Neuropsychological Deficits Chronically Developed after Focal Ischemic Stroke and Beneficial Effects of Pharmacological Hypothermia in the Mouse

• Published in: Aging and disease Vol. 11; no. 1; pp. 1 - 16
• Main Authors: Zhong, Weiwei, Yuan, Yan, Gu, Xiaohuan, Kim, Samuel In-Young, Chin, Ryan, Loye, Modupe, Dix, Thomas A, Wei, Ling, Yu, Shan Ping
• Format: Journal Article
• Language: English
• Published: United States JKL International 01.02.2020; JKL International LLC
• Subjects: Analysis; Antianxiety agents; Depression (Mood disorder); Disabilities; EDTA; Hypothermia; Ischemia; Medical research; Mental disorders; Neurons; Neuropeptides; Neurotensin; Orginal; Phenols (Class of compounds); Psychological research; Stroke patients; post-stroke depression (PSD); oxytocin; BDNF; stroke; pharmacological hypothermia
• ISSN: 2152-5250; 2152-5250
• DOI: 10.14336/AD.2019.0507

Stroke is a leading cause of human death and disability, with around 30% of stroke patients develop neuropsychological/neuropsychiatric symptoms, such as post-stroke depression (PSD). Basic and translational research on post-stroke psychological disorders is limited. In a focal ischemic stroke mouse model with selective damage to the sensorimotor cortex, sensorimotor deficits develop soon after stroke and spontaneous recovery is observed in 2-4 weeks. We identified that mice subjected to a focal ischemic insult gradually developed depression/anxiety like behaviors 4 to 8 weeks after stroke. Psychological/psychiatric disorders were revealed in multiple behavioral examinations, including the forced swim, tail suspension, sucrose preference, and open field tests. Altered neuronal plasticity such as suppressed long-term potentiation (LTP), reduced BDNF and oxytocin signaling, and disturbed dopamine synthesis/uptake were detected in the prefrontal cortex (PFC) during the chronic phase after stroke. Pharmacological hypothermia induced by the neurotensin receptor 1 (NTR1) agonist HPI-363 was applied as an acute treatment after stroke. A six-hr hypothermia treatment applied 45 min after stroke prevented depression and anxiety like behaviors examined at 6 weeks after stroke, as well as restored BDNF expression and oxytocin signaling. Additionally, hypothermia induced by physical cooling also showed an anti-depression and anti-anxiety effect. The data suggested a delayed beneficial effect of acute hypothermia treatment on chronically developed post-stroke neuropsychological disorders, associated with regulation of synaptic plasticity, neurotrophic factors, dopaminergic activity, and oxytocin signaling in the PFC.