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Immunological mechanisms of post-stroke dysfunction and recovery of neurovascular coupling

Periodic Reporting for period 1 - VasoRecovery (Immunological mechanisms of post-stroke dysfunction and recovery of neurovascular coupling)

Reporting period: 2020-05-01 to 2022-04-30

Ischemic stroke is one of the most common causes of disability and death in the EU. Improvements in the treatment and prevention of ischemic stroke have reduced this burden, but consequently, patients living with chronic post-stroke conditions are increasing in number. Addressing this emergent public health problem will require novel rehabilitation interventions at the clinical level. Recovery after stroke correlates closely with cerebral vascular function, such that patients with dysfunction of vascular reactivity exhibit significant functional impairment. On the other side, inflammation in autoimmune and infectious diseases has been demonstrated to also result in dysfunction of cerebral blood flow regulation. However, a potential mechanistic link between the post-stroke inflammatory response and chronically impaired vascular dysfunction after stroke has yet not been studied in detail. Therefore, the goal of this project is to identify the impact of cerebral, neuroinflammatory, and systemic innate immune responses to vascular dysfunction after experimental stroke.

The key objective of my project is to determine mechanistic relationship between specific inflammatory cascades, functional connectivity, and neurovascular impairment in the post-stroke brain. To understand long-term alterations in these fine regulatory processes we developed a novel imaging system. This enabled us to longitudinally follow brain-wise functional changes at high spatial resolution. Using this system, we evaluated how manipulation of local neuroinflammatory, and peripheral immune responses influence functional recovery after stroke.
The overall objective of my project was to identify the impact of cerebral neuroinflammatory and systemic immune responses to functional recovery after experimental stroke. To answer this question, I developed three objectives:

Objective 1: to establish a multimodal imaging system for assessing neurovascular function after stroke.
The main results of the first objective are: a) resting state neurovascular coupling (NVC) functions and brain network plasticity can be reliably tracked at a mesoscale level with an optical multimodal imaging system that I developed during this project. b) Focal ischemic stroke has a quantifiable impact both on the functional connectivity and on the NVC.

Objective 2: to determine the role of neuroinflammation in vascular dysfunction and post-stroke recovery.
The main results of the second objective are: a) there is persistent chronic neuroinflammation in the stroke-affected hemisphere and b) microglia have a sizeable impact on the dynamics of the functional recovery with relatively diverse temporal prominence.

Objective 3: to identify the role of peripheral inflammation in vascular dysfunctions and recovery after stroke.
The main result of the third objective is: Mature B and T cells are crucial accelerators for late-phase regenerative progression in the stroke-affected brain.

To sum it up, I have developed a novel non-invasive multimodal imaging system that assists longitudinal characterization of neurovascular functions and neuronal network activity on the mesoscale level. Utilizing this system, we were able to study prolonged functional impairments after focal ischemic stroke in Thy1GCamp6s reporter mice. We revealed that the inflammatory milieu persists months after the initial damage in the cerebral cortex. Manipulating either the activity or the presence of microglia in the brain have a substantial impact on the post-stroke functional recovery in the chronic phase. While suppression of systemic adaptive immune cascade, by using a lymphocyte deficient line, hindered sub-chronic recovery.

Exploitation and dissemination of the results:
1) The results of this project will be published in a peer-reviewed journal as an original research article, while the methodologies detailing technical novelties will be published separately. Importantly the longitudinal characterization of neuronal network connectivity and neurovascular coupling function in the stroke-impaired cortex can be used in future stroke studies as a reference for monitoring brain damage and functional recovery. On a wider scale, it can be exploited to establish standardized functional readouts in experimental stroke research.

2) I have been very active in disseminating my prepublication results to the scientific community in a form of posters, oral presentations, and flash talks at international and European neuroscience conferences (Stroke Immunology, Brain, BNAS, etc.) despite their scarcity in the recent years. These occasions not only have drastically expanded my network and increased the visibility of my research in my field but also raised a great interest in researchers to the novel techniques I developed.

3) The interdisciplinary work conducted during this project fostered new collaborative opportunities within the framework of the Cluster of Excellence SyNergy and ImmunoStroke Consortia. The scope of these new projects expands beyond the field of experimental stroke research giving me the chance to investigate vascular pathology in other brain disease models.
The development of the imaging tool helped me to deepen my expertise in computer vision, data analysis, data visualization, and software engineering. Computational neuroscience is an ever-growing, cutting-edge, new branch in life sciences. Acquiring competent knowledge in this field is a very competitive skill set for an academic researcher and places me at the pinnacle of young scientist.

In the near future, the utility of the novel imaging setup can be expanded and deployed in new projects, increasing the versatility of the host research group and strengthening collaborative workflow within the SyNergy and the ImmunoStroke Consortia. In the long term, similar imaging setups can be assembled and distributed among wider European Research Groups eager to pursue mesoscale brain network activity and vascular physiology.

Findings resulting from limiting neuroinflammatory and peripheral immune responses highlight the significance of sterile inflammation in post-stroke functional recovery. It will promote new research to better understand the role of specific inflammatory cascades in these processes in order to develop therapeutics aiding stroke recovery and rehabilitation.
Overview of the novel multimodal imaging tools and the impact of focal ischemic stroke on the NVC