Neuronal mechanisms of cortico-subcortical communication in the mammalian brain

New light on cortical connections The cortex connects to numerous subcortical areas via cortico-subcortical synapses (green and magenta clouds). Some of these are thought to function as sensori-motor interfaces. Image provided by Dr. Anton Sumser.

Much has been learned over recent years about how sensory signals are processed in cortical networks, yet the transformation of those signals into behaviour is still not well understood. We spoke to Dr Alexander Groh about his research into connections between the cortex and subcortical areas, which could shed new light on the relationship between the brain and behaviour.

The development of sophisticated brain imaging techniques has allowed researchers to investigate how sensory signals are processed in cortical networks in greater depth than previously possible. The next question is what happens to these signals after they have been processed in the cortex, a topic that Dr Alexander Groh and his colleagues at Heidelberg University are working to address. “We’ve been focusing on a specific cortical interaction with sub-cortical areas, the connection between the cortex and the thalamus. Now we are in the process of extending this work to other subcortical areas,” he explains. This work involves trying to model brain functions, particularly with respect to communication between the cortex and the rest of the brain. “We try to do that by relating neuronal activity to sensory, motor and cognitive processes. We’re interested in complex functions – for example, understanding how an organism can identify what is important in a sensory scene,” outlines Dr Groh.

A range of different techniques are being applied on transgenic mice in this work, including electrophysiology, optogenetics and cell-type specific approaches. “Functions and dysfunctions of the brain rely on neuronal interactions, organized across several temporal and spatial scales, ranging from synaptic interactions to local and long-range interactions between networks. We face two challenges to understand these processes. First, we need to record from different parts of the brain while maintaining the temporal and spatial resolution to understand how single neurons integrate 40

signals from multiple upstream neurons and in turn feed into their downstream partner neurons,” explains Dr Groh. “In addition, we need to be able to probe the function of specific, embedded pathways in order to understand their role in cognitive processes.”

By using optogenetics, Dr Groh and his colleagues can activate specific circuits in the brain. “Optogenetics uses the expression of light sensitive membrane channels. As a result, you can control the activity in specific brain pathways of interest,” he says. These pathways can be either activated or inactivated while the brain is processing sensory information.

“As a functional read-out we mainly record fast electrical signals from neurons, and lately we’ve also been using deep-brain functional imaging techniques, both of which serve as a proxy for how neurons talk to each other,”

explains Dr Groh. “On the anatomical level, we use microscopy to see how neuronal circuits are physically wired to each other; In fact, this work started on the anatomical level, when Anton Sumser and I looked at the connections that are formed between a cortical area and its sub-cortical target structures.”

Cerebral cortex The mammalian cerebral cortex itself is comprised of six layers, each with a specific set of cell types with certain morphological, electro-physiological and connectivity characteristics. The deep cortical layers, layers 5 and 6, are the output layers of the cortex, which connect the cortex to other sub-cortical areas. “Layer 6 connects the cortex to the thalamus, while there is also a very interesting output pathway in layer 5.

Cortical whisker maps in the thalamus (Image provided by Anton Sumser).

EU Research

Emilio Isaias-Camacho and Dr. Jesus MartinCortecero, both in my team focus on the role of these two pathways in behaviour,” outlines Dr Groh. The cortex consists of many networks, which play a central role in sensory and motor functions. “We think of networks in terms of connected neurons. One helpful distinction is to differentiate between local networks and long-range networks,” continues Dr Groh.

“For example, these layer 5 output pathways are a good example of long-range interactions.

Some of these connections in humans go all the way from the cerebral cortex down to the spinal cord, where they control movements.”

Researchers aim to build a deeper picture of these connections and the interplay between the cortex and sub-cortical target networks.

An anatomical map has been developed in the project, looking at how the sensory cortex is connected to subcortical motor circuits, from which several potential targets with a motor function have been identified. These findings have been made on the anatomical level, now Dr Groh aims to investigate these pathways on the functional level. “Previous experiments, including from our own lab, showed that when the sensory cortex is stimulated, it actually evokes a motor movement in the mouse’s whiskers. This really shows that the sensory cortex has a motor function,” he outlines.

“The next important step is to understand this sensori-motor function on the cognitive level. We don’t believe that these circuits that involve the cortex control simple reflexes.”

the hypothesis that these sub-cortical areas are part of the salience network. Therefore, we joined the research consortium ‘SFB 1134’ in Heidelberg (http://sfb1134.uni-heidelberg. de/), in which around 20 labs focus on this one overarching question of the role of functional neuronal ensembles in brain function.”

Professor Groh’s team is part of another research consortium (SFB 1158, https://www. sfb1158.de/), which is focused on investigating the neuronal mechanisms of pain processing.

The team is looking at how these corticalthalamic interactions control how pain is transferred through the thalamus-cortical system. “This work is ongoing,” he says. Dr Groh and his colleagues are specifically interested in pathological pain, so when pain becomes a burden to the individual affected. “It’s widely thought that this is controlled through a central mechanism. The pain experience happens in the brain, and not in the periphery, where maybe the original incident happened,” he explains.

“It almost feeds on itself and then changes the networks in the central brain - we are trying to understand this. The thalamus is a key structure here, as pain signals have to pass through the thalamus before they reach the cortex and become an unpleasant experience.”

These signals become conscious (i.e. as feelings or experiences) in a process that is not understood. Further research in this area could yield more detailed information about the emergence of pain and how it is experienced, and even enable scientists to look at

We’ve been focusing on a specific cortical interaction with sub-cortical areas, the connection between the cortex and the thalamus. Now we want to extend this work to other sub-cortical areas.

Cognitive functions This strand of research centres around investigating how the brain detects or selects those signals which are important or salient at a particular point in time, which Dr Groh and his colleagues plan to model in mice. The mice will be presented with sensory stimuli, with differing levels of saliency. “While the mouse is doing a task, we want to see whether corticosubcortical networks are detecting salient events,” explains Dr Groh. These cognitive processes are thought to be quite complex, so Dr Groh says that neuronal ensembles, rather than single neurons, are thought to be involved. “Information is captured in the activity of groups of neurons that have spatial and temporal relationships, that are activated in a certain sequence for example,” he continues. “Together with Melina Castelanelli, a new member in my group, we are testing

www.euresearcher.com

suppressing pain signals in the thalamus. “This is something that Sailaja Antharvedi-Goda, a postdoc in my team is pursuing at the moment, with the potential of identifying targets for therapeutic strategies. For example, using cortical stimulation to suppress pain,” outlines Dr Groh. This research also holds relevance to our understanding of certain conditions in which sensory inputs are processed differently.

“For example, there are possible connections to attention deficit disorders and conditions in which subjective experience is pathologically altered, for example in schizophrenia or depression. We’re not specifically addressing this at the moment, as we don’t have a framework, a model of attention deficit disorder in mice,” continues Dr Groh. “The aim at the moment is to understand the basics, the function of it, before then looking to develop hypotheses of how these circuits behave in brain diseases.”

Neuronal mechanisms Neuronal mechanisms of cortico-subcortical communication in the mammalian brain Project Objectives

The cerebral cortex is viewed as the cognitive headquarter of the brain, accommodating specific cortical circuits for decision making, conscious perception and coordination of behavior. But how does the cortex communicate with the rest of the brain to fulfill these functions?

The proposed project investigates the structure and functional mechanisms underlying the interplay between the cortex and subcortical target networks by leveraging a combination of in vivo deep-brain electrophysiology, optogenetics, and cell-type-specific approaches in the mouse model system.

Project Funding

Funding: Deutsche Forschungsgemeinschaft (grants: SFB 1158-B10) and GR 3757_3-1

Contact Details

Project Coordinator, Professor Alexander Groh University Heidelberg Im Neuenheimer Feld 364 D-69120 Heidelberg, Germany T: +49 6221 54868 E: groh@uni-heidelberg.de W: https://www.researchgate.net/profile/ Alexander_Groh

2014 Staying focused: Cortico-thalamic pathway filters relevant sensory cues from perceptual input: 13 May 2014, by Stuart Mason Dambrot 2015 Thalamic Relay or Cortico-Thalamic Processing? Old Question, New Answers: Cereb.

Cortex-2015-Ahissar-845-8 2016a Corticothalamic Spike Transfer via the L5BPOm Pathway in vivo: Mease et al.

2017 Organization and somatotopy of corticothalamic projections from L5B in mouse barrel cortex: Sumser et al PNAS

Professor Alexander Groh

Alexander Groh is Professor of Neurophysiology at Heidelberg University’s Institute for Physiology and Pathophysiology. Previously, he was the Heisenberg Research Group Leader Institute for Anatomy and Cell Biology at Heidelberg, while he has held other research positions at institutions in Germany and the USA.

41