Barnett, S.C.

Dalrymple-Alford, J.C.

Hamilton, J.J.

Mercer, S.A.

Perry, B.A.L.

UC Research Repository

Unequal effects of anterior thalamic nuclei and mammillothalamic tract lesions  B.A,L. Perry1, S.A. Mercer1, S.C. Barnett1 , J.J. Hamilton1 and J.C. Dalrymple-Alford 1,2,3  1Department of Psychology, 2Brain Research New Zealand, University of Canterbury, Christchurch New Zealand 3New Zealand Brain research Institute, Christchurch, New Zealand  Introduction Methods Results Methods Results Conclusions               MM MM ML ML L L - 4.52               MM MM ML ML L L - 4.8 - 4.8 - 4.52 IEG expression (zif268) NeuN cell counts in the MB Histology Postsurgery Behaviour Post surg. Water maze Working Memory Three radial arm maze tasks Reduced IEG expression (zif268) Figure 5. #1 Reference memory (12 days) Fixed platform location. Four trials a day, four start points. Figure 6. #2 Working memory (12 days) Platform varied between daily sessions. Four trials a day, from three start points (Trial 1 & 2 same start point). Fig  12. ATN Lesion Example of a control (left) and 1of 8 ATN lesions (right). NeuN stain. Anterior Cingulate Cortex Hippocampal Formation Retrosplenial Cortex ATN MB Fornix MTT Figure 14. ATN, but not MTT lesions, impaired reference memory (p’s<0.001 c.f. control and MTT).  Fig 13.  MTT Lesion example of a control (left) and 1 of 9 complete bilateral MTT lesion (right). Luxol blue + Cresyl violet stain. Figure 1. The extended hippocampal system in the human brain (Adapted from Child and Benarroch, 2013). This system is relevant to memory loss in neurodegenerative disorders stroke and KS. Figure 10.  ROI’s for zif268 IHC. In retrosplenial cortex, a key site in the extended hippocampal system (left) photomicrographs indicate subregions and layers of the retrosplenial cortex (right). Figure 11. ROI’s for NeuN IF. MTT lesions remove the primary efferents of the MB, and ATN lesions the primary efferent target. MB integrity was examined with the neuron specific marker NeuN in three subregions) at two AP coordinates (left). MM = medial mammillary nucleus, ML = medial lateral mammillary nucleus, L = lateral mammillary nucleus. The  anterior thalamic nuclei (ATN), and the mammillothalamic tract (MTT) projection to the ATN from the mammillary bodies (MB), are key parts of the extended hippocampal system. The MTT are associated with diencephalic amnesia after stroke, whereas a combination of ATN degeneration and MB injury is associated with the amnesic Korsakoff’s syndrome. Separate rat studies suggest that ATN lesions may produce more severe memory deficits than MTT lesions. Here, for the first time, the effects of ATN and MTT lesions were directly contrasted on spatial memory tasks and the functional integrity of other structures in the extended hippocampal circuit. Figure 17. ATN and MTT lesions substantially reduced zif268 in the superficial layers of granular b (Rgb) (p<0.001). Only ATN lesions reduced zif268 expression in the deep Rgb (p<0.01). Figure 18. ATN and MTT lesions reduced zif268 in the superficial layers of granular b (p<0.001) in a graded fashion ATN<MTT (p<0.001). However, only ATN lesions reduced zif268 in the deep Rgb, (p<0.001), deep dysgranular (Rdg) (p<0.05) and the superficial Rga regions (p<0.02). Dorsal hippocampus ATN lesions and MTT lesions reduced zif268 expression in CA1 only in a graded fashion ATN<MTT (p<0.001). Anterior cingulate Only ATN lesions reduced zif268 expression in the anterior cingulate cortex (p<0.05 c.f. control). Reduced NeuN Counts in the MB Figure 20. NeuN staining in the mammillary bodies. In MB subregions of a control, MTT and ATN rat at ~ bregma – 4.8. Figure 19. ATN and especially MTT lesions reduced overall NeuN positive cell counts in the MB. Figure 15. Both ATN and MTT lesions equally impaired performance (p< 0.001) Retrosplenial granular b (Rgb) Retrosplenial dysgranular (Rdg) Anterior Cingulate CA1 Dentate gyrus Retrosplenial granular a (Rga) Post Subiculum Auditory Cortex (control) Key Figure 7. #3 Standard working memory (12 days) Same as presurgery Figure 9. #4b Rotation task (example) (4 days) Maze rotated 45ᵒ during the 60 sec delay. Figure 8. #4a Delay task (example) (4 days) 60 sec delay mid-trial after 4 visits. Fig 16. A graded lesion effect was found: ATN lesions produced significantly more errors than MTT lesions across conditions (p’s<0.05). But both ATN and MTT rats made substantially more errors than controls across conditions (p’s<0.001). • These findings suggest that amnesia associated with MTT lesions in humans may depend on the extent of direct additional injury to the ATN and/or other adjacent nuclei.  • ATN and MTT lesions do not  result in equivalent spatial memory impairments.  • ATN lesions produced greater impairments  in reference memory in the water maze and in the RAM. • ATN lesions resulted in greater and more widespread zif268 hypoactivation than MTT lesions, in extended hippocampal structures.  • Mammillary body atrophy is more severe following MTT, than ATN lesions.  MM ML LM 5µm Control MTT ATN # * # # # Post surg. Water maze Reference Memory MTT Lesion Intact MTT Post commissural fornix ~bregma -3.3             AM AV AD ~bregma -1.3 60secs Rotation  + 60secs           Rgb Rdg              Rdg Rgb Rga Superficial Deep Deep Superficial Rostral Caudal -0.4 - 3.6 - 5.8 - 6.8 Rostral Retrosplenial Caudal Retrosplenial # * 0 1000 2000 3000 Rgb sup Rgb deep Rdg sup Rdg deep Rga sup Rga deep Zif268 postive cells per mm2 Control MTT ATN * * # # * Fx MTT Re VRe VM VM MTT Fx VPM VPL LDVL Po VPM  MD LDVL CM VPL Po MD Hb LDDM Hb LPMR PC PC CL CL LDDM iml iml OPC OPC PVP IMD LPMR AM AVVL AD AD Re Rt Rt Re AMV AVDM AVDM AVVL PVA AM AMV PT PT PC PC Surgery Figure 3. MTT lesion.  Site of radiofrequency MTT lesions (red; n = 16) . Control (n = 14) Figure 2. ATN lesion. Target site for neurotoxic (NMDA) ATN lesions (orange, blue & green) (n = 14).  Control (n = 11). (Paxino’s & Watson, 1998) anteromedial nuclei fornix mammillothalamic tract Key thalamic structures anteroventral nuclei anterodorsal nuclei Figure 4. Standard working memory (12 days) All eight arms baited: find all eight baits without re-visits. Used to equate spatial memory for surgery groups Behaviour Presurgery Radial arm maze Water maze Radial arm maze References: Aggleton JP, Dumont JR, Warburton EC. (2011) Unravelling the contributions of the diencephalon to recognition memory: a review. Learn Mem, 18:384-400.: Carlesimo, G. A., Lombardi, M. G., & Caltagirone, C. (2011). Vascular thalamic amnesia : A reapprasial. Neuropsychologica, 49, 777-789; Child ND, Benarroch EE. (2013). Anterior nucleus of the thalamus: functional organization and clinical implications. Neurology; 81:1869-1876; Paxinos, G., & Watson, C. (1998). The rat brain in stereotaxic coordinates (4th ed.). San Diego: Academic Press. Cortical control region No differences in the control region (p = 0.14).  # # # ^ * p <0.05, ^ p< 0.01,  # p < 0.001 # # # # # 

Unequal effects of anterior thalamic nuclei and mammillothalamic tract lesions

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Unequal effects of anterior thalamic nuclei and mammillothalamic tract lesions

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