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Original Article

Recent Res. Devel. Neurosci., 4 (2013): 89-107 ISBN: 978-81-308-0525-2

4. Body and brain plasticity: Unraveling its

principles through blindness

Raquel Martínez-Méndez1,*, Eduardo Martínez-Martínez1

Horacio Villafán-Monroy1, Jessica Alejandra Guzmán-López1

Alma Lilia Fuentes-Farías2, Tania Romo-González3

Anahí Chavarría-Krauser4 and Gabriel Gutiérrez-Ospina1,* 1Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México D.F., 04510, México; 2Laboratorio de Ecofisiología, Facultad de Biología, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, Michoacán, 58030, México

3Área de Biología y Salud Integral, Instituto de Investigaciones Biológicas, Universidad Veracruzana Xalapa, Veracruz, 91190, México; 4Departamento de Medicina Experimental, Facultad de Medicina

Universidad Nacional Autónoma de México, México D.F., 06726, México

Abstract. Phenotype plasticity is by far the most important property of living beings. In no other organ system plasticity has been the focus of such an intense scrutiny than in the nervous system. This is not surprising since constant neural reorganization is assumed to support, for instance, adaptive behavioral responses, individual differences of behavior and numerous neurological disease states (e.g., the phantom limb). With such a long history of research, the study of neural plasticity has already generated explanatory claims that many conceived as general principles that rule neural plastic responses. Information arising from developmental sensory neurobiology is, however,

Correspondence/Reprint request: Dr. Raquel Martínez Méndez, Gabriel Gutierrez-Ospina, Departamento de

Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de

México, Ciudad Universitaria, Coyoacán, México D.F., 04510, México. E-mails: [email protected];

[email protected]

Raquel Martínez-Méndez et al. 90

challenging some of these conceptions. In this chapter, we comment new evidence

emerging from studies on blindness that clearly shift the way we think about neural

plasticity.

List of abbreviations

A1, primary auditory cortex

IC, inferior colliculus

LGN, lateral geniculate nucleus

LPN, lateral posterior nucleus

S1, primary somatosensory cortex

SC, superior colliculus

V1, primary visual cortex

Introduction

Phenotype plasticity is the most important property of biological systems. It may be defined as the constant reorganization of the structural and functional traits of the organism in response to internal and external drives. Although the entire body of complex organisms is subjected to quotidian reorganization, it is in the nervous system where phenotype plasticity has been extensively investigated. Hence, neurobiologists have long sustained that brain plastic responses follow well defined principles. It is believed, for instance, that neuronal circuits may reconfigure their geometry depending on whether they are being used or not. Under this assumption, used connections are strengthened whereas those less used or unused are weakened or eliminated entirely. Contact strengthening manifests by the preservation of connectivity, the increment of the number of neuronal processes or connections and/or the expansion of the representational area of a set of them. Contact weakening, in contrast, is assumed when the number of connections is reduced, the area covered by a set of them shrinkages or if they are literally wiped off the synaptic repertoire. Both processes are believed to result from competitive interactions prompted by the limited availability of target-derived neurotrophic factors, on one hand, and by the greater or lower probability of competing neuronal elements to fire or not together, on the other.

The example provided above is just one recount of numerous principles

postulated by the neurobiological community to explain the plasticity of the

brain. In spite of the abundance of empirical evidence that seems to support

each of these principles, emerging evidence arising from sensory

developmental neurobiology supports alternative principles on brain

plasticity that may shift significantly the way we conceive it.

Blindness and body/brain plasticity 91

Blindness is a sensory impairment that leads to brain intermodal (also called cross-modal) reorganization. It is presumed that such shifts result from increased levels of use-dependent neuronal activity and assumed that they represent an adaptive response that “seeks” sensory compensation. In this chapter we will discuss evidence that supports otherwise. As we will show, neither intermodal reorganization is necessarily promoted by evoked sensory activity, nor does it have an intrinsic adaptive/compensatory value. We also comment on recent discoveries supporting that blindness is not a purely neurological condition, but that it is best viewed as an alternative phenotype of the whole body. All these concepts oblige us to revise conceptions on brain plasticity and their utility to design restorative neurological protocols.

Experimental models to study the biology of blindness

A great deal of the quality and usefulness of the information gathered on a given phenomenon relies on the experimental model and designs chosen to explore it. This is why in this section we briefly comment on the advantages and limitations of the models instrumented to study the phenomenology and the mechanics of brain plasticity in the blind. With this, we hope to provide the reader with a guide to judge objectively the reaching of the information gathered through these models to understand phenotype plasticity through blindness. The animal models used to describe the phenomenology and to understand the mechanics of blindness are summarized in Table 1. By far, the models most widely used commonly prevent the animals of having visual experience either by suturing their eyelids closed or by rearing them in darkness. Since these models retain the integrity of the visual pathway, they allow the experimenter to evaluate also the effects of visual restoration on the brain’s anatomy and function. A pitfall of both models is that they represent conditions of relative blindness. Indeed, they do not prevent intact retinas to convey instructional information to the central nervous system and eyelid suture does not prevent the sensing of environmental illumination. At best, these models may replicate visual impairments (i.e., relative blindness) associated with cataracts, extreme refractive problems and corneal opacities, but they will never provide information on the consequences of the absolute loss of vision on brain structure and function. Many diseased conditions (e.g., macular degeneration, glaucoma, retinitis pigmentosa) deeply compromise the functional anatomy of the retina leading to its partial or total degeneration. Then, those experimental models in which macular photocoagulation or photo-damage of the trabecular meshwork are used to render animals blind seem the most meaningful to replicate these clinical settings. Although these models have the advantage of producing partial or total blindness effectively while keeping the eyes in their anatomical position, they require the use of larger animals (e.g., monkeys or rabbits), the


Table 1. Experimental animal models of blindness.

Model

of

blindness

Species Level of

deprivation

Modifications

in the eyes and

optic nerves

Modifications in

the brain Comparable to Ref

Contact lenses

cat

Absence of form stimulation and some reduction of light perception

Not observed Morphological changes in LGN

Cataract, corneal dystrophies

[1]

Eyelid suture

cat, guinea pig, monkey

Absence of form stimulation and reduction of light perception

No gross morphological modifications in retina and optic nerve

No obvious morphological changes in SC or V1, but changes in the auditory responses of the SC. Morphological changes in LGN and changes in the response of visual cortical cells.

Cataract, corneal dystrophies

[1–

4]

Dark reared

chicken, rat, turtle, tilapia, guinea pig, cat, monkey, human

Absence of light and form perception

Enlarged eyes and reduction in the curvature and thickness of the cornea. Dendritic trees in retina grow faster than normal. Larger fiber diameters of optic nerve axons.

Reduction of retinal fibers, enlarged auditory receptive fields and increase in the number of synaptic vesicles per nerve terminal in the SC. Increase in V1 activity and lack of orientation selective responses of neurons. Activation of V1 by tactile stimuli.

Amblyopia, glaucoma, retinopathy, amaurosis

[3,5

–15]

Enucleation

mice, rat, hamster, cat, monkey

Absence of visual and sensory perception from the eyes

Absence of ocular globe and degeneration of optic nerve

Reduction of the volume of the LGN. Changes in neuronal numbers in the V1 and A1. Projections from the IC neurons to the V1. The spontaneous firing rate of V1 neurons is significantly higher. Activation of V1 by tactile and auditive stimuli and expansion of S1 and A1.

Anophthalmia, retinopathy

[16–

27]

Ontological Bathyergidae family

Absence of light and form perception

Eyes reduced in size and covered by skin and fur. Degeneration of optic nerve.

Degeneration of visual structures and expansion of the S1.

Microphthalmia [28–

30]


Table 1. Continued

(Gnat−/−) Mice Functionally blind

Lack of functional rods

Inappropriate thalamocortical projections.

Nyctalopia, blindness

[31]

H1- ZRDCT-An anophthalmic

Mice

Absence of visual and sensory perception from the eyes

Absence of ocular globe and optic nerve

Decreased neuron number in various visual structures. Greater numbers of projections from the LPN reach V1.

Anophthalmia [32]

Nyx gene (Nob mutant)

Mice Refractive errors

Loss of visual transmission in the ON pathway

Not studied

Complete congenital stationary night blindness (CSNB1)

[33]

need to acquire expensive equipment (e.g., calibrated laser beam sources) and to have specialized training, circumstances all that preclude the sampling of large populations. This aspect becomes important since brain plasticity vary greatly among individuals. Transgenic or genetic animal models in which blindness is expressed as a physical attribute of a phenotype are also frequently used to approach the biology of blindness. Even though these models might provide valuable information on the molecular and cell biological underpinning of blindness, they all share a major drawback with regard to the interpretation of results. Indeed, the underlying genetic condition might influence the way the plastic response of the brain/body unit is organized. Furthermore, since the genetic mutations commonly are not restricted to the eye and may affect other phenotypic traits, we can never be sure whether the visual condition results mainly from ocular and/or extra-ocular factors. Another experimental approach regularly used to study the biology of blindness involves the unilateral or bilateral surgical removal of the eyes. Enucleation is not uncommon in the clinical practice since it is the elective procedure to end the life-threatening risk associated with, for instance, a retinoblastoma. Although undoubtedly this model is rather effective at preventing visual experience, enucleation jeopardizes ocular muscle and lachrymal gland interoception, thus contaminating the interpretation of the results since the absence of neighboring tissues must add up to the observed brain phenotype. Finally, naturally blind animals such as moles are also valuable sources of information on the biology of blindness. These natural models, however, may speak little on the plasticity mechanisms that are engaged when this condition is acquired by sighted animals, especially if blindness is acquired at adult ages. In sum, even though none of the animal models so far developed accommodate the variety of features that blindness imposes on the brain and body, their analyses have revealed some rules and principles that seem to underlie brain and body plasticity following the loss of vision. In the following sections we will revise these principles in more detail.


Blindness and brain plasticity: Lessons and a decalogue of

principles

Human and animal functional anatomical studies have revealed that the brain of the blind is profoundly reorganized (Figure 1). Indeed, we now know that information other than visual, especially auditory and somatosensory, is processed in former visual cortical [16,21,34–39] and subcortical centers [40]. At the same time, auditory and somatosensory relays increase their representational areas across the nervous system [24,25,27,30,38,41–43]. This clearly is a major plastic rearrangement if compared with the functional anatomy of the normal brain. What then can blindness tell us about the principles governing neural reorganization? It has long been claimed that the expansion of the primary somatosensory

(S1) and auditory (A1) cortices observed in the blind’s brain results from

increments in the amount of evoked neuronal activity [24,27,44]. We have

shown, nonetheless, that levels of spontaneous activity in S1 are reduced in

slices obtained from neonatal enucleated rats by the time S1 enlargement

is actively ongoing ([45]; Figure 2). This feature coincides with a decrease of

glutamate and GABA availability [46], both excitatory neurotransmitters at

early developmental stages [47–49]. In addition, no major differences in

cytochrome oxidase activity or H3 2-deoxyglucose uptake were found in S1

when sighted and enucleated rats were compared along postnatal development

Figure 1. Intermdodal plasticity in the brain of blind individuals. At the cortical level, intermodal reorganization has two basic components. The recruitment of former visual centers (blue) by somatosensory (green) and auditory (purple) inputs is one of them. The other is the expansion of cortical territories dedicated to process somatosensory and auditory information. These shifts do no generate functional redundancies. Instead, they truly reflect the relocation and transfer of somatosensory and auditory functions to the former visual cortex.


Figure 2. The number and activity of nerve terminals in columns of the rat primary somatosensory cortex (S1) at postnatal day 7 (PD7) is reduced following

enucleation. A. Photomicrograph illustrating the pattern of S1 staining following the incubation of a representative brain section with FM1-43, a dye used to monitor in vivo synaptic vesicle recycling in nerve terminals. The asterisks indicate S1 layer IV columns. Notice that the relative amount and the intensity of staining appear to be reduced in neonatally enucleated, PD7 rats (C) as compared with their age-matched, sighted littermates (B). The quantification of nerve terminals supports these qualitative results (D).

[50]. Also, whisker cauterization did not prevent the enlargement of S1 in sighted

rats [50]. Interestingly, the enlargement of S1 in neonatal enucleated rats occurs

during the first few days of life [50], well before the rat pups explore actively

their surroundings. Hence, the first lesson learned from studying the role of the

spontaneous and evoked activity on brain plasticity in the blind is that the

increased levels of them are not the primary cause of intermodal plasticity. This

must not be surprising because a wealth of experimental evidence has shown that

reduced neuronal activation promotes the rapid remodeling of sensory afferents

[51,52] and may facilitate axonal elongation through the somatosensory pathway

[53,54]. The contrary is true when evoked neuronal activity increases or when

glutamate is released to the extracellular space. In both cases the axon growth

cone collapse, synapse elimination ensues [55–58] and S1 gets smaller [52].

In the blind, it is assumed that the lack of visual information plays a

central role in promoting the expansion of both S1 and A1, as a well as the

reactivation of the former visual cortex by somatosensory and auditory

inputs. We have found, nonetheless, that S1 expansion does not occur if rats

are dark-reared since birth [50]. This suggests that it is not the loss of visual

information what triggers S1 intermodal plasticity, but is the presence or

absence of the eyes what constitutes the key factor for setting on or not

intermodal plasticity. At first glance, this conclusion might be puzzling but it

is not. It is well known that sensory organs provide trophic information to the

brain. During development this information is used by the cerebral cortex to


map the sensory organs and segregate sensory cortices (nicely reviewed in a

classic book by Purves [59]). Accordingly, neuronal assembles in the

developing retina engage into spontaneous waves of activity [60] that may

inform the brain about the presence or absence of the eyes. When the eyes are

removed or the retina hypotrophies or degenerates before or by eye opening,

the lack of this trophic information might be the primary trigger of

intermodal plasticity. So, the second lesson learned from studying plasticity

of the blind is that the sensory deprivation alone is not sufficient to drive an

intermodal structural plastic response during early development, but it is

necessary to compromise the anatomical integrity of the sensory organ and

of its related sensory pathways. In support of this contention stand the

magnetic resonance imaging studies that have documented that humans with

early onset blindness exhibit a significant reduction of the volume of the

optic nerves, tract and radiation, the dorsal lateral geniculate nucleus (LGN),

the primary visual cortex (V1) and the posterior segment of the corpus

callosum [61,62]. Similar modifications have been reported in the mole rat

[28,29] and in enucleated rodents (mice [17], rats [63] and hamsters [19,64]),

cats [16,20] and monkeys [65]. Also congenital blindness is associated with

decreased neuron number in LGN and fewer projections from this nucleus to

V1 in mice [32].

Laymen and neurobiologist alike have known for a long time that blind

people perform better that sighted people on certain tactile and auditory

psychophysical tasks. The blind´s enhanced somatosensory/auditory abilities

are attributed to the recruitment of former visual structures into

somatosensory/auditory processing [37,38,66]. These findings are compatible

with the idea that intermodal plasticity “seeks” sensory compensation.

However, not all sensory shifts lead to improved abilities in the blind [67].

For instance, blind people perform poorly in taste discrimination tasks [68],

as they do when localizing sounds that move along the vertical plane and

during spatial task solving (Table 2). Although the connectivity underlying

this maladaptive/dysfunctional plasticity is unclear, anatomical evidence

suggest that the extensive reorganization of neural circuitry within and

between/among sensory and non-sensory regions of the brain may explain in

part these behavioral impairments in the blind. For instance, abnormal

projections from the inferior colliculus (normally an auditory relay) to the

lateral geniculate nucleus (normally a visual relay) and to the former visual

cortex have been documented in enucleated hamsters [19], anophthalmic

mice [22] and mole rats [69]. Overrepresented connectivity between former

visual areas and associative and speech regions have been shown in blind

humans [70]. Also, studies have traced abnormal afferents from non-visual

thalamic nuclei to former visual cortex and a greater connectivity from other


Table 2. Sensory psychophysical parameters in blind individuals.

Modality Improvements Deficits / No changes

Somatosensory

Greater cutaneous sensitivity than sighted individuals (reviewed in

[78]).

Absolute tactile detection threshold and tactile pain threshold are similar

between blind and sighted humans

[79].

Enhanced passive tactile acuity [80].

The use of several fingers of each hand to read Braille leads to a

disordered finger somatosensory

representation and thus to finger misidentification [81].

Faster responses to tactile stimuli

[82].

Deficits in spatial solving tasks

(reviewed in [78]).

Auditory

Improved detection of sound

sources moving along the horizontal plane [83–85].

Worse detection of sound location

along the vertical plane [86,87].

Greater incidence of absolute pitch

among blind musicians [88].

No differences in hearing range,

minimum audible angle [19] and auditory detection threshold [79].

Improved detection of pitch

change direction [85].

Faster responses to tone shifts [89].

Other

Shorter reaction times during auditory attentional and language

processing tasks [79,90].

Reduced taste sensitivity [68].

Higher working memory capacities for words and numbers [91,92].

Poor performance in auditory-spatial learning tasks [67].

Enhanced memory for voices [93].

sensory and multisensory cortices to the former visual cortex in blind subjects [23,32]. Hence, the third lesson learned from studying brain phenotypic plasticity in the blind is that it has no intrinsic compensatory/adaptive value. The “quale” of plasticity is absolutely circumstantial. These premises are further furnished by the many examples of maladaptive plasticity published in different neurobiological settings [71–77]. As mentioned before, a fundamental aspect of the intermodal plastic response observed in the blind brain is the rapid activation of the former visual cortex by somatosensory and auditory inputs in many species including the humankind [16,19,21–23,31,34–39,94,95]. The importance of this finding is several-fold. First, it shows that cortical sensory areas are not ultimately specified by the genetic makeup of the organism, so they may be shifted during phenotype plastic responses. Second, it illustrates that intermodal connections remain functional in unimodal sensory areas even in fully constructed brains. Third, it falls down the long standing dogma that has sustained that, during neural development, all redundant connections are eliminated through neuronal


competition. Fourth, it indicates that not only the sprouting of connectivity but also its redundancy, the synaptic unmasking and the adjustments of functional hierarchies (i.e., balance of different input weights) are central events governing brain plasticity and its outcome. And fifth, it documents that sensory functions can be truly transferred/exchange among sensory cortices even in the mature brain. Therefore, the fourth lesson sustains that the neocortex is not parceled in unimodal and multimodal sensory processing fields but that unimodal areas hide, likely through establishing functional hierarchies, their multisensory nature. This view is further supported by anatomical and physiological data showing multisensory integration properties of unimodal neurons (for a recent review see [96]). “Use it or lose it” is an aphorism that captures a central tenet in developmental neuroscience that predicts the retention, reinforcement or strengthening of neuronal connectivity that is being preferentially used and the weakening or eradication of connectivity that is relatively inactive. Then, it is intriguing that the functional reactivation of former visual areas by somatosensory and auditory inputs is unable to prevent neuronal death and the elimination of connectivity along the reactivated former visual relays [1,16,17,19,20,28,29,32,61–65]. In addition, the “use it or lose it” aphorism has also led to the concept that neuronal circuitry is shaped early in development primarily through synaptic, dendritic and axon collaterals elimination. Studies support, nonetheless, that in the rodent S1 neuronal circuits are constructed by adding precisely the very same neuronal elements in a way that is dependent upon the increased availability of neurotrophic factors [97,98]. Since S1 and its constituent parts increase in size following enucleation, S1 expansion in the enucleated rat brain undoubtedly results from constructive rather than from regressive events or retention of transitory connectivity. Hence, the fifth lesson says that the “use it or lose it” aphorism is not an “all or nothing” rule when plastic responses are taking place in the brain and that constructive events underlie S1 intermodal plasticity in the blind. It is generally believed that neural plasticity is a feature characteristic of the “young maturing brain”. In contrast, the adult brain is commonly thought to be an essentially immutable entity. However, a few years ago, work published by Merzenich and others proved this last assumption wrong [99]. Accordingly, research conducted in blind subjects has shown that the adult brain reorganizes its circuitry within periods of hours of having been deprived of vision [100,101]. So, it seems that “the old monkey readily learns new tricks”, as the proverb sentences. These results lead to the sixth lesson; the mature brain is capable of engaging large-scale plastic responses. As discussed before, a recent publication of our authoring supports that the expansion of S1 in enucleated rats is not promoted by increments in evoked neuronal activity. In the same text, we showed that neonatal enucleation accelerates the development and specification of S1 leading to its early expansion. The accelerated rate of S1 development in the blinded rats is associated with an earlier process of histone deacetylation suggesting that the


expansion of S1 is subjected to epigenetic modulation and/or caused by epigenetic influences independent of evoked neuronal activity and associated with the absence of the eyes. Interestingly, when S1 deacetylation was inhibited by administering valproic acid through the mother´s milk, the time of S1 specification was normalized and its expansion was prevented. So, the seventh lesson predicts that the epigenetic control of the temporal organization of postnatal ontogenetic events causes brain phenotypic plasticity. The body is the material mean by which the organism interacts with the environment. It also provides a great deal of trophic information that brings and sustains brain growth, organization, maturation, maintenance and possible aging [102]. Then, if the brain shifts in the blind, his body must do it accordingly, and this is precisely what happens. We have shown that adult neonatally enucleated rats have whisker muscles with increased oxidative activity, expanded motor plates and facilitated neuromuscular transmission [103]. Hence, the message of the eighth lesson is that blindness is not a condition that triggers plastic responses exclusively along central structures of the nervous system, but that it also does it in neural elements placed at peripheral locations of the body. If this phenomenon is also observed following other types of neural plastic responses remains to be elucidated. The body, nonetheless, is not only formed by neural elements, but by a variety of distinct cell types arranged in complex tissues and organs. Would it be possible for blindness to shift the anatomy and physiology of the body outside the neural domain? The answer to this question seems to be positive. We have data showing that the epidermis of seven day old, birth enucleated rats and of adult, birth enucleated mice show increased thickness and hypertrophied keratinocytes as compared with their control littermates (Figure 3; [104]). Structural epidermal shifts parallel those observed in the availability of neurotrophin-3 [103] and in the number of Merkel’s mechanoreceptors [104] across the whisker pad. Thus the ninth lesson is that blindness modifies, in the long run, trophic brain-body interdependencies. This principle is further supported by evidence showing an association between retinal and optic nerve micro-structural changes with larger visual fields in the deaf [105]. The influence of blindness on the body and its functions is even more

pervasive and profound. We have conducted studies that show that neonatal

enucleation leads to an enhanced adult inflammatory response [106] to skin-

contact hypersensitivity allergens. This response is in part due to a reduction in

the number of intraepidermal T lymphocytes (Figure 4) that down regulate

contact hypersensitivity responses. Shifts of the immunological abilities in the

blind are not restricted to the skin, since other studies have shown increased

phagocytic activity of liver Kupffer cells [107] and protracted semi-activation of

microglial cells in enucleated rats and mice, several weeks after enucleation

[108]. Hence, the tenth lesson foretells that blindness is not a purely

neurological condition, but a state of the whole body.


Figure 3. Rats enucleated at birth have increased epidermal thickness. Photomicrographs showing tangential sections of skin samples of the whisker pad in

7 days old sighted (A) and enucleated (B) rats stained with Hematoxylin-Eosin.

Notice that the epidermis is thicker in enucleated rats likely due to the presence of

hypertrophied keratinocytes located in intermediate strata.

Figure 4. Rats enucleated at birth have reduced intra-epidermal dendritic

T lymphocytes when adults. Photomicrographs showing ear epidermal

sheets immunocytochemically stained for CD3 , a specific marker of epidermal

T lymphocytes, obtained from adult sighted (A) and enucleated (B) rats.

Scale bar = 50 µm.

In sum, the evidence commented supports that both the brain and the

body reorganize following visual loss. Since brain reorganization occurs soon

after enucleation and motor and immunological shifts proceed weeks or

months later (see for instance [103]), we suspect that a process of top-down

plasticity underlies the reorganization of the brain/body whole.


Clinical considerations

Basic science not only has important implications on the way we view

and understand nature, it also impacts the way we design protocols aimed at

solving practical problems. Here, we will speak a bit on these matters with

regard to visual restoration.

Visual deficits constitute a major social and financial burden to health

systems worldwide. The World Health Organization estimates that 39 million

people experience visual impairments and blindness (total loss of vision)

associated with cataract, glaucoma, age-related macular degeneration, corneal

opacities, diabetic retinopathy and trachoma [109,110]. Given the magnitude of

the problem, major efforts have been made to restore vision by using

bioelectronic prostheses, highly specialized surgical procedures (e.g., corneal

replacement or refractive surgery) and cell regenerative therapies. Unfortunately,

visual restoration has proven difficult because, we believe, therapeutic attempts

have been focused primarily at trying to reinstall the eyes function without

considering that blindness leads to a large-scale reorganization of the brain/body

whole. So, in the future, we advise new efforts to restoring visual functions in the

blind to consider the influence of ontogenetic and epigenetic elements on the

desired outcome, while keeping in mind that blindness is a condition that

involves the modulation of the entire body’s plasticity.

Fungal, viral and bacterial skin diseases are frequent ailments suffered by

blind children [111,112]. Although all these infections have been suspected

to be secondary to skin injuries and/or the result of poor hygiene habits, the

observations discussed before support other possibilities, namely, that they

might be consequence of essential differences in the way the cutaneous

immune system is organized in the blind.

Lastly, recent studies have demonstrated the participation of T

lymphocytes in hippocampal learning and memory processes [113]. Sightless

rodents, on the other hand, learn faster and solve better than normal spatial

auditory and tactile recognition tasks (mentioned in [114]). Since activated

microglial cells release cytokines that attract T lymphocytes, the fact that

adult neonatally enucleated rats have semi-activated microglial hippocampal

and septal cells [108] could explain in part the differences in learning abilities

observed between enucleated and control rodents.

Conclusions

The plasticity of the brain, whether adult or still maturing, has long

fascinated neuroscientists. Principles governing it have come and gone over

the years as technical and conceptual advances and new experimental models


and approaches appear. In this vein, blindness provides with a unique

opportunity to asses several of the principles assumed to underlie brain

plasticity that have endure the passing of time. As commented throughout the

manuscript the study of blindness is making us re-think the role of evoked

activity in brain plasticity, while it introduces the notion that the body itself

provides information that if lost early in life triggers brain plasticity in a way

independent of sensory experiences. Blindness also offers information that

challenges conventional views on whether brain plasticity is always adaptive /

compensatory or if the mammalian neocortex really contains unimodal

sensory fields that are genetically specified during early development and

remain untouched once adult age is reached. The understanding of

epigenetics of brain plasticity by studying it through blindness is fundamental

if one aspires to modulate large scale neural plasticity to restore visual

function. Finally, blindness has taught us that brain plasticity is not only

neural, but that it involves significant shifts across the body outside of the

neurobiological whereabouts. In sum, the blind is not only a blind, it is a

completely new phenotype, an alternative one, in which the body/brain whole

departs from norm providing new ways to understand who we are in

biological terms.

Authors’ contributions

RMM carried out the biochemical studies aimed at evaluating the

neurochemical parameters in the primary somatosensory cortex of neonatally

enucleated rats [46]. She also participated during the drafting and production

of the final version of the manuscript.

EMM carried out the experiments that revealed neuromuscular and skin

plasticity in neonatally enucleated rats ([103,104]; Figure 3).

HVM performed the experiments that documented deviant immune skin

response in neonatally enucleated mice ([106]; Figure 4).

JAGL performed the experiments that revealed reduced levels of

synaptic activity in brain slices of neonatally enucleated rats ([45]; Figure 2).

ALFF drafted the manuscript, elaborated Figure 1 and participated in the

final editing and production of the manuscript.

TRG/ACK designed and conducted the studies that documented

protracted activation of microglial cells in neonatally enucleated mice

([108]).

GGO drafted, edited and produced the final version of the manuscript.

All authors read and approved the final manuscript. Similarly, all authors

declare to have no conflict of interest of any sort with regard to the data and

concepts discussed here.


Acknowledgements

The authors thank Patricia Padilla Cortés, Jesus Ramírez Santos and

Marcela Palomero Rivero for technical support, and Dr. Gabriel Manjarrez

Gutiérrez for permitting access to HPLC equipment. We are also indebted to

Raymundo Reyes, Ivonne Mora, Martha Carrasco and Dra. Marta Elinos for

providing administrative support. This work was financed by grants from the

Consejo Nacional de Ciencia y Tecnología (38615N and P45872-M),

Dirección General de Asuntos del Personal Académico, Universidad

Nacional Autónoma de México (PAPIIT IX232604). RMM was fellow of the

Consejo Nacional de Ciencia y Tecnología and Ph.D. student of the Programa

de Posgrado en Ciencias Biomédicas, Universidad Nacional Autónoma de

México.

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