Brain networks can support learning by promoting acquisition of task-relevant information or by adhering to validated rules, but the mechanisms involved are poorly understood. Upon learning, local inhibitory parvalbumin (PV)-expressing Basket cell networks can switch to opposite configurations that either favor or interfere with further learning, but how this opposite plasticity is induced and relates to distinct learning requirements has remained unclear. Here, we show that PV Basket cells consist of hitherto unrecognized subpopulations, with distinct schedules of neurogenesis, input connectivities, output target neurons, and roles in learning. Plasticity of hippocampal early-born PV neurons was recruited in rule consolidation, whereas plasticity of late-born PV neurons was recruited in new information acquisition. This involved regulation of early-born neuron plasticity specifically through excitation, and of late-born neuron plasticity specifically through inhibition. Therefore, opposite learning requirements are implemented by distinct local networks involving PV Basket cell subpopulations specifically regulated through inhibition or excitation.

Long-term consolidation of memories depends on processes occurring many hours after acquisition. Whether this involves plasticity that is specifically required for long-term consolidation remains unclear. We found that learning-induced plasticity of local parvalbumin (PV) basket cells was specifically required for long-term, but not short/intermediate-term, memory consolidation in mice. PV plasticity, which involves changes in PV and GAD67 expression and connectivity onto PV neurons, was regulated by cAMP signaling in PV neurons. Following induction, PV plasticity depended on local D1/5 dopamine receptor signaling at 0-5 h to regulate its magnitude, and at 12-14 h for its continuance, ensuring memory consolidation. D1/5 dopamine receptor activation selectively induced DARPP-32 and ERK phosphorylation in PV neurons. At 12-14 h, PV plasticity was required for enhanced sharp-wave ripple densities and c-Fos expression in pyramidal neurons. Our results reveal general network mechanisms of long-term memory consolidation that requires plasticity of PV basket cells induced after acquisition and sustained subsequently through D1/5 receptor signaling.

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Psychosocial stress-particularly in combination with genetic vulnerability-is a critical environmental risk factor for psychiatric diseases in humans. Isolation rearing (IR) and social defeat (SD) paradigms model psychosocial risk factors in rodents, while enriched environment (EE) protects them from behavioural deficits. Studying the influence of various environmental conditions, e.g., on genetic mouse models can help to dissect the complex gene-environment relationships underlying human psychiatric diseases. Such studies may require analysing multiple mouse cohorts; however, the comparability of behavioural experiments is challenging and often compromised by practical limitations such as group sizes and influences of handling. Therefore, protocol standardization as well as appropriate statistical normalization is necessary to compare different experiments. In this study, we analysed two independent cohorts to compare the behavioural profiles of wild-type male mice subjected to IR and SD. In both cases, EE conditions served as a reference. Multivariate statistics was applied to merge the data from individual measures into broader categories (such as curiosity, anxiety and fear memory) by estimating their calibrated joint effect within a category. Plotting and overlaying these calibrated effect sizes in a single graph allowed intuitive comparison of IR and SD behavioural profiles. This approach allows analysing multiple behavioural tests at once, which is more relevant to psychiatric syndromes than focusing on single behavioural measures. Our method revealed that motivation and fear memory are impaired by both conditions, whereas ambulation and pain sensitivity are affected only by IR and curiosity is mainly diminished upon SD. Thus, IR could be a paradigm of choice in studies focusing on positive symptoms, while SD might be more relevant for negative and cognitive symptoms.

No abstract

Repeated experiences may be integrated in succession during a learning process, or they may be combined as a whole within dedicated time windows to possibly promote quality control. Here we show that in Pavlovian, incremental and incidental learning, related information acquired within time windows of 5 h is combined to determine what mice learn. Trials required for learning had to occur within 5 h, when learning-related shared cues could produce association and interference. Upon acquisition, cFos expression was elevated during 5 h throughout specific system-wide neuronal assemblies. Time window function depended on network activity and cFos expression. Local cFos activity was required for distant assembly recruitment through network activity and distant BDNF. Activation of learning-related cFos assemblies was sufficient and necessary for time window function. Therefore, learning processes consist of dedicated 5 h time windows (time units for learning), involving maintenance of system-wide neuronal assemblies through network activity and cFos expression.

No abstract

The transcription factor TCF4 was confirmed in several large genome-wide association studies as one of the most significant schizophrenia (SZ) susceptibility genes. Transgenic mice moderately overexpressing Tcf4 in forebrain (Tcf4tg) display deficits in fear memory and sensorimotor gating. As second hit, we exposed Tcf4tg animals to isolation rearing (IR), chronic social defeat (SD), enriched environment (EE), or handling control (HC) conditions and examined mice with heterozygous deletion of the exon 4 (Tcf4Ex4δ+/−) to unravel gene-dosage effects. We applied multivariate statistics for behavioral profiling and demonstrate that IR and SD cause strong cognitive deficits of Tcf4tg mice, whereas EE masked the genetic vulnerability. We observed enhanced long-term depression in Tcf4tg mice and enhanced long-term potentiation in Tcf4Ex4δ+/− mice indicating specific gene-dosage effects. Tcf4tg mice showed higher density of immature spines during development as assessed by STED nanoscopy and proteomic analyses of synaptosomes revealed concurrently increased levels of proteins involved in synaptic function and metabolic pathways. We conclude that environmental stress and Tcf4 misexpression precipitate cognitive deficits in 2-hit mouse models of relevance for schizophrenia.