Efectos del enriquecimiento ambiental en el desarrollo del SNC

Efectos del enriquecimiento
ambiental en el desarrollo del SNC
Una aproximación a estrategias
neuroprotectoras y neurorescatadoras
Laboratorio de Neurociencia
Clínica y Experimental (LaNCE)
Euskal Herriko Unibertsitatea
http://www.ehu.es/ehusfera/lance
viernes 12 de noviembre de 2010

Efectos del enriquecimiento
ambiental en el desarrollo del SNC
Una aproximación a estrategias
neuroprotectoras y neurorescatadoras
Laboratorio de Neurociencia
Clínica y Experimental (LaNCE)
Euskal Herriko Unibertsitatea
http://www.ehu.es/ehusfera/lance
Enrike G. Argandoña

Desarrollo cortical
Predeterminado genéticamente
Mediado por experiencia

Efectos del entorno en el desarrollo
Lamarck, Haeckel, Darwin and the giraffe

Cambios mediados por la
experiencia
Ramon y Cajal Sherrington

experiencia

experiencia
APRENDIZAJE SIMPLE
Aprendizaje simple
Eric Kandel Aplysia californica
artes 16 de junio de 2009
Aprendizaje simple
ueves 18 de junio de 2009

experiencia
APRENDIZAJE SIMPLE
Aprendizaje simple
Aprendizaje simple
APRENDIZAJE SIMPLE
Aprendizaje simple
martes 16 de junio de 2009
Aprendizaje simple
jueves 18 de junio de 2009

experiencia
APRENDIZAJE SIMPLE
Aprendizaje simple
Aprendizaje simple
APRENDIZAJE SIMPLE
Aprendizaje simple
Aprendizaje simple
Eric Kandel

experiencia
APRENDIZAJE SIMPLE
Aprendizaje simple
Aprendizaje simple
APRENDIZAJE SIMPLE
Aprendizaje simple
Aprendizaje simple

Plasticidad sináptica
TEMA IV
MECANISMOS SINÁPTICOS DE PLASTICIDAD
Previo a la experiencia, se forman las vías mediante:
Axones alcanzan la estación relay
Axones alcanzan capa IV cortical
Se forman conexiones aleatorias
Posteriormente se produce el desarrollo inﬂuido por la
experiencia
Muerte celular programada (neurotroﬁnas)
Cambios en capacidad sináptica

Plasticidad sinápticaTEMA IV
Reducción 50%
Reasignación sináptica
Convergencia sináptica
Competencia sináptica
Inﬂuencias modulatorias
tes 16 de junio de 2009

Reducción 50%
Reasignación sináptica
Convergencia sináptica
Competencia sináptica
Inﬂuencias modulatorias
Locus ceruleus (NA)
Nucleos basales (ACh)

TEMA IV
MECANISMOS SINÁPTICOS DE
PLASTICIDAD
La plasticidad sináptica es un
fenómeno excitatorio
(Glutamato)
NMDA (bloqueado por Mg+
+ y ligado a canal Ca++)
AMPA Na+

experiencia
Incremento sinapsis/neurona
Incremento actividad neuronal
Incremento demanda metabólica
Modiﬁcaciones arquitectura
vascular

Age
Experiencemediatedchanges
4. week
1., 2. and 3. weeks 4., 5. and 6. weeks 7. and 8. weeks
Precritical period Critical period Postcritical period
Periodo crítico

PERIODO CRÍTICO
3ª - 5ª semanas
Age
Experiencemediatedchanges
4. week
1., 2. and 3. weeks 4., 5. and 6. weeks 7. and 8. weeks
Precritical period Critical period Postcritical period
Periodo crítico

Periodo crítico

Sistema visualEstudio efectos de la experiencia

Estudio efectos de la
experiencia
Modiﬁcaciones sobre las
condiciones standard
* Enriquecimiento ambiental
* Empobrecimiento ambiental

Privación visual
Métodos invasivos
Inyección TTX
Sutura párpados
Enucleación mono o bilateral
Extirpación retina

Privación visual
Métodos no invasivos
Cría en oscuridad
Implantación lentillas opacas

Descenso densidad celular
Retraso maduración
Anulación cierre periodo crítico
Privación visual

Cortical parameters

Vascular density

rain Research 732 (1996) 43-51
p=o , 04 p=o,l p=o,oo2 p=o,ol
0 dpn 7 dpn 14 dpn 21 dpn 60 dpn
Fg.
; ’401 p=o,9 p=o,5 p=o,19 p=o,oo12
1204 T-r T
p,m at birth to 500 pm at 7 dpn, or 70% with very high
statistical significance. The second postnatal week, from 7
to 14 dpn, an increase of 587 pm, or 18’ZO,was registered,
but the difference was not statistically significant. At the
third week there was a slight decrease (3%), from 587 to
568 p,m with no significance. Cortical thickness at 60 dpn
was similar to that of 14 dpn, increasing 3Y0from 21 dpn
to reach 587 pm, but without statistical significance (see
Tables 1 and 2).
3.1.2. Dark-reared rats
This behavior was similar in dark-reared rats, but there
was a quantitative difference at each age, with dark-reared
rats scoring lower at all the considered ages, except at 14
dpn.
From birth to 7 dpn there was a statistically significant
50% increase in cortical thickness in dark-reared rats, from
300 to 443 pm. From 7 to 14 dpn the increase was 56Y0,
from 443 to 691 pm, and was highly significant. From 14
to 21 dpn there was a drop from 691 to 525 (25%), which
was very significant. From 21 dpn to 60 dpn there was an
increase of 3%, similar to the one in controls, which was
not significant and reached 543 pm (see Tables 1 and 2).
At 7 dpn cortical thickness was 12% higher in controls,
at 14 dpn it was 1870higher in dark-reared rats, at 21 dpn
it was 13Y0higher in controls and at 60 dpn it was 870
lower in dark-reared rats. The difference was statistically
significant at all ages except at 14 dpn, being very high at
21 and 60 dpn (see Table 1 and Fig. 4).
3.2. Vascular densi~
3.2.1. Controls
The density of vessels increased massively up to 21 dpn
in controls; at this age it reached the maximum level with
a very weak increase from 21 to 60 dpn.
Vascular density increased 12% at the first week, from
44 to 50 vessels per 40000 kmz. From 7 to 14 dpn there
was almost a 50Y0increase, from 50 to 73 vessels. At 21
dpn vascular density increased 54%, from 73 to 112
vessels. At 60 dpn vascular density was similar to that at
Fg.
; ’401 p=o,9 p=o,5 p=o,19 p=o,oo12
1204 T-r T
100
80
1
60
40
20
0
‘c
~
; 30
z I TT p=o,13 P=0,16 p=o . oo l p=o , oo l
Odpn 7 dpn 14 dpn 21 dpn 60 dpn
! Darkreared
! Controls
Fig. 4. Comparison of average measurements between dark-reared and
control groups at each of the ages considered. Horizontal axes show the
age of the animals, Vertical axes show: CT, cortical thickness in pm;
VD, number of intersections between vessels and the overlying grid per
40000 pmz of visual cortex. Nrad, number of vertically oriented intra-
cortical vascular trunks per mm of cortex.
to 14 dpn, an increase of 587 pm, or 18’ZO,was registered,
but the difference was not statistically significant. At the
third week there was a slight decrease (3%), from 587 to
568 p,m with no significance. Cortical thickness at 60 dpn
was similar to that of 14 dpn, increasing 3Y0from 21 dpn
to reach 587 pm, but without statistical significance (see
Tables 1 and 2).
3.1.2. Dark-reared rats
This behavior was similar in dark-reared rats, but there
was a quantitative difference at each age, with dark-reared
rats scoring lower at all the considered ages, except at 14
dpn.
From birth to 7 dpn there was a statistically significant
50% increase in cortical thickness in dark-reared rats, from
300 to 443 pm. From 7 to 14 dpn the increase was 56Y0,
from 443 to 691 pm, and was highly significant. From 14
to 21 dpn there was a drop from 691 to 525 (25%), which
was very significant. From 21 dpn to 60 dpn there was an
increase of 3%, similar to the one in controls, which was
not significant and reached 543 pm (see Tables 1 and 2).
At 7 dpn cortical thickness was 12% higher in controls,
at 14 dpn it was 1870higher in dark-reared rats, at 21 dpn
it was 13Y0higher in controls and at 60 dpn it was 870
lower in dark-reared rats. The difference was statistically
significant at all ages except at 14 dpn, being very high at
21 and 60 dpn (see Table 1 and Fig. 4).
3.2. Vascular densi~
3.2.1. Controls
The density of vessels increased massively up to 21 dpn
in controls; at this age it reached the maximum level with
a very weak increase from 21 to 60 dpn.
Vascular density increased 12% at the first week, from
Fg.
; ’401 p=o,9 p=o,5 p=o,19 p=o,oo12
1204 T-r T
100
80
1
60
40
20
0
‘c
~
; 30
z I TT p=o,13 P=0,16 p=o . oo l p=o , oo l
Odpn 7 dpn 14 dpn 21 dpn 60 dpn
! Darkreared
! Controls
Fig. 4. Comparison of average measurements between dark-reared and
BRAIN
RESEARCH
ELSEVIER Brain Research 732 (1996) 43-51
Research report
Effects of dark-rearing on the vascularization of the developmental rat visual
cortex
E.G. Argandoiia a’*,J.V. Lafuente b
aDepartment of Nursing I, School of Nursing, Euskal Herriko Unibertsitatea – University of the Basque Country, E-48940 Leioa, Spain
b Department of Neuroscience, School of Medicine, Euskal Herriko Unibertsitatea – University of the Basque Country, E-48940 Leioa, Spain
Accepted 16 April 1996
Abstract
Cerebral vascular density corresponds to metabolic demand, which increases in highly active areas. External inputs play an important
role in the modeling and development of the visual cortex. Experience-mediated development is very active during the first postnatal
month, when accurate simultaneous blood supply is needed to satisfy increased demand. We studied the development of visuaf cortex
vascularization in relation to experience, comparing rats raised in darkness with rats raised in standard conditions. The parameters
measured were cortical thickness, vascular density and number of perpendicular vessels, constituting the first stage of cortical vascular
development. Vessels were stained using butyryl cholinesterase histochemis~, which labels some neurons and microvascularization
(vesselsfrom5 to 50 km). Animalsfromboth groupswere sampledat O,7, 14,21 and 60 days postnatal. Vascularization of the brain
starts with vertically oriented intracortical vascular trunks whose density decreases notably after birth in rats reared in standard laboratory
conditions. The most striking finding of our work is the significantly lower decrease in the number of these vessels in dark-reared rats.
Our results also show that cortex thickness and vessel density are significantly lower in dark-reared rats. These results suggest that the
absence of visual stimuli retards the maturation of the visuaf cortex including its vascular bed.
Keywords: Striate cortex; Microvascularization; Development; Butyryl cholinesterase; Histochemistry
1. Introduction
The density of the vascular network corresponds to the
metabolic demand in different brain territories, with the
demand increasing in areas with higher synaptic activity.
Thus vascular density, and especially microvascular den-
sity, becomes higher in these areas [6,7,23,34].
After birth, the neonate is exposed to external stimuli
which modulate cortical development, inducing changes
such as the increase of the dendritic tree, the rise of the
ratio of synapses per neuron and the subsequent increase
of the vascular network. All these changes involve the
thickening of the cortex [14,34,35], Most of the cortical
changes induced by experience occur in what is known as
the critical period [16], which takes place around the 3rd
postnatal week [1,24,30]. In this period, the higher
metabolic demand due to neuronal plasticity mechanisms
gives art extremely important role to adaptive vascular
changes [34]. That is, the external environment induces
vascular changes by an indirect mechanism: cortical devel-
opment brought about by experience induces vascular plas-
ticity to support the increased metabolism. Under standard
rearing conditions blood vessels are essentially completely
developed by the critical period [30].
Although this kind of change takes place all over the
CNS, most studies of the effects of external inputs have
been performed on the striate cortex. The visual system
has a well-defined hierarchical organization which facili-
tates the study of its structures through the interruption of
pathways at different stages or the deprivation of inputs
using either invasive techniques – tetrodotoxin injection
Privación visual

Privación visual
.Brain Research 855 2000 137–142
www.elsevier.comrlocaterbres
Research report
Influence of visual experience deprivation on the postnatal development of
the microvascular bed in layer IV of the rat visual cortex
Enrike G. Argandona a,)
, Jose V. Lafuente b
˜
a
Department of Nursing I, School of Nursing, Euskal Herriko UnibertsitatearUniÕersity of the Basque Country, Leioa, E-48940, Spain
b
Department of Neuroscience, School of Medicine, Euskal Herriko UnibertsitatearUniÕersity of the Basque Country, Leioa, E-48940, Spain
Accepted 16 November 1999
Abstract
Cerebral vascular density is correlated with metabolic demands, which increase in highly active brain areas. External inputs are an
essential requirement in the modeling of the visual cortex. Experience-mediated development is very active during the first postnatal
month, when congruous blood supply is needed. We studied the development of visual cortex vascularization in relation to experience,
comparing rats raised in darkness with rats reared in normal conditions. Vascular density, vascular area and their ratio vs. neuronal
density were calculated. Conventionally stained semi-thin sections were used to measure the vascular area by computer assisted
.morphometry. Animals from both groups were sampled at 14, 21, and 60 days postnatal dpn . We found a significantly lower density of
vessels and neurons as well as a smaller vascular area in dark-reared adult rats while no differences were founded at the other ages. Our
results also show no differences between the ratio of vesselsrneuron, and vascular arearneuron, between both groups. The absence of
visual experience causes decrease of cortical activity which correlates with lower vessels density and vascular area, without their
ratiorneuron being affected. q 2000 Elsevier Science B.V. All rights reserved.
Keywords: Dark-rearing; Microvascularization; Blood vessel; Striatal cortex; Computer assisted morphometry; Synaptic activity
1. Introduction
There is a close relationship between metabolic activity
w xand vascular network in cerebral cortex 3,9,24 . The
metabolic demand, which increases in areas with higher
synaptic activity is matched by the density of blood vessels
w xin these areas 5,6,16,21 . As we have previously reported,
development of vascularization parallels cortical develop-
ment. Our results showed a decrease in vascular density
and a delay in the maturation of the microvascular pattern
Changes in vascular density are related to the different
stages of development. Most of the changes induced by
experience occur during a defined time-window of postna-
tal life called critical period. In this period, there is reorga-
nization of the cortex correlated with experience, when
w xnon-functioning neurons disappear 12,25 . Studies of neu-
ronal density in animals reared in darkness have found a
relative increase due to a decrease in the neuropil; how-
ever, putative changes in neuronal population have not
w xbeen addressed 2,10,23 .
Žstudied for both dark-reared and control groups percentage of
.increaserdecrease and statistical significance, p value
Ž . Ž . Ž .Age period dpn Darkness % p Controls % p
Increase of Õascular density
14–21 51 -0.001 36.4 0.07
21–60 y21.1 -0.001 20 0.001
Increase of neuronal density
14–21 y9.9 0.02 14.3 0.29
21–60 y21.9 -0.001 y13 -0.001
Increase of Õascular area
14–21 y20.6 0.3 28.7 0.2
21–60 25.9 0.01 10.7 0.2
Increase of number of Õessels per neuron
14–21 66.7 -0.001 0 0.4
21–60 0 0.9 66.7 -0.001
Decrease of Õascular area per neuron
14–21 y27.8 0.08 37.7 0.04
21–60 4.3 0.6 y2.6 0.67
Decrease of aÕerage Õascular area
14–21 23.7 0.03 45.8 0.05
21–60 2.1 0.8 26.6 0.03
60 days, there was an increase of 20% which was not
statistically significant.
In dark-reared rats, the number of vessels increased by
51% between 14 and 21 dpn and decreased by 21% from
the 21 to 60 dpn period. Both variations were significant.
Comparing both groups, at 14 dpn, vascular density in
dark-reared rats was 7% higher and at 21 dpn it was 18%
higher. On the other hand, at 60 dpn, vascular density was
22% higher in controls. Differences were statistically sig-
Ž .nificant at 21 and 60 dpn. Fig. 1 .
3.2. Neuronal density
The number of neurons per 2500 mm2
was similar in
all ages in normal rats, being maximal at 21 dpn. Between
14 and 21 dpn, neuronal density increased by 14% but
decreased between 21 and 60 dpn by 13%.
As it happened with the vascular density, the second
increase from 21 to 60 dpn was significant but not the
former from 14 to 21 dpn.
The changes in this parameter throughout postnatal
development in the dark-reared group were the opposite of
controls as there was a progressive decrease from 14 to 60
dpn. From 14 to 21 dpn, this parameter decreased by 10%,
from 16 to 15 neurons per 2500 mm2
. The decrease was
Ž .more noticeable from 21 to 60 dpn 22% , diminishing
from 15 to 11 neurons. Both differences were statistically Fig. 1. Comparison of average measurements between dark-reared and
! ! !

Privación visual Developmental Brain Research 141 (2003) 63–69
www.elsevier.com/locate/devbrainres
Research report
Visual deprivation effects on the s100b positive astrocytic population
in the developing rat visual cortex: a quantitative study
a , b c
*˜Enrike G. Argandona , Marco L. Rossi , Jose V. Lafuente
a
Department of Nursing I, School of Nursing, Euskal Herriko Unibertsitatea/University of the Basque Country, Leioako Campusa, Leioa E-48940,
Spain
b
Department of Neuropathology, Walton Centre for Neurology and Neurosurgery, Liverpool L9 7LJ, UK
c
Department of Neuroscience, School of Medicine, Euskal Herriko Unibertsitatea/University of the Basque Country, Leioa, E-48940 Spain
Accepted 11 December 2002
Abstract
After birth, exposure to visual inputs modulates cortical development, inducing numerous changes of all components of the visual
cortex. Most of the cortical changes thus induced occur during what is called the critical period. Astrocytes play an important role in the
development, maintenance and plasticity of the cortex, as well as in the structure and function of the vascular network. Dark-reared
Sprague–Dawley rats and age-matched controls sampled at 14, 21, 28, 35, 42, 49, 56 and 63 days postnatal (dpn) were studied in order to
elucidate quantitative differences in the number of positive cells in the striate cortex. The astrocytic population was estimated by
immunohistochemistry for S-100b protein. The same quantification was also performed in a nonsensory area, the retrosplenial granular
cortex. S-100b positive cells had adult morphology in the visual cortex at 14 dpn and their numbers were not significantly different in
light-exposed and nonexposed rats up to 35 dpn, and were even higher in dark-reared rats at 21 dpn. However, significant quantitative
changes were recorded after the beginning of the critical period. The main finding of the present study was the significantly lower
astroglial density estimated in the visual cortex of dark-reared rats over 35 dpn as well as the lack of difference at previous ages. Our
results also showed that there were no differences when comparing the measurements from a nonsensory area between both groups. This
led us to postulate that the astrocytic population in the visual cortex is downregulated by the lack of visual experience.
! 2002 Elsevier Science B.V. All rights reserved.
Keywords: Dark-rearing; Immunohistochemistry; Astroglia; Retrosplenial cortex; RSG
1. Introduction vascular density as well as a delay in the development of
the microvascular pattern [2,3].
Postnatal development of the visual cortex is modulated Astrocytes play an important role in the maintenance of
by experience. Extrinsic cues act as epigenetic factors in the structure and function of the endothelium of the
concert with intrinsic developmental programmes to shape cortex’s microvascular network, including the blood–brain
functional and structural cortical architecture [29]. Ex- barrier [8,20]. Astrocytes are also involved in the develop-
perience-mediated changes induce an increase in neuronal ment, plasticity and maintenance of the cerebral cortical
activity, which leads to increased metabolic demands architecture [10,23,24,27]. Therefore, a crucial role in
[6,40], involving the establishment of adaptive changes to coupling neuronal activity to energy metabolism has been
accomplish new requirements such as changes of the proposed [13]. Inversely, both neuronal activity and vas-
vascular network [5,7]. In previous works, we reported the culature influence glial development in a bidirectional
development of vascularisation of the visual cortex in manner [1,18,22,41].
normal and dark-reared rats showing a decrease in the During development, astrocytes guide cortical organisa-
tion by performing different functions, which are reflected
in morphological, electrophysiological and antigenic dif-
ferences [22]. The behaviour of the glia throughout the*Corresponding author. Tel.: 134-94-601-5595; fax: 134-94-464-
postnatal development of the cerebral cortex can be studied9511.
˜E-mail address: nfpguare@lg.ehu.es (E.G. Argandona). using several antigenic markers. The most frequently used
0165-3806/02/$ – see front matter ! 2002 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0165-3806(02)00643-0
morphology of astrocytes. and star shaped processes. S-100b positive cells were
Measurements of each slice of the cortex were made in widely present on all cortical layers in opposition to GFAP,
both hemispheres, for each of the ten slices taken per which was almost absent in middle areas while only some
animal (i.e. 60 fields per animal) and the mean value per isolated astrocytes were present in lower and upper areas.
animal was calculated. The average values per group (eight Outside the cortex, both GFAP and S-100b were present,
animals) were compared at each age by statistical analysis especially in regions such as the hippocampus (Figs. 1 and
(ANOVA) on STATVIEW IIீ Abacus Concepts. 2).
All animal experiments were performed in accordance Comparing both experimental groups at all ages, no
with the European Community Council Directive of 24 morphological differences were found. Thus, we per-
November 1986 (86/609/EEC). formed a quantitative analysis in order to study the
possible differences in the number of astrocytes per area.
The results are shown in Table 1. Quantifying the number
3. Results of positive cells per cortical surface, the following results
were obtained.
We found a significantly lower number of cells per unit
area in the visual cortex of dark-reared rats at 35 dpn, 3.1. Visual cortex
whereas no differences were found between both groups in
younger animals, with the exception of 21 dpn, when The density of S-100b positive cells suffered slight
Fig. 1. (a) S100b positivity throughout the visual cortex at 5 weeks postnatal in dark-reared rats. (b) S100b positivity throughout the visual cortex at 5
weeks postnatal in control rats. (c) GFAP positivity throughout the visual cortex at 5 weeks postnatal in dark-reared rats. Positive cells appear mostly in
lower and upper layers being almost absent in middle layers. Scale line is 150 mm.
Fig.2.S-100bpositivecellsinlayerIVofdarkrearedvisualcortex.Scalelineis75mm.
increasesanddecreasesbetweenalltheagesstudied,butdecreaseswerequantitativelylowerinresultstakenfrom
whenwecomparedthelastofthestudiedages—63dpn—layerIV,showingahigherlevelofhomogeneity.Compar-
whiledensityincontrolswassimilartodensityat14dpn,ingbothgroups,densitywasslightlyhigherindark-reared
itwas25%lowerindark-rearedrats.Increasesandratsupto28dpn,andwassignificantonlyat21dpn.From
Table1
Astroglialdensityatvariousagesofdevelopmentforbothdark-rearedandcontrolgroupsinthevisualandretrosplenialcortex(meannumberofS-100b
2
positivebodiesper250000or10000mm6standarddeviationandstatisticalsignificance,Pvalue)
22
AgeAstrocytesper250000mm(middlelayers)Astrocytesper10000mm(layerIV)
(days)
DarkrearingControlsDiff.(%)PDarkrearingControlsDiff.(%)P
Visualcortex
1446.269.445.9681.90.6216.064.116.263.81.80.86
2158.269.952.5610.210.90.0122.066.117.463.726.40.0001
2847.168.543.268.190.0617.964.316.764.87.20.23
3536.068.35067.12280.000113.263.816.862.6221.40.0001
4231.866.839.967.4220.30.000111.863.315.364.8222.90.0001
4933.969.648.1613.4229.50.000112.263.916.965.4227.80.0001
5637.36942.169.7211.40.00913.96415.463.629.740.03
6334.467.845.367.72240.000112.663.316.964.9227.80.0001
Retrosplenialcortex
1441.8610.448.668.4140.0413.462.817.263.622.20.002
2160.969.248.8614.424.80.00521.56615.863.8360.0005
2844.6610.739.868.7120.1416.964.515.56490.14
3543.56745.668.224.60.3915.264.417.663.613.60.05
4237.167.338.465.323.40.5914.763.612.962.9140.11
4946.5612.351.4612.429.50.0916.365.818.26710.40.17
5640.467.743610.326.70.315.463.415.963.43.1%0.59
6345.567.549.969.928.80.116.064.316.163.620.10.93

20
30
40
50
60
p14 p21 p28 p35 p42 p49 p56 p63
Oscuridad Control
densidad astroglial
astr./250000µm2

Empobrecimiento ambiental
Corteza
somatosensorial
Corteza barrel ratas. Afeitado
vibrisas produce alteraciones
morfologicas y ﬁsiologicas

Empobrecimiento ambiental
* Privación olfativa
* Privación auditiva
Similares efectos al resto de
sentidos, pero de mayor
intensidad
Un elemento común es la plasticidad
compensatoria en los sentidos no empobrecidos
Neuron, Vol. 46, 103–116, April 7, 2005, Copyright ©2005 by Elsevier Inc. DOI 10.1016/j.neuron.2005.02.016
Activity-Dependent Adjustments
of the Inhibitory Network in the Olfactory Bulb
following Early Postnatal Deprivation
Armen Saghatelyan,1
Pascal Roux,2
environmental conditions. The continuous postnatal sup-
ply of newborn inhibitory interneurons to the main olfac-Michele Migliore,3,5
Christelle Rochefort,1,6
tory bulb (MOB) offers an ideal system to study neu-David Desmaisons,1
Pierre Charneau,4
ronal adjustment regulated by sensory experiences.Gordon M. Shepherd,3
and Pierre-Marie Lledo1,
*
Progenitor cells originating from the subventricular zone1
Laboratory of Perception and Memory
(SVZ) of the lateral ventricle first migrate tangentially toPasteur Institute
the MOB, by way of the rostral migratory stream (RMS),Centre National de la Recherche
and then migrate radially within MOB before they dif-Scientifique (URA 2182)
ferentiate into local interneurons (Luskin, 1993; Lois and75015 Paris Cedex
Alvarez-Buylla, 1994). It has been hypothesized that post-France
natal neurogenesis is controlled by levels of sensory2
Platform of Dynamic Imaging
activity (Frazier-Cierpial and Brunjes, 1989; Corotto etPasteur Institute
al., 1994; Kirschenbaum et al., 1999; Saghatelyan et al.,25 rue du Dr. Roux
2003; Lledo et al., 2004). Hence, although proliferation75015 Paris Cedexviernes 12 de noviembre de 2010

Enriquecimiento ambiental
Donald Hebb (1949)
Kresh, Bennett, Rosenzweig, Diamond (60s)
Combinación de complejidad de objetos
inanimados y estimulación social.

* Necesidad de
estandarizar
* Super-
enriquecimiento
* Rol del ejercicio

Cambios anatómicos
Plasticidad neuronal
Sinaptogénesis
Morfología sináptica
Neurogénesis
Neurotroﬁnas (BDNF, NGF, NT-3,VEGF)
Gliogénesis

* Corteza auditiva (Greenough, 1973)
* Corteza olfatoria (Roselli-Austin, 1990)
* Corteza somatosensorial (Coq, 1998)
* Hipocampo (Rampon, 2000)
* Amigdala (Nikolaev. 2002)
* Ganglios basales (Comery, 1996)
* Cerebelo (Greenough, 1986)

Mejora aprendizaje y memoria (Dash, 2009)
Reduce deterioro cognitivo ﬁsiologico (Segovia, 2009)
Reduce ansiedad e incrementa actividad exploratoria
(Benaroya, 204)
Induce neurogenesis en hipocampo (Kempermann 1997)
Reduce comportamientos adictivos a drogas (Solinas
2010)
Madura y consolida la corteza visual en ratas privadas de
luz (Bertoletti 2004)
Acelera el desarrollo de la corteza visual (Cancedda 2004)

Qualitativestudy
LEA
EBA
GluT-1
HistochemistryImmunohistochemistry

LEA EBA
Qualitativestudy

Qualitativestudy EBA GluT-1
EBA + GluT-1

Angiogénesis

Quantitativestudy

VEGFlevels
WESTERN BLOT
ELISA

Western blot

ELISA

VEGF levels
0
1,5
3,0
4,5
6,0
14 dpn 21 dpn 28 dpn 35 dpn 42 dpn 49 dpn 56 dpn 63 dpn
CE
Control
DR
DR-CE

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!#!#

10
12
14
16
18
20
22
24
P21 P28 P35 P42 P49 P56 P63
Primaryvisualcortex
(S-100Bpositiveastrocytedensity)
Postnatal Age
C DR DR-EE DR-EE-Ex DR-Ex

9
12
15
18
21
24
P21 P28 P35 P42 P49 P56 P63
Primarysomatosensorycortex
(S100-Bpositiveastrocytedensity)
Postnatal Age
C DR DR-EE DR-EE-Ex DR-Ex

Patología SNC
TCE
Ictus
Tumores
Patologías neurodegenerativas

Patología SNC
TCE
Ictus
Tumores
Patologías neurodegenerativas
Vascularización

Objetivos terapeúticos
Neuroprotección/neurorescate
Incremento vascularización

TCE en Desarrollo
Mayor capacidad de plasticidad
Interferencia en los
mecanismos ﬁsiológicos
Apoptosis
Plasticidad sináptica (NMDA)

Reserva Cerebral Cognitiva (Nithianantharajah, 2006)

Enfermedades
neurodegenerativas
Alzheimer: reduce deposito ß amiloide (Cracchiolo, 2007),
facilita su eliminación (herring, 2008), mejora deterioro
cognitivo (Levi, 2003)
Hungtington: disminuye deterioro cognitivo (Hannan, 2008)
Parkinson: aumenta resistencia MPTP, (Thiriet, 2008);
reduce deterioro estriado (Bezard, 2003)
S. Rett y Down reduce sintomas motores y cognitivos.
(Martinez-Cue, 2005); (Kondo 2008)

Isquemia
Disminuye secuelas (Saucier, 2010)
Facilita migracion celulas SVZ (Hicks, 2007)
Mejora recuperación funcional (Briones, 2009)
Disminuye amiloidogenesis (Briones, 2009)

TCE
Promueve recuperacion funcion cognitiva (Hamm, 1996)
Reduce daño BHE (Ortuzar, 2010)
Disminuye muerte neuronal y mejora angiogenesis (Ortuzar,
2010)
Recuperacion en rehabilitacion postraumática (Penn, 2009)

Tumores
Volume 142, Issue 1, 9 July 2010, Pages 52-64
Article
Environmental and Genetic
Activation of a Brain-
Adipocyte BDNF/Leptin Axis
Causes Cancer Remission
and Inhibition

e 3
'()(&*+&,+-."+/,&'#0'&)(1+"2*#+.&#3/0(
Rearing schedule

VEGF infusion
18 dpn Long Evans rats
Alzet minipumps for 1 week at a 1 µl /h rate.
VEGF. 25 ng/ml.
anti-VEGF. 25 µg/ml.
PBS.
Untreated rats.

BASIC NEUROSCIENCES, GENETICS AND IMMUNOLOGY - ORIGINAL ARTICLE
Combination of intracortically administered VEGF
and environmental enrichment enhances brain protection
in developing rats
Naiara Ortuzar • Enrike G. Argandonã •
Harkaitz Bengoetxea • Jose´ V. Lafuente
Received: 8 September 2010 / Accepted: 24 September 2010
Ó Springer-Verlag 2010
Abstract Postnatal development of the visual cortex is
modulated by experience, especially during the critical
period. In rats, a stable neuronal population is only
acquired after this relatively prolonged period. Vascular
endothelial growth factor (VEGF) is the most important
angiogenic factor and also has strong neuroprotective,
neurotrophic and neurogenic properties. Similar effects
have been described for rearing in enriched environments.
Our aim is to investigate the vascular and neuronal effects
of combining VEGF infusion and environmental enrich-
ment on the visual cortex during the initial days of the
critical period. Results showed that a small percentage of
Cleaved Caspase-3 positive cells colocalized with neuronal
markers. The lesion produced by the cannula implantation
resulted in decreased vascular, neuronal and Caspase-3
positive cell densities. Rearing under enriched environment
was unable to reverse these effects in any group, whereas
VEGF infusion alone partially corrected those effects. A
higher effectiveness was reached by combining both the
procedures, the most effective combination being when
enriched-environment rearing was introduced only after
minipump implantation. In addition to the angiogenic
effect of VEGF, applied strategies also had synergic neu-
roprotective effects, and the combination of the two strat-
egies had more remarkable effects than those achieved by
each strategy applied individually.
Keywords Critical period Á Enriched environment Á
Neuroprotection Á Neurovascular unit Á VEGF Á
Visual system
Introduction
The development of the central nervous system (CNS), and
more specifically of the sensory systems, is modulated by
experience. This leads to an increase in metabolic demand
(Black et al. 1990) that is satisfied by the adaptive
remodelling of the vascular network (Argandonã and
Lafuente 1996, 2000). Postnatal development of the visual
cortex occurs in two stages. The first is genetically pre-
determined and the second modulated by experience. Most
of the cortical changes induced by experience occur during
the critical period (Hensch 2005). This time window is
specific for each sensory cortex and when experience-
mediated reorganization finishes, sensory functions reach
maturity (Bengoetxea et al. 2008). In rats, the critical
period for the visual system is located between the third
and the fifth postnatal weeks and the maximum peak of
experience-induced changes occurs during the fourth and
the fifth weeks (Fagiolini et al. 1994; Fagiolini and Hensch
2000).
During development, more than half of the initially
formed neurons die by programmed cell death (PCD),
which is of fundamental importance for the correct devel-
opment of the CNS (Finlay 1992). PCD is highly regulated
during development and is maintained under strict control
N. Ortuzar (&) Á E. G. Argandonã Á H. Bengoetxea Á
J. V. Lafuente
Department of Neuroscience, Laboratory of Clinical and
Experimental Neuroscience (LaNCE), Faculty of Medicine and
Odontology, University of the Basque Country UPV/EHU,
Barrio Sarriena s/n, E48940 Leioa, Spain
e-mail: naiara.ortuzar@ehu.es
E. G. Argandonã
Department of Nursing I, University of the Basque Country
UPV/EHU, Barrio Sarriena, E48940 Leioa, Spain
J Neural Transm
DOI 10.1007/s00702-010-0496-2
imary visual cortex images for quantified vascular, neuronal
pase-3 positive cell densities. Sections were stained by
holinesterase histochemistry (a, b), NeuN (c, d) and Cleaved
Caspase-3 (e, f) immunohistochemistry. Densities were esti
the optical dissector method. Scale bar = 100 lm (a, c, e) a
(b, d, f)
d EE enhances brain protection in rats
logical conditions (Nithianantharajah and Hannan 2009).
EE has strong effects on the plasticity of neural con-
nections, especially in the visual cortex, where it has
been demonstrated that rearing from birth in an enriched
pocket was opened in the back for the osmotic minipump
placement (Mod. 1007 D, Alzet, Cupertino, CA, USA).
The brain infusion kit (Mod. Alzet Brain Infusion Kit III,
Alzet) was fixed to the skull with cyanoacrylate and the
Fig. 1 Rearing conditions.
a Standard condition and
b enriched environment
123
Fig. 4 Primary visual cortex images for quantified vascular, neuronal
and Caspase-3 positive cell densities. Sections were stained by
butyryl cholinesterase histochemistry (a, b), NeuN (c, d) and Cleaved
Caspase-3 (e, f) immunohistochemistry. Densities were estimated by
the optical dissector method. Scale bar = 100 lm (a, c, e) and 20 lm
(b, d, f)
VEGF and EE enhances brain protection in rats

Neuronal density

NeuronalDensity
(Opticaldissector)

Densidad vascular
0
5.500
11.000
16.500
22.000
SC EA Lesion Lesion EA Lesion SC-EA Lesion EA-SC
20061
1844918.344
16.935
21.694
18.149

Densidad neuronal
0
25.000
50.000
75.000
100.000
626426110162.642
67.016
90.813
82.161

Densidad Caspasa3
0
5.500
11.000
16.500
22.000
16738
18802
20.254
14.459
19.680
21.110

www.slideshare.net/nfpguare
www.ehu.es/ehusfera/lance
eg.argandona@ehu.es
Contacto

Efectos del enriquecimiento ambiental en el desarrollo del SNC

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