral performance of trained rats based on stimulus- evoked activity of cortical neurons. To establish a causal relation between cortical adaptation and stimulus perception, I then induced the cortical expression of the blue light sensitive ion- channel channelrhodopsin-2. In contrast to whisker stimulation, which causes frequency- dependent adaptation, direct light activation of cortical neurons resulted in non-adapting stimulus-evoked responses. The comparison of behavioral performance with either whisker or light stimulation revealed that circumventing adaptation strongly improves cross-hemispheric discrimination of stimulus frequency while reducing the detection of changes in stimulus intensity. This shows that sensory adaptation critically governs the perception of sensory stimuli, decreasing fidelity under steady-state conditions in favor of change detection. Chapter 3 contains the second study that I conducted during my project, which is currently under revision at the scientific journal Cerebral Cortex. Here, I addressed the importance of SSA for stimulus perception by expanding our behavioral paradigm to a set of different stimulus features. I found that changes in specific stimulus features, such as whisker deflection direction or identity of a stimulated whisker robustly enhances detection of deviant stimuli. Changes in the same features also evoked stronger stimulus responses of single neurons in the barrel cortex. Analysis of neural responses in different cortical depths revealed that deviant responses are enhanced in specific cortical layers, suggesting that stimulus-specific deviance detection is a feature of intracortical information processing. In Chapter 4, I discuss how the different results of the thesis expand the current knowledge on sensory adaptation and their implications for the understanding of sensory processing in cortex

Deviant processing in the primary somatosensory cortex

Stimulus-specific adaptation (SSA) to repetitive stimulation has been proposed to separate behaviorally relevant features from a stream of continuous sensory information. However, the exact mechanisms giving rise to SSA and cortical deviance detection are not well understood. We therefore used an oddball paradigm and multicontact electrodes to characterize single-neuron and local field potential responses to various deviant stimuli across the rat somatosensory cortex. Changing different single-whisker stimulus features evoked robust SSA in individual cortical neurons over a wide range of stimulus repetition rates (0.25–80 Hz). Notably, SSA was weakest in the granular input layer and significantly stronger in the supra- and infragranular layers, suggesting that a major part of SSA is generated within cortex. Moreover, we found a small subset of neurons in the granular layer with a deviant-specific late response, occurring roughly 200 ms after stimulus offset. This late deviant response exhibited true-deviance detection properties that were not explained by depression of sensory inputs. Our results show that deviant responses are actively amplified within cortex and contain an additional late component that is sensitive for context-specific sensory deviations. This strongly implicates deviance detection as a feature of intracortical stimulus processing beyond simple sensory input depression

A flexible Python-based touchscreen chamber for operant conditioning reveals improved visual perception of cardinal orientations in mice

Natural scenes are composed of a wide range of edge angles and spatial frequencies, with a strong overrepresentation of vertical and horizontal edges. Correspondingly, many mammalian species are much better at discriminating these cardinal orientations compared to obliques. A potential reason for this increased performance could be an increased number of neurons in the visual cortex that are tuned to cardinal orientations, which is likely to be an adaptation to the natural scene statistics. Such biased angular tuning has recently been shown in the mouse primary visual cortex. However, it is still unknown if mice also show a perceptual dominance of cardinal orientations. Here, we describe the design of a novel custom-built touchscreen chamber that allows testing natural scene perception and orientation discrimination performance by applying different task designs. Using this chamber, we applied an iterative convergence towards orientation discrimination thresholds for cardinal or oblique orientations in different cohorts of mice. Surprisingly, the expert discrimination performance was similar for both groups but showed large inter-individual differences in performance and training time. To study the discrimination of cardinal and oblique stimuli in the same mice, we, therefore, applied, a different training regime where mice learned to discriminate cardinal and oblique gratings in parallel. Parallel training revealed a higher task performance for cardinal orientations in an early phase of the training. The performance for both orientations became similar after prolonged training, suggesting that learning permits equally high perceptual tuning towards oblique stimuli. In summary, our custom-built touchscreen chamber offers a flexible tool to test natural visual perception in rodents and revealed a training-induced increase in the perception of oblique gratings. The touchscreen chamber is entirely open-source, easy to build, and freely available to the scientific community to conduct visual or multimodal behavioral studies. It is also based on the FAIR principles for data management and sharing and could therefore serve as a catalyst for testing the perception of complex and natural visual stimuli across behavioral labs

Deviant Processing in the Primary Somatosensory Cortex

Stimulus-specific adaptation (SSA) to repetitive stimulation has been proposed to separate behaviorally relevant features from a stream of continuous sensory information. However, the exact mechanisms giving rise to SSA and cortical deviance detection are not well understood. We therefore used an oddball paradigm and multicontact electrodes to characterize single-neuron and local field potential responses to various deviant stimuli across the rat somatosensory cortex. Changing different single-whisker stimulus features evoked robust SSA in individual cortical neurons over a wide range of stimulus repetition rates (0.25–80 Hz). Notably, SSA was weakest in the granular input layer and significantly stronger in the supra- and infragranular layers, suggesting that a major part of SSA is generated within cortex. Moreover, we found a small subset of neurons in the granular layer with a deviant-specific late response, occurring roughly 200 ms after stimulus offset. This late deviant response exhibited true-deviance detection properties that were not explained by depression of sensory inputs. Our results show that deviant responses are actively amplified within cortex and contain an additional late component that is sensitive for context-specific sensory deviations. This strongly implicates deviance detection as a feature of intracortical stimulus processing beyond simple sensory input depression.ISSN:1047-3211ISSN:1460-219

Deviant Processing in the Primary Somatosensory Cortex

Stimulus-specific adaptation (SSA) to repetitive stimulation has been proposed to separate behaviorally relevant features from a stream of continuous sensory information. However, the exact mechanisms giving rise to SSA and cortical deviance detection are not well understood. We therefore used an oddball paradigm and multicontact electrodes to characterize single-neuron and local field potential responses to various deviant stimuli across the rat somatosensory cortex. Changing different single-whisker stimulus features evoked robust SSA in individual cortical neurons over a wide range of stimulus repetition rates (0.25-80 Hz). Notably, SSA was weakest in the granular input layer and significantly stronger in the supra- and infragranular layers, suggesting that a major part of SSA is generated within cortex. Moreover, we found a small subset of neurons in the granular layer with a deviant-specific late response, occurring roughly 200 ms after stimulus offset. This late deviant response exhibited true-deviance detection properties that were not explained by depression of sensory inputs. Our results show that deviant responses are actively amplified within cortex and contain an additional late component that is sensitive for context-specific sensory deviations. This strongly implicates deviance detection as a feature of intracortical stimulus processing beyond simple sensory input depression