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Specificity of cortico-thalamic interactions and its role in frontal cortical functions

Periodic Reporting for period 2 - FRONTHAL (Specificity of cortico-thalamic interactions and its role in frontal cortical functions)

Reporting period: 2019-03-01 to 2020-08-31

The human cerebral cortex represents the pinnacle of complexity attainable in a living organisms. With its 20 billion neurons and astronomical numbers of connections the human cortex is able to solve the highest level of computations required for human actions, imaginations, creativity or memory. Its damage due to neurological, psychiatric or traumatic causes are detrimental and places huge burden to the society and economy. One critical factor, however is forgotten all too often about the functioning of the cerebral cortex. With the exception of primary olfactory information, the cortex is almost entirely isolated from fast, precise information streams arising from the outside world and from the rest of the brain. No fast visual, tactile, auditory, emotional, salient, movement, arousal, sleep related or any other type of information directly reaches its neurons. In contrast, its entrance hall, a deep brain structure called thalamus has it all. As a consequence of an ancient organization principle, which arose in the most primitive vertebrates, almost all fast information dedicated to reach the cortex is first screened in the thalamus. Even the feed-back information from effector centers, which act upon the cortical instruction can reenter the cortex only via the thalamus.
Novel data clarified that thalamus is not really a simple entrance hall. You usually visit the entrance hall only once before you propagate to the rest of the rooms (i.e to the cortex). Thalamus, however, has doors to all rooms in the flat (beside the entrance) and information travel not only from the entrance to the rooms but also in the reverse direction with similar effectivity. In short, the thalamus and the cortex have a complex, perpetual two way communication and, by now, it became clear this two-way communication is absolutely necessary for all cortical functioning. As a direct consequence, the causes of malfunctioning of the human cortex is not really reside in the cortex but in the problem of communication between thalamus and cortex. So e.g. epilepsy is not the aberrant activity of cortex, but that of the so-called “thalamo-cortical loops”, symptoms of the Parkinson’s disease and schizophrenia arise from miscommunication between these two structures, not from an intracortical problems, the case is similar in chronic pain, tinnitus and so, and so on. The main problem is that details of the communication between cortex and thalamus, despite its clear importance in health and disease, is one of the least studied field in neuroscience. Why?
For historical reasons, still not entirely clear, the thalamus has been largely misunderstood in the first 100 year of neuroscience. It was simply regarded as a sensory entrance hall. Even now most textbooks relegate the function of thalamus to transfer primary sensory information to the cortex. According to this scheme, the role of thalamus ends by passing the sensory information to the cortex. All subsequent steps of information processing, which will result in complex behavior, memory formation, decision making, etc. depends on the interaction between different parts of the cortex, thalamus has no role in it. As a direct consequence, the complexity of interactions between cortex and thalamus has been largely neglected. The major aim of the present project is to fill this gap and study the complexity and specificity of interactions between cortex and thalamus.
What is our research question? Cortex consists of many different regions dedicated to different tasks. Some regions work with visual inputs others with somatosensory information or the integration of vision and touch (e.g. when we look at and grasp something). Large cortical areas are dedicated to motor control, planning, decision making or remembering past events. An influential theory on brain function considers cortex a modular structure. I.e. it consists of the multiplication of modules or building blocks (neuronal circuits) with similar internal logic. According to this theory, connectivity between cortex and thalamus is similar across the various regions of cortex and thalamus. We think otherwise. In this project we propose that the logic of various cortical modules are tuned according to their function. Extraction of information needed to perceive a flash of light or planning a complex movement requires different hardware and computation. Accordingly, communication between cortex and thalamus is region specific and tailored to the specific function the thalamocortical circuit performs and we’d like to know its details.
Why is it important? If communication between cortex and thalamus is homogeneous across the various regions, it is not possible to interfere specifically with these circuits in case of focal pathological activity since it will affect all circuits. If there are unique features in the different circuits there is a hope for a special treatment. Aside from specific drug treatments, which are still in the distant future, modern neurological treatments frequently targets thalamus for deep brain stimulation or focal lesions to treat given pathological symptoms (e.g. seizures, tremors, pain etc). Needless to say that rational planning of these intervention requires the understanding of the internal logic of the structure. Our hope is that finding the specificity in thalamo-cortical circuits will provide us with clues for specific treatments. As an example, in a subproject we focus on a specific thalamic cell population, which is known to be involved in arousal, thus may be involved in sleep disturbances. Sleep problems are one of the most prevalent, but all too often overlooked class of brain disease which can have serious negative consequences on mental, psychological and bodily functions.
Can details of functional connectivity between cortex and thalamus studied in the human brain? No. Thus, we need to use mouse models in which specific regions or cell types can be selectively studied, the effect of their activation, inactivation on the activity of other neurons or on the behavior can be investigated. Fortunately, some of the basic organizational principles in thalamocortical system is similar across mammalian species. Still our laboratory places great emphasis on studying to what extent mouse data are applicable to the human. We have the opportunity to investigate postmortem human thalami and can label its different cell types and inputs. If we find a specific circuit in the mouse and can reveal its function with the most up to date physiological and molecular methods we can also check whether the same circuit exists in the human brain. If the ‘hardware’ is similar between the two species, we may assume that they serve similar function. As an example, we recently published (Matyas et al., 2018 Nature Neuroscience) that the thalamic cell population which mediate forebrain arousal and the specificity of its inputs are similar in mouse and man.
Finally, a critical component of our brain is the adaptability to changing conditions, in other words plasticity or learning both during development and in the adulthood. This phenomenon has been extensively studied in cortical circuits but it is much less is known to what extent thalamus is involved in plastic changes in the brain. The final aim of our project is dedicated to identify the structural and functional consequences of learning in the thalamocortical circuits.
In summary we hope that our project will shed new light on the understanding the specificity of interaction between thalamus and cortex which will bring us closer to decipher the principles of human cognition and helps to devise rational interventions to this circuit in pathological conditions.
1) We demonstrated region selective cortical projections from the layer 5 pyramidal cells to the thalamus. Comparison of parietal and frontal cortices revealed distinct organization and physiology of the L5 terminals in different thalamic nuclei.
2) We demonstrated selective and topographic layer 5 innervation of the anterior sector of thalamic reticular nucleus (TRN, the main inhibitory interface of thalamus) from the frontal cortices. Using an optogenetic approach, we demonstrated that L5 of the frontal cortex has very strong, graded impact on TRN cells and controls the synchrony between cortical and thalamic activity.
3) We established and validated a novel motor learning paradigm which will allow to test the plasticity of thalamocortical circuits.
4) We characterized a functionally and neurochemically distinct thalamic neuron population and demonstrated its role in arousal.
5) We mapped the anterior part of the human thalamus using five functionally relevant immunocytochemical markers and revealed a nuclear organization different from the accepted schemes.
1) We progressed beyond the well-accepted view of modular thalamocortical organization and demonstrated that region- and cell-type specific communication characterize the interaction between cortex and thalamus. By the end of the project the functional importance and the neuronal implementation of this paradigm will be revealed.
2) We are developing behavioral tests which are based on the spontaneous behavior of the animals. By the end of the project these will be widely used as described in our Specific Aims.
3) We invented a novel mapping method based on an image analysis approach used in geostatistics. This method allows observer independent segmentation and mapping. By the end of the project, it will be put in a widespread use and a systematic map of the anterior human thalamus will be provided based on data from several individuals.
4) We develop a deep learning based video analysis method to generate a precise movement detection algorithm which allows us to define behavioral states. By the end of the project we expect to be able to segment sleep related behaviors automatically.