Trends in Neurosciences
Feature ReviewSpecial Issue: Circuit Development and RemodelingSynapse rearrangements upon learning: from divergent–sparse connectivity to dedicated sub-circuits
Section snippets
From acquisition to memory consolidation
Learning can be associated with the establishment of new synapses that provide long-lasting memory traces of learned knowledge. In support of this notion, repeated imaging studies of spines in situ have provided evidence that sensory adjustments, skill learning, and Pavlovian conditioning induce new synapses and loss of pre-existing synapses 1, 2, 3, 4. Moreover, subsequent behavioral retrieval of the same skill does not induce more new synapses but does induce re-strengthening of previously
Role of connectivity rearrangements upon learning
When considering rearrangements of synaptic connectivity in the adult it is important to clarify the logic and circumstances under which learning leads to circuit remodeling processes. Given that learning occurs as a daily by-product of experience and that flexibility is a core feature of circuit function, it is unlikely that all learning involves structural rearrangements of synaptic connections. Indeed, neuronal circuits can effectively learn from experience through short- and long-term
Time line of synapse rearrangements upon learning
Any learning-related rearrangement of synaptic connections starts with plasticity induced at subsets of pre-existing synapses and neurons at the time of acquisition (Figure 1). At least some of the plasticity must be enhanced through mechanisms linked to incentives in order to distinguish it from less consequential incidental learning. Whether, at acquisition, incentive-driven plasticity occurs at all systems involved in the particular learning process is not well understood. One possibility is
Molecular mechanisms of synapse assembly and stabilization upon learning
Activity- and incentive-related signaling triggers cascades of cellular and molecular plasticity responses that last for >12 hours and induce synaptic growth (1–2 hours), followed by strengthening and stabilization of some newly formed synapses (Figure 1, Figure 2). Growing synaptic functionality and structure are thereby closely linked to synapse retention [48]. Neurotransmitters [59], growth factors [60], and trans-synaptic cell adhesion molecules are involved in initiating synaptic plasticity
Mechanisms of synapse retention and elimination
Several lines of evidence support the notion that most learning-related synapse rearrangements do not lead to detectable long-lasting changes in total synapse numbers 1, 8, 99. For example, new spines were induced in barrel cortex upon whisker trimming, but their stabilization was accompanied by loss of comparable numbers of pre-existing spines [100]. Likewise, spine densities in the hippocampus and cortical areas increased transiently upon learning of the relevant tasks, but they soon returned
Roles of synapse rearrangements involving inhibitory neurons
Unlike excitatory neurons, the role of most inhibitory neuron subpopulations is to modulate and gate the activity of excitatory neurons and their synapses, either directly or through disinhibition 128, 129, 130. Reflecting these profoundly different roles, the functional rationales of synapse rearrangements onto or by inhibitory neurons differ from those of excitatory synapses onto excitatory neurons 130, 131, 132. These considerations might not apply to GABAergic neurons such as cerebellar
Concluding remarks
Recent results from three research areas investigating learning in the adult (operant conditioning in brain–machine–interface studies, rearrangements of synaptic connectivity upon learning, and connectomics) suggest that brain circuits consist to a large extent of distributed, sparse, and non-selective local connectivity, and that learning of new skills involves selective expansion of some of that connectivity to establish specialized local sub-circuits that support adaptive behavior. These
Acknowledgments
We thank Peter Scheiffele (Biozentrum, University of Basel) and Silvia Arber (Biozentrum and FMI, Basel) for valuable input and comments. A.C. was partially supported by the National Center of Competence in Research Synapsy. The Friedrich Miescher Institut is part of and supported by the Novartis Research Foundation.
Glossary
- Incentive-driven learning
- the term incentive-driven learning is used here to designate learning forms in which a behavioral output is associated with positive or negative reinforcers (reward or punishment). Examples include Pavlovian conditioning, operant conditioning, and trial-and-error reinforced learning forms (e.g., skill learning, song learning, maze learning). Incentive-driven learning involves the assembly of new synapses, whereas incidental learning probably does not.
- Incidental learning
References (153)
Bidirectional activity-dependent morphological plasticity in hippocampal neurons
Neuron
(2004)Rapid functional maturation of nascent dendritic spines
Neuron
(2009)- et al.
Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration
Neuron
(2014) Driving opposing behaviours with ensembles of piriform neurons
Cell
(2011)Ultrastructural analysis of hippocampal neuropil from the connectomics perspective
Neuron
(2010)Transient and persistent dendritic spines in the neocortex in vivo
Neuron
(2005)- et al.
beta-Adducin is required for stable assembly of new synapses and improved memory upon environmental enrichment
Neuron
(2011) New circuits for old memories: the role of the neocortex in consolidation
Neuron
(2004)The molecular and systems biology of memory
Cell
(2014)- et al.
BDNF mechanisms in late LTP formation: a synthesis and breakdown
Neuropharmacology
(2014)
The dendritic branch is the preferred integrative unit for protein synthesis-dependent LTP
Neuron
Activity-dependent clustering of functional synaptic inputs on developing hippocampal dendrites
Neuron
Balance and stability of synaptic structures during synaptic plasticity
Neuron
Structural and molecular remodelling of dendritic spine substructures during long-term potentiation
Neuron
Limbic and cortical information processing in the nucleus accumbens
Trends Neurosci.
Persistence of long-term memory storage requires a late protein synthesis- and BDNF-dependent phase in the hippocampus
Neuron
Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons
Cell
SynCAM 1 adhesion dynamically regulates synapse number and impacts plasticity and learning
Neuron
Neurexin-1beta binding to neuroligin-1 triggers the preferential recruitment of PSD-95 versus gephyrin through tyrosine phosphorylation of neuroligin-1
Cell Rep.
NGL-2 regulates input-specific synapse development in CA1 pyramidal neurons
Neuron
Transsynaptic signaling by activity-dependent cleavage of neuroligin-1
Neuron
CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin
Neuron
The dynamic synapse
Neuron
Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic AMPA receptors
Neuron
The small GTPase Arf1 modulates Arp2/3-mediated actin polymerization via PICK1 to regulate synaptic plasticity
Neuron
Dopaminergic modulation of synaptic transmission in cortex and striatum
Neuron
Remodelling of synaptic morphology but unchanged synaptic density during late phase long-term potentiation (LTP): a serial section electron micrograph study in the dentate gyrus in the anaesthetised rat
Neuroscience
Experience leaves a lasting structural trace in cortical circuits
Nature
Rapid formation and selective stabilization of synapses for enduring motor memories
Nature
Stably maintained dendritic spines are associated with lifelong memories
Nature
Cocaine-induced structural plasticity in frontal cortex correlates with conditioned place preference
Nat. Neurosci.
Dynamics of dendritic spines in the mouse auditory cortex during memory formation and memory recall
Proc. Natl. Acad. Sci. U.S.A.
Opposite effects of fear conditioning and extinction on dendritic spine remodelling
Nature
LTP promotes a selective long-term stabilization and clustering of dendritic spines
PLoS Biol.
Experience-dependent structural synaptic plasticity in the mammalian brain
Nat. Rev. Neurosci.
Long-term depression triggers the selective elimination of weakly integrated synapses
Proc. Natl. Acad. Sci. U.S.A.
Making memories last: the synaptic tagging and capture hypothesis
Nat. Rev. Neurosci.
Synaptic tagging during memory allocation
Nat. Rev. Neurosci.
The synaptic plasticity and memory hypothesis: encoding, storage and persistence
Philos. Trans. R. Soc. Lond. B: Biol. Sci.
Spine growth precedes synapse formation in the adult neocortex in vivo
Nat. Neurosci.
Protracted synaptogenesis after activity-dependent spinogenesis in hippocampal neurons
J. Neurosci.
Coordination of size and number of excitatory and inhibitory synapses results in a balanced structural plasticity along mature hippocampal CA1 dendrites during LTP
Hippocampus
Maximization of the connectivity repertoire as a statistical principle governing the shapes of dendritic arbors
Proc. Natl. Acad. Sci. U.S.A.
Statistical connectivity provides a sufficient foundation for specific functional connectivity in neocortical neural microcircuits
Proc. Natl. Acad. Sci. U.S.A.
Selectivity and sparseness in randomly connected balanced networks
PLoS ONE
Volitional modulation of optically recorded calcium signals during neuroprosthetic learning
Nat. Neurosci.
Volitional control of single cortical neurons in a brain-machine interface
J. Neural Eng.
Thalamic input to the cerebral cortex
Trends Neurosci.
Geometric and functional organization of cortical circuits
Nat. Neurosci.
Functional specificity of local synaptic connections in neocortical networks
Nature
Cited by (71)
Mutant FUS induces chromatin reorganization in the hippocampus and alters memory processes
2023, Progress in NeurobiologyMorris water maze overtraining increases the density of thorny excrescences in the basal dendrites of CA3 pyramidal neurons
2020, Behavioural Brain Research2.39 - Temporal Coherence Principle in Scene Analysis
2020, The Senses: A Comprehensive Reference: Volume 1-7, Second EditionInterfering with a memory without erasing its trace
2020, Neural NetworksCitation Excerpt :These studies have reported widely ranging time intervals over which interference occurs, from 1–4 h (Brashers-Krug et al., 1996; Shadmehr & Brashers-Krug, 1997; Zhang et al., 2008) up to several days (Caithness et al., 2004; Goedert & Willingham, 2002; Yotsumoto, Watanabe, Chang, & Sasaki, 2013). The short-lasting time window following training amenable for eliciting behavioral interference fits roughly with the expression window of late genes controlling synaptic plasticity (Caroni, Chowdhury, & Lahr, 2014; Igaz, Bekinschtein, Vianna, Izquierdo, & Medina, 2004). This can be seen as support for the idea that time-limited latent consolidation is the basis for behavioral interference.
Structural and Functional Remodeling of Amygdala GABAergic Synapses in Associative Fear Learning
2019, NeuronCitation Excerpt :In summary, these findings show bi-directional morphological alterations at BA inhibitory synapses induced by fear conditioning and extinction that are at least in part paralleled by reversible functional changes in synaptic physiology. Studies of learning-dependent structural plasticity have largely focused on excitatory glutamatergic synapses (Caroni et al., 2014; Peters et al., 2017), whereas very little is known about remodeling of GABAergic synapses in mature neural networks. Only recently, in vivo imaging of the visual cortex showed synchronized remodeling of spatially clustered dendritic spines and inhibitory synapses over different timescales ranging from hours to days (Chen et al., 2012, 2015; Villa et al., 2016).
A unifying hypothesis for delirium and hospital-acquired weakness as synaptic dysfunctions
2019, Medical Hypotheses