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SPP1665 Resolving and manipulating neuronal networks in the mammalian brain - from correlative to causal analysis

The German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) funds the Priority Program 1665 (Schwerpunktprogramm) “Resolving and manipulating neuronal networks in the mammalian brain – from correlative to causal analysis”. The program runs for an initial period of three years, a second funding period (another three years) started in 2017.

The mammalian brain accounts for complex sensory, motor, and cognitive abilities by processing environmental and internal information within neuronal networks. A fundamental aim of systems neuroscience is to decipher the mechanisms by which sensory perception and cognitive abilities are encoded onto activity patterns of neuronal networks. However, experimental achievement of this aim has proven notoriously difficult and mostly descriptive and correlative evidences accumulated during the last decades. Until very recently, appropriate methods to monitor and selectively manipulate the activity of single or groups of neurons in behaving animals were lacking. The impressive development of new recording and imaging techniques as well as of electrical nanostimulation and optogenetic tools during the last two-three years had a profound impact on neuroscience. The Priority Program 1665 is an interdisciplinary and seminal collaborative endeavor that aims at capitalizing on this recent technological and analytical progress for elucidating the relationship between neurons, networks and behavior.

Within the first funding period of SPP1665 (2014-2017 on the Jülich side), we were actively involved in two subprojects:

  1. "Optogenetic dissection of the developing prefrontal-hippocampal circuitry that gates mnemonic and executive maturation", led by Ileana Hanganu-Opatz, Peter Hegemann, Thomas Oertner and Michael Denker

    Processing and integration of information within neuronal networks accounts for mnemonic and executive abilities. The relevance of these functional interactions is exemplified in the case of the prefrontal cortex (PFC) and hippocampus (HP). The oscillatory coupling within prefrontal-hippocampal networks emerges during early neonatal development, with discontinuous theta activity in the HP driving the local gamma-band synchrony in the PFC. However, the cellular elements critically underlying the functional communication within developing prefrontal-hippocampal networks remain unknown. The present project aims at elucidating these issues within a collaborative effort of a “troika” by combining the engineering of new optogenetic tools and development of analytic approaches with in vivo and in vitro electrophysiology as well as behavioral investigation. Fast light-activation and silencing of different neuronal subtypes will be achieved at two different wavelengths after delivering by region-specific in utero electroporation newly designed push-pull tandem constructs that contain mutated channelrhodopsins and inhibitory ion pumps. Extracellular recordings in the neonatal PFC and HP using optoelectrodes in vivo followed by synchrony analysis at the spike and population levels will determine the neuronal subtypes (“key neurons”) critically causing prefrontal network oscillations in different frequency bands and the cellular mechanisms of prefrontal-hippocampal communication during early development. Additionally, we aim at ascertaining the long-term functional and behavioral readout of light-activation/silencing of key neurons. The results will the causal relationships between early neuronal activity and correct wiring of developing networks underlying cognitive processing at adulthood.The formation of categories is a fundamental element of cognition, and has been studied extensively to probe the fu

  2. "Causative Mechanisms of Mesoscopic Activity Patterns in Auditory Category Discrimination", led by Frank Ohl, Bertram Schmidt and Sonja Grün

    The formation of categories is a fundamental element of cognition, and has been studied extensively to probe the functional basis of cognition. However, the circuit mechanisms of category formation, especially at the mesoscopic scale bridging single neuron activity to organismal behavior, remain largely unknown. While most previous work on category discrimination has focused on unit activity reflecting category selectivity in higher cortical areas, recent work has started to focus on such mesoscopic circuit mechanisms, especially the emergence of selectivity much earlier in the sensory processing stream, particularly within the primary auditory cortex. We have established a robust model of auditory category discrimination learning in the Mongolian gerbil, using frequency modulated (FM)-sweeps and a go/no-go shuttlebox paradigm. We have shown that mesoscopic spatial patterns of neural population activity as measured by surface ECoG arrays can accurately predict the animals’ behavioral/cognitive decision. In this proposal, we explore the causative mechanisms leading to such mesoscopic neural activity patterns and their behavioral outcome. In particular, we aim to first demonstrate formal neurophysiological causality by testing for both the necessity and sufficiency of the mesoscopic activity for behavioral output, and second, to investigate the single-neuronal circuit mechanisms underlying these mesoscopic patterns, using a combination of behavioral, electrophysiological and optogenetic techniques. We thereby hope to offer an important mesoscopic link between (A) the firing patterns of single neurons and resultant local oscillations, and (B) the total behavioral output of the brain as an organ.

For the second funding period (2017-2020), we are heading the following research projects:

  1. "Cognitive performance as result of coordinated neuronal activity within developing prefrontal-hippocampal circuits", led by Ileana Hanganu-Opatz, Peter Hegemann, Thomas Oertner and Michael Denker

    The co-activation of prefrontal and hippocampal networks in oscillatory rhythms is critical for precise information flow in mnemonic and executive tasks, yet its role for cognitive ontogeny is still unknown. This knowledge gap is mainly due to the absence of suitable tools for interrogation of developing circuits. Within a collaborative effort of a "troika" that joins expertise in engineering and validating light-sensitive proteins with neurophysiological and analytical approaches, we elucidated during the 1st funding period of the Priority Program 1665 the cellular substrate of neonatal prefrontal-hippocampal communication and identified key cellular elements of oscillatory coupling. During early development discontinuous theta activity in the hippocampus (HP) drives the local gamma-band synchrony in prefrontal cortex (PFC) via axonal projections. Using novel high-efficiency mutants of channelrhodopsin in combined extracellular and patch-clamp recordings in vivo and in vitro, we activated / silenced the neuronal activity. We identified prefrontal layer II/III pyramidal neurons projecting to layer V neurons as key neurons for the emergence of beta-low gamma oscillations in the neonatal brain. The present project aims at understanding the role of neuronal and network activity in neonatal prefrontal-hippocampal circuits for the maturation of mnemonic and executive abilities. For this, the previously identified key neurons will be silenced during defined developmental time windows. Short- and long-term consequences of this selective neuronal manipulation for the connectivity and functional communication (synchrony, spiking patterns, long-range causal interactions) within developing prefrontal-hippocampal networks will be assessed. Moreover, the adult behavioral readout of early manipulation will be characterized to decide on the necessity of coordinated activity during development for the maturation of mnemonic and executive abilities.
    See the SPP1665 website for more information.

  2. "Causative mechanisms of mesoscopic activity patterns in auditory category discrimination", led by Frank Ohl, Bertram Schmidt and Sonja Grün
    The formation of categories is a fundamental element of cognition, and has been studied extensively to probe the functional basis of cognition. However, the circuit mechanisms of category formation, especially at the mesoscopic scale bridging single neuron activity to organismal behavior, remain largely unknown. While most previous work on category discrimination has focused on unit activity reflecting category selectivity in higher cortical areas, recent work has started to focus on such mesoscopic circuit mechanisms, especially the emergence of selectivity much earlier in the sensory processing stream, particularly within the primary auditory cortex. We have established a robust model of auditory category discrimination learning in the Mongolian gerbil, using frequency modulated (FM)-sweeps and a go/no-go shuttlebox paradigm. We have shown that mesoscopic spatial patterns of neural population activity as measured by surface ECoG arrays can accurately predict the animals’ behavioral/cognitive decision. In this proposal, we explore the causative mechanisms leading to such mesoscopic neural activity patterns and their behavioral outcome. In particular, we aim to first demonstrate formal neurophysiological causality by testing for both the necessity and sufficiency of the mesoscopic activity for behavioral output, and second, to investigate the single-neuronal circuit mechanisms underlying these mesoscopic patterns, using a combination of behavioral, electrophysiological and optogenetic techniques. We thereby hope to offer an important mesoscopic link between (A) the firing patterns of single neurons and resultant local oscillations, and (B) the total behavioral output of the brain as an organ.

    See the SPP1665 website for more information.


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