An enriched environment improves long-term functional outcomes in mice after intracerebral hemorrhage by mechanisms that involve the Nrf2/BDNF/glutaminase pathway

Abstract

Post-stroke depression exacerbates neurologic deficits and quality of life. Depression after ischemic stroke is known to some extent. However, depression after intracerebral hemorrhage (ICH) is relatively unknown. Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia/reperfusion injury has neuroprotective effects in animal models, but its impact after ICH is unknown. In this study, we investigated the effect of EE on long-term functional outcomes in mice subjected to collagenase-induced striatal ICH. Mice were subjected to ICH with the standard environment (SE) or ICH with EE for 6 h/day (8:00 am–2:00 pm). Depressive, anxiety-like behaviors and cognitive tests were evaluated on day 28 with the sucrose preference test, tail suspension test, forced swim test, light-dark transition experiment, morris water maze, and novel object recognition test. Exposure to EE improved neurologic function, attenuated depressive and anxiety-like behaviors, and promoted spatial learning and memory. These changes were associated with increased expression of transcription factor Nrf2 and brain-derived neurotrophic factor (BDNF) and inhibited glutaminase activity in the perihematomal tissue. However, EE did not change the above behavioral outcomes in Nrf2−/− mice on day 28. Furthermore, exposure to EE did not increase BDNF expression compared to exposure to SE in Nrf2−/− mice on day 28 after ICH. These findings indicate that EE improves long-term outcomes in sensorimotor, emotional, and cognitive behavior after ICH and that the underlying mechanism involves the Nrf2/BDNF/glutaminase pathway.

Molecular insights into enriched environments and behavioral improvements in autism: a systematic review and meta-analysis

“…In the field of neuroscience, EE is increasingly recognized for its potential to enhance synaptic plasticity. Exposure to EE induces an upregulation in BDNF expression and TrkB activation, thereby promoting the formation and maintenance of new synaptic connections ( 6 ). Additionally, EE enhances synaptic plasticity by increasing the formation of new neurons in the hippocampus ( 12 ).…”

“…upregulation in BDNF expression and TrkB activation, thereby promoting the formation and maintenance of new synaptic connections (6). Additionally, EE enhances synaptic plasticity by increasing the formation of new neurons in the hippocampus (12).…”

“…Moreover, researchers have proposed innovative perspectives at the micromechanism level. Environmental enrichment can influence the Nrf/ BDNF pathway, promoting neuronal growth, recombination, and recovery, thereby reducing anxiety and enhancing motor abilities (6). The hippocampus, an important region for learning and memory, has been a focal point, with scientists proposing interventions aiming at altering cell excitability and improving synaptic structure and morphology (7)(8)(9).…”

Spatiotemporal transcriptomic maps of mouse intracerebral hemorrhage at single-cell resolution

“…After being filled with paraffin wax, the glass micropipette was attached to the micro-infusion pump, and collagenase VII-S (0.075 U in 0.5 µL sterile saline, Sigma, St. Louis, MO) was injected into the left striatum using dual-arm brain stereo locator (anterior to bregma 0.8 mm, lateral to the midline 2.0 mm, deep to the surface of the skull 3.5 mm) (Stoelting, 51503D, Stoelting Co., Illinois, Wood Dale, USA). The collagenase was infused with a constant rate of 0.1 µL/min using a micro-infusion pump, Stoelting, Wood Dale, IL, USA) 101 . The mouse body temperature was maintained at 37.0 ± 0.5□ throughout the operation with the help of a body temperature maintenance instrument (RWD, Shenzhen, China).…”

“…The brain tissue was weighed to determine its wet weight, and it was placed in an oven at 100□ for 72 h to obtain its dry weight. Brain edema was calculated by determining brain water content using the formula: brain water content (%) = (wet weight – dry weight)/wet weight×100% 100,101 .…”