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

Projektinformationen

FRONTHAL

ID Finanzhilfevereinbarung: 742595

DOI

10.3030/742595

Projekt abgeschlossen

EK-Unterschriftsdatum 11 August 2017

Startdatum 1 September 2017

Enddatum 31 Mai 2023

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 1 597 575,00

EU-Beitrag

€ 1 597 575,00

Koordiniert durch

HUN-REN KISERLETI ORVOSTUDOMANYI KUTATOINTEZET
Hungary

Periodic Reporting for period 4 - FRONTHAL (Specificity of cortico-thalamic interactions and its role in frontal cortical functions)

Berichtszeitraum: 2022-03-01 bis 2023-05-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Thalamus is a brain structure located in the center of the brain in every vertebrate animal including humans. Except for the primary olfactory information thalamus provides almost all spatially and temporally coordinated, fast nerve signals to the cerebral cortex. In other words, no sensory, emotional, movement, arousal, stress or sleep related information directly reach cortical neurons without a thalamic transfer. The cortex is isolated from the environment and rest of the brain without thalamic inputs.
Thalamus project to and receives information from all parts of the cortex. Cortical regions have different functions. Distinct regions are specialized to vision, audition, motor functions, planning, forming memories or personal traits. Despite this heterogeneity the structure of cortical regions is quite homogeneous. As a consequence it is implicitly assumed that the nature of communication between cortical regions and thalamus is also homogeneous. Thus, the first major objective of the project is to study how cortical regions specialized to different functions communicate with the thalamus.
In the second part of the project, we address how stress can have lasting consequences on cortical activity and behavior and what role thalamus can play in this project. In this part of the project we focused on a specific thalamic nucleus called paraventricular thalamic nucleus, PVT in short. We examined what role this nucleus play in normal arousal when we wake up from sleep and what role it plays after a stressful situation when behavior can persistently changes.
Finally, 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. Thus the third major objective is to compare the organization of human and rodent thalamus.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

1) We demonstrated region selective cortical projections from the layer 5 pyramidal cells to the thalamus. The activity of layer 5 pyramidal cells represents the final cortical output to the rest of the brain. Comparison of parietal and frontal cortices, responsible for sensory and motor functions, respectively, revealed distinct organization and physiology of the L5 terminals in different thalamic nuclei.
2) We demonstrated selective and topographic layer 5 (L5) 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 have demonstrated that frontal L5 target a specialized neuronal compartment in the thalamus called spines. Properties of these structures were similar between cortex and thalamus. Since spines are the neuronal substrate of plasticity of the cortex our data point to an intriguing hypothesis that cortico-thalamic communication can display region specific plasticity and can be involved in learning and neurological alterations linked, specifically to frontal cortex.
4) We characterized a functionally and neurochemically distinct thalamic neuron population and demonstrated its role in arousal.
5) We have shown that same thalamic cell population that has a crucial role in normal arousal persistently change its activity following a stressful situation. This alteration of neuronal activity is causally involved in establishing the maladaptive behavioral phenotype.
6) In relation to out mouse cortico-thalamic studies we have quantitatively mapped the cortical and subcortical excitatory inputs in the anterior part of the human thalamus which receives inputs from the frontal cortex. The resulting functionally relevant map of the human thalamus can be used for rational mapping for intrathalamic deep brain surgery.
7) We invented a novel image segmentation method based on an image analysis approach used in geostatistics. This method allows observer independent segmentation and mapping of any type of image.
man thalamus using five functionally relevant immunocytochemical markers and revealed a nuclear organization different from the accepted schemes.

The results of the project have been published in neuroscience journals of high visibility, disseminated in neuroscience meetings and as book chapters. The results were publicized in internet forums and media and is available on online archives.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

1) L5 innervation of TRN and thalamic spines can regarded as breakthroughs in thalamocortical communications. These observations significantly alter, how we view cortical signal processing in the thalamus. Regional specificity of the L5-TRN connection indicate that both normal pathological activities linked to frontal cortical regions are manifested in a different hardware.

2) L5 innervation of thalamic spines by frontal cortical afferents can significantly alter our view of the communication between cortex and thalamus. Plasticity of neuronal communication is inherently linked to dendritic spines in every region of the brain studied so far. Due to their shape, spines are biophysical and biochemical compartments that allow plastic alterations of synaptic strength during learning. Plasticity in cortico-thalamic communication, however, has never been described, synaptic contacts on spines were also unknown. Our novel data showing a highly specialized contact from L5 neurons to thalamic spines will certainly change this scenario. These data will allow us to test that during learning or pathological activity to what extent plasticity involves the cortico-thalamic pathway.

3) The highly specialized role of paraventricular thalamus (PVT) in normal and abnormal arousal can be logically linked but was unexpected. It can alter how we see the aetiology of post traumatic disorders and their treatment.
Alteration of firing rates in the PVT lasting for several days after a single exposure to the stressful event is completely novel. In the nervous system firing rates of individual neurons are believed to be maintained by a cell-autonomous form of homeostatic plasticity (called “synaptic scaling”). To our knowledge so prolonged change in neuronal activity has not been described in the brain. This certainly shows that PVT/CR+ neurons have a hitherto unrecognized type of plasticity that allows them to adjust their long term behavior for the current state of the animal.
Brief inhibition of PVT cells after the stress was able to correct the long term change in PVT neuronal activity, as well as the the alteration in stress induced behavior. It strengthens the view that PVT/CR+ neurons possess a novel form of long term plasticity but also demonstrates the critical role of these neurons in establishing the stressed phenotype. Finally, it points to a window of opportunity to interact with the system for therapeutic purposes.

4) The comprehensive quantitative map of excitatory inputs in the anterior human thalamus significanlty alters how we view tha function and malfunction of the human thalamus. The data indicated that the nuclear organization of motor thalamus, involved in Parkinson's disease and essential tremor differs from tha accepted view and that thalamic computation of afferent inputs have nucleus specific components.

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