1

2
Experience-Dependent Plasticity
in the Central Nervous System 25
3 José Fernando Maya-Vetencourt
4 and Matteo Caleo

5 Environmental influences play a key role in shaping Because experience-dependent changes of brain func- 31
6 the central nervous system architecture. The interac- tions depend, at least partially, on the expression of genes 32
7 tion of a living organism with the external environment that have evolved to meet specific ­environmental demands, 33
8 is critical for the survival of the species diversity as it we shall consider cellular and molecular mechanisms 34
9 allows an individual to perceive and respond properly to underlying neuronal plasticity in different invertebrate and 35
10 changing environmental conditions. The capacity of the vertebrate species, with particular emphasis on the mam- 36
11 nervous system to change in response to environmental malian central nervous system. The structure and func- 37
12 stimuli, referred to as plasticity, underlies experience- tion of the BDNF gene is a particularly clear example of 38
13 dependent modifications of brain functions. This fea- molecular mechanisms that mediate experience-dependent 39
14 ture is fundamental for neural circuitries to be sculpted plasticity. BDNF promoter areas are regulated by dis- 40
15 by external signals and is of particular relevance in tinct neurotransmitter systems the levels of which vary 41
16 processes of learning and memory. How does sensory in response to environmental inputs. Therefore, BDNF 42
17 experience modify synaptic circuitries in the brain? This expression in the brain is regulated by sensory experience 43
18 will be one of the topics we shall concentrate on along in a spatiotemporal-dependent manner. This neurotrophin 44
19 this chapter. The nervous system translates information is essential for neuronal survival during development and 45
20 from the external world through signals generated by mediates experience-dependent modifications of synaptic 46
21 the electrical activity associated to sensory inputs, and transmission throughout life. Likewise, postsynaptic neu- 47
22 orchestrates adaptive responses to changing environ- rotransmitter receptors such as the (N-methyl-D-aspartate) 48
23 mental conditions. This, in turn, depends upon adapta- NMDA-type glutamate receptor, which upon high or low 49
24 tions of the brain that gathers and processes information neuronal activity modify the efficacy of synaptic trans- 50
25 to increase the probability of an individual to survive mission, epitomize how the nervous system mediates fast 51
26 and reproduce. A bird and a bat, for instance, may share adaptive responses to changing environmental conditions. 52
27 a given ecosystem but how perception of the environ- We shall also address how intracellular signal trans- 53
28 ment occurs in these animals largely differs, as in the duction pathways associated to experience regulate 54
29 former the sense of vision predominates whereas in the changes of chromatin structure that underlie phenom- 55
30 latter it is a world of echolocation. ena of plasticity in the brain. Epigenetic mechanisms 56
that exert a long-lasting control of gene expression by 57

J.F. Maya-Vetencourt (*) altering chromatin structure rather than changing the 58

Italian Institute of Technology, DNA sequence itself, are a common theme in long- 59
Centre for Neuroscience and Cognitive Systems, term plastic changes from vertebrates to invertebrates. 60
Corso Bettini 31, Rovereto 38068, Trento, Italy
e-mail: maya.vetencourt@iit.it
Changes in the pattern of DNA methylation and post- 61
translational modifications of histones such as acetyla- 62
M. Caleo
CNR Neuroscience Institute,
tion, methylation, and phosphorylation have recently 63

Via G. Moruzzi 1, 56124 Pisa, Italy emerged as a conserved process by which the nervous 64
e-mail: caleoin@cnr.it system accomplishes the induction of plasticity. 65

C.G. Galizia, P.-M. Lledo (eds.), Neurosciences - From Molecule to Behavior: a University Textbook, 549
DOI 10.1007/978-3-642-10769-6_25, © Springer-Verlag Berlin Heidelberg 2013
 550 J.F. Maya-Vetencourt and M. Caleo

66 25.1 Genetic Factors and Sensory normal visual development is irreversibly impaired. 114
67 Experience Sculpt the Nervous In summary, proper sensory experience is necessary 115
68 System Architecture for normal perception to occur and the influence of the 116
environment is particularly evident at early stages of 117
69 25.1.1 Electrical Activity Modifies brain development during short-time windows known 118
70 Synaptic Circuitries in the Brain as “critical periods” (see Sect. 25.2.1). Neural activ- 119
ity associated to sensory experience thus provides 120
71 The formation of neural circuitries in the nervous sys- a mechanism by which the environment influences 121
72 tem relies on a tight interaction between genes and brain structure and function. 122
73 environment. Although intrinsic factors mediate the
74 initial assembly of neuronal circuitries in the brain,
75 experience during early postnatal life shapes imma- 25.1.2 Intrinsic Factors and Sensory 123
76 ture circuitries into the organized connectivity that Experience Determine Behavior 124
77 subserve adult brain function. Spontaneous electrical
78 activity as well as activity caused by sensory experi- A variety of sophisticated innate behaviors rely on the 125
79 ence drives neural circuitry formation, promoting the interaction between genetic and environmental factors. 126
80 establishment, elimination, and rearrangement of syn- The behavioral repertoire in most animals including, for 127
81 aptic connections [24]. instance, foraging and mating strategies in insects, birds, 128
82 In the visual system, for instance, intrinsic signals and mammals, consist of an intrinsically predetermined 129
83 guide the projection of retinal inputs to different subcorti- system of adaptive responses that ensures survival and 130
84 cal and cortical structures, creating the neuronal substrate reproduction of a given species. Innate behaviors are 131
85 for a complete retinotopic map of the visual field. In dif- subject to genetic changes through natural selection and 132
86 ferent species (e.g., monkeys and cats) the segregation of reflect adaptive responses to selective pressures of an 133
87 retinal projections into eye-specific patches at the level of individual’s environment. Early postnatal life is a period 134
88 the lateral geniculate nucleus occurs during embryonic of particular sensitivity to environmental influences on 135
89 life. This anatomical segregation is initially driven by animal behavior. It seems to be a brief period of time 136
90 spontaneously generated synchronous firing of action during which the animal acquires an indelible memory 137
91 potentials in the mammalian retina before eye opening. of relevant stimuli in the environment, thus ensuring 138
92 Experimental evidence for such spontaneous patterns of proper development of a given behavior. The ground- 139
93 electrical activity, in fact, has been reported in rodents, breaking work by Konrad Lorenz in the 1960s with gray- 140
94 ferrets and monkeys (e.g., [18]). Other functional charac- lag geese led him to develop the concept of “imprinting” 141
95 teristics in the visual system such as rough orientation to explain predetermined behaviors (see also Chap. 26). 142
96 selectivity of cortical neurons are also present before Based upon the remarkable observation that goslings 143
97 visual experience, indicating that the initial anatomical recognize the first large, moving object they see and 144
98 and functional organization of the visual cortex relies, at hear during the first day of life as a natural tutor – nor- 145
99 least partially, on innate processes. However, once basic mally their mother – the term imprinting was coined 146
100 patterns of neural circuitries are formed sensory experi- to refer to cases of “programmed learning” during the 147
101 ence plays a key role in the refinement of synaptic con- critical period (Fig. 25.1). Lorenz found that this period 148
102 nectivity in the brain, this phenomenon being particularly of particular sensitivity to experience in geese is limited 149
103 prominent during early stages of brain development. to a few hours soon after birth and that once imprint- 150
104 Strabismic or anisometric children that underwent ing occurs it is irreversible. Such built-in behavior and 151
105 no clinical treatment during early development clearly the neural substrates underlying it, is likely to give new- 152
106 illustrate this point. In these children proper visual borns a better chance to survive. 153
107 experience is altered and this, in consequence, causes Imprinting also plays a key role in the establish- 154
108 a marked and permanent impairment of normal visual ment of social behavior and sexual preferences in 155
109 functions (e.g., visual acuity and contrast sensitiv- zebra finches. During sexual imprinting young animals 156
110 ity) later in life. Children with unilateral congenital learn the characteristics of their future partners in two 157
111 cataracts, i.e., opacities of the lenses that interfere stages: an initial very short acquisition period in which 158
112 with the flow of visual inputs face the same problem. features of the social environment are learnt and a sec- 159
113 If ­cataracts are not surgically removed in early life, ond stabilization stage where a preference for a sexual 160
 25  Experience-Dependent Plasticity in the Central Nervous System 551

Fig. 25.1  Konrad Lorenz followed by imprinted geese

161 partner is established upon the previously acquired

162 social information [5].
Fig. 25.2  Critical period, life span, and development of sensory
163 Most mammals possess a poorly developed visual functions. (a) Duration of the critical period for the effects of
164 system at birth, and maternal imprinting relies on unilateral eye-lid suture (monocular deprivation) as a function of
165 olfactory cues (see Chap. 13). During the first week of life span in mammals. The longer the life span of a given spe-
166 postnatal life in rodents, the offspring display odor- cies, the longer the critical period. (b) Development of visual
acuity in humans, monkeys, cats and rats as a function of age and
167 preference learning that ensures attachment to the compared with the critical period for monocular deprivation.
168 mother’s odor, thus facilitating huddling and grooming Full development of visual acuity is completed towards the end
169 behavior both of which ensure pups survival [37]. of the critical period for monocular deprivation (Modified with
permission from Berardi et al. [3])

170 25.2 Plasticity of the Nervous System

171 is High During Critical Periods during the critical period permanently impairs sensory 180
172 but Decreases Thereafter functions and/or behavior. The existence of critical peri- 181
ods has been reported in different modalities of sensory 182
173 25.2.1 Critical Periods During Sensory experience in all species tested so far. Their duration is 183
174 Development normally evaluated in terms of either the induction of 184
sensory deprivation effects or the recovery from sensory 185
175 The critical period is defined as a time frame during deprivation [3]. Interestingly, critical periods in response 186
176 development in which neuronal networks are highly to enhanced sensory experience have been reported as 187
177 sensitivity to experience [3] (Fig.  25.2). Once this well. An expansion of auditory cortical representations, 188
178 period ends, the brain is less affected by environmental for instance, is seen in musicians who learnt to play 189
179 influences. A failure to be exposed to normal experience musical instruments before the age of nine but not later. 190
 552 J.F. Maya-Vetencourt and M. Caleo

191 25.2.2 Birdsong and Human Language the first larval stage of C. elegans causes a significant 237
enhancement of behavioral responses to mechanosen- 238
192 Song in birds and language in humans are two compel- sory stimulation (tap withdrawal model) in adult ani- 239
193 ling examples of critical periods during early develop- mals. This phenomenon also follows a critical period 240
194 ment. In these two groups the quality of early sensory since the same mechanosensory stimulation at late lar- 241
195 experience is the main determinant of perceptual and val stages does not cause similar effects. 242
196 behavioral capabilities later in life. An initial learning
197 phase is necessary for both birdsong and speech to
198 develop properly: birds do not learn to sing normally, 25.2.4 Binocularity in Xenopus Laevis 243
199 nor infants to speak, if they are not exposed to appropri-
200 ate acoustic signals from adult tutors [12]. Congenitally The Xenopus binocular visual system displays activ- 244
201 deaf children, for instance, do not acquire spoken lan- ity-dependent synaptic modifications that follow a 245
202 guage, although they can learn sign language if exposed well-defined critical period during development. In 246
203 to it during early development. Likewise, songbirds frogs, each lobe of the optic tectum receives visual 247
204 still sing when deafened young but they produce abnor- information from both eyes: contralateral informa- 248
205 mal indistinct series of sounds that are much less song- tion is transmitted by direct retinotectal projections 249
206 like than normal song structures. whereas ipsilateral information is relayed via the 250
nucleus isthmi. The ipsilateral pathway appears in 251
late larval animals and is subject to experience-depen- 252
207 25.2.3 Mechanosensory Deprivation dent changes in response to experience during early 253
208 in Caenorhabditis Elegans development. Abnormal visual experience (caused for 254
instance by surgical rotation of one eye in larval stage) 255
209 An experience-dependent critical period has also been causes a dramatic rearrangement of isthmotectal pro- 256
210 described in nematodes. The effects of sensory depriva- jections that requires NMDA-type glutamate receptor 257
211 tion on synaptic transmission and behavior of C. elegans activation. Adult Xenopus, in contrast, do not display 258
212 have been studied by comparing animals raised in isola- a structural rearrangement of isthmotectal axons in 259
213 tion with animals raised in colonies in the tap with- response to abnormal visual inputs [25]. Of note, the 260
214 drawal paradigm. These experiments revealed that ability for isthmotectal projections to undergo expe- 261
215 colony-reared worms showed accelerated development rience-dependent modifications in adulthood can be 262
216 and had larger responses to mechanosensory stimuli. rescued by exogenous administration of NMDA. 263
217 Presynaptic vesicle markers and the expression of
218 AMPA glutamate receptor in C. elegans sensory neu-
219 rons were higher in colony-raised worms when com- 25.3 Experience-Dependent Forms 264
220 pared with isolated ones, suggesting that synaptic of Plasticity in the Visual System 265
221 transmission is increased in these synapses. In the
222 absence of conspecific interactions during early devel- 25.3.1 Anatomical and Functional 266
223 opment, synapses show a weak development in sensory Organization of Visual Pathways 267
224 neurons that cause a decrease in responsiveness to in Mammals 268
225 mechanical stimulation. In contrast, brief mechanosen-
226 sory stimulation during the third larval stage of develop- The extent to which the functional and structural devel- 269
227 ment rescues the effects of isolation in the tap withdrawal opment of the brain depends on early sensory experi- 270
228 response model and leads to the expression of glutamate ence has been extensively studied in the developing 271
229 receptors and presynaptic vesicle markers [41]. mammalian visual system. Early electrophysiological 272
230 These findings indicate that, just as in birds and studies revealed that activity-dependent reorganization 273
231 mammals, there is a sensitive period in C. elegans life of eye-specific inputs during development is a major 274
232 cycle (immediately after hatching) in which high levels mechanism by which neuronal connectivity is estab- 275
233 of mechanosensory stimulation can rescue the behav- lished in the primary visual cortex. 276
234 ioral effects of sensory deprivation. This period ends Visual perception begins in the retina (see Chap. 277
235 by the third larval stage. Noteworthy, the delivery of 18). Retinal ganglion cells project to diverse subcorti- 278
236 an increased pattern of mechanosensory stimulation in cal structures. Most retinal ganglion cells project to the 279
 25  Experience-Dependent Plasticity in the Central Nervous System
Fig. 25.3  Columnar organization of the striate cortex. The
structural and functional organization of the visual system is
such that inputs from both eyes remain segregated in separate
layers at the level of the lateral geniculate nucleus (pattern of
alternating dark gray and light gray stripes). In many species,
including most primates and carnivores, these afferent projections
remain segregated in ocular dominance columns of layer IV, the
primary cortical target of lateral geniculate neurons. Layer IV
neurons send their axons to other cortical layers. It is at this
stage that the information from the two eyes converges onto
individual neurons
280 lateral geniculate nucleus in the thalamus and to the
281 superior colliculus in the midbrain. From the thalamus
282 geniculocortical afferents project to the visual cortex
283 and segregate into a pattern of alternating stripes called
284 ocular dominance columns, which are driven by stimu-
285 lation of one or the other eye [31] (Fig. 25.3). All cells
286 in a column perpendicular to visual cortical layers
287 show a preferred stimulus orientation, and as one goes
288 across adjacent columns a gradual shift of orientation
289 preference occurs, an observation from which the con-
290 cept of functional “orientation columns” arises.
291 Columnar organization in the primary visual cortex
292 was initially evidenced anatomically in monkeys and
293 cats, by injecting one eye of the animal with a radioac-
294 tive tracer, which was carried by trans-neuronal trans-
295 port to geniculate neurons and up to cortical layer IV
296 of striate cortex. Afferents related to each eye were
297 evidenced by autoradiography as alternate ocular dom-
298 inance patches from each eye distributed throughout
299 the binocular area of the primary visual cortex.
553
a b
Fig. 25.4  Histograms of ocular dominance distributions in stri-
ate cortex of normal and monocularly deprived kittens. Cells in
the ocular dominance groups 1 and 7 are exclusively activated
by the contralateral and ipsilateral eye, respectively. Class 2/3
cells show a marked dominance by the contralateral eye whereas
class 5/6 have a marked ipsilateral dominance. Class 4 cells
equally driven by both eyes. (a) In the visual cortex of normally
reared cats, the contralateral eye drives most visual cortical neu-
rons. (b) In kittens reared with monocular deprivation cells stop
responding to the contralateral, deprived eye, and become domi-
nated by the ipsilateral eye. Monocular deprivation in adult cats
does not alter the ocular dominance distribution in striate cortex
although it reduces overall activity. NR not responsive cells
25.3.2 Unilateral Eyelid Suture During 300
the Critical Period Impairs Visual 301
Function 302
The groundbreaking work of Hubel and Wiesel in the 303
early 1960s provided the first evidence for structural and 304
functional modifications of the visual system in response 305
to sensory deprivation [49]. In an ­extraordinary influential 306
set of experiments performed in cats and monkeys Hubel 307
and Wiesel observed that the ocular dominance distribu- 308
tion in the binocular area of the primary visual cortex dra- 309
matically changes in response to unilateral eyelid suture 310
(monocular deprivation) during the critical period. The 311
number of cells responding to the deprived eye is reduced 312
and the number of neurons activated by the open eye is 313
increased (Fig. 25.4a, b). At the anatomical level, the ocu- 314
lar dominance columns related to the open eye are greatly 315
expanded in layer IV while the columns for the closed 316
eye are shrunken [31]. Accordingly, the arborization of 317
single ­geniculocortical terminals serving the deprived eye 318
is reduced while spread of terminals serving the open eye 319
is increased [1]. In addition, the deprived eye becomes 320
 554
Fig. 25.5  The transplant of a third eye in frogs induces the
formation of alternating ocular dominance columns in the optic
tectum. The figure depicts coronal sections of the midbrain of
the frog (Reproduced from Constantine-Paton and Law [10]
with permission) following injection of a labelled amino acid
into the contralateral eye. The amino acid is transported into the
contralateral tectum. (a) A continuous synaptic zone is innervated
321 amblyopic: its visual acuity and contrast sensitivity are
322 markedly impaired. Because monocular deprivation does
323 not cause amblyopia in adulthood, this period of early life
324 in which neural circuitries are highly susceptible to expe-
325 rience is a typical example of a critical period.
326 Most cortical cells remain responsive to both eyes
327 (and there is no shrinkage of ocular dominance col-
328 umns) following a period of binocular deprivation in
329 juvenile age. Thus, afferents from the two eyes com-
330 pete for cortical territory, and the relative rather than the
331 absolute amount of activity of the two eyes determines
332 the outcome of this competitive process. The notion of
333 a competition between afferent fibers for postsynaptic
334 space is confirmed by classical experiments performed
335 in frogs by Constantine-Paton and Law [10]. As previ-
336 ously described, in frogs, axons from the retina project
337 only to the contralateral tectum. In order to generate
338 competition for postsynaptic cells in the tectum, a third
J.F. Maya-Vetencourt and M. Caleo
by the contralateral eye in normal frogs. (b) After transplantation
of a third eye next to the normal contralateral eye, the injection
of a radiolabel into one eye shows alternating stripes in the
contralateral optic tectum. The normally continuous synaptic
area of the contralateral eye becomes divided into alternating
columns due to the activity-dependent competition between
retinotectal projections for postsynaptic cells in the tectum
eye was transplanted into the frog’s head near one of the 339
normal eyes early in larval development. Retinal axons 340
from the transplanted eye projected to the contralat- 341
eral tectum, where they formed periodic, eye-specific 342
bands that alternated with those serving the normal, 343
nearby eye (Fig. 25.5). Thus, competition between two 344
sets of inputs generates alternating domains that are 345
occupied by the terminals of each afferent structure. 346
25.3.3 Sensory Deprivation by Dark Rearing 347
Affects Cortical Development 348
Another classical paradigm used to assess the impact of 349
experience on the brain is rearing animals in total dark- 350
ness from birth (dark rearing). Total absence of visual 351
inputs leads to a delay in the maturation of ­striate cor- 352
tex as indicated by a reduced spatial resolution (acuity) 353
 25  Experience-Dependent Plasticity in the Central Nervous System 555

354 and longer latency of response to visual stimuli [14].

355 Furthermore, visual cortical neurons have larger recep-
356 tive field sizes, indicating an immature state of the
357 visual cortex. Moreover, the size and density of den-
358 dritic spines are reduced in dark-reared animals with
359 respect to normally reared ones. Of note, dark rearing
360 also extends the critical period and prolongs neuronal
361 plasticity beyond its ­normal limits [3, 14].
362 It is worth mentioning that while visual deprivation
363 delays maturation of the visual cortex, raising animals
364 under enriched environmental conditions (with increased
365 motor activity, and enhanced sensory and social stimu-
366 lation) appears to accelerate visual system development. Fig. 25.6  Inhibitory processes control the time-course of the
367 Enriched animals actually show an acceleration of visual critical period. Sensitivity to monocular deprivation in mice is
restricted to the critical period that begins about 1 week after eye
368 acuity maturation and a precocious closure of the criti- opening and peaks nearly 1 month after birth. The onset of plas-
369 cal period for ocular dominance plasticity [8]. ticity can be delayed by preventing the maturation of inhibition
(e.g., by dark rearing or by deletion of GAD65) (red arrow).
Conversely, enhancing GABA transmission (e.g., by benzodiaz-
epine treatment, BDNF or Otx2) results in a precocious onset of
370 25.4 Molecular and Cellular Mechanisms the critical period (blue arrow)
371 that Control Critical Period
372 Plasticity in the Visual System
enhancing inhibitory transmission by means of ben- 397
373 Recent experimental research has shed light into the zodiazepine treatment (agonist of GABAA receptors). 398
374 mechanisms that regulate experience-dependent plas- Thus, a reduction of GABA during early postnatal life 399
375 ticity in the mammalian visual cortex. In the following, halts the onset of the critical period, an effect that is 400
376 we will cover a number of different signaling molecules rescued by enhancing inhibition. 401
377 including, neurotrophic factors, extracellular matrix A second inhibitory threshold that causes the clo- 402
378 molecules, NMDA-type glutamate receptors, GABA- sure of the critical period is reached over postnatal 403
379 mediated inhibitory transmission and neuromodulatory development as well. Transgenic animals that show 404
380 systems, which all have been recognized as important an accelerated maturation of intracortical inhibitory 405
381 regulators of visual cortical plasticity [32]. circuitries, due to overexpression of BDNF in fore- 406
brain regions, actually display a precocious end of the 407
critical period for ocular dominance plasticity [23]. In 408
382 25.4.1 Inhibitory Processes Regulate summary, an initial threshold of inhibition triggers the 409
383 the Time Course of the Critical Period developmental period in which neuronal networks in 410
the visual system are highly susceptible to experience, 411
384 Intracortical inhibitory processes play a key role in the whereas a second inhibitory threshold signals the end 412
385 regulation of visual cortex plasticity [21] (Fig.  25.6). of this phase of enhanced plasticity (Fig. 25.6). 413
386 The maturation of GABAergic inhibition sets the Inhibition triggers plasticity through GABAA recep- 414
387 threshold for the start of the critical period for expe- tors containing the alpha-1 subunit. These receptors 415
388 rience-dependent plasticity by enabling visual cortical are enriched at somatic synapses on pyramidal neurons 416
389 neurons to detect differences in the activity between made by large basket cells (a class of parvalbumin- 417
390 competing retinal inputs. Actually, transgenic mice positive GABAergic interneurons that extend horizon- 418
391 with reduced levels of intracortical inhibition, due to tally across ocular dominance columns). Recent studies 419
392 the absence of one isoform of the GABA synthesizing indicate that visual experience controls the time-course 420
393 enzyme (­glutamate decarboxylase of 65 kDa – GAD65), of the critical period by promoting the transfer of the 421
394 show no susceptibility to monocular deprivation during homeoprotein Otx2 from the retina to the visual cor- 422
395 their entire lifespan. The impairment of experience- tex, where it seems to trigger the maturation of parval- 423
396 ­dependent plasticity in these animals is rescued by bumin-positive GABAergic interneurons [44]. 424
 556 J.F. Maya-Vetencourt and M. Caleo

425 25.4.2 Plasticity Involves the Remodeling 25.4.3 The Maturation of Intracortical 472
426 of Extracellular Matrix Components Myelination Down-Regulates 473
Plasticity 474
427 An emerging view in the field of neuronal plasticity
428 is that the effects caused by early sensory experience Myelin-associated proteins are glia-derived pro- 475
429 in the remodeling of visual cortical circuitries are teins that  have an important role in controlling neurite 476
430 actively preserved throughout life by the late appear- ­outgrowth. Not surprisingly, these proteins are also 477
431 ance of molecular factors in the extracellular milieu involved in the regulation of the critical period. In par- 478
432 that restrict plasticity. Some components of the extra- ticular, proteins of the myelin sheath including Nogo-A 479
433 cellular matrix in the central nervous system, in fact, and myelin-associated glycoprotein (MAG), act as mol- 480
434 need to be removed for experience-dependent plas- ecules that are inhibitory for plasticity by binding to the 481
435 ticity to occur. The proteolytic activity of tissue plas- Nogo receptor (NgR). NgRs are expressed on cortical 482
436 minogen activator (tPA), for instance, increases after neurons, and their activation triggers intracellular sig- 483
437 monocular deprivation during the critical period. naling cascades that inhibit neurite growth. Moreover, 484
438 When tPA is inhibited pharmacologically, the shift of the maturation of intracortical myelination correlates 485
439 ocular dominance following unilateral eyelid suture is with the end of the critical period. In NgR knockout 486
440 reduced, showing that tPA plays a permissive role for mice ocular dominance plasticity actually persists well 487
441 plasticity. Experience-dependent plasticity during the into adulthood [36]. Adult transgenic animals lacking 488
442 critical period is impaired in tPA-knockout mice and the NgR ligand Nogo-A display a similar susceptibil- 489
443 this impairment is rescued by exogenous tPA admin- ity to monocular deprivation thus confirming that NgR- 490
444 istration. Changes of binocularity in response to mon- dependent mechanisms participate directly in restricting 491
445 ocular deprivation are accompanied by rapid structural experience-dependent plasticity in the developing visual 492
446 changes of the dendritic spines in deep and superficial system. The paired immunoglobulin-like receptor B 493
447 layers of the primary visual cortex. This effect is mim- (PirB) also has a high affinity for Nogo-A and MAG. 494
448 icked by exogenous tPA administration suggesting that When activated, PirB restricts ocular dominance plastic- 495
449 its proteolytic activity is involved in the structural plas- ity in the visual cortex [45]. 496
450 ticity of dendrites.
451 Proteins in the extracellular matrix play a key role
452 in exerting the inhibitory function that terminates 25.4.4 Neurotrophins Mediate Experience- 497
453 the critical period for cortical plasticity. In rodents, Dependent Forms of Plasticity 498
454 the glycoproteins chondroitin sulfate proteoglycans
455 (CSPGs) are inhibitory for experience-dependent plas- Neurotrophins are growth factors released by neu- 499
456 ticity. Degrading sugar chains of CSPGs by exogenous ronal and glial cells that promote the growth of target 500
457 administration of the bacterial enzyme chondroitinase- neurons, i.e., the development of their axonal and/or 501
458 ABC reactivates ocular dominance plasticity in the dendritic arborizations. “Nerve growth factor” (NGF), 502
459 adult rat [38]. Similarly, chondroitinase-ABC treat- “brain-derived neurotrophic factor” (BDNF), and “neu- 503
460 ment ­promotes structural and functional recovery from rotrophin-4” (NT-4), are three neurotrophins involved 504
461 visual deficits in long-term deprived rats, although in various forms of synaptic plasticity. Neurotrophins 505
462 the same treatment seems not to be as much effec- act via specific receptors: NGF binds to trkA receptors 506
463 tive in adult amblyopic cats [47]. It is important to while BDNF and NT-4 bind to trkB receptors. These 507
464 remark that degradation of CSPGs may alter the ratio receptors act via several intracellular second messen- 508
465 of inhibitory/excitatory transmission in the visual cor- gers, including PKA, ERK1/2, CaMKII, ultimately 509
466 tex, as these glycoproteins condense in perineuronal controlling transcription factors such as CREB, which 510
467 nets (PNNs) mainly around parvalbumin-positive activate the CRE promoter (see Chap. 6). Typically, 511
468 GABAergic interneurons. Alternatively, or in addition, neurotrophins function in an activity-dependent­ 512
469 CSPGs may influence structural plasticity by modify- manner. Actually, release of neurotrophins only acti- 513
470 ing dendritic spine dynamics and associated functional vates those synapses that were electrically active (see 514
471 modifications in the visual cortex. Chap. 26). This activity-dependent growth stimulant 515
 25  Experience-Dependent Plasticity in the Central Nervous System 557

NT-4, whereas growth of apical dendrites is stimulated by 548

all neurotrophins. BDNF acts on those dendrites and ter- 549
minals that are activated by presynaptic transmission, 550
providing a mechanism for selective stabilization of active 551
synapses. Actually, inhibition of spontaneous activity 552
abolishes the effects of BDNF on dendritic arborization. 553
In rodents, BDNF is expressed in the retina and 554
anterogradely transported along the optic nerve to the 555

Fig. 25.7  Potential mechanism of action of neurotrophins on geniculate nucleus and to the superior colliculus. 556
visual cortical plasticity: the hypothesis of activity dependent Levels of BDNF in the retina influence not only devel- 557
reward. LGN fibers driven by the nondeprived eye display a rich opment of the lateral geniculate nucleus and superior 558
electrical discharge and receive a strong neurotrophic support (thick
colliculus, but also ocular dominance plasticity in the 559
arrow) from the postsynaptic cell. In consequence, synaptic inputs
are strengthened. In contrast, LGN fibers driven by the deprived cortex. In particular, monocular deprivation reduces 560
eye, having a poor discharge, get a weak neurotrophic support (thin BDNF levels in the deprived retina and microinjection 561
arrow). This causes synaptic connections to weaken of BDNF into the deprived eye counteracts the shift of 562
ocular dominance following eyelid suture. 563
516 is ideally suited for developmental plasticity: active The neurotrophin BDNF appears to be a critical 564
517 afferents compete for a limited amount of neurotro- mediator of the effects of early sensory experience in 565
518 phins, and those afferents that are electrically active structural and functional maturation of the visual cor- 566
519 benefit most [7]. The notion that neurotrophins medi- tex. In this scenario, visual afferent activity drives the 567
520 ate different forms of plasticity initially came from the production and release of BDNF, that then promotes 568
521 observation that exogenous NGF administration pre- the development of intracortical inhibitory circuitries 569
522 vents the loss of visual acuity and the shift of ocular that underlie normal visual functions. In keeping with 570
523 dominance caused by monocular deprivation in the rat this, BDNF overexpression in the forebrain allows for 571
524 visual system. This finding suggests that ocular domi- normal development of basic physiological properties 572
525 nance plasticity involves the competition between of the visual cortex even in the total absence of visual 573
526 geniculocortical projections from either eye for a neu- experience [19]. 574
527 rotrophic factor, which is produced and released by
528 visual cortical neurons in an activity-dependent man-
529 ner (Fig. 25.7). Consistent with this view, infusion of 25.4.5 Long-Distance Diffusely Projecting 575
530 either BDNF or NT-4 into kitten visual cortex desegre- Systems Modulate Visual Cortical 576
531 gates ocular dominance columns [6]. Plasticity 577
532 The NGF-induced regulation of ocular dominance
533 plasticity depends on afferent electrical activity. The The major modulatory systems in the brain (i.e., 578
534 inactivation of NGF signaling by specific antibodies not noradrenaline, dopamine, histamine, acetylcholine, 579
535 only impairs the anatomical and functional development serotonin) regulate complex functions of the central 580
536 of the rat visual system but also prolongs the critical nervous system such as cognition, behavior, and medi- 581
537 period into adult life. In kittens, intraventricular, but not ate different forms of neuronal plasticity. Experience- 582
538 intracortical, infusion of NGF attenuates the effects of dependent modifications of cortical circuitries are not 583
539 eyelid suture, indicating that NGF does not act directly determined solely by local correlations of electrical 584
540 on visual cortical neurons but is likely to activate sub- activity but are also influenced by attentional mecha- 585
541 cortical structures bearing NGF receptors such as affer- nisms [43]. Sensory signals, for instance, promote 586
542 ents from the cholinergic system in the basal forebrain. marked modifications of neural circuitries only when 587
543 The primary NGF receptor trkA, indeed, is mostly but animals attend to sensory input and use this information 588
544 not exclusively expressed in cholinergic fibers. for the control of behavior. Early studies performed in 589
545 Different neurotrophins act at specific sites. For cats demonstrated that changes of visual cortical cir- 590
546 instance, the arborization of basal dendrites in ferret cuitries in response to experience during early life, 591
547 visual cortex is stimulated by trkB ligands BDNF and are lessened when noradrenergic, cholinergic, and 592
 558 J.F. Maya-Vetencourt and M. Caleo

593 serotonergic projections to the cortex are inactivated. Blocking NMDARs inhibits the effects of monocu- 639
594 Additionally, there is evidence that these neuromodu- lar deprivation in kittens showing that NMDARs are 640
595 latory systems mediate forms of plasticity in the adult important for visual cortical plasticity. Interestingly, 641
596 visual system of cats and rodents (e.g., [34]). knockout mice with deletion of the NR2A subunit have 642
a normal sensitivity to deprivation by eyelid suture and 643
the effects of monocular deprivation are restricted to 644
597 25.5 Hebbian Plasticity and NMDA-Type early stages of development, suggesting that the switch 645
598 Glutamate Receptors from NR2B to NR2A may not be crucial for the ter- 646
mination of the critical period. Nevertheless, NMDAR 647
599 The amount and pattern of neural activity specify subunit composition influences the outcome of devel- 648
600 synaptic modifications [24]. As we have seen in the opmental plasticity. In wild-type mice, eyelid suture 649
601 neurotrophins section, the simultaneous activation of during the critical period induces two different pro- 650
602 the pre- and postsynaptic neuron leads to an increase cesses: an initial input-specific weakening of synapses 651
603 in the synaptic strength between those cells. This from the deprived eye and a later strengthening of syn- 652
604 is summarized by Hebb’s principle: “neurons that apses from the open eye [17]. Interestingly, the rapid 653
605 fire together wire together”, whereas neurons that depression of inputs from the deprived eye is absent 654
606 fire out of synchrony lose their link. NMDA recep- in transgenic animals that lack the NR2A subunit. 655
607 tors (NMDARs) play a key role in mediating these Instead, these mice exhibit a precocious potentiation 656
608 processes as they function as coincidence detec- of open eye inputs. 657
609 tors in synaptic plasticity (see Chap. 26). NMDARs
610 mediate excitatory synaptic transmission and open
611 only when the presynaptic release of glutamate is 25.6 Long-Term Potentiation (LTP) 658
612 coupled with the postsynaptic depolarization, thus and Long-Term Depression (LTD) 659
613 implementing Hebb’s rule at the molecular level.
614 Under resting conditions, NMDARs are blocked by Modifications of synaptic transmission in response to 660
615 Mg2+, which is removed from the ion channel by sensory experience have long been studied in terms 661
616 intense depolarization, thus allowing Ca2+ neuronal of LTP and LTD (see Chap. 26). In the visual system, 662
617 inflow that eventually activates intracellular signal LTP and LTD can be induced by different patterns of 663
618 transduction pathways. This phenomenon leads to electrical stimulation. Brief and strong episodes of 664
619 lasting modifications of synaptic efficacy known as high-frequency stimulation promote LTP while pro- 665
620 long-term potentiation (see Chap. 26). Interestingly, longed low-frequency stimulation yields LTD. The 666
621 NMDARs are not all alike. NMDARs are heterote- Bienenstock-Cooper-Munro (BCM) theory was devel- 667
622 tramers composed of different subunits, two obliga- oped to explain features of experience-dependent 668
623 tory NR1 subunits and two regulatory subunits which plasticity in the kitten visual cortex and describes 669
624 come in four types: NR2A to NR2D. Composition of the extent of LTP and LTD occurrence as a function 670
625 NMDARs determines the functional properties and of spiking activity in postsynaptic cells [4]. Synaptic 671
626 amount of Ca2+ influx through them. The NR1/NR2A input at high frequency that activates postsynaptic cells 672
627 heteromeric channel exhibits higher open probability above a certain threshold, results in an increase in syn- 673
628 and faster deactivation than the NR1/NR2B chan- aptic strength (LTP), whereas low-frequency input that 674
629 nel, therefore NR1/NR2A channels tend to open and produces only low levels of postsynaptic firing results 675
630 close earlier than NR1/NR2B channels. In the visual in a decreased synaptic efficacy (LTD). An important 676
631 system of cats and rodents, NMDAR subunit com- feature of the model is that the threshold is not fixed 677
632 position is regulated by age and experience. Early in but is itself a function of postsynaptic activity. It does 678
633 development receptors containing the NR2B subunit slide as to make potentiation more likely whenever 679
634 predominate but later there is a progressive inclusion average activity is low, and less likely when it is high 680
635 of the subunit NR2A. Accordingly, NMDA currents (Fig.  25.8). What role do these phenomena play in 681
636 are progressively shortened thus enabling NMDARs OD plasticity? The initial weakening of visual inputs 682
637 to work as high fidelity coincidence detectors of pre- from the deprived eye that occurs after brief monocular 683
638 and postsynaptic activity. deprivation may be mediated by homosynaptic LTD. 684
 25  Experience-Dependent Plasticity in the Central Nervous System
Fig. 25.8  Schematic representation of the BCM model. The
solid curve at center represents the starting condition: when
postsynaptic activity is below (or above) a threshold (x-inter-
cept), presynaptic activity produces depression (or potentiation).
If average postsynaptic activity drops to lower values, the entire
curve shifts to the left (dashed line), making potentiation more
likely. If, instead, it rises to higher values, the curve shifts to the
right (dotted line), making depression more likely
685 Indeed in vivo occurring LTD occludes LTD induction
686 ex vivo: this means that when a cortical slice is taken
687 from an eyelid sutured young animal, LTD can no
688 longer be induced, because LTD is already saturated.
689 LTD is induced by decreased afferent activity from
690 the deprived eye, which causes a reduced activation of
691 NMDARs and thus a low-amplitude rise in Ca2+ concen-
692 tration. This activates postsynaptic protein phosphatases
693 (see Chap. 8), which dephosphorylate and internalize
694 AMPA receptors (AMPARs). Less AMPARs mean a
695 decreased sensitivity to glutamate, and thus a depres-
696 sion of synaptic transmission from the deprived eye.
697 The BCM theory also predicts that open-eye potentia-
698 tion following monocular deprivation is mediated by
699 homosynaptic LTP. This ­potentiation could be favored
700 by the shift of the modification threshold to the left
701 due to a reduced afferent input from the deprived eye
702 that decreases average activity. Specific mechanisms
703 remain unclear, but in analogy to LTP in other systems
704 (see Chap. 26), correlated synaptic inputs from the not-
705 deprived eye may activate NMDARs, thus increasing
706 Ca2+ levels. Ca2+-activated protein kinases eventually
707 increase AMPAR insertion into the postsynaptic mem-
708 brane enhancing sensitivity to glutamate (see Chap. 8).
559
Fig. 25.9  Sketch of long-term potentiation (LTP) experiments
in visual cortical slices. High-frequency stimulation of layer IV
in visual cortical slices of both young and adult rats induces
reliable LTP of synaptic responses in layer II–III. Conversely,
electrical stimulation of the white matter yields LTP in layer
II–III only in young animals. This form of synaptic plasticity
(WM-LTP) follows the time-course of the critical period for
ocular dominance plasticity and it can be restored in adult slices
only if GABAergic inhibition is reduced (e.g., by exogenous
administration of GABAA receptor antagonists). Stimulation
sites are indicated by lightning bolts
Support to this notion comes from the occurrence of 709
NMDAR-dependent forms of LTP in the rat visual sys- 710
tem and from the fact that OD plasticity is impaired in 711
mice lacking the protein kinase CaMKII, a key player 712
in LTP expression. 713
LTP differs across the layers of the visual cortex. 714
Remember that the thalamocortical fibers synapse 715
onto pyramidal cells in layer IV, and these in turn 716
synapse onto cells in other layers, notably layer II/III. 717
High frequency stimulation of layer IV in visual corti- 718
cal slices of both young and adult rats induces reliable 719
LTP of synaptic responses in layer II/III (Fig.  25.9). 720
In contrast, stimulation of thalamocortical afferents in 721
the white matter (WM-LTP) induces LTP in layer II/ 722
III only in young animals. WM-LTP can be rescued in 723
adult life when GABAA receptor antagonists are applied 724
to adult visual cortex slices. Therefore, the maturation 725
of inhibitory circuitries in layer IV might be one of 726
the mechanisms responsible for the downregulation 727
of WM-LTP over development. Notably, susceptibil- 728
ity to WM-LTP roughly coincides with the critical 729
period for OD plasticity and, as the critical period, 730
 560 J.F. Maya-Vetencourt and M. Caleo

731 can be prolonged by dark rearing [28]. Accordingly, strength in visual cortex, as measured by the increase 776
732 BDNF-overexpressing mice, which show an acceler- in the amplitude of miniature excitatory postsynaptic 777
733 ated maturation of intracortical inhibition, display an currents (mEPSCs). Measurements of activity using 778
734 accelerated developmental decline of WM-LTP in the calcium-sensitive dyes and two-photon imaging have 779
735 visual cortex [23]. demonstrated that homeostatic response regulation 780
736 A role for BDNF in controlling developmental plas- contributes to changes of eye-specific responsiveness 781
737 ticity of the visual system via LTP/LTD in  vivo has after monocular deprivation in mouse visual cortex. 782
738 been shown in the developing retinotectal system of Similar adaptations in excitatory synaptic transmis- 783
739 Xenopus laevis. Application of BDNF into the tectum sion are also observed in auditory cortex following 784
740 leads to a persistent potentiation of retinotectal syn- hearing loss, suggesting that homeostatic regulation 785
741 apses. This potentiation spreads retrogradely to the of cortical synapses by sensory experience is a general 786
742 retina, with a significant enhancement of synaptic phenomenon. 787
743 inputs at the dendrites of retinal ganglion cells [13]. In
744 developing neural circuits, the induction of retrograde
745 modifications of neurotransmission can be important 25.8 Structural Underpinnings 788
746 for allowing coordinated adjustments of synaptic of Experience-Dependent Plasticity 789
747 inputs in neuronal networks.
Experience-dependent functional changes of neu- 790
ral circuitries are accompanied by extensive struc- 791
748 25.7 Homeostatic Plasticity tural rearrangements in neurons. Dendritic spines, 792
which are the sites of excitatory synaptic input to 793
749 Hebbian mechanisms, based on the idea that corre- ­pyramidal cells, are particularly sensitive to expe- 794
750 lated pre- and postsynaptic activity strengthens syn- rience. A total lack of visual experience early in 795
751 apses, provide an important framework for the life (dark rearing), for instance, induces profound 796
752 interpretation of experience-dependent changes in the changes in spine morphology and density, which 797
753 brain. However, due to positive feedback, Hebbian are partially reversible by subsequent light expo- 798
754 plasticity would lead to rapid saturation of synaptic sure. Similarly, monocular deprivation influences 799
755 strength in the absence of proper constraints. Several motility, turnover, number, and morphology of den- 800
756 lines of evidence indicate the presence of homeostatic dritic spines in the visual cortex. A crucial question 801
757 plasticity, i.e., regulatory adjustments that work to is whether and to what extent these forms of struc- 802
758 maintain the stability and functionality of neural net- tural plasticity contribute to experience-dependent 803
759 work subject to Hebbian changes [46]. The BCM changes in neural connectivity. Longitudinal two- 804
760 model is an example of such homeostatic plasticity, photon imaging experiments in mouse neocortex 805
761 since the crossover point between potentiation and show that spine dynamics is maximal during early 806
762 depression moves as to make potentiation less likely stages of development and decreases thereafter, in 807
763 when average postsynaptic activity is high (Fig. 25.8). parallel to declining plasticity in adulthood [22]. 808
764 Other mechanisms for homeostatic plasticity include Structural changes of dendritic spines outlast the 809
765 synaptic scaling (scaling of the strength of excitatory original experience, and thereby provide a mor- 810
766 synapses depending on average activity of the post- phological basis for long-term information storage. 811
767 synaptic neuron) and regulation of intrinsic excitabil- Visual experience-dependent structural alterations 812
768 ity (i.e., changing the way in which postsynaptic have also been demonstrated in the optic tectum of 813
769 neurons integrate synaptic inputs and fire action amphibians and flies. In particular, light stimulation 814
770 potentials). of Xenopus leavis tadpoles triggers dendritic arbor 815
771 Several experiments have shown that cortical neu- growth in tectal cells. In the laboratory fruitfly 816
772 rons engage in homeostatic adaptations in response Drosophila melanogaster, alterations in visual 817
773 to changes in afferent activity, for instance, follow- experience (monocular deprivation or rearing in 818
774 ing sensory deprivation. Specifically, a few days of darkness) modify the size of the optic lobes and the 819
775 visual deprivation can scale up excitatory synaptic terminals of photoreceptor cell axons. 820
 25  Experience-Dependent Plasticity in the Central Nervous System 561

821 25.9 Short Noncoding RNAs by shifting the intracortical inhibitory/excitatory (I/E) 865
822 and the Regulation of ratio in favor of excitation (see, e.g., [33]). This has 866
823 Experience-Dependent Plasticity prompted the search for endogenous factors with the 867
potential to enhance plasticity in adult life by modulat- 868
824 Recent experimental evidence supports a role for short ing the intracortical I/E balance. The process of plastic- 869
825 noncoding RNAs (microRNAs), which interact with ity reactivation in adulthood is a multifactorial event that 870
826 and control translation of mRNA targets, in the regu- comprises the action of different cellular and molecular 871
827 lation of experience-dependent plasticity. MicroRNAs mechanisms, working in parallel or in series, the sum 872
828 are powerful regulators of gene expression and act by of which results in the activation of intracellular signal 873
829 binding to the 3¢-untranslated region (3¢-UTR) of the transduction pathways regulating the expression of plas- 874
830 target mRNA, making it possible for a single microRNA ticity genes. In rodents, experimental paradigms based 875
831 to control expression of multiple genes that posses the upon the enhancement of environmental stimulation lev- 876
832 same sequence in this region of the mRNA. els, genetic manipulations, and pharmacological treat- 877
833 A role of microRNAs in synaptic plasticity was ments have revealed that either the enhanced action of 878
834 first indicated by the observation that a brain-specific long-distance projection systems (e.g., serotonergic and 879
835 microRNA, miRNA-134, localizes to the synapto- cholinergic transmission) or IGF-I signaling modulate 880
836 dendritic compartment mediating the effects of neu- the intracortical inhibitory/excitatory balance in favor 881
837 rotrophins such as BDNF on structural plasticity of of excitation, which, in turn, sets in motion intracellular 882
838 dendritic spines in rat hippocampal neurons [42]. In the events that eventually mediate the expression of genes 883
839 visual cortex, another microRNA, ­miRNA-132, is rap- associated with structural and functional modifications 884
840 idly up-regulated after eye opening and its expression of neural circuitries in the adult visual system. 885
841 may control dendritic spine rearrangements associ- Experience-dependent modifications of chromatin 886
842 ated with functional plasticity triggered by monocular structure that control gene expression are, in fact, 887
843 deprivation in early life. Thus, miRNA-132 appears to recruited as targets of plasticity-associated processes. 888
844 be a molecular transducer of the action of visual expe- The plastic outcome caused by fluoxetine in adult rats, 889
845 rience on developing visual circuitries, possibly acting is actually mediated by a transitory expression of the 890
846 through modulation of dendritic spine plasticity. neuron-specific transcription factor NPAS4 through a 891
mechanism that involves a reduction in the methyla- 892
tion status at the NPAS4 promoter region [35], this epi- 893
847 25.10 The Process of Plasticity genetic modification being normally associated to gene 894
848 Reactivation in the Adult transcription activation. Furthermore, NPAS4 overex- 895
849 Visual System pression in the visual cortex of adult naive animals 896
restores ocular dominance plasticity whereas NPAS4 897
850 As previously mentioned, the developmental matura- down-regulation during fluoxetine treatment effec- 898
851 tion of intracortical inhibitory circuitries causes the end tively prevents the process of plasticity reactivation 899
852 of plasticity in the visual system [21]. In line with this [35]. Of note, NPAS4 mediates BDNF expression and 900
853 notion, it is possible to restore plasticity in adult life by drives the formation of inhibitory synapses on excit- 901
854 reducing levels of inhibition. A direct demonstration atory neurons in the rodent visual cortex. Hence, 902
855 that GABAergic transmission is a crucial brake limiting NPAS4 seems to turn on a transcriptional program that 903
856 visual cortex plasticity derives from the observation that regulates the expression of plasticity genes while facil- 904
857 a pharmacological reduction of inhibitory transmission itating, in parallel or in series, a functional reorganiza- 905
858 effectively restores ocular dominance (OD) plasticity tion of inhibitory circuitries that might contribute to 906
859 in adulthood [20]. This is consistent with the fact that the homeostasis of cortical excitability during this 907
860 experimental paradigms such as dark exposure, environ- phase of enhanced plasticity. The role of this transcrip- 908
861 mental enrichment, food restriction, long-term fluoxetine tion factor in mediating phenomena of brain plasticity, 909
862 treatment (a selective serotonin reuptake inhibitor, is further highlighted by the observation that it is criti- 910
863 SSRI), and exogenous IGF-I (insulin-like growth fac- cally involved in processes of memory formation and 911
864 tor 1) administration, all promote plasticity late in life consolidation, at least, in rodents. 912
 562 J.F. Maya-Vetencourt and M. Caleo

913 In summary, histone posttranslational modifications

914 seem to be, at least, one of the epigenetic mechanisms
915 (see Chap. 6) underlying the expression of genes that
916 act as downstream effectors of plasticity in the ner-
917 vous system (Fig.  25.10). The reinstatement of adult
918 visual cortex plasticity caused by intracortical infu-
919 sion of serotonin, for instance, is partially mediated
920 by 5-HT1A receptors signaling and accompanied by
921 a transitory increment of BDNF expression. This is
922 paralleled by an enhanced histone acetylation status
923 at the activity-dependently regulated BDNF promoter
924 regions and by a decreased expression of histone
925 deacetylase (HDACs) enzymes [34]. Accordingly,
926 environmental enrichment, long-term fluoxetine treat-
927 ment, and food restriction, all increase acetylation of
928 histones in the hippocampus and cortex in adult life.
929 Moreover, a developmental down-regulation of histone
930 posttranslational modifications controls critical period
931 plasticity in the mouse visual system [40] whereas
932 pharmacologically increasing acetylation of histones
933 by treatment with HDACs inhibitors effectively reacti-
934 vates susceptibility to monocular deprivation and pro-
935 motes a complete recovery of visual functions in adult
936 amblyopic animals [34, 40].

Fig. 25.10  The reinstatement of plasticity in adulthood is

937 25.11 Early Experience Influences associated with signal transduction pathways that involve the
938 Rodents’ Behavior by Modifications enhanced action of either neuromodulatory projection systems
939 of Chromatin Structure (e.g., serotonin and acetylcholine) or IGF-1 signaling, which all
set in motion physiological processes that modulate the inhibi-
tory/excitatory ratio. A reduction of the inhibitory/excitatory
940 In rodents, some dams give more care (licking/groom-
balance in the visual cortex may directly activate intracellular
941 ing) to their offspring than others. Later in life, “high- mechanisms that eventually promote epigenetic modifications
942 licked/groomed” pups are less anxious than their of chromatin structure (e.g., posttranslational modifications of
943 “low-licked/groomed” counterparts and they perform histones), which in turn allow for the expression of genes that
act as down-stream effectors of plastic phenomena in adult life.
944 better in tests of learning and memory. This effect
A pharmacological reduction of intracortical inhibition enhances
945 emerges over the first week of postnatal life and is plasticity while promoting the activity-dependent BDNF expres-
946 reversed with cross fostering: if “high licking/groom- sion and degradation of extracellular matrix (ECM) components
947 ing” dams rear the biological offspring of “low licking/ that are inhibitory for plasticity. BDNF-trkB signaling might
up-regulate the expression of additional genes associated with
948 grooming” mothers, the offspring will behave as “high-
functional modifications in the visual cortex. Degradation of
949 licked/groomed” pups [48]. These changes are induced ECM components may modify the inhibition/excitation ratio in
950 by epigenetic regulation of gene expression, i.e., chro- the visual system. The interaction between BDNF-trkB signaling
951 matin structure changes that control gene transcription, and extracellular matrix reorganization has yet to be explored.
Continuous arrows represent established interactions between
952 including DNA methylation and histone posttransla-
the molecular and cellular processes mentioned (boxes). Dashed
953 tional modifications (see Chap. 6). lines represent interactions that remain to be ascertained. The
954 Maternal care increases the expression of the gluco- potential for the reactivation of plasticity to promote the recovery
955 corticoid receptor as well as that of the transcription fac- of sensory functions after long-term sensory deprivation in adult
life, has been reported using amblyopia as a paradigmatic model
956 tor zif-268, and leads to a decreased DNA methylation
 25  Experience-Dependent Plasticity in the Central Nervous System 563

957 pattern at the glucocorticoid receptor gene promoter in of the sound at each ear. One important function of 998
958 the hippocampus [48]. In addition, changes at the level auditory localization is the guidance of reflexive orient- 999
959 of chromatin structure in “high-licked/groomed” pups ing responses that shift attention towards unexpected 1000
960 include higher levels of acetylation at lysine-9 on his- sounds in the environment [27]. This is accomplished 1001
961 tone-3 (H3K9): a marker of gene transcription activa- at the level of the midbrain (inferior and superior col- 1002
962 tion. Increasing H3K9 acetylation by central infusion of liculus). In particular the deep layers of the superior 1003
963 the histone deacetylase inhibitor trichostatin-A in rats colliculus/optic tectum integrate several cues to build a 1004
964 born to “low-licking/grooming” mothers causes the map of auditory space that is aligned with a map of 1005
965 methylation pattern to change to that of animals brought visual space. Indeed, the discharge of superior collicu- 1006
966 up by “high-licking/grooming” dams. Behaviorally, lus neurons is enhanced when auditory and visual 1007
967 “low-licked/groomed” pups treated with the HDAC ­stimuli are presented in close spatial and temporal 1008
968 inhibitor trichostatin-A are less anxious than vehicle- proximity. 1009
969 treated “low-licked/groomed” counterparts and display Several paradigms have been adopted to study the 1010
970 no difference at behavioral level when compared to influence of an altered sensory experience on the sound 1011
971 “high-licked/groomed” pups. localization pathway in the midbrain. In the guinea pig, 1012
the normal map of auditory space appears in the deep 1013
layers of the superior colliculus at 32  days after birth 1014
972 25.12 Experience-Dependent Plasticity (P32). Formation of this map is prevented by rearing 1015
973 in the Auditory System animals from birth in an environment of omnidirectional 1016
white noise (i.e., an auditory stimulus that contains 1017
974 Considerable plasticity exists in neural circuits that every frequency within the audible range). Collicular 1018
975 process auditory information. Auditory information responses from such noise-reared animals reveal large 1019
976 ascends via the lateral lemniscus to the midbrain (infe- auditory spatial receptive fields, and the representation 1020
977 rior and superior colliculus) and is then relayed to the of auditory space in the colliculus shows no topographic 1021
978 medial geniculate nucleus (nucleus ovoidalis in birds). order. Importantly, exposure to omnidirectional white 1022
979 The geniculate neurons project in turn to the primary noise after P30 (postnatal day 30) produces no effect on 1023
980 auditory cortex (A1; field L in birds) (see Chap. 17). the collicular map, pointing to a well-defined critical 1024
981 Neurophysiological studies in animals raised with period for map development. Thus, establishment of 1025
982 abnormal sensory inputs have shown that the function topographic order in the representation of auditory space 1026
983 of these auditory circuits is potently shaped by envi- in the colliculus requires normal sensory experience 1027
984 ronmental influences. As described above for the visual during a sensitive phase of development. 1028
985 system, the effects of experience are particularly prom- One second type of manipulation of auditory expe- 1029
986 inent during critical periods in early development. rience has involved raising animals with unnatural 1030
987 However, auditory circuits retain the capacity for binaural cues produced by plugging one of the ears, 1031
988 experience-dependent plasticity throughout adulthood, reminiscent of unilateral eyelid suture in the visual sys- 1032
989 even if the conditions for plasticity to occur are much tem. These experiments, performed in ferrets and barn 1033
990 more stringent in adults than in juveniles [26]. The fol- owls, reveal remarkable adaptive changes in sound 1034
991 lowing sections describe examples of plasticity in the localization performance, especially in young animals 1035
992 neural circuits that subserve sound localization and the [27, 29]. Initially, monaurally occluded animals mis- 1036
993 analysis of sound frequency. localize sounds towards the side of the open ear [29]. 1037
However, after several weeks of monaural occlusion, 1038
young animals can perform a sound localization task 1039
994 25.12.1 Plasticity of Sound Localization just as accurately as normal controls, indicating that 1040
they progressively compensate for the presence of the 1041
995 To localize sounds, the central nervous system uses earplug [27, 29]. Compensation is much less efficient 1042
996 several cues including interaural time differences, inter- after a comparable period of monaural occlusion in 1043
997 aural volume differences, and the frequency spectrum adulthood [27], again pointing to the existence of a 1044
 564 J.F. Maya-Vetencourt and M. Caleo

1045 critical period for circuit rearrangement. In keeping to auditory orienting behaviors; the ICX also receives 1094
1046 with the behavioral data showing greater compensa- visual information via a feedback projection from the 1095
1047 tion in juvenile than in adult age, neurophysiological tectum (Fig. 25.11a) [29]. In juvenile owls reared with 1096
1048 examination reveals an adaptive change in the auditory prisms, response to sound localization cues (such as 1097
1049 space map in the superior colliculus when ear occlu- interaural time difference, ITD) in the ICX and optic 1098
1050 sion is performed in young animals, but not in adult- tectum change to match the visual field displacement 1099
1051 hood. Indeed, the correspondence between the auditory (Fig. 25.11b–d). These new, learned responses become 1100
1052 and the visual map in the superior colliculus of young progressively dominant, while responses to the normal 1101
1053 ferrets with an earplug is similar to that of normally ITD range (normal responses recorded before prism 1102
1054 reared ferrets, while there is no significant realignment experience) disappear over several weeks. 1103
1055 of the two maps in ferrets that are subjected to a simi- This remarkable plasticity includes both anatomi- 1104
1056 lar period of monaural occlusion as adults [27]. cal and functional rearrangements. At the morpho- 1105
1057 Monaural occlusion experiments performed in logical level, there is a robust axonal remodeling in 1106
1058 young barn owls have yielded comparable results. the projection from the ICC to the ICX. The ICX 1107
1059 Young owls subjected to monaural occlusion are capa- receives auditory input from the central nucleus of the 1108
1060 ble of recovering accurate sound localization responses. inferior colliculus (ICC) via topographic axonal con- 1109
1061 In this species, the earplug induces a compensatory nections; in prism-reared owls, these projections are 1110
1062 shift in the tuning of auditory neurons towards the broader than normal, and axon terminals are located 1111
1063 abnormal interaural time and level differences. both in their normal target territory and in an abnor- 1112
1064 Another experimental protocol consists in perturb- mal zone where they can support the new, learned 1113
1065 ing the normal alignment of the auditory and visual responses (Fig.  25.12a). Thus, the formation of an 1114
1066 map. Barn owls can be raised with displacing prisms adaptive neural circuit is mediated, at least in part, by 1115
1067 mounted in spectacle frames in front of the eyes; these axonal sprouting; importantly, the naïve circuit also 1116
1068 prismatic spectacles cause a horizontal shift of the visual persists, indicating that these normal projections must 1117
1069 field of about 20° (Fig. 25.11a–c). Over the course of be somehow silenced at the completion of learning 1118
1070 several weeks, the animals wearing prisms adjust their (see below). 1119
1071 sound localization mechanisms to match their shifted The expression of new, learned responses in the 1120
1072 visual worlds. Basically, prism-reared owls challenged ICX depends on the activation of NMDARs. After a 1121
1073 with a sound stimulus orient to the side of the source by few weeks of prism experience, ICX neurons show 1122
1074 an amount that corresponds to the prismatic displace- both naïve and new responses; focal application into 1123
1075 ment of the visual field. Thus, vision has a dramatic the ICX of a selective blocker of the NMDA receptor 1124
1076 impact on auditory space processing and dominates it. wipes out learned responses, while normal responses 1125
1077 This learning is adaptive because the owls bring their are reduced only by about 50  % [29]. In contrast, 1126
1078 auditory and visual worlds back into mutual alignment blockade of AMPA glutamate receptors tends to affect 1127
1079 (Fig. 25.11b–d). A critical period exists for these adap- normal responses more than new responses. These 1128
1080 tive rearrangements, as adult owls cannot adjust sound pharmacological data indicate that synapses mediating 1129
1081 localization in response to a large prismatic displace- adaptive plasticity in the ICX have a high NMDA/ 1130
1082 ment of the visual field. However, when the prismatic AMPA ratio (Fig. 25.12b); since the NMDA receptor 1131
1083 shift is experienced in small increments, maps of sound is gated by both glutamate and voltage, synapses that 1132
1084 localization do change also in adults. are newly formed in the ICX during the process of 1133
1085 Where does this plasticity take place, and how does plasticity may faithfully transmit information only 1134
1086 it occur? The external nucleus of the inferior colli- when the postsynaptic cell is depolarized. Such depo- 1135
1087 culus (ICX) has been shown to be a site of large-scale larization is provided by an instructive signal from the 1136
1088 ­plasticity during experience-driven modification of the visually responsive neurons in the optic tectum to the 1137
1089 auditory space map. The ICX is located in the midbrain ICX; retinotopic activity in the optic tectum could 1138
1090 of the barn owl and contains an ordered map of auditory serve as the template that instructs the auditory space 1139
1091 space. It receives information from the central nucleus map. A small lesion in the optic tectum eliminates 1140
1092 of the superior colliculus (ICC) and projects its auditory plasticity in the corresponding portion of the auditory 1141
1093 space map to the optic tectum (OT), thus contributing space map in the ICX. Thus, excitatory projections 1142
 25  Experience-Dependent Plasticity in the Central Nervous System
a b¢
c d
Fig. 25.11  Plasticity of the midbrain pathway that mediates
sound localization in the barn owl. (a) Schematic view of the
barn owl brain showing the position of ICC, ICX, and OT.
Information is transferred from the central nucleus of the infe-
rior colliculus (ICC) to the external nucleus of the inferior col-
liculus (ICX), where a map of auditory space is created. The
ICX projects to the optic tectum (OT), where the auditory map
merges with a visual map of space. In turn, the OT sends a feed-
back projection to the ICX. Green arrows indicate excitatory
synaptic connections between areas. (b) Effects of prism rear-
ing on the auditory spatial receptive fields of neurons in the
midbrain. Visual (V) and auditory (A) receptive fields are nor-
mally in close correspondence (b¢). Wearing prisms shifts the
visual receptive field by 20° and disrupts the alignment of visual
and auditory receptive fields (b¢¢). Over several weeks of prism
experience, the auditory receptive field shifts to align with the
new position of the visual receptive field (b¢¢¢). VM vertical
meridian. (c) Plasticity of auditory tuning in the optic tectum of
a juvenile barn owl after prismatic displacement of the visual
1143 from the optic tectum could promote plasticity in the
1144 ICX by stabilizing auditory synapses that contribute to
1145 activity patterns that match those evoked by the visu-
1146 ally based template signal [29] (Fig. 25.12b).
565
b¢¢ b¢¢¢
field is accompanied by a corresponding change in the response
to sound localization cues (ITD interaural time differences).
The graph shows the response of cells in the optic tectum,
before (open symbols) and after (filled symbols) several weeks
of prism experience (learned responses). The neuron normally
responds maximally to 0 ITD and has a visual receptive field on
the vertical meridian (0° azimuth). After wearing prisms for
8 weeks, the cell responds to a value of ITD (50 ms) that exactly
corresponds to the amount of visual field displacement (20°). L
left ear leading, R right ear leading (Adapted from Keuroghlian
and Knudsen [26], with permission). (d) The shift in the projec-
tion of information from the ICC to the ICX (black and red
arrows) that results from early prism experience. Left normal
responses, right after several weeks of prism experience. Note
that units that normally respond to 0 ITD (receptive field at 0°
azimuth, i.e., vertical meridian), following prism experience
are tuned to 50 ms ITD (corresponding to 20° from the vertical
meridian) (Adapted from Keuroghlian and Knudsen [26], with
permission)
Another key player in the plasticity mechanisms 1147
induced by prism rearing is GABAergic inhibition. 1148
Iontophoretic application of a GABAA antagonist into 1149
the ICX of prism-reared owls at the completion of the 1150
 566 J.F. Maya-Vetencourt and M. Caleo

a 25.12.2 Plasticity of Frequency Tuning 1163

Neurons in the primary auditory area (A1) of adult 1164

mammals are arrayed in a tonotopic map according 1165
to their characteristic (preferred) frequencies of the 1166
sound stimulus; this organization is not predetermined 1167
but rather emerges during a sensitive period of post- 1168
natal development. Soon after the onset of hearing, 1169

b neurons in A1 have relatively high thresholds and 1170

broad tuning for stimulus frequency, and the tonotopic 1171
organization is poorly defined. Over the subsequent 1172
days, these physiological properties are refined; sen- 1173
sory experience plays a crucial role in this functional 1174
maturation. This is similar to what happens in primary 1175
visual cortex whose functional properties are poorly 1176
developed at the onset of vision, and undergo a pro- 1177
gressive, visual experience-dependent maturation dur- 1178
ing a critical period. 1179
Several reports have examined the impact of audi- 1180
tory experience on the emergence of a systematic 1181
tonotopic organization in A1 during development. 1182

Fig. 25.12  Mechanisms of plasticity in the barn owl following When rat pups are exposed to a single frequency tone 1183
prism experience. (a) Plasticity of the ICC-ICX projection. Left for several hours a day during the critical period (sec- 1184
normal anterograde labelling, right anterograde labelling in owls ond postnatal week) there is an expansion of the A1 1185
wearing prisms for 8 weeks. Note that axons from the ICC ter-
area devoted to the representation of the presented 1186
minate in a broader zone of the ICX following prism experience,
thus supporting new, learned responses (Modified from Knudsen frequency, and a corresponding reduction in the area 1187
[29], with permission). (b) Schematics of the pattern of neuronal tuned to other frequencies (Fig.  25.13). Thus, A1 1188
connectivity in the ICX following prism experience. A pyrami- comes to over-represent the experienced frequency, 1189
dal neuron (triangle) and an inhibitory, GABAergic neuron
and in this sense becomes customized to the acous- 1190
(circle) are shown. On the left are normal (blue) as well as
sprouting inputs (red) from the ICC; on the right, inputs from tic environment experienced by the subject. The tono- 1191
the optic tectum are depicted. During the first phases of plastic- topic modifications induced by early exposure to a 1192
ity, sprouting axons from the ICC signal to the pyramidal cell single frequency are long-lasting and persist unaltered 1193
mainly via NMDA receptors (green channels, NMDARs) and
throughout adulthood [11, 50]. No significant changes 1194
therefore require a coincident input from the optic tectum to reli-
ably activate the postsynaptic neuron. The new set of inputs of the primary auditory cortex are detected following 1195
from the ICC apparently suppress expression of the naïve map monotonic stimulation in adult rats. 1196
by GABAA-mediated inhibition Another experiment has shown that when rat pups 1197
are chronically exposed to white noise during the criti- 1198
1151 learning process (i.e., in animals in which the newly cal period, the functional properties of A1 neurons do 1199
1152 learned ITD responses are fully mature) causes the not properly mature and remain very similar to those 1200
1153 immediate appearance of normal responses in ICX neu- recorded in very young infant control pups [9]. In par- 1201
1154 rons. This indicates that in the ICX of prism-reared owls, ticular, while naïve A1 neurons are characterized by 1202
1155 excitatory connections supporting normal and learned high selectivity for sound frequency, cells of animals 1203
1156 responses coexist (in agreement with the anatomical exposed to the degrading white noise rather exhibit 1204
1157 data showing intact normal ICC-ICX projections after a broad tuning. The exposure to masking noise not 1205
1158 prism rearing), but responses to normal inputs are only disturbs the functional development of A1 but 1206
1159 masked by GABAergic inhibition (Fig. 25.12b). Thus, also leaves cortical circuits more malleable to sensory 1207
1160 the functional selection of the behaviorally appropriate experience, thus extending the critical period for plas- 1208
1161 map is accomplished by GABAA-mediated inhibition ticity. In rats raised under white noise until P50 and 1209
1162 of the inappropriate, naïve map. then exposed to persistent stimulation with a single fre- 1210
 25  Experience-Dependent Plasticity in the Central Nervous System
1211 quency, A1 becomes dominated by the representation
1212 of the experienced frequency [9]. It is worth recalling
1213 that such chronic monotone stimulation has absolutely
1214 no effect on the naïve P50 cortex. Thus, as in other
1215 sensory modalities, degradation of the normal sensory
1216 experience causes the sensitive period to be extended.
1217 Under certain conditions, however, auditory cir-
1218 cuits, including A1, retain the ability for experience-
1219 dependent plasticity throughout adulthood. Stimuli
1220 must be behaviorally relevant in order to induce
a at any frequency; overall, however, rats in both groups
b c
Fig. 25.13  Effect of early exposure to a single frequency on the
tonotopic organization in primary auditory cortex. (a) Schematics
of the rat brain showing location of the primary auditory cortex
(blue spot). (b, c) Plasticity of the tonotopic map. The color of
each polygon indicates the frequency at which neurons in that
site are most sensitive (CF characteristic frequency, in kHz).
Panel (b) shows the CF map from a naïve P18 rat, while panel
(c) represents the map of a P18 rat exposed to 7 kHz pure tones.
Note that the experienced and nearby frequencies (yellow and
green polygons) are over-represented in the cortex of the stimu-
lated animal with respect to the naïve cortex. D dorsal, A ante-
rior. Scale bars = 0.5 mm. The arrow indicates the frequency of
stimulation (Data reproduced from de Villers-Sidani et al. [11],
with permission)
a b
Fig. 25.14  Task-specific tonotopic reorganization of the adult
primary auditory cortex. Representative tonotopic maps from
A1 in adult control rats (a), rats trained to respond to a frequency
of 5  kHz (b), and rats trained to detect sound levels (c). The
color of each polygon indicates the frequency at which neurons
in that site are most sensitive (CF characteristic frequency, in
567
significant plasticity in adulthood [26]. For instance, 1221
animals must be conditioned to attend to (i.e., respond 1222
to) the frequency, usually accomplished via positive or 1223
negative reinforcement for altering frequency repre- 1224
sentation and tuning in the adult A1. In one experi- 1225
ment, rats were presented with tones of different 1226
frequencies and volume levels, and were trained to 1227
detect either the frequency or level of the sounds [39]. 1228
A subset of animals were rewarded for responding to a 1229
particular frequency at any sound level, whereas other 1230
rats were rewarded for responding to a particular level 1231
1232
were exposed to the same stimuli. In animals rewarded 1233
for detecting a particular frequency, the proportion of 1234
neurons responding to that frequency increased by a 1235
factor of two in primary auditory cortex. This expan- 1236
sion did not occur in animals trained to detect sound 1237
level, indicating the specificity of the effect (Fig. 25.14). 1238
In another experiment, monkeys were trained to dis- 1239
criminate a specific frequency. They received a juice 1240
reward for moving the head immediately after hearing 1241
the target frequency tone; learning of this task was 1242
accompanied by a significant sharpening of frequency 1243
tuning curves that was selective for the target fre- 1244
quency. Collectively, these data demonstrate that plas- 1245
ticity can be triggered in the adult A1 by stimuli that 1246
are behaviorally relevant; in addition, the plasticity 1247
that is induced appears to be specific for the acoustic 1248
feature to which the animal has attended. 1249
The critical importance of attention and reward 1250
for triggering plasticity in the adult A1 suggests the 1251
involvement of activating, diffuse neuromodulatory 1252
systems. One of such neuromodulators is acetylcho- 1253
line, which is released in the cortex by axonal terminals 1254
of cholinergic neurons located in the basal forebrain 1255
c
kHz); gray-shaded polygons indicate recording sites with CF
values close to 5 kHz. Note expansion of the representation of
the 5 KHz frequency in adult rats trained to recognize that fre-
quency. The arrows indicate dorsal (D) and anterior (A) orienta-
tions. Scale bar = 0.5  mm (Data reproduced from Polley et  al.
[39], with permission)
 568 J.F. Maya-Vetencourt and M. Caleo

1256 (nucleus basalis). These cholinergic neurons are acti- a

1257 vated as a function of the behavioral significance of
1258 stimuli and provide the cortex with such information.
1259 Pairing a specific tone with nucleus basalis stimulation
1260 results in a robust remodeling of cortical area A1, with
1261 a clear expansion of the region of the cortex that repre-
1262 sents the paired frequency. This cortical reorganization
1263 is remarkably similar to that obtained in animals trained
1264 to attend to a specific frequency. Thus, behavioral rel-
1265 evance of the sensory stimulus, signaled by an increase
1266 in neuromodulators such as acetylcholine, enhances the b c
1267 effectiveness of plasticity mechanisms in adult cortical
1268 networks, enabling them to overcome the restrictions
1269 on plasticity that exist in mature circuits [26].

1270 25.13 Experience-Dependent Plasticity

1271 in the Somatosensory System
Fig. 25.15  Plasticity in the rodent barrel cortex. (a) Schematics
1272 Experience-dependent plasticity has been amply docu- of the mouse brain showing the somatosensory cortex and the
1273 mented in the primary somatosensory cortex. One of representation of the different body parts. Note the wide area
1274 the most successful model systems for analyzing devoted to whisker representation (barrel cortex). (b, c)
Schematized tangential view of layers II–III of barrel cortex
1275 ­plasticity is the rodent barrel cortex (Fig.  25.15a). showing functional whisker maps in normal animals (b) and ani-
1276 Whiskers are the main tactile organs in rodents, and mals with all whiskers trimmed apart from whisker D1 (c).
1277 the barrel cortex is the area of somatosensory cortex Colored regions represent cortical areas responding to different
1278 that contains the representation of the whiskers. The whiskers. In normal rodents (b), each whisker activates a corti-
cal area slightly larger than the cortical column defined by its
1279 neurons in layer IV are arranged in discrete groups layer IV barrel (barrel outlines are shown in black). Removing
1280 called barrels; each barrel receives inputs from the all but the D1 whisker in adolescent rodents causes expansion of
1281 thalamus carrying information from a single whisker the spared, D1 whisker and a depression of deprived, nearby
1282 (called the principal whisker); the barrels are arranged whiskers within the map (c). Scale bar = 0.5 mm (Modified from
Feldman and Brecht [15], with permission)
1283 in a pattern that corresponds to the topography of the
1284 whiskers on the animal’s snout (Fig. 25.15a). very early in development (within the first days after 1302
1285 The microcircuitry of the barrel cortex corresponds birth). For instance, trimming all whiskers during a 1303
1286 to other cortical areas: thalamic inputs terminate on narrow critical period during the second postnatal 1304
1287 pyramidal neurons in layer IV, in each barrel these week (at the peak of layers II–III synaptic develop- 1305
1288 project to neurons in superficial layers (layers II–III) ment) causes neurons in superficial layers to adopt 1306
1289 within the same radial column. This feed-forward path- broad, unfocused receptive fields and a disordered 1307
1290 way drives strong responses to each column’s princi- whisker map, while the layer-IV map remains normal. 1308
1291 pal whisker, but there is also a spread of excitation to These cortical effects are reminiscent of the deficits in 1309
1292 nearby columns, mainly mediated by horizontal con- synaptic maturation and map formation observed by 1310
1293 nections (Fig. 25.15b). Spread of excitation within and deprivation of experience in other sensory modalities, 1311
1294 across functional columns is precisely regulated by the e.g., vision (see above). 1312
1295 action of several classes of inhibitory interneurons. Experiments with trimming of some whiskers in 1313
1296 Plasticity can be readily induced in barrel cortex by young animals (age around P30–P60) have shown two 1314
1297 whisker deprivation (i.e., by trimming some of the different processes: down-regulation of the deprived 1315
1298 whiskers) during adolescence and in adulthood [15]. input (depression) and up-regulation of the spared input 1316
1299 This plasticity involves rearrangements of layers II–III (potentiation). These processes have different kinetics, 1317
1300 circuitry, while plasticity of thalamocortical connec- which implies two mechanistically distinct processes 1318
1301 tions can generally be induced only by manipulations for plasticity. Depression and potentiation combine 1319
 25  Experience-Dependent Plasticity in the Central Nervous System 569

1320 to produce an expansion of the cortical representation This mechanism of STDP also accounts for the addi- 1369
1321 of spared whiskers into the representation of adja- tional depression observed by sparing some whiskers. 1370
1322 cent deprived whiskers (Fig. 25.15b–c). Interestingly, Spared vibrissae inputs can drive neurons in nearby 1371
1323 in adulthood (after 6  months of age) plasticity only deprived columns via horizontal connections, and this 1372
1324 depends on potentiation of spared vibrissae input in increases the number of presynaptic depolarizations 1373
1325 layers II–III. occurring out of synchrony with the random presynap- 1374
1326 Weakening of evoked responses to deflection of the tic activity, thus promoting LTD. 1375
1327 trimmed whiskers is the first plastic event induced by Plasticity observed following whisker trimming 1376
1328 sensory deprivation in the adolescent barrel cortex, also involves potentiation of the responses to the spared 1377
1329 and precedes synaptic potentiation. Depriving all of whisker. Potentiation is seen both in adolescent and 1378
1330 the whiskers causes depression, but the reduction of adult rats, and involves both intracolumnar and extra- 1379
1331 the response is much greater if only a few vibrissae are columnar circuitry. First, when a single whisker is 1380
1332 trimmed. These results imply that one component of spared, there is a potentiation of synaptic transmission 1381
1333 depression certainly resides in the reduction of input from layer IV to layers II–III within the spared barrel 1382
1334 activity: leaving only spontaneous activity in the affer- column. This is seen electrophysiologically as an 1383
1335 ent pathway from the whisker follicles to the cortex is increased responsiveness of layers II–III neurons to 1384
1336 capable of inducing depression in the cortex. However, spared whisker stimulation. This enhancement of 1385
1337 superimposed on this effect is the suppressive action response is likely due to the removal of phasic inhibi- 1386
1338 of the remaining whiskers, which causes competitive tion exerted by the nearby cortical barrel columns. 1387
1339 depression. This result is conceptually similar to that Second, potentiation of spared whisker response also 1388
1340 obtained in the visual cortex, where deprivation of occurs in the surrounding deprived barrels over a 1389
1341 input from both eyes (via either dark rearing or bin- period of several days [16]. The possibility of interac- 1390
1342 ocular deprivation) causes some depression, but mon- tion between several active barrel columns has also 1391
1343 ocular occlusion causes far greater weakening of the been tested by imposing on the animals a “chessboard” 1392
1344 closed eye pathway. pattern of deprivation, in which every other whisker is 1393
1345 Depression of responses evoked by trimmed whis- trimmed. In this case, potentiation of spared responses 1394
1346 kers is primarily caused by a reduction in the efficacy occurs faster than with a single spared whisker. This 1395
1347 of the excitatory synaptic connections between layer implies that there is a cooperative interaction in the 1396
1348 IV and layers II–III. Experiments using local gluta- deprived barrel columns between the input activities 1397
1349 mate uncaging to activate neurons in specific layers generated by the spared whiskers. 1398
1350 show that layer II–III pyramidal neurons no longer Structural changes at the level of axons, dendrite 1399
1351 receive a strong input from layer IV following whisker branches, and dendrite spines underlie some of the 1400
1352 trimming. This depression involves a presynaptic plastic changes induced by whisker trimming in the 1401
1353 reduction in neurotransmitter release probability, and barrel cortex. In particular, there is a remodeling of the 1402
1354 is likely generated by a Hebbian mechanism of spike axonal arbor of excitatory connections in layers II–III. 1403
1355 timing-dependent plasticity (STDP) (see Chap. 26). In Experiments with longitudinal two-photon imaging 1404
1356 the intracolumnar layer IV-layer II–III pathway of the have also provided clear support for a role of growth 1405
1357 barrel cortex, LTP is induced when the layer-IV cell and retraction of dendritic spines in experience-depen- 1406
1358 fires 0–20  ms before layers II–III cells, and LTD is dent plasticity of the barrel cortex. Spines are the main 1407
1359 induced when firing order is reversed, for spiking site of excitatory input and are highly dynamic struc- 1408
1360 delays of 0 to 50–100 ms. These observations provide tures. Induction of plasticity stabilizes new spines 1409
1361 a possible mechanism for response depression in (13–15 %, compared with 5 % under baseline condi- 1410
1362 the deprived barrels. In the deprived pathways, whis- tions) on pyramidal neurons over 2–3  weeks after 1411
1363 ker trimming abolishes the close correlation between whisker trimming. These data support the idea that 1412
1364 pre- and postsynaptic activity, thus rendering LTP spine growth provides a structural basis for response 1413
1365 unlikely; moreover, any spontaneous, random presyn- potentiation, as seen in the visual cortex (see above). 1414
1366 aptic activity tends to cause depression rather than There are several other examples of how experience 1415
1367 potentiation, since the time window for depression is alters the somatosensory maps in the cortex. One cru- 1416
1368 greater (50–100 ms) than that for potentiation (20 ms). cial experiment has assessed the effect of training on 1417
 570 J.F. Maya-Vetencourt and M. Caleo

1418 the representation of the fingers in the somatosensory Glutamatergic synapses show long-term potentiation 1464
1419 cortex of the monkey. In this experiment, monkeys are (LTP) in an early stage of interneuron maturation 1465
1420 trained to touch a rotating disk with the tips of their (shortly after cell arrival in the bulb). LTP fades as the 1466
1421 middle three fingers to obtain food. After several newborn neurons mature. Thus, neurogenesis provides 1467
1422 months of training, the cortical representation of the a basis for lifelong plasticity in the adult olfactory bulb 1468
1423 tips of the stimulated fingers is substantially enlarged. circuit. 1469
1424 This occurs at the expense of the representation of the Another system in which neurogenesis plays a key 1470
1425 adjacent proximal phalanges. Examples of large-scale role in experience-dependent plasticity is the olfactory 1471
1426 reorganizations of somatosensory maps are also avail- pathway of decapods crustaceans. In these animals 1472
1427 able in humans, specifically in musicians. In particular, adult neurogenesis occurs in the olfactory lobe: the 1473
1428 in string players the cortical representation of the dig- first synaptic relay in the brain that receives informa- 1474
1429 its of the left hand (the fingering hand) is larger than in tion from olfactory receptor neurons. As previously 1475
1430 controls. This cortical reorganization is more pro- described in vertebrates, plasticity in the crustaceans’ 1476
1431 nounced in musicians who have begun their musical olfactory lobe is regulated by sensory experience. 1477
1432 training at an early age. This is again consistent with Unilateral ablation of the olfactory sensilla (containing 1478
1433 the idea that experience-dependent cortical rearrange- olfactory receptor neurons) down-regulates the gener- 1479
1434 ments, although available in adulthood to support life- ation and survival of newborn cells in the crayfish 1480
1435 long learning, are particularly prominent during early olfactory lobe. Impoverished (individuals isolated in 1481
1436 stages of development. small spaces) and enriched (animals living together in 1482
large areas) rearing conditions also influence neuro- 1483
genesis by altering the proliferation of precursor cells 1484
1437 25.14 Plasticity in the Olfactory System and survival of newly generated neurons. Adult neuro- 1485
genesis may contribute to increase the resolution of 1486
1438 The olfactory system is particularly plastic since it odorant decoding and allow adaptation of the olfactory 1487
1439 exhibits lifelong turnover of both peripheral sensory system in crustaceans to ever changing odor environ- 1488
1440 neurons and bulbar interneurons. In the olfactory epi- ments. Thus regulation of neurogenesis by environ- 1489
1441 thelium, cell renewal persists throughout adult life to mental influences and its role in olfactory system 1490
1442 replace olfactory sensory neurons; the newly gener- function and plasticity appear to be conserved themes 1491
1443 ated sensory neurons must extend their axons and con- from invertebrates to vertebrates. 1492
1444 tact the proper targets in the bulb. The turnover of
1445 sensory neurons in the olfactory epithelium is tightly
1446 regulated by environmental factors. Indeed, neurogen- 25.15 Cross-Modal Developmental 1493
1447 esis is enhanced by ablation of the olfactory bulb, Plasticity 1494
1448 while blocking airflow through one side of the nasal
1449 cavity causes an ipsilateral reduction in cell prolifera- Several reports have shown that sensory deprivation in 1495
1450 tion (see Chap. 13). one modality (especially when it occurs early in devel- 1496
1451 Another site of plasticity is represented by newly opment) can have striking effects on the development 1497
1452 generated bulbar interneurons [30]. Indeed, the number of the remaining modalities. This phenomenon is 1498
1453 of newborn interneurons influences olfactory memory. referred to as cross-modal plasticity. Deaf or blind 1499
1454 Exposure of mice to a complex olfactory environment humans have provided convincing behavioral, electro- 1500
1455 (olfactory enrichment) leads to increased newborn cell physiological, and neuroimaging evidence of increased 1501
1456 survival and improvements in olfactory memory. capabilities and compensatory expansion in their 1502
1457 Furthermore, in the female mouse olfactory system, remaining modalities [2]. For instance, congenitally 1503
1458 cell proliferation increases after mating and during blind subjects display better sound localization 1504
1459 gestation and lactation, suggesting that adult neurogen- ­abilities than sighted individuals and have better two- 1505
1460 esis is important for the high olfactory perceptual and point tactile discrimination skills. What is the basis for 1506
1461 memory demands associated with reproduction. these enhanced abilities? Functional imaging studies 1507
1462 Synaptic properties of newly generated interneurons in of people who are blind from an early age reveal that 1508
1463 the bulb differ from those of pre-existing neurons. Braille reading and other tactile discrimination tasks 1509
 25  Experience-Dependent Plasticity in the Central Nervous System 571

1510 activate their primary visual cortex. Using transcranial molecular players, such as neurotrophins and extra- 1556
1511 magnetic stimulation to disrupt the function of visual cellular matrix molecules. Signal transduction cas- 1557
1512 cortex in blind people during Braille reading induces cades driving gene expression changes ultimately 1558
1513 errors in Braille reading and distorts the tactile percep- result in long-lasting alterations in synaptic structure 1559
1514 tions of blind subjects. Thus, blindness from an early and function. 1560
1515 age recruits the visual cortex to process somatosensory
1516 information in a functionally relevant way.
1517 Is there a critical period for cross-modal plasticity? References 1561
1518 This question has been tackled by examining activation
1519 of visual cortical areas by Braille reading in subjects 1. Antonini A, Stryker MP (1993) Rapid remodeling of axonal 1562
arbors in the visual cortex. Science 260:1819–1821 1563
1520 who became blind after age 14 years, after a period of 2. Bavelier D, Neville HJ (2002) Cross-modal plasticity: where 1564
1521 normal vision (late-onset blind). Functional neuroim- and how? Nat Rev Neurosci 3:443–452 1565
1522 aging indicates that the visual cortex is not activated 3. Berardi N, Pizzorusso T, Maffei L (2000) Critical periods dur- 1566
1523 in the late-onset blind group; moreover, repetitive ing sensory development. Curr Opin Neurobiol 10:138–145 1567
4. Bienenstock EL, Cooper LN, Munro PW (1982) Theory for 1568
1524 transcranial magnetic stimulation applied to inactivate the development of neuron selectivity: orientation specificity 1569
1525 visual cortical areas does not disrupt their Braille read- and binocular interaction in visual cortex. J Neurosci 2: 1570
1526 ing. These data indicate that a critical period does exist 32–48 1571
1527 for the visual cortex to be recruited to a role in soma- 5. Bischof HJ, Rollenhagen A (1999) Behavioural and neuro- 1572
physiological aspects of sexual imprinting in zebra finches. 1573
1528 tosensory processing, and this critical period does not Behav Brain Res 98:267–276 1574
1529 extend beyond 14 years of age in humans. 6. Cabelli RJ, Hohn A, Shatz CJ (1995) Inhibition of ocular 1575
1530 One explanation how cross-modal plasticity is dominance column formation by infusion of NT-4/5 or 1576
1531 accomplished involves the stabilization of long-range BDNF. Science 267:1662–1666 1577
7. Caleo M, Maffei L (2002) Neurotrophins and plasticity in 1578
1532 cortico-cortical connections between sensory modali- the visual cortex. Neuroscientist 8:52–61 1579
1533 ties. These connections have been described in imma- 8. Cancedda L, Putignano E, Sale A, Viegi A, Berardi N, 1580
1534 ture cats and hamsters. In adult monkeys there is a Maffei L (2004) Acceleration of visual system development 1581
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