Abstract
Lesions to the anterior thalamic nuclei (ATN) in rats produce robust spatial memory deficits that reflect their influence as part of an extended hippocampal system. Recovery of spatial working memory after ATN lesions was examined using a 30-day administration of the neurotrophin cerebrolysin and/or an enriched housing environment. As expected, ATN lesions in standard-housed rats given saline produced severely impaired reinforced spatial alternation when compared to standard-housed rats with sham lesions. Both cerebrolysin and enrichment substantially improved this working memory deficit, including accuracy on trials that required attention to distal cues for successful performance. The combination of cerebrolysin and enrichment was more effective than either treatment alone when the delay between successive runs in a trial was increased to 40 s. Compared to the intact rats, ATN lesions in standard-housed groups produced substantial reduction in c-Fos expression in the retrosplenial cortex, which remained low after cerebrolysin and enrichment treatments. Evidence that multiple treatment strategies restore some memory functions in the current lesion model reinforces the prospect for treatments in human diencephalic amnesia.
Similar content being viewed by others
References
Aggleton JP (2008) EPS Mid-Career Award 2006. Understanding anterograde amnesia: disconnections and hidden lesions. Q J Exp Psychol (Hove) 61(10):1441–1471. doi:10.1080/17470210802215335
Aggleton JP (2010) Understanding retrosplenial amnesia: insights from animal studies. Neuropsychologia 48(8):2328–2338. doi:10.1016/j.neuropsychologia.2009.09.030
Aggleton JP, Nelson AJ (2014) Why do lesions in the rodent anterior thalamic nuclei cause such severe spatial deficits? Neurosci Biobehav Rev. doi:10.1016/j.neubiorev.2014.08.013
Aggleton JP, Neave N, Nagle S, Sahgal A (1995) A comparison of the effects of medial prefrontal, cingulate cortex, and cingulum bundle lesions on tests of spatial memory: evidence of a double dissociation between frontal and cingulum bundle contributions. J Neurosci 15(11):7270–7281
Aggleton JP, Amin E, Jenkins TA, Pearce JM, Robinson J (2011) Lesions in the anterior thalamic nuclei of rats do not disrupt acquisition of stimulus sequence learning. Q J Exp Psychol (Hove) 64(1):65–73. doi:10.1080/17470218.2010.495407
Albasser MM, Poirier GL, Warburton EC, Aggleton JP (2007) Hippocampal lesions halve immediate-early gene protein counts in retrosplenial cortex: distal dysfunctions in a spatial memory system. Eur J Neurosci 26(5):1254–1266. doi:10.1111/j.1460-9568.2007.05753.x
Alcaraz F, Naneix F, Desfosses E, Marchand AR, Wolff M, Coutureau E (2014) Dissociable effects of anterior and mediodorsal thalamic lesions on spatial goal-directed behavior. Brain Struct Funct. doi:10.1007/s00429-014-0893-7
Amin E, Wright N, Poirier GL, Thomas KL, Erichsen JT, Aggleton JP (2010) Selective lamina dysregulation in granular retrosplenial cortex (area 29) after anterior thalamic lesions: an in situ hybridization and trans-neuronal tracing study in rats. Neuroscience 169(3):1255–1267. doi:10.1016/j.neuroscience.2010.05.055
Baird AL, Putter JE, Muir JL, Aggleton JP (2004) On the transience of egocentric working memory: evidence from testing the contribution of limbic brain regions. Behav Neurosci 118(4):785–797. doi:10.1037/0735-7044.118.4.785
Carlesimo GA, Lombardi MG, Caltagirone C (2011) Vascular thalamic amnesia: a reappraisal. Neuropsychologia 49(5):777–789. doi:10.1016/j.neuropsychologia.2011.01.026
Czajkowski R, Jayaprakash B, Wiltgen B, Rogerson T, Guzman-Karlsson MC, Barth AL, Trachtenberg JT, Silva AJ (2014) Encoding and storage of spatial information in the retrosplenial cortex. Proc Natl Acad Sci USA 111(23):8661–8666. doi:10.1073/pnas.1313222111
Dudchenko PA (2001) How do animals actually solve the T maze? Behav Neurosci 115(4):850–860
Dumont JR, Amin E, Poirier GL, Albasser MM, Aggleton JP (2012) Anterior thalamic nuclei lesions in rats disrupt markers of neural plasticity in distal limbic brain regions. Neuroscience 224:81–101. doi:10.1016/j.neuroscience.2012.08.027
Dupire A, Kant P, Mons N, Marchand AR, Coutureau E, Dalrymple-Alford J, Wolff M (2013) A role for anterior thalamic nuclei in affective cognition: interaction with environmental conditions. Hippocampus 23(5):392–404. doi:10.1002/hipo.22098
Encinas JM, Hamani C, Lozano AM, Enikolopov G (2011) Neurogenic hippocampal targets of deep brain stimulation. J Comp Neurol 519(1):6–20. doi:10.1002/cne.22503
Fellows BJ (1967) Chance stimulus sequences for discrimination tasks. Psychol Bull 67(2):87–92
Fiedler K, Kutzner F, Krueger JI (2012) The long way from α-error control to validity proper problems with a short-sighted false-positive debate. Perspect Psychol Sci 7(6):661–669
Francis-Turner L, Valouskova V (1996) Nerve growth factor and nootropic drug Cerebrolysin but not fibroblast growth factor can reduce spatial memory impairment elicited by fimbria-fornix transection: short-term study. Neurosci Lett 202(3):193–196
Garden DL, Massey PV, Caruana DA, Johnson B, Warburton EC, Aggleton JP, Bashir ZI (2009) Anterior thalamic lesions stop synaptic plasticity in retrosplenial cortex slices: expanding the pathology of diencephalic amnesia. Brain 132(Pt 7):1847–1857. doi:10.1093/brain/awp090
Gold JJ, Squire LR (2006) The anatomy of amnesia: neurohistological analysis of three new cases. Learn Mem 13(6):699–710. doi:10.1101/lm.357406
Hamani C, Stone SS, Garten A, Lozano AM, Winocur G (2011) Memory rescue and enhanced neurogenesis following electrical stimulation of the anterior thalamus in rats treated with corticosterone. Exp Neurol 232(1):100–104. doi:10.1016/j.expneurol.2011.08.023
Harding A, Halliday G, Caine D, Kril J (2000) Degeneration of anterior thalamic nuclei differentiates alcoholics with amnesia. Brain 123(Pt 1):141–154
Harland BC, Collings DA, McNaughton N, Abraham WC, Dalrymple-Alford JC (2014) Anterior thalamic lesions reduce spine density in both hippocampal CA1 and retrosplenial cortex, but enrichment rescues CA1 spines only. Hippocampus 24(10):1232–1247. doi:10.1002/hipo.22309
Hartbauer M, Hutter-Paier B, Skofitsch G, Windisch M (2001) Antiapoptotic effects of the peptidergic drug cerebrolysin on primary cultures of embryonic chick cortical neurons. J Neural Trans 108(4):459–473
Henry J, Petrides M, St-Laurent M, Sziklas V (2004) Spatial conditional associative learning: effects of thalamo-hippocampal disconnection in rats. Neuro Report 15(15):2427–2431
Hirase H, Shinohara Y (2014) Transformation of cortical and hippocampal neural circuit by environmental enrichment. Neuroscience. doi:10.1016/j.neuroscience.2014.09.031
Jenkins TA, Dias R, Amin E, Aggleton JP (2002a) Changes in Fos expression in the rat brain after unilateral lesions of the anterior thalamic nuclei. Eur J Neurosci 16(8):1425–1432 (2211 [pii])
Jenkins TA, Dias R, Amin E, Brown MW, Aggleton JP (2002b) Fos imaging reveals that lesions of the anterior thalamic nuclei produce widespread limbic hypoactivity in rats. J Neurosci 22(12):5230–5238 (22/12/5230 [pii])
Jenkins TA, Vann SD, Amin E, Aggleton JP (2004) Anterior thalamic lesions stop immediate early gene activation in selective laminae of the retrosplenial cortex: evidence of covert pathology in rats? Eur J Neurosci 19(12):3291–3304. doi:10.1111/j.0953-816X.2004.03421.x
Juarez I, Gonzalez DJ, Mena R, Flores G (2011) The chronic administration of cerebrolysin induces plastic changes in the prefrontal cortex and dentate gyrus in aged mice. Synapse 65(11):1128–1135. doi:10.1002/syn.20950
Leger M, Quiedeville A, Paizanis E, Natkunarajah S, Freret T, Boulouard M, Schumann-Bard P (2012) Environmental enrichment enhances episodic-like memory in association with a modified neuronal activation profile in adult mice. PLoS One 7(10):e48043. doi:10.1371/journal.pone.0048043
Loukavenko EA, Ottley MC, Moran JP, Wolff M, Dalrymple-Alford JC (2007) Towards therapy to relieve memory impairment after anterior thalamic lesions: improved spatial working memory after immediate and delayed postoperative enrichment. Eur J Neurosci 26(11):3267–3276. doi:10.1111/j.1460-9568.2007.05879.x
Mair RG, Onos KD, Hembrook JR (2011) Cognitive activation by central thalamic stimulation: the yerkes-dodson law revisited. Dose Response Publ Int Hormesis Soc 9(3):313–331. doi:10.2203/dose-response.10-017.Mair
Marchand A, Faugere A, Coutureau E, Wolff M (2013) A role for anterior thalamic nuclei in contextual fear memory. Brain Struct Funct 219(5):1575–1586. doi:10.1007/s00429-013-0586-7
Mendez-Lopez M, Arias JL, Bontempi B, Wolff M (2013) Reduced cytochrome oxidase activity in the retrosplenial cortex after lesions to the anterior thalamic nuclei. Behav Brain Res 250C:264–273. doi:10.1016/j.bbr.2013.04.052
Mitchell AS, Dalrymple-Alford JC (2006) Lateral and anterior thalamic lesions impair independent memory systems. Learn Mem 13(3):388–396. doi:10.1101/lm.122206
Odagiri S, Meguro R, Asano Y, Tani T, Ichinohe N (2011) Single axon branching analysis in rat thalamocortical projection from the anteroventral thalamus to the granular retrosplenial cortex. Front Neuroanat 5:63. doi:10.3389/fnana.2011.00063
Olson AK, Eadie BD, Ernst C, Christie BR (2006) Environmental enrichment and voluntary exercise massively increase neurogenesis in the adult hippocampus via dissociable pathways. Hippocampus 16(3):250–260. doi:10.1002/hipo.20157
Paxinos G, Watson C (1998) The rat brain in stereotaxic coordinates, 4th edn. Academic Press, San Diego
Pergola G, Suchan B (2013) Associative learning beyond the medial temporal lobe: many actors on the memory stage. Front Behav Neurosci 7:162. doi:10.3389/fnbeh.2013.00162
Plosker GL, Gauthier S (2009) Cerebrolysin: a review of its use in dementia. Drugs Aging 26(11):893–915. doi:10.2165/11203320-000000000-00000
Poirier GL, Aggleton JP (2009) Post-surgical interval and lesion location within the limbic thalamus determine extent of retrosplenial cortex immediate-early gene hypoactivity. Neuroscience 160(2):452–469. doi:10.1016/j.neuroscience.2009.02.021
Poirier GL, Shires KL, Sugden D, Amin E, Thomas KL, Carter DA, Aggleton JP (2008) Anterior thalamic lesions produce chronic and profuse transcriptional de-regulation in retrosplenial cortex: a model of retrosplenial hypoactivity and covert pathology. Thalamus Relat Syst 4(1):59–77. doi:10.1017/S1472928808000368
Pothuizen HH, Aggleton JP, Vann SD (2008) Do rats with retrosplenial cortex lesions lack direction? Eur J Neurosci 28(12):2486–2498. doi:10.1111/j.1460-9568.2008.06550.x
Pothuizen HH, Davies M, Albasser MM, Aggleton JP, Vann SD (2009) Granular and dysgranular retrosplenial cortices provide qualitatively different contributions to spatial working memory: evidence from immediate-early gene imaging in rats. Eur J Neurosci 30(5):877–888. doi:10.1111/j.1460-9568.2009.06881.x
Pothuizen HH, Davies M, Aggleton JP, Vann SD (2010) Effects of selective granular retrosplenial cortex lesions on spatial working memory in rats. Behav Brain Res 208(2):566–575. doi:10.1016/j.bbr.2010.01.001
Rockenstein E, Mante M, Adame A, Crews L, Moessler H, Masliah E (2007) Effects of Cerebrolysin on neurogenesis in an APP transgenic model of Alzheimer’s disease. Acta Neuropathol 113(3):265–275. doi:10.1007/s00401-006-0166-5
Savage LM, Hall JM, Resende LS (2012) Translational rodent models of Korsakoff syndrome reveal the critical neuroanatomical substrates of memory dysfunction and recovery. Neuropsychol Rev 22(2):195–209. doi:10.1007/s11065-012-9194-1
Sharma HS, Sharma A, Mossler H, Muresanu DF (2012) Neuroprotective effects of cerebrolysin, a combination of different active fragments of neurotrophic factors and peptides on the whole body hyperthermia-induced neurotoxicity: modulatory roles of co-morbidity factors and nanoparticle intoxication. Int Rev Neurobiol 102:249–276. doi:10.1016/B978-0-12-386986-9.00010-7
Sheth A, Berretta S, Lange N, Eichenbaum H (2008) The amygdala modulates neuronal activation in the hippocampus in response to spatial novelty. Hippocampus 18(2):169–181. doi:10.1002/hipo.20380
Shibata H (1993a) Direct projections from the anterior thalamic nuclei to the retrohippocampal region in the rat. J Comp Neurol 337(3):431–445. doi:10.1002/cne.903370307
Shibata H (1993b) Efferent projections from the anterior thalamic nuclei to the cingulate cortex in the rat. J Comp Neurol 330(4):533–542. doi:10.1002/cne.903300409
Shibata H, Honda Y (2012) Thalamocortical projections of the anterodorsal thalamic nucleus in the rabbit. J Comp Neurol 520(12):2647–2656. doi:10.1002/cne.23057
Shibata H, Kato A (1993) Topographic relationship between anteromedial thalamic nucleus neurons and their cortical terminal fields in the rat. Neurosci Res 17(1):63–69
Struthers WM, DuPriest A, Runyan J (2005) Habituation reduces novelty-induced FOS expression in the striatum and cingulate cortex. Exp Brain Res 167(1):136–140. doi:10.1007/s00221-005-0061-7
Toda H, Hamani C, Fawcett AP, Hutchison WD, Lozano AM (2008) The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation. J Neurosurg 108(1):132–138. doi:10.3171/JNS/2008/108/01/0132
Ubhi K, Rockenstein E, Vazquez-Roque R, Mante M, Inglis C, Patrick C, Adame A, Fahnestock M, Doppler E, Novak P, Moessler H, Masliah E (2013) Cerebrolysin modulates pronerve growth factor/nerve growth factor ratio and ameliorates the cholinergic deficit in a transgenic model of Alzheimer’s disease. J Neurosci Res 91(2):167–177. doi:10.1002/jnr.23142
Valouskova V, Gschanes A (1999) Effects of NGF, b-FGF, and cerebrolysin on water maze performance and on motor activity of rats: short- and long-term study. Neurobiol Learn Mem 71(2):132–149. doi:10.1006/nlme.1998.3877
Van der Werf YD, Jolles J, Witter MP, Uylings HB (2003a) Contributions of thalamic nuclei to declarative memory functioning. Cortex 39(4–5):1047–1062
Van der Werf YD, Scheltens P, Lindeboom J, Witter MP, Uylings HB, Jolles J (2003b) Deficits of memory, executive functioning and attention following infarction in the thalamus; a study of 22 cases with localised lesions. Neuropsychologia 41(10):1330–1344
Van Groen T, Vogt BA, Wyss JM (1993) Interconnections between the thalamus and retrosplenial cortex in the rodent brain. In: Vogt BA, Gabriel M (eds) Neurobiology of cingulate cortex and limbic thalamus. Birkhäuser, Boston, pp 123–150
Vann SD (2010) Re-evaluating the role of the mammillary bodies in memory. Neuropsychologia 48(8):2316–2327. doi:10.1016/j.neuropsychologia.2009.10.019
Vann SD, Aggleton JP (2005) Selective dysgranular retrosplenial cortex lesions in rats disrupt allocentric performance of the radial-arm maze task. Behav Neurosci 119(6):1682–1686. doi:10.1037/0735-7044.119.6.1682
Vann SD, Albasser MM (2009) Hippocampal, retrosplenial, and prefrontal hypoactivity in a model of diencephalic amnesia: evidence towards an interdependent subcortical-cortical memory network. Hippocampus 19(11):1090–1102. doi:10.1002/hipo.20574
Vazquez-Roque RA, Ramos B, Tecuatl C, Juarez I, Adame A, de la Cruz F, Zamudio S, Mena R, Rockenstein E, Masliah E, Flores G (2012) Chronic administration of the neurotrophic agent cerebrolysin ameliorates the behavioral and morphological changes induced by neonatal ventral hippocampus lesion in a rat model of schizophrenia. J Neurosci Res 90(1):288–306. doi:10.1002/jnr.22753
Warburton EC, Aggleton JP (1999) Differential deficits in the Morris water maze following cytotoxic lesions of the anterior thalamus and fornix transection. Behav Brain Res 98(1):27–38
Warburton EC, Baird AL, Aggleton JP (1997) Assessing the magnitude of the allocentric spatial deficit associated with complete loss of the anterior thalamic nuclei in rats. Behav Brain Res 87(2):223–232. doi:10.1016/S0166-4328(97)02285-7
Ward-Robinson J, Coutureau E, Good M, Honey RC, Killcross AS, Oswald CJ (2001) Excitotoxic lesions of the hippocampus leave sensory preconditioning intact: implications for models of hippocampal function. Behav Neurosci 115(6):1357–1362
Will B, Galani R, Kelche C, Rosenzweig MR (2004) Recovery from brain injury in animals: relative efficacy of environmental enrichment, physical exercise or formal training (1990–2002). Prog Neurobiol 72(3):167–182. doi:10.1016/j.pneurobio.2004.03.001
Windisch M (2000) Approach towards an integrative drug treatment of Alzheimer’s disease. J Neural Transm Suppl 59:301–313
Wirtshafter D (2005) Cholinergic involvement in the cortical and hippocampal Fos expression induced in the rat by placement in a novel environment. Brain Res 1051(1–2):57–65. doi:10.1016/j.brainres.2005.05.052
Wolff M, Gibb SJ, Dalrymple-Alford JC (2006) Beyond spatial memory: the anterior thalamus and memory for the temporal order of a sequence of odor cues. J Neurosci 26(11):2907–2913
Wolff M, Gibb SJ, Cassel JC, Dalrymple-Alford JC (2008a) Anterior but not intralaminar thalamic nuclei support allocentric spatial memory. Neurobiol Learn Mem 90(1):71–80
Wolff M, Loukavenko EA, Will BE, Dalrymple-Alford JC (2008b) The extended hippocampal-diencephalic memory system: enriched housing promotes recovery of the flexible use of spatial representations after anterior thalamic lesions. Hippocampus 18(10):996–1007. doi:10.1002/hipo.20457
Zangenehpour S, Chaudhuri A (2002) Differential induction and decay curves of c-fos and zif268 revealed through dual activity maps. Brain Res Mol Brain Res 109(1–2):221–225
Acknowledgments
We are grateful to Dr Moessler of EBEWE Arzneimittel, Austria, for supply and unrestricted use of cerebrolysin used in this study. EAL received personal support from the Foundation for Research Science and Technology, New Zealand. The authors are also grateful for financial support from the Health Research Council of New Zealand, the Neurological Foundation of New Zealand, and the University of Canterbury, New Zealand.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding authors
Additional information
E. A. Loukavenko and M. Wolff contributed equally.
Rights and permissions
About this article
Cite this article
Loukavenko, E.A., Wolff, M., Poirier, G.L. et al. Impaired spatial working memory after anterior thalamic lesions: recovery with cerebrolysin and enrichment. Brain Struct Funct 221, 1955–1970 (2016). https://doi.org/10.1007/s00429-015-1015-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00429-015-1015-x