Ventral midline thalamus and systems-level consolidation of spatial memories – THALAME

Four partners will decipher the role played by ReRh in memory persistence. The establishment of a spatial memory requires accurate early information processing during goal-oriented navigation. Therefore, electrophysiological recordings of place cells in the HIP and of goal-encoding cells in the mPFC will be performed in rats with permanent, fiber-sparing ReRh lesions. We will also examine how the ReRh is functionally connected with both the HIP and the mPFC to promote spatial memory persistence and/or retrieval. To do so, we will combine tract-tracing, including state-of-the-art viral-mediated monosynaptic tracing, and cellular imaging techniques. Retrieval of remote memory is accompanied by an engagement of the mPFC. This engagement could be disrupted after ReRh lesions, which effects will be investigated using immediate early-gene expression (c-fos, zif268, arc). Consolidation is supported by neuronal network remodeling which implies formation of new synapses in the mPFC when memories become remote. Thus, recent and remote memory-related synapse formation will be assessed in the mPFC and HIP after ReRh lesions. Systems-level consolidation seems to involve adult-generated hippocampal neurons. As ReRh projections to the HIP (on CA1) could participate in the regulation of hippocampal neurogenesis or/and in the recruitment of newly formed neurons, the impact of ReRh lesions on neurogenesis and new neurons maturation will be explored (preliminary results suggest an impact of ReRh lesions on the maturation of new neurons). Consolidation and memory persistence is supported by epigenetic regulations such as histone acetylation on chromatin. As ReRh lesions could disrupt such regulations, their epigenetic effects will be investigated in the mPFC and the HIP. When relevant, the aforementioned ReRh lesion-induced changes will be assessed under baseline and spatial learning conditions.

Partner 1 (Strasbourg): The effects of a ReRh lesion on memory persistence have been confirmed. When rats have been enriched (physically + socially) during 40 postsurgical days, the lesion effect is reduced. Immediate early gene quantification has shown that enrichment changed the functional balance between the mPFC, the HIP and the amygdala. Results on dendritic spines analyses suggest that ReRh lesions prevent the increase of synaptic contacts in the prefrontal cortex and their persistence at an increased level in the hippocampus.
Partner 2 (Marseille): Hippocampal place cells activity has been recorded in rats after ReRh lesions during a continuous exploration task in a familiar or unfamiliar arena. ReRh lesions have no effect on baseline characteristics of the place cells. However, they change the stability of spatial representations implemented by place cells.
Partner 3 (Toulouse): Research on neurogenesis has just started. Rats have been operated on in Strasbourg and brain sections transferred to Toulouse for staining and analyses.
Partner 4 (Bordeaux): Using methods of descriptive neuroanatomy to characterize the cortical connectivity of the thalamus, this partner has found a region adjacent to the reuniens, the submedius nucleus, of which the functional contribution has been evaluated. It is involved in the flexible use of predictive cues regarding a goal. This partner now concentrates on the ReRh nuclei.

Partner 1: Will complete stereological quantifications and progress in the counting of hippocampal and cortical spines after ReRh lesions in the rat. We will go on with the preparation of the rats for the evaluation of neurogenesis as well as the molecular biology studies dealing with histone acetylation.
Partner 2: Has finished all hippocampal recordings, analyses are underway, and a manuscript encompassing all collected data is in preparation.
Partner 3: Will characterize neurogenesis (proliferation and survival) after a ReRh lesion (tissues send by partner 1) under both baseline and learning conditions.
Partner 4: Will further staining experiments and their quantifications. Discussions will be started with partner 1 to organize behavioral testing coupled to viral disconnection experiments.

* Alcaraz F, Marchand AR, Vidal E, Guillou A, Faugere A, Coutureau E, Wolff M (2015) Journal of Neuroscience 35:13183-13193 (partner 4).
* Alcaraz F, Marchand A, Courtand G, Coutureau E, Wolff M (2016) European Journal of Neuroscience 44 : 1972-1986 (partner 4).
* Cassel JC, Pereira de Vasconcelos A (2015) Progress in Brain Research, Vol 219, pp 145-161 (partner 1).
* Pereira de Vasconcelos A, Cassel JC (2015) Neuroscience & Biobehavioral Reviews 5: 175-196 (partner 1).
* Ali M, Cholvin T, Muller MA, Cosquer B, Cassel JC, Pereira de Vasconcelos A (2017) Neurobiology of Learning and Memory 141: 108-123 (partner 1).
* One manuscript will be submitted in the near future by partner 2.

Our recent and remote memories define both our identity and the range of our knowledge and capabilities. Before becoming lasting, they undergo gradual consolidation, a process supported by changes at both synaptic and systems-levels. We recently discovered that fiber-sparing lesions of the reuniens and rhomboid nuclei (ReRh), which belong to the ventral midline thalamus, alter spatial memory persistence in the Morris water maze, but neither its initial acquisition nor its recent retrieval (Loureiro et al., J Neurosci 32, 2012). Neuroanatomical and electrophysiological evidence (Cassel et al., Prog Neurobiol 111, 2013, for review) place the ReRh in a hub position between the medial prefrontal cortex (mPFC) and the hippocampus (HIP), with which it has reciprocal connections. Therefore, the ReRh are likely to support functional interactions between the mPFC and the HIP, both believed to be essential to systems-level consolidation and memory persistence. While research on memory consolidation is highly competitive, there is currently no other published work regarding the implication of the ReRh nuclei in spatial memory persistence.
Complementary approaches by 4 Partner-laboratories (Strasbourg-UMR7364, Marseille-UMR7291, Toulouse-UMR5169, Bordeaux-UMR5287) will decipher the role played by ReRh in memory persistence. Our objectives are the following: a) the establishment of a spatial memory requires accurate early information processing (encoding, hippocampal-triggered consolidation…); when inaccurate, it could lead to non-lasting memories. In addition, optimal memory performance requires an accurate use of the memory during goal-oriented navigation. Therefore, electrophysiological recordings of place cells in the HIP and of goal-encoding cells in the mPFC will be performed in rats with permanent, fiber-sparing ReRh lesions; b) we will examine how the ReRh is functionally connected with both the HIP and the mPFC to promote spatial memory persistance and/or retrieval. To do so, we will combine tract-tracing, including state-of-the-art viral-mediated monosynaptic tracing, and cellular imaging techniques; c) retrieval of remote memory is accompanied by an engagement of the mPFC. This engagement could be disrupted after ReRh lesions, which effects will be investigated using immediate early-gene expression (c-fos, zif268, arc); d) consolidation is supported by neuronal network remodeling which implies formation of new synapses in the mPFC when memories become remote. Thus, recent and remote memory-related synapse formation will be assessed in the mPFC and HIP after ReRh lesions; e) systems-level consolidation seems to involve adult-generated hippocampal neurons. As ReRh projections to the HIP (on CA1) could participate in the regulation of hippocampal neurogenesis or/and in the recruitment of newly formed neurons, the impact of ReRh lesions on neurogenesis and new neurons maturation will be explored (preliminary results suggest an impact of ReRh lesions on the maturation of new neurons); f) consolidation and memory persistence is supported by epigenetic regulations such as histone acetylation on chromatin. As ReRh lesions could disrupt such regulations, their epigenetic effects will be investigated in the mPFC and the HIP. When relevant, the aforementioned ReRh lesion-induced changes will be assessed under baseline and spatial learning conditions.
This innovative project aims to unravel the mechanisms by which the ReRh nuclei of the ventral midline thalamus do indeed contribute to spatial memory persistence. Our approach could point to these nuclei as an ideal target for deep brain stimulations in future preclinical investigations aiming to improve memory functions after brain disease.