1. WHY ARE THERE PARALLEL HIPPOCAMPAL - DIENCEPHALIC PATHWAYS FOR EVENT MEMORY? Wellcome Trust Project JOHN AGGLETON SHANE O’MARA JONATHAN ERICHSEN SERALYNNE VANN

2. Presentation format Introduction to synaptic plasticity and memory Hippocampal-diencephalic system (HDS) Mammillary bodies (MB) Anterior thalamic nuclei (ATN) Lesion studies Subiculum Overview

3. Synaptic plasticity >> Memory Different types of: memory memory circuits plasticity involved cells synaptic plasticity plasticity induction plasticity cellular targets intracellular mechanisms Plasticity Sjöström and Nelson, Curr Op Neurobiol, 2002 Sjöström and Nelson, Curr Op Neurobiol 2002 Introduction

4. Long term synaptic plasticity in hippocampal related circuits >> Episodic memory Introduction

5. Hippocampus related circuits Introduction

6. Hippocampus related circuits Introduction

7. Hippocampus related circuits Introduction

8. Hippocampal - diencephalic system Lesion studies : the hippocampal - diencephalic system is required for the encoding of episodic information. Still the functional significance of this system for the memory formation is under construction. HDS

9. Significance of the parallel thalamic projections (direct and via MB) Hippocampal –diencephalic circuit (Papez’s circuit): hippocampal formation → MB → anterior thalamus → cingulate cortex → parahippocampal gyrus → hippocampal formation MB are part of the extended hippocampal - diencephalic system HDS

10. Medial & lateral diencephalic systems Rec Stim Rec/Stim HDS

11. Methods and approaches Retrograde markers tracing Lesion application + Behavioural examination (learning tasks) IEG activity immunohistochemistry Field EPSP recording under anaesthesia Field EPSP + Lesion application under anaesthesia EEG under anaesthesia and in freely moving rats Unit recording under anaesthesia and in freely moving rats Others (fMRI, microdialysis) PPF LTP LTD STDP Theta Methodology

12. Medial & lateral diencephalic systems HDS

13. Significance of the parallel thalamic projections (direct and via MB) MMB involvement in spatial working memory tasks: - lesion techniques - c-fos protein expression - cytochrome oxidase (CO) aczivity (Conejo et al., 2004). MB

14. MB lesions – the mildest outcome Spatial deficits after MB damage are not as severe as those found after hippocampectomy and are typically less severe than those associated with ATN damage. Anatomical or functional bypassing possibility? MB

15. MMB coordinates - AP: 4.5 - 5.2 mm MB

16. MB function: relayers of hippocampal theta rhythm - to the ATN and beyond theta-related cells in the MB seem to be driven by descending projections from the hippocampus and are especially correlated with the CA1 theta generators. MB

17. MB function: relayers of hippocampal theta rhythm - to the ATN and beyond Propolsals about the significance of this relay: 1. relaying of theta by the mammillary bodies might reduce interference by helping to separate encoding and retrieval (Hasselmo et al., 2002) 2. theta activity im parallel with head direction processing facilitates the transmission and plasticity of LMN – AD thalamus - retrosplenial information (Vertes et al., 2004). 3. theta oscillations of MMB facilitate the information current in Papez’s circuit MB

18. ATN convergence has a gating effect on theta and its potential to act upon the retrosplenial cortices and back upon the hippocampus. Synaptic plasticity and hippocampo-diencephalic system MB

19. Anterior thalamus and theta Approximately 75% of ventral ANT cells fire synchrony with hippocampal theta rhythm. Active locomotion increases peak firing rates of anterodorsal thalamic head direction cells. The level of locomotor activity provides a statedependent modulation of the response magnitude of AD HD cells (Zugaro et al., 2001). ATN

20. Anterior thalamus nuclei (ATN) ATN

21. ATN coordinates ATN

22. ATN coordinates - AP: 1.4 mm ATN

23. Hippocamal – diencephalic plasticity lesion studies Lesion studies

24. Postcommissural fornix lesions Pilot studies postcommissural fornix lesions. Lesion studies

25. Mammillothalamic tract lesions Vann and Aggleton, 2003; Vann et al., 2003: mammillothalamic tract lesions (MTTx) coordinates of the lesion relative to ear-bar zero were AP +4.2 and L +0.9, and the depth from top of cortex was +6.9 mm. Lesion studies

26. Subiculum – the major challange of the project Subiculum

27. Ventral vs. dorsal subiculum Naber and Witter, 1998 Subiculum

28. Subicular coordinates Transverse sections perpendicular to the long axis of the hippocampal formation (Ishizuka 2001). Subiculum

29. Subicular AP coordinates: 5.2 - 5.6 mm Subiculum

30. AP spatial configuration of all electrodes MM: 4.5 – 5.2 Sub: 5.2 – 5.6 ATN: 1.4 – 2.1 Overview

31. PLASTICITY IN THE PROJECTION FROM THE ATN TO THE ANTERIOR CINGULATE CORTEX (Gemmell and O‘Mara, 2002) Hippocampal - diencephalic plasticity, system approach Overview

32. Regional specific long-term synaptic plasticity Physiological substrate of hippocampal diencephalic plasticity – possible key to the encoding of temporal sequences (episodes). Overview

33. Hippocampal - diencephalic system: basic approach to the episodic memory Overview

34. Thank you for your attention