Rostral intralaminar thalamic deep brain stimulation (ILN-DBS) has been shown to enhance attention and cognition through neuronal activation and brain plasticity. We examined whether rostral ILN-DBS can also attenuate memory deficits and impaired synaptic plasticity and protect glutamatergic transmission in the rat intraventricular β-amyloid (Aβ) infusion model of Alzheimer’s disease (AD). Spatial memory was tested in the Morris water maze (MWM), while structural synaptic plasticity and glutamatergic transmission strength were estimated by measuring dendritic spine densities in dye-injected neurons and tissue expression levels of postsynaptic density protein 95 (PSD-95) in medial prefrontal cortex (mPFC) and hippocampus. All these assessments were compared among the naïve control rats, AD rats, and AD rats with ILN-DBS. We found that a single rostral ILN-DBS treatment significantly improved MWM performance and reversed PSD-95 expression reductions in the mPFC and hippocampal region of Aβ-infused rats. In addition, ILN-DBS preserved dendritic spine densities on mPFC and hippocampal pyramidal neurons. In fact, MWM performance, PSD-95 expression levels, and dendritic spine densities did not differ between naïve control and rostral ILN-DBS treatment groups, indicating near complete amelioration of Aβ-induced spatial memory impairments and dendritic regression. These findings suggest that the ILN is critical for modulating glutamatergic transmission, neural plasticity, and spatial memory functions through widespread effects on distributed brain regions. Further, these findings provide a rationale for examining the therapeutic efficacy of ILN-DBS in AD patients.
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Ansari MA, Roberts KN, Scheff SW (2008) A time course of contusion-induced oxidative stress and synaptic proteins in cortex in a rat model of TBI. J Neurotrauma 25(5):513–526. https://doi.org/10.1089/neu.2007.0451
Barondes SH, Cohen HD (1968) Arousal and the conversion of "short-term" to “long-term” memory. Proc Natl Acad Sci USA 61:923–929
Bero AW, Yan P, Roh JH et al (2011) Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci 14(3):750–756. https://doi.org/10.1038/nn.2801
Bliss TV, Gardner-Medwin AR (2009) Design and development of a new facility for teaching and research in clinical anatomy. Anatomical Sciences Education 2:357–374
Chen J-R, Chen JR, Yan Y-T et al
Chen J-R, Wang T-J, Huang H-Y et al (2009b) Fatigue reversibly reduced cortical and hippocampal dendritic spines concurrent with compromise of motor endurance and spatial memory. Neuroscience 161:1104–1113. https://doi.org/10.1016/j.neuroscience.2009.04.022
Chen J-R, Wang T-J, Lim S-H et al (2013) Testosterone modulation of dendritic spines of somatosensory cortical pyramidal neurons. Brain Struct Funct 218:1407–1417. https://doi.org/10.1007/s00429-012-0465-7
Cholvin T, Loureiro M, Cassel R et al (2016) Dorsal hippocampus and medial prefrontal cortex each contribute to the retrieval of a recent spatial memory in rats. Brain Struct Funct 221:91–102. https://doi.org/10.1007/s00429-014-0894-6
Deng Y, Xiong Z, Chen P et al (2014) β-Amyloid impairs the regulation of N-methyl-D-aspartate receptors by glycogen synthase kinase 3. Neurobiol Aging 35:449–459. https://doi.org/10.1016/j.neurobiolaging.2013.08.031
Furuyashiki T, Fujisawa K, Fujita A, Madaule P, Uchino S, Mishina M, Bito H, Narumiya S (1999) Citron, a Rho-target, interacts with PSD-95/SAP-90 at glutamatergic synapses in the thalamus. J Neurosci 19(1):109–118
Gold JJ, Squire LR (2006) The anatomy of amnesia: neurohistological analysis of three new cases. Learn Mem 13:699–710. https://doi.org/10.1101/lm.357406
Guan J-S, Haggarty SJ, Giacometti E et al (2009) HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459:55–60. https://doi.org/10.1038/nature07925
Hamani C, McAndrews MP, Cohn M et al (2008) Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol 63:119–123. https://doi.org/10.1002/ana.21295
Hamani C, Stone SS, Garten A et al (2011) Memory rescue and enhanced neurogenesis following electrical stimulation of the anterior thalamus in rats treated with corticosterone. Exp Neurol 232:100–104. https://doi.org/10.1016/j.expneurol.2011.08.023
He H, Mahnke AH, Doyle S et al (2012) Neurodevelopmental role for VGLUT2 in pyramidal neuron plasticity, dendritic refinement, and in spatial learning. J Neurosci 32:15886–15901. https://doi.org/10.1523/JNEUROSCI.4505-11.2012
Herrington TM, Cheng JJ, Eskandar EN (2016) Mechanisms of deep brain stimulation. J Neurophysiol 115:19–38. https://doi.org/10.1152/jn.00281.2015
Hescham S, Lim LW, Jahanshahi A et al (2013a) Deep brain stimulation of the forniceal area enhances memory functions in experimental dementia: the role of stimulation parameters. Brain Stimul 6:72–77. https://doi.org/10.1016/j.brs.2012.01.008
Hescham S, Lim LW, Jahanshahi A et al (2013b) Deep brain stimulation of the forniceal area enhances memory functions in experimental dementia: The role of stimulation parameters. Brain Stimul 6:72–77. https://doi.org/10.1016/j.brs.2012.01.008
Hescham S, Jahanshahi A, Schweimer JV et al (2016) Fornix deep brain stimulation enhances acetylcholine levels in the hippocampus. Brain Struct Funct 221:4281–4286. https://doi.org/10.1007/s00429-015-1144-2
Hescham S, Temel Y, Schipper S et al (2017) Fornix deep brain stimulation induced long-term spatial memory independent of hippocampal neurogenesis. Brain Struct Funct 222:1069–1075. https://doi.org/10.1007/s00429-016-1188-y
Laxton AW, Tang-Wai DF, McAndrews MP et al (2010) A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann Neurol 68:521–534. https://doi.org/10.1002/ana.22089
Leoutsakos JS, Yan H, Anderson WS, Asaad WF, Baltuch G, Burke A, Chakravarty MM, Drake KE, Foote KD, Fosdick L, Giacobbe P, Mari Z, McAndrews MP, Munro CA, Oh ES, Okun MS, Pendergrass JC, Ponce FA, Rosenberg PB, Sabbagh MN, Salloway S, Tang-Wai DF, Targum SD, Wolk D, Lozano AM, Smith GS, Lyketsos CG (2018) Deep brain stimulation targeting the fornix for mild alzheimer dementia (the ADvance Trial): a two year follow-up including results of delayed activation. J Alzheimer's Dis 64(2):597–606. https://doi.org/10.3233/JAD-180121
Leplus A, Lauritzen I, Melon C et al (2019) Chronic fornix deep brain stimulation in a transgenic Alzheimer's rat model reduces amyloid burden, inflammation, and neuronal loss. Brain Struct Funct 224:363–372. https://doi.org/10.1007/s00429-018-1779-x
Li S, Jin M, Zhang D et al (2013) Environmental novelty activates β2-adrenergic signaling to prevent the impairment of hippocampal LTP by Aβ oligomers. Neuron 77:929–941. https://doi.org/10.1016/j.neuron.2012.12.040
López-Bendito G, Molnár Z (2003) Thalamocortical development: how are we going to get there? Nat Rev Neurosci 4:276–289. https://doi.org/10.1038/nrn1075
Luebke JI, Weaver CM, Rocher AB et al (2010) Dendritic vulnerability in neurodegenerative disease: insights from analyses of cortical pyramidal neurons in transgenic mouse models. Brain Struct Funct 214:181–199. https://doi.org/10.1007/s00429-010-0244-2
Mair RG, Hembrook JR (2008) Memory enhancement with event-related stimulation of the rostral intralaminar thalamic nuclei. J Neurosci 28:14293–14300. https://doi.org/10.1523/JNEUROSCI.3301-08.2008
Mair RG, Onos KD, Hembrook JR (2011) Cognitive activation by central thalamic stimulation: the Yerkes–Dodson law revisited. Dose Response 9:313–331. https://doi.org/10.2203/dose-response.10-017.Mair
Malm T, Ort M, Tähtivaara L et al (2006) beta-Amyloid infusion results in delayed and age-dependent learning deficits without role of inflammation or beta-amyloid deposits. Proc Natl Acad Sci USA 103:8852–8857. https://doi.org/10.1073/pnas.0602896103
Meyer D, Bonhoeffer T, Scheuss V (2014) Balance and stability of synaptic structures during synaptic plasticity. Neuron 82(2):430–543. https://doi.org/10.1016/j.neuron.2014.02.031
Nakamura S, Nakamura S, Murayama N et al (2001) Progressive brain dysfunction following intracerebroventricular infusion of beta1–42-amyloid peptide. Brain Res 912:128–136. https://doi.org/10.1016/S0006-8993(01)02704-4
Nitta A, Nitta A, Itoh A et al (1994) β-Amyloid protein-induced Alzheimer's disease animal model. Neurosci Lett 170:63–66. https://doi.org/10.1016/0304-3940(94)90239-9
O’hare E, Weldon DT, Mantyh PW et al (1999) Delayed behavioral effects following intrahippocampal injection of aggregated Aβ(1–42). Brain Res 815:1–10. https://doi.org/10.1016/S0006-8993(98)01002-6
Ovsepian SV, O'Leary VB, Záborszky L (2016) Cholinergic mechanisms in the cerebral cortex: beyond synaptic transmission. Neuroscientist 22:238–251. https://doi.org/10.1177/1073858415588264
Saab BJ, Georgiou J, Nath A et al (2009) NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory. Neuron 63:643–656. https://doi.org/10.1016/j.neuron.2009.08.014
Saalmann YB (2014) Intralaminar and medial thalamic influence on cortical synchrony, information transmission and cognition. Front Syst Neurosci 8:83. https://doi.org/10.3389/fnsys.2014.00083
Scarpini E, Scheltens P, Feldman H (2003) Treatment of Alzheimer's disease: current status and new perspectives. The Lancet Neurology 2:539–547
Schiff ND, Giacino JT, Kalmar K et al (2007) Behavioural improvements with thalamic stimulation after severe traumatic brain injury. Nature 448:600–603. https://doi.org/10.1038/nature06041
Schubert D, Kötter R, Staiger JF (2007) Mapping functional connectivity in barrel-related columns reveals layer- and cell type-specific microcircuits. Brain Struct Funct 212:107–119. https://doi.org/10.1007/s00429-007-0147-z
Shirvalkar P, Seth M, Schiff ND, Herrera DG (2006) Cognitive enhancement with central thalamic electrical stimulation. Proc Natl Acad Sci USA 103:17007–17012. https://doi.org/10.1073/pnas.0604811103
Shirvalkar PR, Rapp PR, Shapiro ML (2010) Bidirectional changes to hippocampal theta-gamma comodulation predict memory for recent spatial episodes. Proc Natl Acad Sci USA 107:7054–7059. https://doi.org/10.1073/pnas.0911184107
Smith AC, Shah SA, Hudson AE et al (2009) A Bayesian statistical analysis of behavioral facilitation associated with deep brain stimulation. J Neurosci Methods 183:267–276. https://doi.org/10.1016/j.jneumeth.2009.06.028
Spires-Jones T, Knafo S (2011) Spines, plasticity, and cognition in Alzheimer's model mice. Neural Plasticity
Spires-Jones TL, Meyer-Luehmann M, Osetek JD et al (2007) Impaired spine stability underlies plaque-related spine loss in an Alzheimer's disease mouse model. Am J Pathol 171:1304–1311. https://doi.org/10.2353/ajpath.2007.070055
Srivareerat M, Tran TT, Alzoubi KH, Alkadhi KA (2009) chronic psychosocial stress exacerbates impairment of cognition and long-term potentiation in—amyloidrat model of Alzheimer’s disease. BPS 65:918–926. https://doi.org/10.1016/j.biopsych.2008.08.021
Staudigl T, Zaehle T, Voges J et al (2012) Memory signals from the thalamus: early thalamocortical phase synchronization entrains gamma oscillations during long-term memory retrieval. Neuropsychologia 50:3519–3527. https://doi.org/10.1016/j.neuropsychologia.2012.08.023
Stone SSD, Teixeira CM, Devito LM et al (2011) Stimulation of entorhinal cortex promotes adult neurogenesis and facilitates spatial memory. J Neurosci 31:13469–13484. https://doi.org/10.1523/JNEUROSCI.3100-11.2011
Sui L, Huang S, Peng B et al (2014) Deep brain stimulation of the amygdala alleviates fear conditioning-induced alterations in synaptic plasticity in the cortical–amygdala pathway and fear memory. J Neural Transm 121:773–782. https://doi.org/10.1007/s00702-014-1183-5
Suthana N, Haneef Z, Stern J et al (2012) Memory enhancement and deep-brain stimulation of the entorhinal area. N Engl J Med 366:502–510. https://doi.org/10.1056/NEJMoa1107212
Tampellini D, Capetillo-Zarate E, Dumont M et al (2010) Effects of synaptic modulation on beta-amyloid, synaptophysin, and memory performance in Alzheimer's disease transgenic mice. J Neurosci 30:14299–14304. https://doi.org/10.1523/JNEUROSCI.3383-10.2010
Toda H, Hamani C, Fawcett AP et al (2008) The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation. J Neurosurg 108:132–138. https://doi.org/10.3171/JNS/2008/108/01/0132
Tsai S-T, Chen L-J, Wang Y-J et al (2016) Rostral intralaminar thalamic deep brain stimulation triggered cortical and hippocampal structural plasticity and enhanced spatial memory. Stereotact Funct Neurosurg 94:108–117. https://doi.org/10.1159/000444759
Van der Werf YD, Witter MP, Groenewegen HJ (2002) The intralaminar and midline nuclei of the thalamus. Anatomical and functional evidence for participation in processes of arousal and awareness. Brain Res Brain Res Rev 39:107–140
Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858. https://doi.org/10.1038/nprot.2006.116
Walker RH, Moore C, Davies G et al (2012) Effects of subthalamic nucleus lesions and stimulation upon corticostriatal afferents in the 6-hydroxydopamine-lesioned rat. PLoS ONE 7:e32919. https://doi.org/10.1371/journal.pone.0032919
Xu W (2011) PSD-95-like membrane associated guanylate kinases (PSD-MAGUKs) and synaptic plasticity. Curr Opin Neurobiol 21:306–312. https://doi.org/10.1016/j.conb.2011.03.001
Yamada K, Nabeshima T (2000) Animal models of Alzheimer's disease and evaluation of anti-dementia drugs. Pharmacol Ther 88:93–113. https://doi.org/10.1016/S0163-7258(00)00081-4
Záborszky L, Gombkoto P, Varsanyi P et al (2018) Specific basal forebrain–cortical cholinergic circuits coordinate cognitive operations. J Neurosci 38:9446–9458. https://doi.org/10.1523/JNEUROSCI.1676-18.2018
We are grateful to Professor Yu-Ru Kou and Dr. Ben S. Huang for discussion, comments, and English editing of the paper.
Tzu Chi University: TCIRP 104001-0, 104001-05, 107001-01, and 107001-04; Ministry of Science and Technology of Taiwan: 104-2320-B-320-001-MY3; 107-2320-B-320-006 and 108-2314-B-303-014.
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Tsai, S., Chen, S., Lin, S. et al. Rostral intralaminar thalamic deep brain stimulation ameliorates memory deficits and dendritic regression in β-amyloid-infused rats. Brain Struct Funct (2020). https://doi.org/10.1007/s00429-020-02033-6
- Cortical plasticity
- Deep brain stimulation
- Alzheimer’s disease