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). Last but not least, we investigated whether the circuit mechanisms of memory consolidation and plasticity might be affected in a genetic mouse model of schizophrenia. We discovered that they not only are dramatically and specifically affected in a network that had been implicated in mental health by previous studies, but that their pharmacological rescue within that same network during a critical period late in adolescence is sufficient to produce a long-lasting rescue of cognition in this model of high-penetrance schizophrenia. These results suggest that a severe mental health condition such as schizophrenia might be treatable upon targeting of specific network deficits during a critical period late in adolescence, when patients exhibit first episode of their condition (Mukherjee et al., Cell, 2019).
In summary, our specific approach focusing on circuit and network mechanisms of memory-related plasticity has yielded novel insights into network mechanisms of flexible learning in the brain. In parallel, the same approach led to novel insights into network mechanisms leading to schizophrenia, uncovering a potential approach for long-lasting treatment of this severe and chronic condition. These findings were disseminated through publications addressing broad audiences of scientists, as well as through international Conferences and releases to the press.
