Learning and memory processes can be influenced by recent experience, but the mechanisms involved are poorly understood. Enhanced plasticity during critical periods of early life is linked to differentiating parvalbumin (PV)-interneuron networks, suggesting that recent experience may modulate learning by targeting the differentiation state of PV neurons in the adult. Here we show that environmental enrichment and Pavlovian contextual fear conditioning induce opposite, sustained and reversible hippocampal PV-network configurations in adult mice. Specifically, enrichment promotes the emergence of large fractions of low-differentiation (low PV and GAD67 expression) basket cells with low excitatory-to-inhibitory synaptic-density ratios, whereas fear conditioning leads to large fractions of high-differentiation (high PV and GAD67 expression) basket cells with high excitatory-to-inhibitory synaptic-density ratios. Pharmacogenetic inhibition or activation of PV neurons was sufficient to induce such opposite low-PV-network or high-PV-network configurations, respectively. The low-PV-network configuration enhanced structural synaptic plasticity, and memory consolidation and retrieval, whereas these were reduced by the high-PV-network configuration. We then show that maze navigation learning induces a hippocampal low-PV-network configuration paralleled by enhanced memory and structural synaptic plasticity throughout training, followed by a shift to a high-PV-network configuration after learning completion. The shift to a low-PV-network configuration specifically involved increased vasoactive intestinal polypeptide (VIP)-positive GABAergic boutons and synaptic transmission onto PV neurons. Closely comparable low- and high-PV-network configurations involving VIP boutons were specifically induced in primary motor cortex upon rotarod motor learning. These results uncover a network plasticity mechanism induced after learning through VIP-PV microcircuit modulation, and involving large, sustained and reversible shifts in the configuration of PV basket-cell networks in the adult. This novel form of experience-related plasticity in the adult modulates memory consolidation, retrieval and learning, and might be harnessed for therapeutic strategies to promote cognitive enhancement and neuroprotection.

The contributions of brain networks to information processing and learning and memory are classically interpreted within the framework of Hebbian plasticity and the notion that synaptic weights can be modified by specific patterns of activity. However, accumulating evidence over the past decade indicates that synaptic networks are also structurally plastic, and that connectivity is remodelled throughout life, through mechanisms of synapse formation, stabilization and elimination 1. This has led to the concept of structural plasticity, which can encompass a variety of morphological changes that have functional consequences. These include on the one hand structural rearrangements at pre-existing synapses, and on the other hand the formation or loss of synapses, of neuronal processes that form synapses or of neurons. In this Review we focus on plasticity that involves gains and/or losses of synapses. Its key potential implication for learning and memory is to physically alter circuit connectivity, thus providing long-lasting memory traces that can be recruited at subsequent retrieval. Detecting this form of plasticity and relating it to its possible functions poses unique challenges, which are in part due to our still limited understanding of how structure relates to function in the nervous system.We review recent studies that relate the structural plasticity of neuronal circuits to behavioural learning and memory and discuss conceptual and mechanistic advances, as well as future challenges. The studies establish a number of strong links between specific behavioural learning processes and the assembly and loss of specific synapses. Further areas of substantial progress include molecular and cellular mechanisms that regulate synapse dynamics in response to alterations in synaptic activity, the specific spatial distribution of the syn aptic changes among identified neurons and dendrites and the relative roles of excitation and inhibition in regulating structural plasticity.The new findings provide exciting early vistas of how learning and memory may be implemented at the level of structural circuit plasticity. At the same time, they highlight major gaps in our understanding of plasticity regulation at the cellular, circuit and systems levels. Accordingly, achieving a better mechanistic understanding of learning and memory processes is likely to depend on the development of more effective techniques and models to investigate ensembles of identified synapses longitudinally, both functionally and structurally. Molecular mechanisms of synapse remodellingA remarkable feature of excitatory and inhibitory synapses is their high level of structural variability 2 and the fact that their morphologies and stabilities change over time 3 . This phenomenon is regulated by activity, and the size of spine heads correlates with synaptic strength 4 , presynaptic properties 5 and the long-term stability of the synapse 6 . The morphological characteristics of synapses thus reveal important features of their function and stabilit...

Abstract:The neural representation of space relies on a network of entorhinal-hippocampal cell types with firing patterns tuned to different abstract features of the environment. To determine how this network is set up during early postnatal development, we monitored markers of structural maturation in developing mice, both in naïve animals and after temporally restricted pharmacogenetic silencing of specific cell populations. We found that entorhinal stellate cells provide an activity-dependent instructive signal that drives maturation sequentially and unidirectionally through the intrinsic circuits of the entorhinal-hippocampal network The findings raise the possibility that a small number of autonomously developing neuronal populations operate as intrinsic drivers of maturation across widespread regions of cortex. Main Text:To create a neural representation of the external world, sensory stimuli are topographically mapped onto highly organized neural networks spanning multiple sensory areas in the neocortex (1-4). The early development of such topographical sensory representations depends strongly on spontaneous 2 and sensory-driven neural activity spreading bottom-up from sensory receptors to sensory cortices (5-8).Like in the sensory systems, the brain's representation of space relies on an extended network of specialized cell types spanning multiple interconnected brain regions. Cell types involved in the representation of space include place cells in the hippocampus, and grid, border, head direction and speed cells in the medial entorhinal cortex (MEC) (9). Properties of these cells are thought to reflect the intrinsic connectivity of the MEC (10) as well as the unique unidirectional organization of entorhinal projections through the hippocampus (11-14) (Fig. S1A). However, in contrast to the primary sensory cortices, little is known about how the entorhinal-hippocampal microcircuit is assembled during development, or what role neural activity has in refining the connectivity and maturation of the circuit. Place, border and head direction cells exhibit adult-like features from the onset of spatial navigation at 2-3 weeks of age, (15)(16)(17)(18), while the periodic firing pattern of grid cells emerges later, at approximately 4 weeks (15,16). The spatial accuracy of place cells evolves with a similarly protracted time course (15,16,19), suggesting that early interactions between subregions of the network might be crucial for the eventual emergence of spatially specific firing.With these parallels in mind, we sought to determine how structural elements of the entorhinalhippocampal circuit are wired together during development. We monitored network-wide developmental changes in the expression of maturation-related anatomical markers, taking advantage of targeted pharmacogenetic silencing methods to determine whether activity in any elements of the circuit had particular functions in organizing maturation across the network as a whole. Our data show that the entorhinal-hippocampal circuit matures in a linear ...

The extent to which individual neurons are interconnected selectively within brain circuits is an unresolved problem in neuroscience. Neurons can be organized into preferentially interconnected microcircuits, but whether this reflects genetically defined subpopulations is unclear. We found that the principal neurons in the main subdivisions of the hippocampus consist of distinct subpopulations that are generated during distinct time windows and that interconnect selectively across subdivisions. In two mouse lines in which transgene expression was driven by the neuron-specific Thy1 promoter, transgene expression allowed us to visualize distinct populations of principal neurons with unique and matched patterns of gene expression, shared distinct neurogenesis and synaptogenesis time windows, and selective connectivity at dentate gyrus-CA3 and CA3-CA1 synapses. Matched subpopulation marker genes and neuronal subtype markers mapped near clusters of olfactory receptor genes. The nonoverlapping matched timings of synaptogenesis accounted for the selective connectivities of these neurons in CA3. Therefore, the hippocampus contains parallel connectivity channels assembled from distinct principal neuron subpopulations through matched schedules of synaptogenesis.

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.

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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