Angiogenesis and Neurogenesis Key to Exercise-Induced Cognitive Gains

Angiogénesis y
neurogénesis
Dos caminos paralelos

martes 15 de noviembre de 2011

“De humani corporis fabrica”


Carmeliet and Tessier-Lavigne, Nature. 2005


Zacchigna et al., Nature Reviews Neuroscience. 2008


Desarrollo cortical

Predeterminado genéticamente
Mediado por experiencia


Desarrollo cortical

Predeterminado genéticamente
Mediado por experiencia

PERIODO CRÍTICO
3ª - 5ª semanas


Neurogenesis Angiogenesis

?


Neurogenesis Angiogenesis

Nicho vascular (neurogenesis). Palmer 2000.

Incremento demanda. Black 1987.

Coordinados. Carmeliet 2005.


Desarrollo neurovascular
Evento coordinado
Respuesta común a señales
comunes
VEGF
Neurotroﬁnas (NGF, BDNF, NTs)
Neuropilinas (Nrp1, Nrp2)
Semaforinas (Sema3A)
Efrinas/Ephs (EphB-ephrinB)
Angiopoyetinas (Ang2)


Neuroscience 171 (2010) 214 –226

ANGIOGENESIS BUT NOT NEUROGENESIS IS CRITICAL et al. / Neuroscience 171 (2010) 214 –226
A. L. Kerr FOR
NORMAL LEARNING AND MEMORY ACQUISITION
A. L. KERR,1 E. L. STEUER, V. POCHTAREV AND cognitive performance on a variety of tasks including the
R. A. SWAIN* Morris water maze (MWM), contextual fear conditioning,
University of Wisconsin-Milwaukee, Milwaukee, WI, USA extinction of contextual fear, and radial arm maze (Ander-
son et al., 2000; Baruch et al., 2004; Fordyce and Wehner,
1993; Gobbo and O’Mara, 2004; Pietropaolo et al., 2006;
Abstract—Aerobic exercise has been well established to pro-
mote enhanced learning and memory in both human and Powell, 2005; Vaynman et al., 2004). In humans, exercise
non-human animals. Exercise regimens enhance blood per- has been associated with improved cognitive performance in
fusion, neo-vascularization, and neurogenesis in nervous young adult, aging adult, and brain-injured populations
system structures associated with learning and memory. The (Churchill et al., 2002; Grealy et al., 1999; Kramer and Erick-
impact of specific plastic changes to learning and memory son, 2007; Kramer et al., 2006; Winter et al., 2007) and has
performance in exercising animals are not well understood. been shown to protect against the onset of various demen-
The current experiment was designed to investigate the con-
tias, including Alzheimer’s disease (Laurin et al., 2001).
tributions of angiogenesis and neurogenesis to learning and
memory performance by pharmacologically blocking each The means by which experience facilitates learning
process in separate groups of exercising animals prior to and memory are not fully understood. However, the sur-
visual spatial memory assessment. Results from our experi- vival of new neurons may contribute to learning and mem-
ment indicate that angiogenesis is an important component ory changes following exercise. It has been consistently
of learning as animals receiving an angiogenesis inhibitor shown that both enriched environments and exercise (vol-
exhibit retarded Morris water maze (MWM) acquisition. Inter- untary and forced) promote neurogenesis in the adult hip-
estingly, our results also revealed that neurogenesis inhibi-
pocampus, specifically in the dentate gyrus (DG) (Christie
tion improves learning and memory performance in the
MWM. Animals that received the neurogenesis inhibitor dis-
et al., 2008; Kempermannn et al., 1997, 1998; Kim et al.,
played the best overall MWM performance. These results 2002; Olson et al., 2006; Uysal et al., 2005; Van der Borght
point to the importance of vascular plasticity in learning and et al., 2006; van Praag et al., 2005), and exercise-induced
memory function and provide empirical evidence to support neurogenesis is correlated with improved learning and mem-
the use of manipulations that enhance vascular plasticity to ory performance (Uysal et al., 2005; van Praag et al., 2005).
improve cognitive function and protect against natural cog- However, there are also reports that manipulation of neuro-
nitive decline. © 2010 IBRO. Published by Elsevier Ltd. All
genesis does not impact learning and memory function in the
rights reserved.
MWM (Meshi et al., 2006; Shors et al., 2002) or contextual
Key words: vascular plasticity, exercise-induced facilitation, fear conditioning (Clark et al., 2008; Shors et al., 2002),
Morris water maze. indicating that neurogenesis may not be the sole supporter of
enhanced cognitive performance following exercise.
The contribution of neurogenesis to learning and mem-
Aerobic exercise promotes enhanced learning and memory function is further complicated by recent evidence sug-
ory in both human and non-human animals. At the cellular gesting that newly proliferated neurons are not immedi-
level, exercise is associated with increased angiogenesis ately and functionally incorporated into existing learning
(the sprouting of new capillaries from preexisting blood networks. While it is clear that new neurons do become
vessels) and/or neurogenesis in various areas of the brain functionally integrated into the existing circuitry eventually,
including the hippocampus, motor cortex and cerebellum several recent reports indicate that this integration is a
(Black et al., 1991; Clark et al., 2009; Isaacs et al., 1992; somewhat delayed process taking between 3 and 4 weeks
Kim et al., 2002; Sikorski et al., 2008; Swain et al., 2003; to complete (Kee et al., 2007; Overstreet et al., 2004; van
van Praag et al., 2005). Aerobic exercise in rodents is also Praag et al., 2002). These data are supported by behav-
associated with improved recovery following ischemic in- ioral studies indicating that impaired neurogenesis does
sult (Lee et al., 2003a,b; Sim et al., 2004) and improved not affect visual spatial memory in the MWM immediately
1
Present address: University of Texas, Austin, TX, USA. following treatment but impairs performance when memory
*Corresponding author. Tel: 1-414-229-5883; fax: 1-414-229-5219. is tested 28 days later (Hu et al., 2008).
martes 15 deABC, avidin-biotin complex;Swain). 4.AZT-injected vol-
E-mail address: rswain@uwm.edu (R. A.
Abbreviations: noviembre de 2011 Fig. The current experiment investigated the relative con-
AZT-VX, BrdU quantification and NeuN colabel. Tissue was treated with immunohistochemical antibodies targeting BrdU to label dividing cells (indi

Neuroscience 171 (2010) 214 –226

ANGIOGENESIS BUT NOT NEUROGENESIS IS CRITICAL FOR
NORMAL LEARNING AND MEMORY ACQUISITION
A. L. KERR,1 E. L. STEUER, V. POCHTAREV AND cognitive performance on a variety of tasks including the
R. A. SWAIN* Morris water maze (MWM), contextual fear conditioning,
University of Wisconsin-Milwaukee, Milwaukee, WI, USA extinction of contextual fear, and radial arm maze (Ander-
son et al., 2000; Baruch et al., 2004; Fordyce and Wehner,
1993; Gobbo and O’Mara, 2004; Pietropaolo et al., 2006;
Abstract—Aerobic exercise has been well established to pro-
mote enhanced learning and memory in both human and Powell, 2005; Vaynman et al., 2004). In humans, exercise
non-human animals. Exercise regimens enhance blood per- has been associated with improved cognitive performance in
fusion, neo-vascularization, and neurogenesis in nervous young adult, aging adult, and brain-injured populations
system structures associated with learning and memory. The (Churchill et al., 2002; Grealy et al., 1999; Kramer and Erick-
impact of specific plastic changes to learning and memory son, 2007; Kramer et al., 2006; Winter et al., 2007) and has
performance in exercising animals are not well understood. been shown to protect against the onset of various demen-
The current experiment was designed to investigate the con-
tias, including Alzheimer’s disease (Laurin et al., 2001).
tributions of angiogenesis and neurogenesis to learning and
memory performance by pharmacologically blocking each The means by which experience facilitates learning
process in separate groups of exercising animals prior to and memory are not fully understood. However, the sur-
visual spatial memory assessment. Results from our experi- vival of new neurons may contribute to learning and mem-
ment indicate that angiogenesis is an important component ory changes following exercise. It has been consistently
of learning as animals receiving an angiogenesis inhibitor shown that both enriched environments and exercise (vol-
exhibit retarded Morris water maze (MWM) acquisition. Inter- untary and forced) promote neurogenesis in the adult hip-
estingly, our results also revealed that neurogenesis inhibi-
pocampus, specifically in the dentate gyrus (DG) (Christie
tion improves learning and memory performance in the
MWM. Animals that received the neurogenesis inhibitor dis-
et al., 2008; Kempermannn et al., 1997, 1998; Kim et al.,
played the best overall MWM performance. These results 2002; Olson et al., 2006; Uysal et al., 2005; Van der Borght
point to the importance of vascular plasticity in learning and et al., 2006; van Praag et al., 2005), and exercise-induced
memory function and provide empirical evidence to support neurogenesis is correlated with improved learning and mem-
the use of manipulations that enhance vascular plasticity to ory performance (Uysal et al., 2005; van Praag et al., 2005).
improve cognitive function and protect against natural cog- However, there are also reports that manipulation of neuro-
nitive decline. © 2010 IBRO. Published by Elsevier Ltd. All
genesis does not impact learning and memory function in the
rights reserved.
MWM (Meshi et al., 2006; Shors et al., 2002) or contextual
Key words: vascular plasticity, exercise-induced facilitation, fear conditioning (Clark et al., 2008; Shors et al., 2002),
Morris water maze. indicating that neurogenesis may not be the sole supporter of
enhanced cognitive performance following exercise.
The contribution of neurogenesis to learning and mem-
Aerobic exercise promotes enhanced learning and memory function is further complicated by recent evidence sug-
ory in both human and non-human animals. At the cellular gesting that newly proliferated neurons are not immedi-
level, exercise is associated with increased angiogenesis ately and functionally incorporated into existing learning
(the sprouting of new capillaries from preexisting blood networks. While it is clear that new neurons do become
vessels) and/or neurogenesis in various areas of the brain functionally integrated into the existing circuitry eventually,
including the hippocampus, motor cortex and cerebellum several recent reports indicate that this integration is a
(Black et al., 1991; Clark et al., 2009; Isaacs et al., 1992; somewhat delayed process taking between 3 and 4 weeks
Kim et al., 2002; Sikorski et al., 2008; Swain et al., 2003; to complete (Kee et al., 2007; Overstreet et al., 2004; van
van Praag et al., 2005). Aerobic exercise in rodents is also Praag et al., 2002). These data are supported by behav-
WM one probe trials. (A) All animals ischemic equivalentstudies indicating time in the correct quadrant during the first probe trial. (B) All animals
associated with improved recovery following spent in- ioral amounts of that impaired neurogenesis does
sult (Lee et al., 2003a,b; Sim et al., 2004) and improved not affect visual spatial memory in the MWM immediately
ilar amounts of time in the SW quadrant, which is directlytreatment but impairs performance when memory represents the greatest distance from the plat
1
Present address: University of Texas, Austin, TX, USA. following
opposite the target quadrant and
als can search.author. Tel: 1-414-229-5883; fax: 1-414-229-5219. trial, SU5416-VX later (Hu et al., 2008).
*Corresponding (C) During the remote probe is tested 28 days and VEH-IC animals spent significantly less time in the correct quadrant
E-mail address: rswain@uwm.edu (R. A. Swain).
The current experiment investigated the relative con-

Sistema visual
Sistema Visual


Periodo crítico
4ª semana
Cambios mediados por experiencia

1º-3ª semanas 4ª-6ª semanas 7ª y 8ª semanas

Periodo precritico Periodo crítico Periodo postcrítico
Age


Empobrecimiento ambiental

Descenso densidades neuronal,
glial y vascular
Retraso maduración
Anulación cierre periodo
crítico


Empobrecimiento ambiental


Cortical parameters


Vascular density


Results
120
25
100
20
80
15
Oscuridad
60
Controles
10
40

5
20

0
0
0 DPN 7 DPN 14 DPN 21 DPN 60 DPN
0 DPN 7 DPN 14 DPN 21 DPN 60 DPN

Number of
Vascular Density perpendicular vessels


Enriquecimiento ambiental
Donald Hebb (1949)

Kresh, Bennett, Rosenzweig, Diamond (60s)
Combinación de complejidad de objetos
inanimados y estimulación social.

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

Gliogénesis

Reduce el deﬁcit de memoria tras ictus (Dahlqvist, 2004)
Mejora la recuperiación funcional tras lesión estriatal
(Dobrossy 2004)
Induce neurogenesis en hipocampo (Kempermann 1997)
Reduce los efectos del Hungtington (Spires 2004)
Madura y consolida la corteza visual en ratas privadas de
luz (Bertoletti 2004)
Revierte los efectos del stress prenatal (Morley-Fletcher
2003)
Acelera el desarrollo de la corteza visual (Cancedda 2004)



Edades :

. 14 dpn, 21 dpn Pre-critical

. 28 dpn, 35 dpn, 42 dpn Critical period

. 49 dpn, 56 dpn, 63 dpn Postcritical


Estudio cualitativo

Inmunohistoquimia Histoquimia
LEA

EBA

GluT-1

LEA EBA
Estudio cualitativo


Estudio cualitativo EBA GluT-1

EBA + GluT-1



Angiogénesis


Estudio cuantitativo


VEGF

WESTERN BLOT

ELISA


ELISA


VEGF levels
6,0 CE
Control
DR
DR-CE
4,5

3,0

1,5

0
14 dpn 21 dpn 28 dpn 35 dpn 42 dpn 49 dpn 56 dpn 63 dpn

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Patología SNC
TCE
Ictus
Tumores
Patologías neurodegenerativas


Patología SNC
TCE
Ictus
Tumores
Vascularización


Neuroprotección mediante
enriquecimiento ambiental
Parkinson
Alzheimer
Hungtinton
Ictus
TCE

Objetivos terapeúticos

Neuroprotección/neurorescate
Incremento vascularización


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


Angiogenesis and Neurogenesis Key to Exercise-Induced Cognitive Gains

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