S1 long-term plasticity
|Daniel Shulz and Valerie Ego-Stengel (2012), Scholarpedia, 7(10):7615.||doi:10.4249/scholarpedia.7615||revision #150516 [link to/cite this article]|
S1 long-term plasticity refers to persistent modifications in the structure or functioning of the primary somatosensory cortex (S1). These modifications are proposed to underlie learning and memory of tactile information, as well as recovery of function after injury. As in other primary cortical areas, long-term plasticity can arise as a result of peripheral injury (lesion-induced plasticity) or after changes in the spatial or temporal pattern of the sensory input (use-dependent and experience-dependent plasticity). This article focuses on studies of long-term changes in the barrel cortex, the area of S1 containing a topographic map of the whiskers found on the snout of rodents. It only describes plasticity in the adult brain, as opposed to developmental plasticity in the young during a critical period. Indeed, in the 1960s, it was thought that functional properties in primary sensory cortices were fixed in the adult. In the 1980s, the first experimental evidence for adult plasticity was provided by exploring the interaction between sensory representations and behavioral learning. Plastic modifications fall in two broad categories. Structural plasticity identifies changes in anatomical properties of neurons and circuits and is relatively restricted in the adult brain. Functional plasticity refers to changes in the response properties of neurons and neural networks, and can be mediated by intrinsic plasticity or synaptic plasticity.
Adult plasticity of primary sensory cortices is more readily observed after peripheral injury than after mere alterations of the sensory experience. For the whisker to barrel cortex system, lesion studies have employed either electrolytic or surgical ablation of whisker follicles, or sections of the infraorbital nerve, the branch of the trigeminal nerve that carries sensory information from the whiskers. These experimental protocols have two consequences. First, they result in the removal of all sensory evoked activity, and thus cause changes similar to those observed in experience-dependent plasticity. Second, the physical damage to axons or nerve endings triggers additional factors such as the release of neurotrophic factors, which are responsible for modifications at all levels of the system. Peripherally, this is visible by the degeneration and sprouting of nerve endings, and eventually their regeneration (Waite, 2001). At the cortical level, lesion-induced plasticity is also more pronounced than experience-dependent plasticity and resembles in some ways developmental plasticity (Fox & Wong, 2005), albeit on an attenuated scale and without exhibiting the profound structural changes that can be triggered in neonates. After nerve transection or ablation of all follicles, electrophysiological recordings reveal a long-term expansion of the representation of body surfaces adjacent to that of the whisker pad into the area initially corresponding to the barrel cortex (Kis et al., 1999, Waite, 2001). If peripheral reinnervation is permitted, neurons can regain responsiveness to whiskers or to the scar tissue replacing the whiskers. Otherwise, a central cortical zone stays unresponsive. Cortical mapping of active regions by 2-deoxyglucose autoradiography after ablation of all follicles in the adult rat led to the same result (Siucinska & Kossut, 1994). When some follicles were ablated and others spared, the area activated by the spared vibrissae progressively increased and invaded the neighbouring deprived barrels in the rat (Kossut et al., 1988) and in the mouse (Melzer & Smith, 1995, 1998).
The characteristics of experience-dependent plasticity in the barrel cortex depend on the nature of the altered experience. Most protocols involve removal of the sensory input from one or several whiskers, either by trimming or by careful whisker plucking sparing the follicle and its innervation. The whiskers are allowed to grow back before testing functional responses. However, the reorganization of cortical networks following a drastic modification of the afferent activity represents an extreme form of plasticity. During the interaction of the animal with its environment, more subtle and specific modifications result from the differential use of peripheral receptors. Modifications in the functional organization of the cortex intervene after sensory discrimination learning or after a classical conditioning procedure.
Plasticity following sensory input deprivation
Deprivation of input from all whiskers but one for 18 days results in an expansion of the cortical area in which individual neurons respond to the spared whisker (Glazewski et al., 1996). In the deprived barrels, responses for the spared whisker typically increase by a factor of two, while responses for surround deprived whiskers decrease by about 50 %, and responses to the principal whisker remain constant. More complex deprivation patterns have been used, such as sparing two adjacent whiskers (whisker-pairing), sparing a row of whiskers, removing a single whisker or a single row, or implementing a chessboard pattern. They all conclude that adult cortical plasticity is largely the result of a slow potentiation of responses to the spared peripheral input, on a time course of a few days to several weeks depending on the particular deprivation. Depression for the deprived input, which is dominant and rapid in the developing brain, seems limited in the adult brain (Fox & Wong, 2005), although it is sometimes still present (Diamond et al., 1993). Notably, the group of Feldman has shown that the connections from layer IV to layer II/III do exhibit depression in the mature brain after whisker deprivation (Bender et al., 2006). Overall, similar results are obtained by other techniques such as 2-deoxyglucose mapping (Kossut, 1998) and functional magnetic resonance imaging (Alonso et al., 2008).
Plasticity following changes in vibrissal sensory experience
Rapid changes in receptive field properties occur when stimulation of an individual whisker is immediately and repeatedly followed by stimulation of a bundle of whiskers in the awake rat. Excitatory responses are enhanced and suppressive responses decreased so that the stimulated whiskers elicit more overall discharge (Delacour et al., 1987). Aversive or appetitive classical conditioning using a row of vibrissae as the conditioned stimulus also results in an expansion of the cortical area active after stimulation of the trained row compared to the contralateral one (Siucinska & Kossut, 1996, Kossut, 2001a). This is in agreement with the enhanced responses recorded by evoked potentials in the awake rat during aversive classical conditioning (Wrobel & Kublik, 2001). Alterations of sensory experience can also induce shrinkage of cortical areas, in contrast with the expansions and enhancements more predominantly observed. Passive overstimulation of three whiskers in a row leads to a decrease of their representation measured by autoradiographic deoxyglucose uptake (Welker et al., 1992). Similarly, continued naturalistic experience over weeks leads to a sharpening of the map such that individual whisker representations viewed by intrinsic optical imaging shrink to about half their original size (Polley et al., 2004). Whisker trimming coupled to daily naturalistic experience results in a shrinkage of the cortical representation of the spared input, contrary to the expansion observed in rats remaining in their home cage (Polley et al., 1999).
Mechanisms of long-term plasticity
Any sensory alteration is likely to set into motion multiple plasticity mechanisms operating at multiple sites within a large functionally interconnected circuit (Nelson & Turrigiano, 2008). Gross observation can cancel out or mask underlying subtle modifications. Thus, measuring the distributed parallel changes requires a detailed approach that is slowly revealing different components of long-term plasticity.
Cortical vs subcortical sites of plasticity
Modifications of cortical responses could in principle result from modifications in the subcortical structures that provide the sensory input to the cortex, from changes in the intracortical network itself or from both. At present, most studies have concluded that subcortical plasticity in the adult brain is very limited and cannot explain cortical changes. This is in contrast to plasticity in the neonate, where cortical modifications are considerable and largely reflect cytoarchitectural and functional changes in the brainstem and thalamus (Kossut, 2001b). Arguments in favor of a cortical origin of plasticity in the adult vibrissal system fall in several categories:
- Response changes are absent in the brainstem and thalamus after sensory experience alterations (Glazewski et al., 1998, Wallace & Fox, 1999) and much smaller than cortical changes after peripheral injury (Klein et al., 1998, Kis et al., 1999). Furthermore, regions showing adjacent reorganization in the cortex are not necessarily adjacent in the thalamic map, suggesting that the intracortical circuitry is the anatomical substrate (Waite, 2001).
- If postsynaptic activity is blocked in the barrel cortex by local muscimol application, the plasticity normally induced by a sensory deprivation does not occur anymore, even though the thalamus responses are intact (Wallace et al., 2001).
- The earliest changes in cortical responses are observed in supragranular layers and, although less prominently, in infragranular layers. In the thalamorecipient layer IV, changes are generally absent (Diamond et al., 1994, Glazewski et al., 1996, Polley et al., 2004). However, several studies have found significant response changes in layer IV barrels (Welker et al., 1992, Siucinska & Kossut, 1994, Wallace & Fox, 1999). It is likely that these layer IV modifications occur on a longer timescale and as a consequence of supragranular changes (Kossut, 2001a, Feldman & Brecht, 2005).
- Modifications of the short-latency component of cortical responses, which corresponds to direct thalamocortical excitation, occur very slowly. In contrast, changes in the late component, thought to arise from intracortical connections, are rapid (Armstrong-James et al., 1994). This differential modulation is compatible with the superposition of two plasticity processes, one purely cortical and rapidly induced, and a second on a longer timescale recruiting the cortico-thalamo-cortical loop.
- The potentiated response to a spared whisker in surround barrels is reduced or abolished by a focal lesion in the spared barrel, or by a cut between the spared and surround barrels, indicating that neural activity takes a cortical route (Fox, 1994).
- Structural changes can be directly observed in the cortex (see below).
In contrast to the profound cytoarchitectural changes that can be observed when manipulations are carried out during development, up to the absence of barrel formation, structural changes are rarely detected in the adult brain and limited to subtle modifications of the circuitry among existing neurons. Maturation of layer IV and its thalamocortical afferents seems to be irreversibly fixed after the end of the critical period, even following peripheral injury. Only one study reported a surprising enlargement of the barrel cortex along the arc axis after long-term naturalistic experience (Polley et al., 2004), which is yet to be explained.
- Axonal remodeling
Axonal intracortical projections remain susceptible to structural changes in the adult after destruction of afferents. Focal anatomical tracings show that after ablation of all follicles but one, the spared barrel column both sends and receives more elongated and more branching projections to neighbouring barrel columns than deprived ones (Kossut & Juliano, 1999). Evidence is sparser in experience-dependent plasticity. In a whisker deprivation study involving whisker trimming, subtle axonal remodeling between neurons already synaptically connected has been shown in adolescent animals (Cheetham et al., 2008). Whisker plucking probably has a stronger effect, inducing axonal restructuring involving both retraction and elongation of inhibitory and excitatory neurons (Marik et al., 2010).
- Axonal endings and bouton dynamics
Despite the general stability of the overall axon structure, high-resolution two-photon microscopy in vivo has revealed substantial axonal dynamics in the adult brain even in normal conditions (DePaola et al., 2006). This remodeling of branch endings and boutons is cell-type specific. It is highly likely that it also exists, perhaps at an enhanced rate, during long-term plasticity, and thus could participate in the storage of new memories.
- Dendritic growth
Dendritic branches of excitatory neurons are remarkably stable in the adult barrel cortex in normal conditions, or during experience-dependent plasticity (Trachtenberg et al., 2002). In contrast, as for the axonal structure, changes in dendritic trees have been observed two months after follicle ablation (Tailby et al., 2005). Interestingly, contrary to excitatory neurons, the dendritic trees of cortical inhibitory interneurons display substantial dynamics even in normal conditions, at least in the visual cortex (Lee et al., 2008).
- Spine turnover and spine morphology changes
Most dendritic spines are firmly stabilized by the extracellular matrix in the adult brain, so that spine density is roughly fixed after adolescence. Large spines are the postsynaptic substrate of persistent synapses. Based on the measured geometry of axons and dendrites, and on the maximal distance between a presynaptic and a postsynaptic process required for a synapse to form, it has been estimated that about 10% of all possible synapses actually exist and are persistent in the adult brain (Stepanyants et al., 2002). Spine morphology dynamics and turnover are limited to a small fraction of transient spines constantly trying out new connections. Spine formation and elimination has been shown to be modulated by prolonged altered sensory experience (Zuo et al., 2005, Holtmaat et al., 2006). These studies suggest that during long-term plasticity, a subset of the transient spines eventually forms synapses with presynaptic boutons and stabilizes into large persistent spines (Knott et al., 2006). Concomitantly, some previously-persistent spines are lost (Holtmaat et al., 2006). Both new excitatory and inhibitory synapses may be formed, probably depending on the specific connection considered and the precise nature of the plasticity protocol (Knott et al., 2002, 2006).
Functional Synaptic changes
Modifications of functional connectivity may occur by changes of synaptic strength. In the adult barrel cortex, because plasticity first appears in layer II/III, focus has been on synapses from layer IV neurons to layer II/III pyramidal neurons. Changes in short-term dynamics and LTD-like depression have been observed after whisker deprivation (Finnerty et al., 1999, Allen et al., 2003). These synapses are indeed susceptible in vitro to spike-timing dependent plasticity (STDP, Feldman, 2000; for a general review on STDP see Shulz & Feldman, 2011). Remarkably, the timing of inputs to layer II/III neurons changes from one favoring LTP to one favoring LTD during adult cortical map plasticity protocols (Celikel et al., 2004), confirming that plasticity is likely to occur as a result of changes in precise temporal patterns of activity in this system. Although not yet compelling, evidences for the STDP rule in the intact brain, including S1 cortex, have been provided recently (see e.g. Bell et al., 1997; Meliza and Dan, 2006; Cassenaer and Laurent, 2007; Jacob et al., 2007). From insects to mammals, the presentation of precisely timed sensory inputs drives synaptic and functional plasticity in the intact central nervous system, with similar timing requirements than the in vitro defined STDP rule. Indirect evidence for STDP in the primary somatosensory cortex comes from a combined electrical stimulation of somatosensory afferents and transcranial magnetic stimulation (TMS) of the somatosensory cortex in humans (Wolters et al., 2005). Evoked potentials induced by the TMS were either enhanced or depressed as a function of the order of the paired associative stimulation. More direct evidence of STDP at the synaptic level comes from studies in the primary somatosensory cortex of anesthetized adult rats. Pairing of spontaneous or electrically induced postsynaptic action potentials with afferent excitation elicited by whisker deflections lead to depression of responses to the paired whisker with no significant changes to the unpaired whisker (Jacob et al., 2007; review in Shulz and Jacob, 2010). Synaptic strength changes have also been documented in horizontal connections, notably in the supragranular layers (Lebedev et al., 2000, Cheetham et al., 2007).
The initial events in the plasticity processes are stabilized into long-term changes by triggering intracellular protein cascades which eventually lead to modifications in the anatomical and electrical properties of cells and synapses. For example, the presence of the regulatory enzyme alpha-CAMKII and of the transcription factor CREB, both known to underlie various plastic changes, are required for barrel cortex adult plasticity (Fox, 2008). Similarly, there is abundant evidence for changes in the glutamatergic and GABAergic systems, both in lesion-induced and experience-dependent plasticity. AMPA and NMDA glutamate receptors, GABA receptors and local GABA synthesis show modifications whose amplitude and direction depend on the particular protocol employed (Skangiel-Kramska, 2001).
General homeostatic phenomena
Sudden changes in the afferent sensory drive necessarily result in downstream modifications in the patterns of activity flowing through the sensory system, so that the balance between the different inputs to a postsynaptic neuron may be lost. This can lead to saturation or silencing of the neuron, preventing any form of information processing. Homeostatic mechanisms work to restore the balance of activity and thus stabilize the function of neurons and networks (Nelson & Turrigiano, 2008).
- Unmasking of previously ineffective afferents
After loss of sensory input, a well-known immediate effect in the corresponding cortex is the appearance of a novel response for stimulation of a neighboring input (Wall, 1977). This unmasking of previously ineffective input is thought to result from a sudden release from inhibition, triggered by the unbalance of activity of the recorded cell. Evidence has been observed for this short-term mechanism in the barrel cortex after sensory experience manipulation (Kelly et al., 1999, Lebedev et al., 2000) and after peripheral injury (Waite, 2001). In the long-term, it is thought to give way to structural and functional changes that it might contribute to trigger.
- Upregulation of inhibition
A potentiation of the inhibitory system has been observed, in particular in layer IV and after protocols shown to induce modifications in that layer. For example, an associative fear learning paradigm results in a selective increase in the frequency of spontaneous IPSPs in layer IV excitatory neurons (Tokarski et al., 2007). It has been proposed that the upregulation of inhibition suppresses chronic inputs that are not behaviorally relevant (Welker et al., 1992, Gierdalski et al., 2001), thus leading to a form of sensory habituation.
- Excitability changes
Conversely, a decrease in the excitability of inhibitory FS interneurons has been observed after 3-week whisker trimming in the mouse, as measured by changes in the intrinsic properties of these cells. These changes were not present in non-FS non-pyramidal cells, suggesting that subnetworks can be regulated independently (Sun, 2009).
Influence of the neuromodulatory context
The activity within primary sensory cortices is influenced by neuromodulatory afferents, which carry information about the general state of the animal, notably the attention level and cognitive aspects of the ongoing behavior. In addition to their role in sensory perception, neuromodulatory inputs are involved in the cortical plasticity accompanying learning and memory, and in the cellular and synaptic events thought to underlie it (Gu, 2002). Studies of adult plasticity in the barrel cortex have focused in particular on one of the neuromodulators, acetylcholine. Cortical cholinergic afferents originate in the nucleus basalis magnocellularis (NBM) in the basal forebrain (Mesulam et al., 1983). Two main approaches have been used: manipulations of the cholinergic system preventing its action on cortical targets, and direct sensori-cholinergic pairing protocols.
- blockade of cholinergic actions
Lesions of the basal forebrain cholinergic system generally prevent cortical plasticity from occurring. For example, the plasticity induced by trimming all whiskers but two is reduced if the cortical cholinergic input is selectively lesioned with Ig-saporin (Baskerville et al., 1997; Sachdev et al.,1998). Likewise, systemic or local administration of a cholinergic antagonist prevent the cortical changes in evoked responses observed after pairing two temporally-ordered vibrissal stimuli (Delacour et al., 1990, Maalouf et al., 1998). However, a later study showed that if the animals are engaged in learning a vibrissal task requiring the barrel cortex, plasticity is restored (Sachdev et al., 2000 ). This suggests that acetylcholine may be necessary for passive experience-dependent plasticity, but that behaviorally-relevant learning triggers other factors that can compensate the cholinergic depletion.
- pairing a sensory event with a cholinergic input
Two studies have directly tested whether the association between a sensory stimulus and a cholinergic manipulation can induce long-lasting changes in cortical processing. The first one has used pairing of a vibrissal stimulation at a particular frequency with local application of acetylcholine. Response to the paired stimulus was enhanced relative to responses to other frequencies of stimulation. Interestingly, this was only true when acetylcholine was supplied again, suggesting that not only the induction of plasticity but also its expression are dependent on the cholinergic system (Shulz et al., 2000, Ego et al., 2001, Shulz et al., 2003). In the second study, an aversive-conditioning protocol was modified by replacing the unconditioned stimulus (classically an electric shock) by an electrical stimulation of the NBM in an anesthetized animal. Cortical changes in evoked responses were very similar to those observed in an awake animal undergoing the normal aversive-conditioning protocol (Wrobel & Kublik, 2001).
The role of other neuromodulators, like NA, DA or 5HT in adult barrel cortex plasticity has not been investigated, except for one study suggesting that noradrenaline may also play a permissive role (Levin et al., 1988). In the light of what has been observed in other primary sensory cortices (Bao et al., 2001), it is possible that other neuromodulators than ACh influence the induction and the expression of functional plasticity. Cortical release of noradrenaline for example, produces a reduction of spontaneous and evoked activity in the visual cortex (Ego-Stengel et al., 2002). Through this inhibitory action, the noradrenergic system might provide a reset signal (Dayan and Yu, 2006), which is broadcast to the whole cortex, leading to an optimized level of activity for the induction of spike timing dependent plasticity. Other neuromodulators can dynamically regulate timing-based plasticity rules by modifying the biophysical properties of dendrites and the efficacy of spike back propagation (Tsubokawa and Ross, 1997; Sandler and Ross, 1999). In vitro experiments combining STDP induction protocols concomitant with an increase in neuromodulatory concentrations (Lin et al., 2003; Couey et al., 2007; Seol et al., 2007; Pawlak and Kerr, 2008; Zhang et al., 2009) explored how local rules of synaptic plasticity are regulated by global factors acting on several spatial (dendrites, neurons, network) and temporal (milliseconds to minutes) scales.
S1 long-term plasticity encompasses a wide range of phenomena, underlied by different mechanisms depending on the particular functional modification considered. Many of these mechanisms, if not all, also take place in the plasticity of other sensory cortices or other regions of the brain, and sometimes during development. One challenge of future studies will be to disentangle this complexity and assign identified computational properties in the framework of information processing to each of these modifications.
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