Elise Gondard1, Hien N Chau1, Amandeep Mann1, Travis S Tierney2, Clement Hamani3, Suneil K Kalia4, Andres M Lozano5. 1. Toronto Western Research Institute, Krembil Discovery Tower, University Health Network, 60 Leonard Street, Toronto, ON, M5T 2S8, Canada. 2. Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. 3. Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada; Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada; Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada. 4. Toronto Western Research Institute, Krembil Discovery Tower, University Health Network, 60 Leonard Street, Toronto, ON, M5T 2S8, Canada; Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada. 5. Toronto Western Research Institute, Krembil Discovery Tower, University Health Network, 60 Leonard Street, Toronto, ON, M5T 2S8, Canada; Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University of Toronto, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada. Electronic address: lozano@uhnresearch.ca.
Abstract
BACKGROUND: The forniceal area is currently being evaluated as a target for deep brain stimulation (DBS) to improve cognitive function in patients with Alzheimer's disease. The molecular changes at downstream targets within the stimulated circuit are unknown. OBJECTIVE: To analyze the modulation of hippocampal protein expression following 1 h of fornix DBS in the rat. METHODS: Animals underwent bilateral forniceal DBS for 1 h and sacrificed at different time-points after the initiation of the stimulation (1 h, 2.5 h, 5 h, 25 h). Bilateral hippocampi were isolated for western blot analyses. RESULTS: Forniceal DBS led to a dramatic elevation of cFos post-stimulation, suggesting that forniceal DBS activates the hippocampus. There was also a significant increase in candidate proteins including several trophic factors, such as brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) but not glial cell-derived neurotrophic factor (GDNF). There was in addition, increased expression of the synaptic markers growth associated protein 43 (GAP-43), synaptophysin and α-synuclein. No changes were observed at the studied time-points in Alzheimer's-related proteins including amyloid precursor protein (APP), tau, phosphorylated tau (ptau), or selected chaperone proteins (HSP40, HSP70 and CHIP). CONCLUSIONS: Forniceal DBS triggers hippocampal activity and rapidly modulate the expression of neurotrophic factors and markers of synaptic plasticity known to play key roles in memory processing. The clinical effects of DBS of the fornix may, in part, be mediated by producing changes in the expression of these proteins.
BACKGROUND: The forniceal area is currently being evaluated as a target for deep brain stimulation (DBS) to improve cognitive function in patients with Alzheimer's disease. The molecular changes at downstream targets within the stimulated circuit are unknown. OBJECTIVE: To analyze the modulation of hippocampal protein expression following 1 h of fornix DBS in the rat. METHODS: Animals underwent bilateral forniceal DBS for 1 h and sacrificed at different time-points after the initiation of the stimulation (1 h, 2.5 h, 5 h, 25 h). Bilateral hippocampi were isolated for western blot analyses. RESULTS: Forniceal DBS led to a dramatic elevation of cFos post-stimulation, suggesting that forniceal DBS activates the hippocampus. There was also a significant increase in candidate proteins including several trophic factors, such as brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) but not glial cell-derived neurotrophic factor (GDNF). There was in addition, increased expression of the synaptic markers growth associated protein 43 (GAP-43), synaptophysin and α-synuclein. No changes were observed at the studied time-points in Alzheimer's-related proteins including amyloid precursor protein (APP), tau, phosphorylated tau (ptau), or selected chaperone proteins (HSP40, HSP70 and CHIP). CONCLUSIONS: Forniceal DBS triggers hippocampal activity and rapidly modulate the expression of neurotrophic factors and markers of synaptic plasticity known to play key roles in memory processing. The clinical effects of DBS of the fornix may, in part, be mediated by producing changes in the expression of these proteins.
Authors: Elise Gondard; Lucy Teves; Lihua Wang; Chris McKinnon; Clement Hamani; Suneil K Kalia; Peter L Carlen; Michael Tymianski; Andres M Lozano Journal: J Neurosci Date: 2019-01-29 Impact factor: 6.167
Authors: Jeannie-Marie S Leoutsakos; Haijuan Yan; William S Anderson; Wael F Asaad; Gordon Baltuch; Anna Burke; M Mallar Chakravarty; Kristen E Drake; Kelly D Foote; Lisa Fosdick; Peter Giacobbe; Zoltan Mari; Mary Pat McAndrews; Cynthia A Munro; Esther S Oh; Michael S Okun; Jo Cara Pendergrass; Francisco A Ponce; Paul B Rosenberg; Marwan N Sabbagh; Stephen Salloway; David F Tang-Wai; Steven D Targum; David Wolk; Andres M Lozano; Gwenn S Smith; Constantine G Lyketsos Journal: J Alzheimers Dis Date: 2018 Impact factor: 4.472
Authors: Max I Bogorad; Jackson G DeStefano; Raleigh M Linville; Andrew D Wong; Peter C Searson Journal: J Cereb Blood Flow Metab Date: 2019-06-17 Impact factor: 6.960
Authors: Andres M Lozano; Nir Lipsman; Hagai Bergman; Peter Brown; Stephan Chabardes; Jin Woo Chang; Keith Matthews; Cameron C McIntyre; Thomas E Schlaepfer; Michael Schulder; Yasin Temel; Jens Volkmann; Joachim K Krauss Journal: Nat Rev Neurol Date: 2019-03 Impact factor: 42.937
Authors: Andres M Lozano; Lisa Fosdick; M Mallar Chakravarty; Jeannie-Marie Leoutsakos; Cynthia Munro; Esther Oh; Kristen E Drake; Christopher H Lyman; Paul B Rosenberg; William S Anderson; David F Tang-Wai; Jo Cara Pendergrass; Stephen Salloway; Wael F Asaad; Francisco A Ponce; Anna Burke; Marwan Sabbagh; David A Wolk; Gordon Baltuch; Michael S Okun; Kelly D Foote; Mary Pat McAndrews; Peter Giacobbe; Steven D Targum; Constantine G Lyketsos; Gwenn S Smith Journal: J Alzheimers Dis Date: 2016-09-06 Impact factor: 4.472
Authors: Nathan C Rowland; Suneil K Kalia; Lorraine V Kalia; Paul S Larson; Daniel A Lim; Krystof S Bankiewicz Journal: Mol Ther Methods Clin Dev Date: 2016-01-13 Impact factor: 6.698