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Network representations of contextual memory in a neocortical circuit

Periodic Reporting for period 1 - RSCmemory (Network representations of contextual memory in a neocortical circuit)

Reporting period: 2018-04-01 to 2020-03-31

How are memories stored in the brain and how do we remember? Since the famous case of patient ‘H.M.’ who, in the 1950’s, underwent surgical removal of both hippocampi to treat intractable epilepsy, we know that the hippocampus is important for memory. According to the classical model of memory encoding and retrieval, memories that initially depend on the hippocampus, mature over time, and become increasingly dependent on distributed networks in the neocortex. While there has been great progress in understanding the molecular and genetic substrates of memory, how memories are represented by neuronal ensembles is still poorly understood. To study how the neocortex supports memories, we studied a circuit called the retrosplenial cortex (RSC). This structure receives dense and direct input from the hippocampus and is therefore a key network to study memory. By combining chronic two-photon calcium imaging and electrophysiological recordings in vivo we provide new insights into how memories are represented in cortical neuronal ensembles.

The objectives of the project were:
- O1: Characterizing network activity in the RSC during memory processing.
- O2: Characterizing hippocampal-cortical interactions during memory processing.
- O3: Elucidating whether RSC activity is critical to memory processing.
O1: What is the network activity of RSC during memory processing?
Using two-photon calcium imaging and mouse behavior, we found that a proportion of neuronal responses in the RSC respond either to the presentation of sensory stimuli or to specific time points between the presented stimuli. While responses to sensory stimuli were relatively reliable over days, neuronal responses representing temporal information varied at a timescale of hours to days. The representation of temporal information between the presented sensory stimuli was context-dependent. Thus, neuronal responses differed depending on the identity of the preceding sensory stimulus.

O2: What is the relationship between the hippocampus and RSC during memory processing?
By recording hippocampal oscillations and simultaneously imaging neurons in the RSC we showed that the presentation of sensory stimuli not only evoke neuronal discharges in RSC, but also synchronize neuronal oscillations in the hippocampus. Thus, responses in RSC are phase-locked to hippocampal oscillations.

O3: Is RSC activity critical for memory processing?
Silencing neuronal activity in the RSC did not reveal a clear effect on memory performance. In other words, diminished RSC activity does not lead to worse memory performance. Mouse behavior underlying memory processing in our study therefore does not critically depend on RSC activity. However, we found that silencing neuronal activity in the medial septum, the brain’s theta rhythm generator (also see O2), diminishes the strength of hippocampal theta oscillations. In addition, diminished strength of hippocampal theta oscillations the decreases the overall number of RSC neurons that process sensory and temporal information, respectively. Thus, memory processing in the RSC is mediated by hippocampal oscillatory activity at 4-8
Alongside space, we hypothesize that our findings allow for the temporal organization of episodic memories. Understanding how temporal context is represented in the RSC may lead to new insights into the mechanisms of disturbed memory processing during ageing. Notably, evidence of functional abnormalities in the RSC during early stages of Alzheimer’s disease suggest that the RSC is linked to the observed early cognitive abnormalities.

This work enabled a detailed investigation of memory processing. It relied on mechatronics for precise stimulus control, genetic methods to dissect cortical circuits in vivo and advanced analysis tools. In addition, this is one of the first studies using simultaneous electrophysiological recordings of the hippocampus while imaging large populations of neocortical cells in behaving animals. The results of this project therefore advance our understanding of memory processing in neuronal ensembles of the RSC.

We are fortunate that Europeans see an increasing life expectancy due to advances in our health care system. However, this comes at a cost. We will also see an increasing number of elderly affected by disorders of age, such as Alzheimer’s disease. This introduces great burdens to the affected individual and family but also to European society in general. This project supports developing a critical mass to manifest Norway’s, and thus Europe’s, leading role in memory research to find new approaches in fighting neurodegenerative diseases.
Figure for project RSCmemory 800104