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Fiberoptic hemodynamic spectroscopy reveals abnormal cerebrovascular reactivity in a freely moving mouse model of Alzheimer's disease.

ABSTRACT: Many Alzheimer's disease (AD) patients suffer from altered cerebral blood flow and damaged cerebral vasculature. Cerebrovascular dysfunction could play an important role in this disease. However, the mechanism underlying a vascular contribution in AD is still unclear. Cerebrovascular reactivity (CVR) is a critical mechanism that maintains cerebral blood flow and brain homeostasis. Most current methods to analyze CVR require anesthesia which is known to hamper the investigation of molecular mechanisms underlying CVR. We therefore combined spectroscopy, spectral analysis software, and an implantable device to measure cerebral blood volume fraction (CBVF) and oxygen saturation (S_O2) in unanesthetized, freely-moving mice. Then, we analyzed basal CBVF and S_O2, and CVR of 5-month-old C57BL/6 mice during hypercapnia as well as during basic behavior such as grooming, walking and running. Moreover, we analyzed the CVR of freely-moving AD mice and their wildtype (WT) littermates during hypercapnia and could find impaired CVR in AD mice compared to WT littermates. Our results suggest that this optomechanical approach to reproducibly getting light into the brain enabled us to successfully measure CVR in unanesthetized freely-moving mice and to find impaired CVR in a mouse model of AD.

SUBMITTER: Gareau DS

PROVIDER: S-EPMC10350529 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Fiberoptic hemodynamic spectroscopy reveals abnormal cerebrovascular reactivity in a freely moving mouse model of Alzheimer's disease.

Gareau Daniel S DS RochaKim Nicholas N Choudhury Arnab A Bamkole Michael M Snuderl Matija M Zou Julia J Yaroslavsky Anna A Jacques Steven L SL Strickland Sidney S Krueger James G JG Ahn Hyung Jin HJ

Frontiers in molecular neuroscience 20230703

Many Alzheimer's disease (AD) patients suffer from altered cerebral blood flow and damaged cerebral vasculature. Cerebrovascular dysfunction could play an important role in this disease. However, the mechanism underlying a vascular contribution in AD is still unclear. Cerebrovascular reactivity (CVR) is a critical mechanism that maintains cerebral blood flow and brain homeostasis. Most current methods to analyze CVR require anesthesia which is known to hamper the investigation of molecular mecha ...[more]

PMID: 37465366

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Project description:The cerebral vascular network regulates blood flow distribution by adjusting vessel diameters, and consequently resistance to flow, in response to metabolic demands (neurovascular coupling) and changes in perfusion pressure (autoregulation). Deliberate changes in carbon dioxide (CO2) partial pressure may be used to challenge this regulation and assess its performance since CO2 also acts to change vessel diameter. Cerebrovascular reactivity (CVR), the ratio of cerebral blood flow (CBF) response to CO2 stimulus is currently used as a performance metric. However, the ability of CVR to reflect the responsiveness of a particular vascular region is confounded by that region's inclusion in the cerebral vascular network, where all regions respond to the global CO2 stimulus. Consequently, local CBF responses reflect not only changes in the local vascular resistance but also the effect of changes in local perfusion pressure resulting from redistribution of flow within the network. As a result, the CBF responses to CO2 take on various non-linear patterns that are not well-described by straight lines. We propose a method using a simple model to convert these CBF response patterns to the pattern of resistance responses that underlie them. The model, which has been used previously to explain the steal phenomenon, consists of two vascular branches in parallel fed by a major artery with a fixed resistance unchanging with CO2. One branch has a reference resistance with a sigmoidal response to CO2, representative of a voxel with a robust response. The other branch has a CBF equal to the measured CBF response to CO2 of any voxel under examination. Using the model to calculate resistance response patterns of the examined branch showed sigmoidal patterns of resistance response, regardless of the measured CBF response patterns. The sigmoid parameters of the resistance response pattern of examined voxels may be mapped to their anatomical location. We show an example for a healthy subject and for a patient with steno-occlusive disease to illustrate. We suggest that these maps provide physiological insight into the regulation of CBF distribution.

Project description:The entopeduncular nucleus (EPN) is often termed as one of the output nuclei of the basal ganglia owing to their highly convergent anatomy. The rodent EPN has been implicated in reward and value coding whereas the primate analog internal Globus Pallidus has been found to be modulated by some movements and in some circumstances. In this study, we sought to understand how the rodent EPN might be coding kinematic, reward, and difficulty parameters, particularly during locomotion. Furthermore, we aimed to understand the level of movement representation: whole-body or specific body parts. To this end, mice were trained in a freely moving two-alternative forced choice task with two periods of displacement (return and go trajectories) and performed electrophysiological recordings together with video-based tracking. We found (1) robust reward coding but not difficulty. (2) Spatio-temporal variables better explain EPN activity during movement compared to kinematic variables, while both types of variables were more robustly represented in reward-related movement. (3) Reward-sensitive units encode kinematics similarly to reward-insensitive ones. (4) Population dynamics that best account for differences between these two periods of movement can be explained by allocentric references like distance to reward port. (5) The representation of paw and licks is not mutually exclusive, discarding a somatotopic muscle-level representation of movement in the EPN. Our data suggest that EPN activity represents movements and reward in a complex way: highly multiplexed, influenced by the objective of the displacement, where trajectories that lead to reward better represent spatial and kinematic variables. Interestingly, there are intertwining representations of whole-body movement kinematics with a single paw and licking variables. Further, reward-sensitive units encode kinematics similarly to reward-insensitive ones, challenging the notion of distinct pathways for reward and movement processing.

Dataset Information

Fiberoptic hemodynamic spectroscopy reveals abnormal cerebrovascular reactivity in a freely moving mouse model of Alzheimer's disease.

Publications

Fiberoptic hemodynamic spectroscopy reveals abnormal cerebrovascular reactivity in a freely moving mouse model of Alzheimer's disease.

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