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Functional studies of neuronal assemblies that encode memories have progressed dramatically due to recent technological advances. This review shows how a focus on assembly formation and consolidation provides a powerful conceptual framework to relate mechanistic studies of synaptic, neuronal and circuit plasticity to behaviorally relevant aspects of learning and memory. Learning and memory are associated with the formation and modification of neuronal assemblies: populations of neurons that encode what has been learned and mediate memory retrieval upon recall. Functional studies of neuronal assemblies have progressed dramatically thanks to recent technological advances. Here we discuss how a focus on assembly formation and consolidation has provided a powerful conceptual framework to relate mechanistic studies of synaptic and circuit plasticity to behaviorally relevant aspects of learning and memory. Neurons are likely recruited to particular learning-related assemblies as a function of their relative excitabilities and synaptic activation, followed by selective strengthening of pre-existing synapses, formation of new connections and elimination of outcompeted synapses to ensure memory formation. Mechanistically, these processes involve linking transcription to circuit modification. They include the expression of immediate early genes and specific molecular and cellular events, supported by network-wide activities that are shaped and modulated by local inhibitory microcircuits.

Prefrontal cortical areas mediate flexible adaptive control of behavior, but the specific contributions of individual areas and the circuit mechanisms through which they interact to modulate learning have remained poorly understood. Using viral tracing and pharmacogenetic techniques, we show that prelimbic (PreL) and infralimbic cortex (IL) exhibit reciprocal PreL↔IL layer 5/6 connectivity. In set-shifting tasks and in fear/extinction learning, activity in PreL is required during new learning to apply previously learned associations, whereas activity in IL is required to learn associations alternative to previous ones. IL→PreL connectivity is specifically required during IL-dependent learning, whereas reciprocal PreL↔IL connectivity is required during a time window of 12–14 h after association learning, to set up the role of IL in subsequent learning. 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. Prelimbic (PL) and infralimbic (IL) cortical areas are known to have complementary roles in learning and decision making. Here the authors report reciprocal connectivity between the two areas and elucidate their functional impact on different aspects of learning.

Key Points Recent advances have provided evidence that the loss of pre-existing synapses and the assembly and retention of new synapses may be integral components of behavioural learning and memory processes. Specific synapse gains and losses have been related conclusively to animal learning and to structural traces of the learning. Causality relationships between the new assembly of identified synapses upon learning and the behavioural expression of the learned memories could be established in at least one case. Learning triggers enhanced synapse turnover, and repeated training produces a selective long lasting retention of some of the new synapses. These are frequently clustered spatially. Mutations in many gene products important for synapse stabilization are associated with mental retardation and psychiatric conditions. Long-term potentiation experiments in slice cultures have revealed that new synapses tend to be retained in spatial clusters, suggesting mechanisms of local co-regulation for synapses that may involve the same or related learning-related memories. Behaviourally related synapses are assembled and lost within spatially close (<2 μm) stretches of dendrites in vivo , suggesting that they may encode specific memories. Enhanced plasticity promoting learning, for example, upon environmental enrichment, involves higher rates of both synapse assembly and disassembly. The presence of larger numbers of dynamic synapses before learning may facilitate learning. Reducing inhibition enhances plasticity, and augmenting inhibition closes critical periods of increased plasticity during early postnatal life. Likewise, enhancing excitation also enhances plasticity. In the adult, plasticity is reduced by molecular mechanisms that function as 'brakes' on plasticity. Structural plasticity involving inhibitory neurons can precede that by excitatory neurons and may have a critical role in regulating circuit plasticity during learning. Mechanisms regulating plasticity during critical periods of development and in the adult may involve similar major roles for inhibitory connectivity regulation. Challenges for future research include: defining the relationships between gains and losses of identified individual synapses upon learning, and the memory of what was learned at the microcircuit and systems level; and relating genes involved in psychiatric conditions to synapse and microcircuit remodelling upon learning under control and disease conditions. Future progress will depend on methods to monitor the structure and function of synaptic networks in vivo , as well as on the development of synaptic network models that combine changes in synaptic function and connectivity. Behavioural learning is accompanied by loss and gain of synapses, which is thought to be the mechanism by which circuits are altered and 'memory traces' established. Recent research, reviewed here, suggests that learning and memory events involve the rearrangement of ensembles of adjacent synapses on short stretches of dendrites. Recent studies have provided long-sought evidence that behavioural learning involves specific synapse gain and elimination processes, which lead to memory traces that influence behaviour. The connectivity rearrangements are preceded by enhanced synapse turnover, which can be modulated through changes in inhibitory connectivity. Behaviourally related synapse rearrangement events tend to co-occur spatially within short stretches of dendrites, and involve signalling pathways partially overlapping with those controlling the functional plasticity of synapses. The new findings suggest that a mechanistic understanding of learning and memory processes will require monitoring ensembles of synapses in situ and the development of synaptic network models that combine changes in synaptic function and connectivity.

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. Learning often involves multiple exposures and trials, but it is not known whether those are treated independently, or integrated during dedicated time windows. Here, Chowdhury and Caroni show mice learn new associations during 5 h time windows, where related experiences are integrated in a process requiring coordinated cFos-activated neuronal assemblies.

In adult animals, fear conditioning induces a permanent memory that is resilient to erasure by extinction. In contrast, during early postnatal development, extinction of conditioned fear leads to memory erasure, suggesting that fear memories are actively protected in adults. We show here that this protection is conferred by extracellular matrix chondroitin sulfate proteoglycans (CSPGs) in the amygdala. The organization of CSPGs into perineuronal nets (PNNs) coincided with the developmental switch in fear memory resilience. In adults, degradation of PNNs by xnondroitinase ABC specifically rendered subsequently acquired fear memories susceptible to erasure. This result indicates that intact PNNs mediate the formation of erasure-resistant fear memories and identifies a molecular mechanism closing a postnatal critical period during which traumatic memories can be erased by extinction.

This study shows that a mouse's trial-and-error learning in the Morris water maze is mediated by a stereotyped sequence of hippocampus activation along its ventral-to-dorsal axis. Using anatomical or molecular lesions and a previously validated morphological readout of mossy fiber circuit refinement, the authors show that the ventral hippocampus in mice has an early role in goal-oriented learning and searching. Most behavioral learning in biology is trial and error, but how these learning processes are influenced by individual brain systems is poorly understood. Here we show that ventral-to-dorsal hippocampal subdivisions have specific and sequential functions in trial-and-error maze navigation, with ventral hippocampus (vH) mediating early task-specific goal-oriented searching. Although performance and strategy deployment progressed continuously at the population level, individual mice showed discrete learning phases, each characterized by particular search habits. Transitions in learning phases reflected feedforward inhibitory connectivity (FFI) growth occurring sequentially in ventral, then intermediate, then dorsal hippocampal subdivisions. FFI growth at vH occurred abruptly upon behavioral learning of goal-task relationships. vH lesions or the absence of vH FFI growth delayed early learning and disrupted performance consistency. Intermediate hippocampus lesions impaired intermediate place learning, whereas dorsal hippocampus lesions specifically disrupted late spatial learning. Trial-and-error navigational learning processes in naive mice thus involve a stereotype sequence of increasingly precise subtasks learned through distinct hippocampal subdivisions. Because of its unique connectivity, vH may relate specific goals to internal states in learning under healthy and pathological conditions.

Memories made with precision Learning and memory tasks are associated with the addition of new synapses in the brain, but the function of this structural plasticity is not clear. A study of the rearrangement of circuits within the hippocampus and cerebellum in response to learning reveals a robust, long-lasting and reversible increase in the number of synapses that trigger feedforward inhibition. This synapse growth has a vital role in maintaining the precision of the memory and the learned behaviour. In the adult brain, new synapses are formed and pre-existing ones are lost, but the function of this structural plasticity has remained unclear 1 , 2 , 3 , 4 , 5 . Learning of new skills is correlated with formation of new synapses 6 , 7 , 8 . These may directly encode new memories, but they may also have more general roles in memory encoding and retrieval processes 2 . Here we investigated how mossy fibre terminal complexes at the entry of hippocampal and cerebellar circuits rearrange upon learning in mice, and what is the functional role of the rearrangements. We show that one-trial and incremental learning lead to robust, circuit-specific, long-lasting and reversible increases in the numbers of filopodial synapses onto fast-spiking interneurons that trigger feedforward inhibition. The increase in feedforward inhibition connectivity involved a majority of the presynaptic terminals, restricted the numbers of c-Fos-expressing postsynaptic neurons at memory retrieval, and correlated temporally with the quality of the memory. We then show that for contextual fear conditioning and Morris water maze learning, increased feedforward inhibition connectivity by hippocampal mossy fibres has a critical role for the precision of the memory and the learned behaviour. In the absence of mossy fibre long-term potentiation in Rab3a −/− mice 9 , c-Fos ensemble reorganization and feedforward inhibition growth were both absent in CA3 upon learning, and the memory was imprecise. By contrast, in the absence of adducin 2 (Add2; also known as β-adducin) 10 c-Fos reorganization was normal, but feedforward inhibition growth was abolished. In parallel, c-Fos ensembles in CA3 were greatly enlarged, and the memory was imprecise. Feedforward inhibition growth and memory precision were both rescued by re-expression of Add2 specifically in hippocampal mossy fibres. These results establish a causal relationship between learning-related increases in the numbers of defined synapses and the precision of learning and memory in the adult. The results further relate plasticity and feedforward inhibition growth at hippocampal mossy fibres to the precision of hippocampus-dependent memories.

This study shows that learning-induced plasticity of local parvalbumin (PV) basket cells is specifically required for long-term, but not short to intermediate-term, memory consolidation in mice. PV plasticity depends on local D1/5 dopamine receptor signaling 12–14 h after acquisition for its continuance, ensuring enhanced sharp-wave ripple densities and memory consolidation. 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.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.