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Projekte: Entwicklungs-assoziierte Erkrankungen des Gehirns

Hahn T. DFG - Deutsche Forschungsgemeinschaft HA 7018/3-1: Modeling time perception and its dopaminergic modulation. 04/2018-03/2020.

Accurate perception and estimation of time is a crucial ability to many species, including humans. The very same action can often be either a success or a failure, given on whether it is executed at the right time – be it hitting a ball in a sports game or evading the paw of a deadly predator. Timing also plays an important role in communication, such as speech or music. On a more abstract level, the sense of time also helps to organize reality into past, present and future, which is a basis for planning ahead or remembering complex courses of events. Thus, the ability to tell time is required for almost everything we do, from simple perceptions and actions to complex cognitive functions. Distortion of time perception is also an important symptom of severe psychiatric diseases (Buhusi and Meck, 2005; Allman and Meck, 2012) such as Schizophrenia (affecting 1% of the German population during lifetime, causing 4.4 to 9.2 billion € cost or 2-4% of the annual total health and social budget, Gaebel and Wölwer, 2010) or Attention-Deficit Disorder (5% life time prevalence in Germany, 260 million € annual cost, Schlander, Trott and Schwarz, 2010). It has even been argued that the disorganization of time and the inability to accurately perceive its passage lies at the core of these diseases (Bonnot et al. 2011; Castellanos and Tannock, 2002; Toplak, Dockstader and Tannock, 2006). Recognizing the importance of time perception, researchers have conducted a wealth of experimental and theoretical studies to many of its aspects, including the anatomical location of time perception within the nervous system (Allman et al., 2014), its electrophysiological correlates (Matell et al., 2014), psychophysical properties in rodents, monkeys and man (Lejeune and Wearden, 2006; Wearden and Lejeune, 2008), modulation of time perception by drugs and diseases (Buhusi and Meck, 2005) and theoretical models of neural timing circuits (Buonomano and Karmarkar, 2002; Hass and Herrmann, 2012; Hass and Durstewitz, 2014). A recurrent finding in all these lines of research is the involvement of fronto-striatal circuits (Lewis and Miall, 2006) and their modulation by dopamine (Buhusi and Meck, 2004), which is also believed to be centrally involved in the distortions of time perception in psychiatric diseases (Allman and Meck, 2012). Despite substantial progress in all of these areas, there is currently no consensus about the mechanisms of time perception and the nature of its dopaminergic modulation. This is partly due to an insufficient integration of results from all the different levels of investigation. The present Project has the overall objective to obtain such an integrated understanding, based on a combination of computational modelling, in vivo electrophysiology, psychophysics and pharmacology in rats performing time perception tasks, with a focus on the prefrontal cortex and the striatum. In the following, we elaborate on the current state of the art in each of the fields mentioned above, including our own contributions, and point out major open issues which we intend to address in the current project. We restrict ourselves to intervals in the range of hundreds of milliseconds to several seconds, which are most important for motion, communication and cognition (Buonomano and Karmarkar, 2002).

DFG - Deutsche Forschungsgemeinschaft : Netzwerkdynamiken und computationale Mechanismen des Regellernens II. 10/2016-09/2019.

Lernvorgänge bei Tieren werden häufig als eher langsame, graduelle Prozesse angesehen, die in der inkrementellen Stärkung assoziativer Verbindungen zwischen Stimuli, Reaktionen und Rückmeldungen aus der Umwelt bestehen. Basierend auf statistischen Analysen individueller Lernvorgänge und Beobachtungen zu plötzlichen Sprüngen zwischen Regel-repräsentierenden neuronalen Populationszuständen im präfrontalen Kortex (PFC) etabliert sich in den letzten Jahren aber zunehmend die Sichtweise vom Lernen als aktivem Inferenz- und Entscheidungsprozess. Ergebnisse aus der letzten Antragsperiode legen nahe, dass 'neuronale Sprünge' eher den Wechsel der Entscheidung bzgl. alternativer Regeln abbildet, als einen durch Unsicherheit initiierten Übergang in eine Explorationsphase, und dass dieser Wechsel durch das dopaminerge System beeinflusst wird. Basierend auf diesen und anderen Beobachtungen werden wir drei weitergehende Fragestellungen mithilfe einer Kombination aus Multizellableitungen, optogenetischen Manipulationen und fortgeschrittenen Zeitreihen- und auf computationalen Modellen basierenden statistischen Analysemethoden untersuchen: 1) Wie genau sind neuronale Zellverbände im PFC und im ventralen tegmentalen Areal (VTA) während des Regellernens zeitlich koordiniert und welche Einflüsse hat Dopamin im Einzelnen auf verschiedene computationale Teilprozesse (z.B. Werteinferenz oder Antwortselektion); 2) Können von uns postulierte Modelle der zugrundeliegenden neurodynamischen Mechanismen die in verschiedenen PFC-Arealen beobachteten Aktivitätsmuster unter unterschiedlichen experimentellen Bedingungen prädizieren und erklären; 3) Lassen sich bestimmte, mit einfacheren Modellen nur schwer erklärbare Verhaltensbeobachtungen in diesem Kontext durch Modelle des Strukturlernens und der aktiven Informationssuche erfassen, und wie sind diese höheren Prozesse neuronal realisiert? Zentraler Gedanke unseres Projektes ist damit weiterhin, Regellernen als aktiven Inferenzprozess in seinen neurophysiologischen, -dynamischen und -computationalen Grundlagen zu verstehen. Animal learning is often conceived as a gradual process that develops over many trials and involves the incremental strengthening of associations among stimuli, responses, and outcomes. However, in recent years there is mounting evidence that animal learning is better understood as an active inference and decision making process. This view comes from careful statistical examination of the individual, trial-by-trial learning progress, and from the observation of sudden transitions among neural ensemble states coding for different behavioral rules in prefrontal cortex (PFC) which accompany the learning process. Results from the last funding period suggest that a) these sudden neural transitions may reflect a change in choice between the different rules (following a crossover of value signals) rather than reflecting a period of uncertainty and/or exploration, and b) that dopamine may also primarily affect the choice process rather than value updating. Building on these results and other observations, here we aim to further validate and extend our current understanding along three major directions, using a combination of multi-tetrode recordings, optogenetic manipulations, and advanced time series and computational model based analysis of the learning process: 1) We will dissect in more detail the task periods during which dopamine input is most crucial, how dopamine neuron activity is coordinated with PFC activity as the task progresses, and how it impacts on various subcomponents of rule learning like action selection and value updating; 2) We will address in more detail specific hypotheses regarding the neurodynamical mechanisms underlying the active inference process in various subdivisions of the rat PFC; 3) Through variations of the basic behavioral task design, we will further explore learning in terms of structural inference and active information seeking. Thus, we will continue toward our goal of a comprehensive understanding of rule learning as active inference at the neurophysiological, neuro-dynamical, and neuro-computational levels.

DFG - Deutsche Forschungsgemeinschaft HA 7018/1-1: Netzwerkdynamiken und computationale Mechanismen der Regellernens. 01/2013-12/2016.

BMBF - Bundesministerium für Bildung und Forschung : Mechanisms of Persistent Activity in the Entorhinal cortex In Vivo. 01/2010-12/2015.

Hahn T. BMBF - Bundesministerium für Bildung und Forschung 01GQ1003B: BCCN TP B6: Polymorphisms & PFC networks in vivo. 05/2010-04/2015.



Zentralinstitut für Seelische Gesundheit (ZI) - https://www.zi-mannheim.de