Longitudinal tracing of neurochemical metabolic disorders in working memory neural circuit and optogenetics modulation in rats with vascular cognitive impairment

Abstract

Objective: Chronic cerebral ischemia leads to vascular cognitive impairment (VCI) that exacerbates along with ischemia time and eventually develops into dementia. Recent advances in molecular neuroimaging contribute to understand its pathological characteristics. We previously traced the anisotropic diffusion of water molecules suggests that chronic cerebral ischemia leads to irreversible progressive damage to white matter integrity. However, the abnormalities of gray matter activity following chronic cerebral ischemia remains not entirely understood.Methods: In this study, in vivo hydrogen proton magnetic resonance spectroscopy (1H-MRS) was applied to longitudinally track the neurochemical metabolic disorder of gray matter associated with working memory, and optogenetics modulation of neurochemical metabolism was performed for targeted treatment of VCI. Results: The results showed that the concentration of N-acetylaspartate (NAA) in the right hippocampus, left hippocampus, right medial prefrontal cortex (mPFC) and mediodorsal thalamus was decreased as early as 7 days after chronic cerebral ischemia, subsequently gamma-aminobutyric acid (GABA) declined whereas myo-inositol (mI) and glutamate (Glu) increased at 14 days, as well as choline (Cho) lost at 28 days, concurrently the change of Glu and GABA in the mPFC and hippocampus was ischemia time-dependent manner within 1 month. Behaviorally, working memory and object recognition memory were impaired at 14 days, 28 days that significantly correlated with neurochemical metabolic disorders. Interestingly, using optogenetics modulation of PV neurons in the mPFC, the metabolic abnormalities of NAA and GABA in working memory neural circuit could be repaired after chronic cerebral ischemia, together with behavior improvements. Conclusions: These findings suggested that as early as 1~4 weeks after chronic cerebral ischemia, the metabolism of NAA, Glu, mI and Cho was synchronously impaired in neural circuit of hippocampus-mediodorsal thalamus-mPFC, and the loss of GABA delayed in the hippocampus, and optogenetics modulation of parvalbumin (PV) neurons in the mPFC can improve the neurochemical metabolism of working memory neural circuit and enhance working memory.

Research hotspots and trends of multimodality MRI on vascular cognitive impairment in recent 12 years: A bibliometric analysis

“…In recent years, studies have increasingly used DTI, MRS, and other imaging techniques to detect the neurovascular pathology of VCI and participate in targeted therapy. [45] Over the past 2 years, it has become a global trend to explore the factors that influence cognitive decline to identify the disease as early as possible, and timely prevention has been a frontier topic of research in recent years.…”

“…[44] A previous study utilized MRS to longitudinally track neurochemical metabolic disorders of gray matter associated with working memory and to regulate neurochemical metabolism by optogenetics for targeted treatment of VCI induced by chronic cerebral ischemia. [45] The hotspots study focuses on exploring the neuropathological changes of VCI by fMRI, DTI, ASL, and MRS. A large number of clinical or experimental studies have been carried out for the early detection, prevention and treatment of diseases to provide convincing imaging evidence.…”

Effect and Mechanism of Yisui Fuyongtang (YSFYT) Decoction on Cognitive Function and Synaptic Plasticity in Rats with Vascular Cognitive Impairment

“…As VCI has a short life expectancy, it impairs the social function and even motor function of the patient after onset, resulting in an apparent decline in quality of life for patients. It is therefore that this disease has gained increasing attention in recent years [25]. For VCI research, one prerequisite is to construct an animal model that is consistent with the disease, through which the pathogenesis, pathological changes, and how to effectively intervene early VCI can be investigated.…”