title: Environmental enrichment delays limbic epileptogenesis and restricts pathologic synaptic plasticity.
abstract: OBJECTIVE
  Environmental exposures impart powerful effects on vulnerability to many brain diseases, including epilepsy. Mesial temporal lobe epilepsy (MTLE) is a common form of epilepsy, and it is often accompanied by neuropsychiatric comorbidities. This study tests the hypothesis that environmental enrichment (EE) confers antiepileptogenic, psychoprotective, and neuroprotective effects in the amygdala kindling model of MTLE, and explores potential neurobiologic mechanisms.
  
  
  METHODS
  At weaning, male Wistar rats were allocated into either EE (large cages containing running wheels and toys; n = 43) or standard housing (SH; standard laboratory cages; n = 39) conditions. At P56, a bipolar electrode was implanted into the left amygdala, and rats underwent rapid amygdala kindling until experiencing five class V seizures (Racine scale, fully kindled). The elevated plus maze was used to assess anxiety. Postmortem histologic and molecular analyses investigated potential biologic mediators of effects.
  
  
  RESULTS
  EE significantly delayed kindling epileptogenesis, with EE rats requiring a significantly greater number of kindling stimulations to reach a fully kindled state compared to SH rats (p < 0.05). EE and kindling both reduced anxiety (p < 0.05). Timm's staining revealed significant reductions in aberrant mossy fiber sprouting in EE rats (p < 0.05), and these effects of EE were accompanied by reduced expression of TrkB and CRH genes.
  
  
  CONCLUSIONS
  We identify beneficial effects of EE on vulnerability to limbic epileptogenesis and anxiety, and identify reduced pathologic neuroplasticity and plasticity-related gene expression as potential underlying mechanisms. Enhanced environmental stimulation represents a potential antiepileptogenic strategy that might also mitigate the common psychiatric comorbidities of MTLE.
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Meng
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Ezgi
authors.initials: E
authors.lastname: Ozturk
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, The University of Melbourne, Melbourne, Victoria, Australia.|Department of Psychiatry, St Vincent's Hospital, Melbourne, Victoria, Australia.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Salzberg
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rees
authors.affiliation: Department of Pharmacology, UNSW Australia, Sydney, New South Wales, Australia.
authors.forename: Margaret
authors.initials: M
authors.lastname: Morris
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.affiliation: Department of Medicine (Royal Melbourne Hospital), Melbourne Brain Centre, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Nigel C
authors.initials: NC
authors.lastname: Jones
mesh_terms: D000679:Amygdala / Q000503:physiopathology; D000818:Animals; D004777:Environment; D004833:Epilepsy, Temporal Lobe / Q000473:pathology / Q000503:physiopathology*; D006799:Housing, Animal; D008297:Male; D009473:Neuronal Plasticity / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
keywords: Anxiety; Brain-derived neurotrophic factor; Corticotropin-releasing hormone; Environmental enrichment; Kindling; Limbic epilepsy; Mossy fiber sprouting