Neural circuits of cognition – Marie Carlén group

The prefrontal cortex (PFC) in the frontal lobes integrates internally generated information with information from the external world. Prefrontal processing is most important when behavior must be guided by internal intentions (often referred to as goal-directed behavior), and in line with this proper PFC functioning is essential to cognitive processes such as attention, working memory, planning, and decision-making.

In the lab we use systems neuroscience approaches to elucidate how neurons and circuits modulate network activity in the encoding and causation of behavior. We have a strong focus on the prefrontal cortex (PFC) and studies in rodents (mus musculus and rattus norvegicus).

Most projects involve electrophysiological recordings (tetrodes or silicon probes, including Neuropixels) or imaging (microendoscopes, fiber photometry, or 2-photon microscopy) of neuronal activity in behaving animals (head-fixed or freely moving) in combination with circuit tracing and cell-type specific manipulations (optogenetics, genetic). Slice electrophysiology and voltage imaging are used for detailed ex vivo circuit studies.

Our research is rooted in the firm belief that only experiments in relation to behavioral functions can directly address when and how the brain’s circuits exert their unique actions.

The prefrontal cortex

The PFC still lacks a conclusive definition, and the structure and function of this brain area across species remain unresolved. The PFC is implicated in perceptual, emotional, social, motivational, and numerous other brain processes, and is considered to enable cognition and flexible behavior. In following, disturbed PFC functioning has been connected to most, if not all, mental disorders, including drug addiction. Naturally, deciphering of the structure and function(s) of the PFC is of great importance to medicine.

Present-day preclinical researchers increasingly utilize mice (Mus musculus) as model animals. However, lack of understanding of the structure and function of the brain hampers the understanding of which findings are transferable between species. While class-common functions and class-common behaviors involving the PFC have been firmly established, effort must also be put into clarifying dissociations and differences between species. Ultimately, understanding of what makes the human PFC unique will build on comparative studies in different species.

We are utilizing the unique technological toolbox available to studies in mice, with the aim to provide a comprehensive view of the structure and function of the mouse PFC. A blueprint of the mammalian PFC could serve as a source for investigation of homologies between species and shed light on the translational value of studies in distinct species. 

The mouse PFC

Large-scale mappings of the connectivity of the mouse cortex indicates the presence of a prefrontal module. Regions within a cortical module display particularly high interconnectivity and are suggested to be dedicated to similar functions. Hodology thus gives support for the presence of a distinct prefrontal region in the mouse brain. However, how hodology and cytoarchitectural features relate to functional features is highly unclear.

The connectivity indicates that the prefrontal module in mice sits on the top of the cortical hierarchy. Further, there is also hodological support for the presence of functional subnetworks within the moue PFC, each being defined by its specific brain connectivity. The presence of subnetworks, high interconnectivity, and a location on the top of the cortical hierarchy collectively strongly suggest that the mouse prefrontal module has a prominent role in feedback and holds both distributed and integrated information processing. These findings align with the theories on what the mammalian PFC is and does.

Our research

Using large-scale Neuropixels recordings in head-fixed mice we are mapping neuronal and network signatures across the layers and subregions of the suggested prefrontal module in a series of tasks engaging distinct brain states and cognitive processes. Our ultimate goal is to characterize neuronal and network activities that define the functional features of the mouse PFC. We have a specific interest in the circuit functions of inhibition and GABA-ergic interneurons, particularly the parvalbumin (PV)-expressing interneurons, and as in our previous work neuronal oscillations are included in our analyses.

Our work also involves long-term electrophysiological recordings of prefrontal activity in freely moving rats. For this we are employing tetrode recordings and optogenetic tagging of select prefrontal cell-types using microdrives and transgenic Cre rats developed in the lab. This enables probing of cognitive processing in conjunction with motoric processing in the PFC. 

The generation of complex behaviors depends on the integration of top-down signals from the PFC with action-selection programs in the striatum. How projections from different types of PFC output neurons target and control the striatal circuitry to support cognitive control and decision-making remains unknown. The PFC-Striatum pathway has been implicated as a primary site of circuit imbalance in cognitive and emotional disorders, notably autism spectrum disorder (ASD). In a large-scale project conducted in collaboration with the laboratory of Konstantinos Meletis, KI, we are characterizing PFCs interactions with the striatum, focusing on processing involved in decision-making. This work involves whole-brain circuit tracing, genetic targeting, and registration of neuronal activities using imaging and electrophysiology in behaving mice. 

Our behavior needs to dynamically change to adapt to ever-shifting environmental affordances – a process described as learning. An influential theory in both neuroscience and computer science known as reinforcement learning postulates that actions with a positive outcome (e.g., reward) are reinforced, while outcomes with a negative outcome (e.g., punishment) are devalued. The neuronal basis of effective and complex learning in brain-wide circuits remains to be established. One current proposal states that the PFC through its widespread and reciprocal connectivity directs the dynamic and long-term adaptions in synaptic transmission underlying learning processes. Using circuit tracing, 2-photon imaging and Neuropixels recordings in head-fixed mice we are investigating signatures of learning in the mouse PFC and their transmission to downstream sensory cortical areas. The involvement of dopamine signaling is also investigated. This project, as the PFC-striatum project, is part of our efforts to establish how information from the PFC is utilized in downstream brain regions.

Visiting researchers

• Cleiton Lopez Aguiar, PhD, University of São Paolo, Brazil
• Leonardo Rakauskas Zacharias, University of São Paolo, Brazil

Postdocs

• Charlotte Alme, PhD
• Anna Paula Crestani, PhD
• Ziauddin Darokhan, PhD
• Martin Hägglund, PhD
• Daniel Kaping, PhD
• Åsa Konradsson-Geuken, PhD
• Calvin Young, PhD

Research assistants

• Linn Andréasson, 2023
• Loran Heymans, 2023
• Eleni Moysiadou, 2023
• Sabine Gnodde, 2022
• Angelo Guadagno, 2021
• Cantin Ortiz, 2019
• Fredrik Wernstål, 2019

Master / bachelor students

2022

• Eleni Moysiadou, Stockholm University
• Loran Heymans, Stockholm University

2021

• Gabrielle Dolisie, ENS Lyon, France
• Simon Mayer, Technical University of Munich, Germany
• Mariam Shahata, KI, Sweden
• Moritz Stingl, University of Heidelberg, Germany

2020

• Gregor Ehmer, Stockholm University, Sweden
• Karyn Lewis, KI, Sweden
• Ram Yahya, Stockhom University, Sweden

2019

• Laura Heezen, University of Utrecht, The Netherlands
• Jana Immenschuh, Stockholm University, Sweden
• Agnieszska Limiszewska, Stockholm University, Sweden
• Hyunsoo Park, KI

2018

• Emily Cox, University of Calgary, Canada
• Cantin Ortiz, Royal Institute of Technology (KTH), Sweden
• Leonardo Rakauskas, University of São Paolo, Brazil
• Yicheng Wu, KI, Sweden

2017

• Joseph Clerke, University of Glasgow, Scottland
• Lovisa Franzén, Stockholm University, Sweden
• Michal Miazga, University of Warsaw, Poland

2016

• Leonidas Georgiu, University of Glasgow, Scottland
• Laura Heikkinen, KI, Sweden
• Solmaz Yazdani, KI, Sweden

2015

• Charlotta Henningson, University of Edingburgh, Scotland

2013

• Marieke Oudelaar, KI, Sweden

2012

• Cilla Gottfries, KI, Sweden
• John-Peter Vinnars, KI, Sweden
• Chan Shi Yu, National University of Singapore, Singapore