For many years, modulators of the renin angiotensin system (RAS) have been trusted by clinicians for the control of essential hypertension. It was recently demonstrated that these modulators have other pleiotropic properties independent of their hypotensive effects, such as enhancement of cognition. Within the brain, different components of the RAS have been extensively studied in the context of neuroprotection and cognition. Interestingly, a crosstalk between the RAS and other systems such as cholinergic, dopaminergic and adrenergic systems have been demonstrated. In this review, the preclinical and clinical evidence for the impact of RAS modulators on cognitive impairment of multiple etiologies will be discussed. In addition, the expression and function of different receptor subtypes within the RAS such as: Angiotensin II type I receptor (AT1R), Angiotensin II type II receptor (AT2R), Angiotensin IV receptor (AT4R), Mas receptor (MasR), and Mas-related-G protein-coupled receptor (MrgD), on different cell types within the brain will be presented. We aim to direct the attention of the scientific community to the plethora of evidence on the importance of the RAS on cognition and to the different disease conditions in which these agents can be beneficial.

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Introduction: Unfortunately, over 40% of stroke victims have pre-existing diabetes which not only increases their risk of stroke up to 2-6 fold, but also worsens both functional recovery and the severity of cognitive impairment. Our lab has recently linked the chronic inflammation in diabetes to poor functional outcomes and exacerbated cognitive impairment, also known as post-stroke cognitive impairment (PSCI). Although we have shown that the development of PSCI in diabetes is associated with the upregulation and the activation of pro-inflammatory microglia, we have not established direct causation between the two. To this end, we evaluated the role of microglia in the development of PSCI.Methods: At 13 weeks of age, diabetic animals received bilateral intracerebroventricular (ICV) injections of short hairpin RNA (shRNA) lentiviral particles targeting the colony stimulating factor 1 receptor (CSF1R). After 14 days, animals were subjected to 60 min middle cerebral artery occlusion (MCAO) or sham surgery. Adhesive removal task (ART), novel object recognition (NOR), and 2-trial Y-maze were utilized to evaluate sensorimotor and cognitive function. Tissue from freshly harvested brains was analyzed by flow cytometry and immunohistochemistry.Results: CSF1R silencing resulted in a 94% knockdown of residential microglia to relieve inflammation and improve myelination of white matter in the brain. This prevented cognitive decline in diabetic animals. Conclusion: Microglial activation after stroke in diabetes may be causally related to the development of delayed neurodegeneration and PSCI.

Functional electrical stimulation (FES) is rapidly gaining traction as a therapeutic tool for mediating the repair and recovery of the injured central nervous system (CNS). However, the underlying mechanisms and impact of these stimulation paradigms at a molecular, cellular and network level remain largely unknown. In this study, we used embryonic stem cell (ESC)-derived neuron and glial co-cultures to investigate network maturation following acute administration of L-glutamate, which is a known mediator of excitotoxicity following CNS injury. We then modulated network maturation using chronic low frequency stimulation (LFS) and direct current stimulation (DCS) protocols. We demonstrated that L-glutamate impaired the rate of maturation of ESC-derived neurons and glia immediately and over a week following acute treatment. The administration of chronic LFS and DCS protocols individually following L-glutamate infusion significantly promoted the excitability of neurons as well as network synchrony, while the combination of LFS/DCS did not. qRT-PCR analysis revealed that LFS and DCS alone significantly up-regulated the expression of excitability and plasticity-related transcripts encoding N-methyl-D-aspartate (NMDA) receptor subunit (NR2A), brain-derived neurotrophic factor (BDNF) and Ras-related protein (RAB3A). In contrast, the simultaneous administration of LFS/DCS down-regulated BDNF and RAB3A expression. Our results demonstrate that LFS and DCS stimulation can modulate network maturation excitability and synchrony following the acute administration of an inhibitory dose of L-glutamate, and upregulate NR2A, BDNF and RAB3A gene expression. Our study also provides a novel framework for investigating the effects of electrical stimulation on neuronal responses and network formation and repair after traumatic brain injury.

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Functional electrical stimulation (FES) is rapidly gaining traction as a therapeutic tool for mediating the repair and recovery of the injured central nervous system (CNS). However, the underlying mechanisms and impact of these stimulation paradigms at a molecular, cellular and network level remain largely unknown. In this study, we used embryonic stem cell (ESC)-derived neuron and glial cocultures to investigate network maturation following acute administration of Lglutamate, which is a known mediator of excitotoxicity following CNS injury. We then modulated network maturation using chronic low frequency stimulation (LFS) and direct current stimulation (DCS) protocols. We demonstrated that L-glutamate impaired the rate of maturation of ESC-derived neurons and glia immediately and over a week following acute treatment. The administration of chronic LFS and DCS protocols individually following L-glutamate infusion significantly promoted the excitability of neurons as well as network synchrony, while the combination of LFS/DCS did not. qRT-PCR analysis revealed that LFS and DCS alone significantly up-regulated the expression of excitability and plasticity-related transcripts encoding N-methyl-D-aspartate (NMDA) receptor subunit (NR2A), brain-derived neurotrophic factor (BDNF) and Ras-related protein (RAB3A). In contrast, the simultaneous administration of LFS/DCS down-regulated BDNF and RAB3A expression. Our results demonstrate that LFS and DCS stimulation can modulate network maturation excitability and synchrony following the acute administration of an inhibitory dose of L-glutamate, as well as an upregulation of NR2A, BDNF and RAB3A gene expression. Our study also provides a novel framework for investigating the effects of electrical stimulation on neuronal responses and network formation/repair after traumatic brain injury.

Unfortunately, over 40% of stroke victims have pre-existing diabetes which not only increases their risk of stroke up to 2-6 fold, but also worsens both functional recovery and the severity of cognitive impairment. Our lab has recently linked the chronic inflammation that persists in diabetic animals to their poor functional outcomes and exacerbated cognitive impairment, also known as post-stroke cognitive impairment (PSCI). Although we have shown that the development of PSCI in diabetes is associated with the upregulation and activation of pro-inflammatory microglia, we have not established a direct causation between the two. We tested the hypothesis that microglia depletion in the post-stroke recovery period prevents sustained inflammation and attenuates PSCI in diabetes. Methods: Diabetes was induced by a high fat diet (HFD) and low dose streptozotocin (STZ) combination. At 13 weeks of age, diabetic animals received bilateral intracerebroventricular (ICV) injections of short hairpin RNA (shRNA) lentiviral particles targeted at the colony stimulating factor 1 receptor (CSF1R), a key factor for microglia survival. After 14 days, animals were subjected to 60 min middle cerebral artery occlusion (MCAO) or sham surgery. Novel object recognition (NOR), and 2-trial Y-maze were utilized to evaluate cognitive function. Brains were analyzed by flow cytometry (B-D slice containing the prefrontal cortex through the hippocampus) and immunohistochemistry (B slice) 3 weeks post-MCAO. Results: CSF1R silencing resulted in a drastic 94% knockdown of residential microglia to relieve inflammation and decrease the macrophage infiltration by 74%. This also led to improved myelination of white matter in the brain and improved cognition in diabetic animals. Conclusion: Neuroinflammation, through microglial and macrophage polarization, is largely responsible for the development of PSCI in diabetes.

Angiotensin signaling is known to be sexually dimorphic and although a well‐studied target for intervention in stroke and cognitive impairment in males, studies in females are rare. With females suffering a disproportionately greater negative impact of stroke and dementia vs. males, effective interventions are of utmost urgency. The aim of the current study was to determine the impact of stimulation of the angiotensin receptor subtype 2 (AT2R) with compound 21 (C21) on the development of post‐stroke cognitive impairment after experimental ischemic stroke. Ovariectomized (OVX), spontaneously hypertensive rats (SHRs) were subjected to 1 hour of middle cerebral artery occlusion (MCAO) using the suture model. At 24 hours, rats with a significant neurologic deficit were randomized to receive either saline or C21 (0.03 mg/kg/day) intraperitoneally (IP) for 5 days, then orally (0.12 mg/kg/day) for a total of 6 weeks. In a separate cohort of female SHRs, mean arterial pressure (MAP) was monitored continuously using telemetry units (Data Sciences International, St. Paul, MN). Rats were then randomized to the following treatment groups: low dose C21 (0.216 mg/kg/day, SC, Alzet Pump, Cupertino, CA), high dose C21 (0.432 mg/kg/day, SC), or surgical sham control. MAP was monitored for an additional 2 weeks. Outcomes measured were sensorimotor and cognitive function, brain structure by MRI and vascular architecture by microCT Angiography. Compound 21 preserved cognitive function, specifically spatial memory, without a significant effect on sensorimotor function or infarct size as measured by MRI. Interestingly, animals treated with C21 had a 2‐fold increase in vascular density in the ischemic hemisphere at 6 weeks, reflecting both arteriogenesis and angiogenesis. Neither low nor high dose C21 affected MAP. In conclusion, C21 prevented cognitive impairment after stroke independent of changes in MAP, likely through a mechanism involving vascular protection and restoration. Support or Funding Information R01NS104573 to AE and SCF. Jowdy Professorship to SCF Data are mean ± SEM Saline C21 MAP (mmHg) 128±2 Low dose: 136±54# High Dose: 134±4# Bederson at Randomization 2.9 ± 0.4 2.5 ± 0.42# Bederson at 6 weeks 5 ± 0.33 N=10 5.87 ± 0.47 N =8# Infarct Size by MRI (% contralateral side) 18.74 ±1.82 N=6 14.76 ± 4.16 N=5# Sham Stroked Saline C21 Saline C21 Passive Avoidance (Latency in seconds) 276 ± 8.9, N=5 286.3 ± 3.8, N=4 91.83 ± 50.14, N=6 279 ± 5.8a, N=5 Object Placement Test (% time with moved object) 55.06 ± 4.0 N=9 45.27 ± 4.0 N=8 41.77 ± 3.72 N=10 71.6 ± 6.9a N8 MicroCT Angiography Vessel Volume/Total Volume 0.45 ± 0.08 N=4 0.51 ± 0.07 N=4 0.29 ± 0.06 N=4 0.81 ± 0.09a N=3 Vessel Number 0.04±0.007 0.04 ± 0.006 0.03 ± 0.007 0.08 ± 0.011a Vessel Thickness 0.1002± 0.007 0.1101± 0.007 0.0902± 0.007 0.0948± 0.011# Vessel Separation 1.59± 0.03 1.48 ± 0.16 1.91± 0.14 1.37± 0.12b#p>0.05 vs saline,apost‐hoc Bonferoni p< 0.01 vs stroke saline,bpost‐hoc Bonferoni p<0.05 vs stroke saline.