A Locus Coeruleus- dorsal CA1 dopaminergic circuit modulates memory linking

Abstract

SummaryIndividual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and this is known to depend on temporary increase in excitability that drive the overlap between dorsal CA1 (dCA1) hippocampal ensembles encoding the linked memories. Here, we show that the Locus Coeruleus (LC) cells projecting to dCA1 have a key permissive role in contextual memory linking, without affecting contextual memory formation, and that this effect is mediated by dopamine and not by noradrenaline. Additionally, we found that LC to dCA1 projecting neurons modulate the excitability of dCA1 neurons, and the extent of overlap between dCA1 memory ensembles, as well as the stability of coactivity patterns within these ensembles. This discovery of a neuromodulatory system that specifically affects memory linking without affecting memory formation, reveals a fundamental separation between the brain mechanisms that modulate these two distinct processes.

Distinct catecholaminergic pathways projecting to hippocampal CA1 transmit contrasting signals during navigation in familiar and novel environments

“…In our experiment, exposure to a novel environment caused an increase in LC axon activity but not in VTA DA axon activity, supporting findings that novel experiences induce activity of LC neurons [Takeuchi et al, 2016 ]. The activity of LC neurons in turn increases hippocampal neuron activity [Wagatsuma et al, 2018 ], increases efficacy of Schaffer Colateral synapses [Takeuchi et al, 2016 ], stabilizes place cells across days [Wagatsuma et al, 2018 ] and memory persistence [Wagatsuma et al, 2018, Takeuchi et al, 2016, Chowdhury et al, 2022 through dopamine receptor dependent mechanisms. Importantly, while LC inputs to CA1 have been shown to cause an increase in activity [Wagatsuma et al, 2018, Chowdhury et al, 2022, shape over-representation of novel reward locations [Kaufman et al, 2020 ], and modulate memory linking [Chowdhury et al, 2022 ], they have not been shown to play a role in the formation of contextual memories [Chowdhury et al, 2022 ] or stabilization of place cell maps across days [Wagatsuma et al, 2018 ] in dCA1.…”

“…The activity of LC neurons in turn increases hippocampal neuron activity [Wagatsuma et al, 2018 ], increases efficacy of Schaffer Colateral synapses [Takeuchi et al, 2016 ], stabilizes place cells across days [Wagatsuma et al, 2018 ] and memory persistence [Wagatsuma et al, 2018, Takeuchi et al, 2016, Chowdhury et al, 2022 through dopamine receptor dependent mechanisms. Importantly, while LC inputs to CA1 have been shown to cause an increase in activity [Wagatsuma et al, 2018, Chowdhury et al, 2022, shape over-representation of novel reward locations [Kaufman et al, 2020 ], and modulate memory linking [Chowdhury et al, 2022 ], they have not been shown to play a role in the formation of contextual memories [Chowdhury et al, 2022 ] or stabilization of place cell maps across days [Wagatsuma et al, 2018 ] in dCA1. However, it is possible this novelty induced activity in LC inputs to dCA1 impacts the formation of instant place fields observed in novel environments [Sheffield et al, 2017, Dong et al, 2021.…”

Postsynaptic burst reactivation of hippocampal neurons enables associative plasticity of temporally discontiguous inputs

“…Interestingly, it was recently reported that DA released by LC cells projecting to dCA1 have a key permissive role in contextual memory linking (Chowdhury et al, 2021). Moreover, the rule could also accommodate a temporally discontiguous instructive learning signal or a specific supervisory feedback signal.…”

Intrinsic neural excitability induces time-dependent overlap of memory engrams

“…As a result, time-varying excitability may account for overlapping neural ensembles encoding memories of events that are temporally linked (Sehgal et al ., 2018), namely events spaced by a short temporal delay, as observed in the lateral amygdala (Rashid et al ., 2016), the hippocampal dorsal CA1 (Cai et al ., 2016; Shen et al ., 2022), and the retrosplenial cortex (Sehgal et al ., 2021). Previous theoretical works have described how the dynamics of plasticity-related proteins and excitability can lead to co-allocation of memories at the dendritic level (Kastellakis et al ., 2016; Sehgal et al ., 2021; Chowdhury et al ., 2021). Attractor networks (Amit, 1989) have been previously used to describe the recurrent network properties of overlapping memory engrams (Gastaldi et al ., 2021) but without taking excitability into account.…”

“…Previous theoretical works have described how the dynamics of plasticity-related proteins and excitability can lead to co-allocation of memories at the dendritic level (Kastellakis et al, 2016;Sehgal et al, 2021;Chowdhury et al, 2021). Attractor networks (Amit, 1989) have been previously used to describe the recurrent network properties of overlapping memory engrams (Gastaldi et al, 2021) but without taking excitability into account.…”