Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - MemoryDynamics (Writing and editing of memories from acquisition to long-term consolidation)

Teaser

Nervous systems produce adaptive behaviour, arguably their most important function, through learning and memory. Memories ensure that what is learned will be available for later retrieval. Upon the initial learning process, synaptic plasticity important for memory...

Summary

Nervous systems produce adaptive behaviour, arguably their most important function, through learning and memory. Memories ensure that what is learned will be available for later retrieval. Upon the initial learning process, synaptic plasticity important for memory consolidation is triggered within minutes, but whether, and in which form memories will be retained more permanently can be influenced by information and insights gained after the initial trigger. This research program addresses the functional roles of learning-related plasticity processes unfolding subsequent to acquisition in learning and memory. We investigate how hippocampal memories are shaped during several hours after acquisition through network activity and addition of new information through experience, and how these processes involve dedicated neuronal circuits and systems. Furthermore, we study how shaped memories are then long-term consolidated for future use, and how memories are further modified through subsequent learning. This research produces fundamental insights into how learning leads to adaptive behaviour through writing and editing of memories.

Work performed

We have made progress in understanding the role of parvalbumin (PV) interneuron plasticity in the consolidation of memories. We found that learning-induced plasticity of local PV basket cells is specifically required for long-term memory consolidation, presumably to support off-line network activity. Upon induction, PV neuron plasticity depended on local D1/5 dopamine receptor signaling during the first 5h to regulate its magnitude, and at 12-14h after initial acquisition for its sustainment, ensuring memory consolidation. Our results reveal general network mechanisms of long-term memory consolidation requiring plasticity of PV basket cells induced upon acquisition, and sustained subsequently through D1/5 receptor signaling (Karunakaran et al., Nature Neurosci. 2016). In a study addressing network mechanisms of memory consolidation, we investigated whether repeated experiences might be integrated individually as they occur, or whether they might be combined within dedicated time windows, possibly promoting quality control. We discovered that learning processes consist of dedicated 5h time units, involving maintenance of specific system-wide neuronal assemblies through network activity and expression of the immediate early gene cFos (Chowdhury and Caroni, Nature Commun., 2018). We further addressed systems mechanisms of memory consolidation and modification in flexible learning. We focused on the specific contributions of two prefrontal cortical areas, prelimbic (PreL) and infralimbic (IL) cortex. We found that PreL is required during new learning to apply previously learned associations, whereas activity in IL is required to learn associations alternative to the previous ones. Notably, the role of IL for alternative learning was established 12-14h after the initial learning process, that is off-line, presumably through processes of systems consolidation. Our results define specific and opposing roles of PreL and IL to together flexibly support new learning, and provide circuit evidence that IL-mediated learning of alternative associations depends on direct reciprocal PreL<->IL connectivity (Mukherjee and Caroni, Nature Commun., 2018). Furthermore, we investigated whether PV neuron plasticity might be altered in a mouse model of schizophrenia (LgDel+/-), and whether there might exist a sensitive period, possibly at late adolescence, to long-lastingly prevent progression to schizophrenia. We found that adult LgDel+/- mice exhibit evidence of system-wide PV neuron recruitment deficits, which include chronic low-PV plasticity specifically in early-born PV neurons, and recruitment failure upon direct chemogenetic activation of PV neurons or recall of fear memory. Inducing low-PV plasticity in mPFC of adult wildtype mice was sufficient to transiently mimic reduced gamma activity detected in LgDel+/- mice. In the adult, D2R antagonists, drugs with potent antipsychotic properties, rapidly and transiently rescued low-PV plasticity, PV neuron recruitment and cognitive dysfunctions when delivered systemically. The antagonists affected PV neurons globally when delivered locally to vH or mPFC, but only locally when delivered to other brains areas. Notably, repeated D2R antagonist treatment or repeated direct chemogenetic activation of PV neurons locally in vH or mPFC during a 6-10-day time window at late adolescence effectively prevented the escalation of network and cognitive dysfunctions in adult LgDel+/- mice. Our results provide evidence that the emergence of schizophrenia-like dysfunctions in a genetic mouse model can be prevented by targeted interventions that support network recruitment during a sensitive time period at late adolescence. Given the similarities between our findings concerning PV neuron involvement, network dysfunction, late adolescence progression and D2R antagonist responsiveness in LgDel+/- mice and those reported in patients, we suggest that comparable interventions might prevent progression to schizophrenia in at

Final results

We have made inroads in understanding processes of memory consolidation and modification linked to specific neuronal assemblies, their modulation through dopamine signaling, and how specific interactions between dedicated brain areas bring about adaptive flexible learning. In addition to defining the role of subpopulations of neurons within neuronal assemblies for learning and memory, we anticipate to make fundamental progress in elucidating how specific networks of brain areas and their associated neuronal assemblies bring about flexible learning. These cellular and systems studies should provide insights into how brain areas work together to produce flexible adaptive behavior, thereby advancing our understanding of the functional organization of cognition in the brain. We further made important progress in linking PV neuron plasticity to mechanisms underlying cognitive dysfunctions in schizophrenia, and could show that interventions supporting PV neuron plasticity in ventral hippocampus and prefrontal cortex during a sensitive period at late adolescence permanently prevents progression to schizophrenia in a genetic mouse model. Given the close similarities between the genetic mouse model and defects consistently found in patients, these findings suggest that similar strategies targeting the dopamine system and PV neuron plasticity at late adolescence might prevent the outbreak of schizophrenia in at risk patients.