RETRACTED ARTICLE: Decreased neuroinflammation and increased brain energy homeostasis following environmental enrichment after mild traumatic brain injury is associated with improvement in cognitive function

Abstract

BackgroundPersistent neuroinflammation and disruptions in brain energy metabolism is commonly seen in traumatic brain injury (TBI). Because of the lack of success of most TBI interventions and the documented benefits of environmental enrichment (EE) in enhancing brain plasticity, here we focused our study on use of EE in regulating injury-induced neuroinflammation and disruptions in energy metabolism in the prefrontal cortex and hippocampus. Adult male Wistar rats were used in the study and randomly assigned to receive either: mild TBI (mTBI) using the controlled cortical injury model or sham surgery. Following surgery, rats from each group were further randomized to either: EE housing or standard laboratory housing (CON). After 4 weeks of recovery, cognitive testing was performed using the non-matching-to-sample and delayed non-matching-to-sample tasks. After completion of behavioral testing, levels of the pro-inflammatory cytokines IL-1β and TNF-α and the anti-inflammatory cytokine IL-10 were measured. In addition, levels of AMPK (adenosine monophosphate-activated protein kinase), phosphorylated AMPK and uMtCK (ubiquitous mitochondrial creatine kinase) were assessed as measures of brain energy homeostasis.ResultsOur results showed that EE: (1) decreased the pro-inflammatory cytokines IL-1β and TNF-α and enhanced levels of the anti-inflammatory cytokine IL-10 after mTBI; (2) mitigated mTBI-induced cognitive impairment; and (3) attenuated mTBI-induced downregulation in pAMPK/AMPK ratio and uMtCK levels.ConclusionsOur data demonstrated the potential of EE to modulate the persistent: (1) neuroinflammatory response seen following mTBI, and (2) persistent disturbance in brain energy homeostasis. It is possible that through the mechanism of modulating neuroinflammation, EE housing was able to restore the disruption in energy metabolism and enhanced functional recovery after mTBI.

The Therapeutic Efficacy of Environmental Enrichment and Methylphenidate Alone and in Combination after Controlled Cortical Impact Injury

“…14,[22][23][24][25][26][27][28][29][30][31][32]35 Concurrently, many other therapeutic interventions have also been reported to enhance behavioral outcome after TBI using various pre-clinical models; [9][10][11][12][13][14][15][16][17][18] however, most of these strategies have not successfully translated from the bench to the bedside. 19,20 While numerous factors may account for the lack of translation, one salient reason may be the use of single therapies for a disease that exhibits multiple pathophysiological events.…”

“…57 While we only administered a 5 mg/kg daily dose of MPH, it is not unreasonable to consider that in combination with EE, it may have reduced DA transporter activity to suboptimal levels, such that an overabundance of DA failed to provide additional spatial learning benefits on MWM performance in the TBI+EE+MPH group. While MPH induces therapeutic benefit by primarily targeting DA neurotransmission, EE supports post-injury recovery through multiple pathways or mechanisms including DA system regulation, 55 reductions in pro-inflammatory cytokines, 27 increased neurogenesis, nerve growth factor, and dendritic arborization, [58][59][60][61] or attenuation of medial septal cholinergic cell loss. 28 A recent study demonstrated that rats raised in EE exhibit decreased maximal transport velocity (Vmax) for [ 3 H]DA uptake in medial prefrontal cortex, but increased Vmax for [ 3 H]DA uptake in the orbitofrontal cortex, thus suggesting that EE produces regiondependent long-lasting alterations in DA transporter function via a trafficking-independent mechanism, 62 which may influence the overall effectiveness of MPH treatment when provided concurrently.…”

“…EE has consistently been shown to promote neurogenesis, attenuate histopathology, and enhance cognitive and behavioral recovery after experimental TBI in both CCI and fluid percussion injury models. [22][23][24][25][26][27][28][29][30][31][32] The second strategy, daily methylphenidate (MPH) administration, which is a dopamine (DA) reuptake inhibitor acting on the DA transporter and a D 2 receptor agonist, 33 has also been shown to confer benefits to cognitive recovery after experimental TBI. 14,35,36 MPH has been associated with improvements in motor speed, attention, memory, processing speed, and mental fatigue in clinical patients with TBI.…”

A Combined Therapeutic Regimen of Buspirone and Environmental Enrichment Is More Efficacious than Either Alone in Enhancing Spatial Learning in Brain-Injured Pediatric Rats

“…[18][19][20][21][22][23][24][25][26] Likewise, EE has also been shown to confer neurobehavioral and histological benefits in adult male rats after CCI 20,23,[26][27][28][29][30][31][32][33][34] and fluid percussion brain injury. [35][36][37][38][39][40] Recently, the benefits of EE have also been extended to female rats after CCI.…”

“…Environmental enrichment (EE), in particular, has been evaluated extensively in adult, and to a much lesser extent, in pediatric rodents as a pre-clinical model of neurorehabilitation. EE consists of expansive accommodations, which include cognitive and social stimulation that results in the reduction of histological damage and enhancement of functional recovery 27 induced by either controlled cortical impact (CCI) 20,23,[26][27][28][29][30][31][32][33][34] or fluid percussion. [35][36][37][38][39][40] Given that the 5-HT 1A receptor agonist buspirone and EE confer recovery in adult rats after brain trauma, the goals of this study were to evaluate the potential efficacy of these therapies alone and in combination after pediatric TBI.…”