Perinatal Asphyxia in the Rat has Lifelong
Effects on Morphology, Cognitive Functions,
and Behavior
Rachel Weitzdoerfer, Arnold Pollak, and Barbara Lubec
Perinatal asphyxia (PA) is a major determinant of neurological morbidity and mortality in the
neonatal period. Many studies have been investigating neurological deficits following PA, including
seizures, cerebral palsy, mental retardation, as well as psychiatric deficits. Most research performed
so far has been focusing on acute or subacute sequelae and has uncovered a variety of morphological,
neurochemical, behavioral, and cognitive changes following PA. However, information on long-term
sequelae of animals that underwent a period of PA is scanty. Perinatally asphyxiated rats at the end
of their life span present with immunohistochemical and synaptic changes as well as changes in brain
protein expression. Furthermore, deficits in cognitive function tested in the Morris water maze and
changes in social behavior were described. In this review, we are summarizing and discussing
reported effects of global PA on morphology, cognitive functions, and behavior in rats at the end of
their life span.
© 2004 Elsevier Inc. All rights reserved.
erinatal asphyxia (PA) is a major determinant of neurological morbidity in the pediatric population. The incidence of systemic PA is
2-4 per 1000 full-term infants and approaches
60% in premature newborns,1 thus being the
most common cause of neurological impairment. PA may lead to a variety of brain disorders, including spasticity, epilepsy, mental retardation, attention deficit disorders,2,3 and
minimal brain disorder syndromes, and may
form the basis for psychiatric and neurodegenerative diseases later in life.4-6
Much of our current understanding concerning the pathophysiology of PA has come from
animal studies over the past three decades providing important information regarding underlying mechanisms of perinatal hypoxic-ischemic
brain damage.
The immature rat model has proved especially useful for numerous studies of perinatal
hypoxic-ischemic brain damage and presently is
utilized by many investigators. The 7-day postnatal rat was originally chosen for study because, at
this stage of development, the animal’s brain is
histologically similar to that of a 32- to 34-week
gestation human fetus or newborn infant, ie,
cerebral cortical neuronal layering is complete,
the germinal matrix is involuting, and white matter as yet has undergone little myelination.
Asphyxia has been induced by unilateral carotid artery ligation—this model being exten-
P
sively used with some variations, by exposure to
hypobaric hypoxia7 or by the use of a noninvasive model for graded perinatal asphyxia.8,9 This
model, where uterus horns still containing the
rat pups are placed into a water bath for various
asphyxiating periods, resembles the clinical situation as all criteria of PA as acidosis, hypercapnia, and hypoxia are respected, thus contrasting
studies of the brain insult type.
This rat model of PA has been well characterized in biochemical, metabolic, morphological,
and functional terms.10-12
Most research performed so far has focused
on acute sequelae of PA, although the major
concern in human hypoxic ischemic encephalopathy (HIE) is the long-term effect on the
brain. Reviewing the literature, however, the
paucity of long-term neurological and neuropathological outcomes assessed in animal models is surprising. In this review, we intend to
summarize and discuss long-term effects of PA
on brain morphology, cognitive functions, and
behavior in the aged rat.
From the Division of Neonatology, Department of Pediatrics, Medical
University of Vienna, Vienna, Austria.
Address reprint requests to Rachel Weitzdoerfer, MD, University of
Vienna, Department of Neonatology, AKH, Waehringer Guertel
18-20, A-1090, Vienna, Austria; e-mail: rachel_weitzdoerfer@
yahoo.com
© 2004 Elsevier Inc. All rights reserved.
0146-0005/04/2804-0000$30.00/0
doi:10.1053/j.semperi.2004.08.001
Seminars in Perinatology, Vol 28, No 4 (August), 2004: pp 249-256
249
250
Weitzdoerfer, Pollak, and Lubec
Morphological and Immunohistochemical
Changes
Studies on morphological and biochemical alterations focus on the acute or subacute phase of
PA, not extending early adulthood of the rat
with a history of PA.
Delayed neuronal death in the cerebellum of
rat pups with PA has been described previously.13
In the identical rat model of PA at 3 months
following the asphyxiating insult, neuronal loss was
found in CA1 area of hippocampus,10 and myelination deficits were observed in the cerebellum of
animals with 20-minute PA.11
Knowledge on lifelong morphological sequelae of PA in brain regions known to be hypoxia-sensitive is limited to a few reports.
In a previous study performed on 24-monthold rats with a history of 20 minutes of PA,
neuronal density and white matter structure in
the hippocampus were comparable between
groups and no difference in GFAP immunoreactivity, used as a marker for astrocytic gliosis,
was found. Cerebellar weight and volume of the
cerebellar layers as well as stereological results of
granular cells and Purkinje cells did not reveal
any difference either (see Table 1). Gross morphological changes, such as edema, infarction,
scarring, demyelination, or hypointense pathologies indicating apoplexy, could be ruled out by
MRI imaging (see Fig 1).14
Van de Berg and coworkers performed a
study using stereological methods in 22-monthold rats with PA using the same animal model15:
As cognitive ability was shown to be related to
the quantity and to the organization of synapses
and as ischemia has been described to increase
synaptic numbers, they aimed to link the cognitive and behavioral deficits seen in young adult
rats with PA12,16 to synaptic bouton number in
striatum and cerebellum. Therefore, brains of
22-month-old rats perinatally asphyxiated for the
period of 20 minutes were removed from the
skull and cut into coronal sections and subsequently stained with synaptophysin, a specific
marker of presynaptic boutons. Brain regions
were then delineated and stereological tech-
Table 1. Cerebellar Weight and Volume of the Cerebellar Layers and Stereological Results on Purkinje Cells
and Granular Cells
Group (n)
Cerebellar weight in mg
Molecular layer (mm3)
Granular layer (mm3)
White matter (mm3)
Total Purkinje cell
number/cerebellum
Total granular cell
number/cerebellum
Geometric mean volume
of the Purkinje cell
soma (␮m3)
Geometric mean volume
of the Purkinje cell
nucleus (␮m3)
Nucleus-Soma
Relation (%)
Control
(7)
10-min asphyxia
(6)
20-min asphyxia
(7)
Median
(MinimumMaximum)
Median
(MinimumMaximum)
Median
(MinimumMaximum)
273.40
(255.80-296.80)
56.27
(46.70-75.05)
42.94
(31.03-50.52)
29.46
(24.22-30.58)
380439
(244568-468012)
1.613000E⫹08
(1.054000E⫹082.001000E⫹08)
4361.3
(4286.5-4976.7)
283.75
(234.90-300.70)
67.56
(47.82-72.56)
42.90
(31.23-51.09)
31.26
(18.67-32.47)
372497
(348083-463979)
1.552000E⫹08
(1.286000E⫹081.754000E⫹08)
4660.3
(4358.3-5419.5)
288.70
(253.90-298.40)
62.02
(43.44-83.15)
48.59
(31.97-52.31)
30.19
(23.34-35.94)
416424
(217121-464227)
1.731000E⫹08
(1.042000E⫹082.239000E⫹08)
4481.4
(3874.9-5363.0)
n.s.
914.0
(737.8-1031.9)
1007.7
(855.3-1178.7)
886.5
(742.5-1149.9)
n.s.
28%
29%
27%
n.s.
*, P ⬍ 0.05; **, P ⬍ 0.01; ***, P ⬍ 0.001; n.s., ⫽ not significant.
Reprinted with permission by Birkhäuser AG, Basel.14
Statistical
significance
(comparison of
asphyxiated groups
to normoxia group)
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
Effects of Perinatal Asphyxia
Figure 1. Reprinted with permission by Birkhäuser
AG, Basel.14 (A) A magnetic resonance image in the
coronal plane of a rat with 20-minute PA. Abbreviations:
CP, Comissura posterior; GD, Gyrus dentatus; LM, Lemniscus medialis; H, Hippocampus; RP, Recessus pinealis;
SN, Substantia nigra; V III, 3rd ventricle. No hypointense areas were found in the hippocampal area. Two
control and two animals with PA showed hyperintense
areas that may be due to edema, infarctions, scarring, or
demyelination. Nevertheless, no significant difference in
hippocampus was found between control animals and
animals with PA. (B) A magnetic resonance image in
sagittal plane performed on the brain of a rat exposed to
20 minutes of PA. Abbreviations: CB, Cerebellum; TH,
Thalamus; H, Hippocampus; OB, Olfactory bulb. The
anatomical structure of the cerebellum is normal and no
hypo- or hyperintense areas are visible, indicating that
edema, infarction, demyelination, and apoplexy can be
ruled out.
251
nique was applied. Van de Berg and coworkers
found an increase of striatal volume leading to
an increase in presynaptic bouton numbers in
this area and in parietal cortex. The authors
show that an asphyxiating injury during development of the brain can have a long-lasting effect
on the synaptic organization of the brain. The
observed region-specific increase in presynaptic
bouton numbers in striatum and parietal cortex
in asphyxiated rats supports the hypothesis that
brain damage during brain development can
not only lead to synaptic loss but also to the
formation of new synaptic connections. An increase in presynaptic bouton numbers would
allow for more neuronal communication and
could compensate for a loss of neurons. The
mechanisms of this type of synaptic plasticity,
though, are not yet known. Moreover, this compensation mechanism could not compensate
cognitive impairment in these rats, as discussed
below.
A cascade of several mechanisms leading to
deterioration of brain function and neuronal
death in PA has been proposed and several neurotransmitter systems have been incriminated,
but information on neuronal transmission is still
incomplete.
Immunohistochemical investigations at the
age of 3 months showed deterioration of the
monoaminergic system as reflected by decreased
IR-TH in all brain regions investigated, ie, frontal cortex, striatum, cerebellum, hippocampus,
thalamus, and a significant increase of IR-VMAT
in striatum, possibly reflecting compensation of
decreased monoamines by increased monoamine transport, the striatum being particularly
susceptible to asphyxiating neuronal damage.17
TH can be used as a marker for the dopaminergic system responsible for a series of psychomotor functions and, indeed, motor behavior was impaired in a study using rats 1 month
following PA,18 but impairment was not evident
at the age of 3 months, indicating that, clinically,
the TH dopaminergic deficit may be compensated.12 Cholinergic and glutamatergic alterations shown by a decrease of IR-VAChT in striatum and an increase of IR-EAAC1 in frontal
cortex could be found at the same time, indicating individual susceptibility of individual brain
regions to graded PA.
The only study evaluating neurotransmitter
changes in the aged rat published so far is limited to immunohistochemistry of the hippocam-
252
Weitzdoerfer, Pollak, and Lubec
pus showing that IR-VAChT and IR-VMAT is
comparable between ashyxiated and control animals, but revealing a statistically significant increase of SERT immunoreactivity in CA2 of rats
with a history of 20-minute asphyxia (see Table
2).14 Alterations of the immunoreactivity of
SERT—a marker for the serotoninergic system—indicate an aberrant serotoninergic innervations in the CA2 region. As shown in literature, changes in the serotoninergic system are
associated with changes in the ability to perform
the MWM test as discussed below.19-23 To further
elucidate long-term alterations, additional parameters for further evaluation have to be investigated.
Changes in Protein Expression
There exist several publications indicating deficits of the protein synthetic machinery24,25 and
aberrant expression of individual brain proteins
following PA or global hypoxic-ischemic
states.26-33 All these reports describe changes of
individual proteins, focusing on hypoxia-sensitive proteins, including hypoxia inducible factor-1 (HIF-1) in the acute or subacute period of
perinatal asphyxia (PA). Long-term changes of
protein expression, however, have never been
reported before, with the exception of a recent
study.34
Hippocampal tissue of 2-year-old rats with PA
was dissected from brain, and proteins were run
on two-dimensional gel electrophoresis with ingel-digestion and subsequent identification of
proteins by MALDI-TOF followed by quantification of protein spots by specific software. A series
of 134 proteins have been unambiguously identified; 34 of these 134 proteins were selected for
quantification based on criteria for fair spot separation.
Stress proteins protein disulfide isomerase A3
precursor and stress-induced phosphoprotein-1
were significantly increased, whereas the microtubule-associated protein dynamin-1 was significantly reduced. As the vast majority of proteins
was unchanged, this finding can be considered
specific and not due to protein derangement by
deficient protein machinery described in PA.25
Increased stress protein levels may represent
long-term effects of PA or, alternatively, could
reflect conditioning of the stress protein machinery known to occur as a neuroprotective
principle following hypoxic-ischemic conditions.
Decreased dynamin-1 levels may be considered a
long-term effect on the exocytotic system, possibly reflecting or leading to impaired neuronal
transport and vesicle-trafficking in PA of the rat
of advanced age.
Our findings of up-regulated stress proteins
and decreased dynamin-1 may be irrelevant for
impaired brain function found in parallel experiments14 and are possibly reflecting preconditioning by hypoxia early in life.35
Salchner and coworkers investigated the effects of PA on neuronal responsiveness toward a
stressful situation.36 The immediate early gene
c-fos is a marker of neuronal activity and has
been shown to be induced by a variety of condi-
Table 2. Results of Histology and Immunohistochemistry
Group
GFAP Hippocampus (n) fibers/mm2
vAChT Hippocampus CA1 cells/mm2 (n)
vAChT Hippocampus CA2 cells/mm2 (n)
vAChT Hippocampus CA3 cells/mm2 (n)
vAChT Cerebellum Str. gran. % positive
granular cells (n)
vMAT Hippocampus (n) white matter
dent.gyrus fibers/mm2
vMAT Cerebellum (n) fibers white matter/mm2
Sert Hippocampus CA1 cells/mm2 (n)
SERT Hippocampus CA2 cells/mm2 (n)
SERT Hippocampus CA3 cells/mm2 (n)
SERT Cerebellum % positive Purkinje cells (n)
Control
20-min asphyxia
Statistical
significance
9.14 ⫾ 4.62 (7)
8.74 ⫾ 4.15 (5)
5.46 ⫾ 3.82 (6)
5.46 ⫾ 4.46 (6)
51.86 ⫾ 6.62 (7)
11.65 ⫾ 4.00 (5)
9.86 ⫾ 6.19 (7)
8.34 ⫾ 5.46 (7)
3.09 ⫾ 1.38 (7)
51.43 ⫾ 6.50 (7)
n.s.
n.s.
n.s.
n.s.
n.s.
913.98 ⫾ 301.67 (6)
917.68 ⫾ 339.12 (5)
n.s.
468.10 ⫾ 276.02 (5)
29.12 ⫾ 11.90 (7)
15.07 ⫾ 6.44 (7)*
4.70 ⫾ 4.04 (7)
67.20 ⫾ 17 (5)
335.04 ⫾ 153.91 (7)
33.27 ⫾ 14.49 (7)
29.63 ⫾ 11.61 (7)*
9.86 ⫾ 6.88 (7)
59.58 ⫾ 10.76 (6)
n.s.
n.s.
P ⬍ 0.05
n.s.
n.s.
*, P ⬍ 0.05; **, P ⬍ 0.01; ***, P ⬍ 0.001; n.s., not significant.
Reprinted with permission by Birkhäuser AG, Basel.14
253
Effects of Perinatal Asphyxia
tional and unconditional stimuli in the rodent
brain.37-41 Taken together, such studies have established a detailed map of the stress-responsive
brain circuit. Because several of these studies
used swimming as a stressor, it was possible to
directly assess the consistency of findings concerning the spatial distribution and relative magnitude of the response.37,38 The pattern of Fos
expression as a marker of neuronal activation
was therefore evaluated in 24-month-old rats exposed to a 20-minute PA insult postnatally as a
response to acute swim stress. Asphyxiated rats
displayed a higher number of stress-induced Fospositive cells in certain brain areas as compared
with controls. Although it is unclear as to
whether or not the observed effects of PA are
direct or indirect, the selective nature of its action on c-fos immunoreactivity provides functional anatomical evidence that PA has life-long
effects on neuronal communication and leads to
an abnormal, augmented neuronal responsiveness to stress in specific brain areas, particularly
in the main telencephalic target regions of the
mesencephalic dopamine projections as well as
in functionally related set of brain region associated with autonomic and neuroendocrine regulation.
Cognitive Functions, Behavior, and
Neurology
Various studies have addressed cognitive, neurological, and behavioral effects produced by PA in
the young adult animal. Open field (OF) studies
revealed hyperactive behavior in asphyxiated/
hypoxic/anoxic rats. Hershkowitz and coworkers demonstrated that, after postnatal anoxia,
3-week-old rats displayed hyperactivity,42 a finding which was confirmed by studies of Speiser
and coworkers, Dell⬘ Ánna and coworkers, as
well as Iuvone and coworkers.43-45 At the age of 3
months, Hoeger et al. described reduced anxiety-related behavior of rats tested in the elevated
plus-maze (EPM) that underwent a long exposure to PA. OF studies at the same time point did
not show any difference in behavior between
control and asphyxiated rats.12 Additionally,
Loidl and coworkers showed that behavior in the
OF of 5-month-old female rats was not affected
even by long periods of PA, whereas a significant
hypoactivity was found in male rats with severe
PA.46
Neurologically, motor deficits possibly linked
to cerebellar lesions were observed in rat PA at
very early stages ranging from days to several
weeks,47 which seem to be compensated at the
age of 3 months.12
Nonetheless, there is almost no information
that links PA to behavioral, cognitive, and neurological deficits in the aged animal.
In the above-mentioned study of Van de
Berg,15 the authors show that PA leads to an
exaggerated age-related long-term memory impairment in 18-month-old rats using the Morris
water maze (MWM). However, PA did not lead
to deficits in learning ability or short-term mem-
Table 3. Results of Morris Water Maze
Group (n)
Time to reach the
platform (1.trial)
Time to reach the
platform (2.trial)
Time to reach the
platform (3.trial)
Time to reach the
platform (memory)
Time to reach the
platform (relearning)
Control
(11)
10-min asphyxia
(10)
20-min asphyxia
(6)
Median
(MinimumMaximum)
Median
(MinimumMaximum)
Median
(MinimumMaximum)
Statistical significance
(comparison of
asphyxiated groups
to normoxia group)
38.0 (2-88)
44.5 (4-120)
54.5 (12-120)
n.s.
43.0 (5-120)
49.5 (5-120)
14.0 (5-95) (n ⫽ 5)
n.s.
89.0 (11-120)
n.s.
69.0 (19-120)
55 (12-120)
29 (14-91)
49.5 (20-120)
58.5 (4-120)
n.s.
7.5 (4-36) (n ⫽ 10)
26.5 (3-120)
74** (22-120)
**, P ⬍ 0.01 between
control and 20-min
asphyxia group
*, P ⬍ 0.05; **, P ⬍ 0.01; ***, P ⬍ 0.001; n.s., not significant.
Reprinted with permission by Birkhäuser AG, Basel.14
254
Weitzdoerfer, Pollak, and Lubec
Table 4. Means and SD of the Evaluated Parameters of the Social Interaction Test
Frequency of social-sniffing
Frequency of social-grooming
Frequency of mounting
Frequency of rubbing
Time spent fighting
Time spent resting
Time spent running together
Time spent running alone
Control in
interaction with control
[Mean ⫾ SD (n ⫽ 9)]
Asphyxiated rat in
interaction with control
[Mean ⫾ SD (n ⫽ 10)]
Statistical significance
22.2 ⫾ 10.00
115 ⫾ 73.44
13.1 ⫾ 9.37
15.25 ⫾ 11.15
6.4 ⫾ 2.41
106.41 ⫾ 82.26
39.04 ⫾ 19.68
52.61 ⫾ 41.18
14.81 ⫾ 7.69**
145.02 ⫾ 74.62*
7.13 ⫾ 4.96
8.20 ⫾ 5.70
3.76 ⫾ 1.44*
83.74 ⫾ 79.86
26.80 ⫾ 22.42**
85.07 ⫾ 53.60***
P ⫽ 0.0071
P ⫽ 0.048
n.s.
n.s.
P ⫽ 0.031
n.s.
P ⫽ 0.0064
P ⫽ 0.0006
*, P ⬍ 0.05; **, P ⬍ 0.01; ***, P ⬍ 0.001; n.s., not significant.
Reprinted with permission by Karger AG, Basel.48
ory. Weitzdoerfer and coworkers tested cognitive
functions in the 2-year-old animal at the end of
its life span, revealing a statistically significant
reduction in relearning ability of rats with PA in
the MWM, indicating deficits in hippocampal
function. Impairment of relearning was reflected by swimming in the original training
quadrant for a longer period than control animals, remaining in the latter localization of the
platform rather than looking for a new possibility to escape (see Table 3).14 Differences in
swimming ability and motivation as well as motor
deficits could be ruled out because escape latencies during learning and memory trial were comparable as were motor functions, including the
rota-rod. Learning ability was shown to be comparable between asphyxiated and control animal, confirming the above discussed results by
Van de Berg.
A subsequent study investigated whether PA
also affected anxiety-related and social behavior
in 2-year-old rats with a history of 20-minute PA
performing tests in the OF, elevated plus-maze
(EPM) and a social interaction test.48
In this setting, significantly decreased social
aggressiveness and increased social contact behavior as well as increased anxiety levels in the
asphyxiated animals were observed.
These findings indicate that the asphyxiating
event during the perinatal period potentiates
age-related behavioral changes. Taken together,
the authors conclude that PA leads to changes in
social behavior patterns in the aged animal, resulting in decreased social exploration and aggressiveness, together with increased contact
and appeasing behavior (see Table 4). Furthermore, it is proposed that PA increases anxietybased responses in the aged rat.
The aforementioned findings provide preliminary evidence for a potentiating effect of PA on
brain deficits of the ageing rat, including morphological, cognitive, and behavioral impairment. The limited information on the effect of
PA on neurobiology of aging challenges further
research on this subject. Major open questions
include the nature and mechanisms of anxiety-,
stress-related, and social behavior and cognitive
alterations.
Acknowledgments
This work was supported by the Verein “Unser Kind,”
Verein zur Durchführung der wissenschaftlichen Forschung auf dem Gebiet der Neonatologie und Kinderintensivmedizin.
References
1. Vannucci R, Connor J, Mauger D, et al: Rat model of
perinatal hypoxic-ischemic brain damage. J Neurosci Res
55:158-163, 1999
2. Hill A, Volpe J: Perinatal asphyxia: Clinical aspects. Clin
Perinat 16:435-457, 1989
3. Chen Y: Perinatal Asphyxia in the Rat, Stockholm, Repro
Print AB, 1997
4. Hill A: Current concepts of the hypoxic-ischemic cerebral injury in the term newborn. Pediatr Neurol 7:317325, 1991
5. Younkin D: Hypoxic-ischemic brain injury in the newborn-statement of the problem and overview. Brain
Pathol 2:209-210, 1992
6. Lewis S, Murray S: Obstetric complications, neurodevelopmental deviance and risk of schizophrenia. J Psychol
Res 21:413-421, 1987
7. Roohey T, Raju N, Moustogiannis A: Animal models for
the study of perinatal hypoxic-ischemic encephalopathy:
A critical analysis. Early Hum Dev 47:115-146, 1997
8. Bjelke B, Andersson K, Ögren S, et al: Asphyctic lesion:
Proliferation of tyrosine hydroxylase immunoreactivity
Effects of Perinatal Asphyxia
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
nerve cell bodies in the rat substantia nigra and functional changes in dopamine neurotransmission. Brain
Res 543:1-9, 1991
Herrera-Marschitz M, Loidl C, Andersson K, et al: Prevention of mortality induced by perinatal asphyxia: Hypothermia or glutamate antagonism? Amino Acids
5:413-419, 1993
Kohlhauser C, Kaehler S, Mosgoeller W, et al: Histological changes and neurotransmitter levels three months
following perinatal asphyxia in the rat. Life Sci 64:21092124, 1999
Kohlhauser C, Mosgoeller W, Hoeger H: Myelination
deficits in brain of rats following perinatal asphyxia. Life
Sci 67:2355-2368, 2000
Hoeger H, Engelmann M, Bernert G, et al: Long term
neurological and behavioral effects of graded perinatal
asphyxia in the rat. Life Sci 66:947-962, 2000
Dell⬘ Anna E, Chen Y, Engidawork E, et al: Delayed
neuronal death following perinatal asphyxia in rat. Exp
Brain Res 115:105-115, 1997
Weitzdoerfer R, Gerstl N, Hoeger H, et al: Long-term
sequelae of perinatal asphyxia in the aging rat. Cell Mol
Life Sci 59:519-526, 2002
Van de Berg W, Blokland A, Cuello A, et al: Perinatal
asphyxia results in changes in presynaptic bouton number in striatum and cerebral cortex- a stereological and
behavioral analysis. J Chem Neuroanatomy 20:71-82,
2000
Boksa P, Krishnamurthy A, Brooks W: Effects of a period
of asphyxia during birth on spatial memory and learning. Pediatr Res 37:489-496, 1995
Kohlhauser C, Mosgoeller W, Hoeger H, et al: Cholinergic, monoaminergic and glutamatergic changes following perinatal asphyxia in the rat. Cell Mol Life Sci
55:1491-1501, 1999
Chen Y, Ogren S, Bjelke B, et al: Nicotine treatment
counteracts perinatal asphyxia induced changes in the
meso-striatal/limbic dopamine system and in motor behavior in the four week old male rat. Neuroscience
68:531-538, 1995
Malleret G, Hen R, Guillou JL, et al: 5-HT1B receptor
knock-out mice exhibit increased exploratory activity
and enhanced spatial memory performance in the Morris water maze. J Neurosci 19:6157-6168, 1999
Sarnyai Z, Sibille EL, Pavlides C, et al: Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin1A
receptors. Proc Natl Acad Sci USA 97:14731-14736, 2000
Tecott LH, Logue SF, Wehner JM, et al: Perturbed dentate gyrus function in serotonin 5-HT2C receptor mutant mice. Proc Natl Acad Sci USA 95:15026-15031, 1998
Pitsikas N, Brambilla A, Borsini F: DAU 6215, a novel
5-HT3 receptor antagonist, improves performance in
the aged rat in the Morris water maze. Neurobiol Aging
14:561-564, 1993
Fontana DJ, Daniels SE, Wong EHF, et al: The effects of
novel, selective 5-Hydroxytryptamine (5-HT)4 receptor
ligands in rat spatial navigation. Neuropharmacology
36:689-696, 1997
Mosgoeller W, Kastner P, Fang-Kircher S, et al: Brain
RNA Polymerase and nucleolar structure in perinatal
asphyxia of the rat. Exp Neurology 161:174-182, 2000
Kastner P, Mosgoeller W, Fang-Kircher S, et al: Deficient
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
255
brain RNA polymerase and altered nucleolar structure
persists until day 8 after perinatal asphyxia of the rat.
Pediatr Res 53:62-71, 2003
Jiang BH, Rue E, Wang GL, et al: Dimerization, DNA
binding, and transactivation properties of hypoxia-inducible factor 1. J Biol Chem 271:17771-17778, 1996
Carrero P, Okamoto K, Coumailleau P, et al: Redoxregulated recruitment of the transcriptional coactivators
CREB-binding protein and SRC-1 to hypoxia-inducible
factor 1␣. Mol Cell Biol 20:402-415, 2000
Ema M, Hirota K, Mimura J, et al: Molecular mechanisms of transcription activation by HLF and HIF1alpha
in response to hypoxia: Their stabilization and redox
signal-induced interaction with CBP/p300. EMBO J 18:
1905-1914, 1999
Gradin K, McGuire J, Wenger RH, et al: Functional
interference between hypoxia and dioxin signal transduction pathways: Competition for recruitment of the
Arnt transcription factor. Mol Cell Biol 16:5221-5231,
1996
Hogenesch JB, Chan WK, Jackiw VH, et al: Characterization of a subset of the basic-helix–loop– helix-PAS superfamily that interacts with components of the dioxin signaling pathway. J Biol Chem 272:8581-8593, 1997
Ravi R, Mookerjee B, Bhujwalla ZM, et al: Regulation of
tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1␣. Genes Dev 14:34-44, 2000
An WG, Kanekal M, Simon MC, et al: Stabilization of
wild-type p53 by hypoxia-inducible factor 1␣. Nature
392:405-408, 1998
Arany Z, Huang LE, Eckner R, et al: An essential role for
p300/CBP in the cellular response to hypoxia. Proc Natl
Acad Sci USA 93:12969-12973, 1996
Kitzmueller E, Krapfenbauer K, Hoeger H, et al: Lifelong effects of perinatal asphyxia on stress-induced proteins and dynamin 1 in rat brain. Neurochem Res (in
press)
Burda J, Hrehorovska M, Bonilla L, et al: Role of protein
synthesis in the ischemic tolerance acquisition induced
by transient forebrain ischemia in the rat. Neurochem
Res 28:1213-1219, 2003
Salchner P, Engidawork E, Hoeger H, et al: Perinatal
asphyxia exerts lifelong effects on neuronal responsiveness to stress in specific brain regions in the rat. J Invest
Med 51:288-294, 2003
Cullinan WE, Herman JP, Battaglia DF, et al: Pattern and
time course of immediate early gene expression in rat
brain following acute stress. Neuroscience 64:477-505,
1995
Duncan GE, Johnson KB, Breese GR: Topographic patterns of brain activity in response to swim stress: Assessment by 2-deoxyglucose uptake and expression of Foslike immunoreactivity. J Neurosci 13:3932-3943, 1993
Beck CH, Fibiger HC: Conditioned fear-induced
changes in behavior and in the expression of the immediate early gene c-fos: With and without diazepam pretreatment. J Neurosci 15:709-720, 1995
Campeau S, Hayward MD, Hope BT, et al: Induction of
the c-fos proto-oncogene in rat amygdala during unconditioned and conditioned fear. Brain Res 565:349-352,
1991
Pezzone MA, Lee WS, Hoffman GE, et al: Induction of
c-Fos immunoreactivity in the rat forebrain by condi-
256
42.
43.
44.
45.
Weitzdoerfer, Pollak, and Lubec
tioned and unconditioned aversive stimuli. Brain Res
597:41-50, 1992
Hershkowitz M, Grimm VE, Speiser Z: The effects of
postnatal anoxia on behavior and on the muscarinic and
beta-adrenergic receptors in the hippocampus of the
developing rat. Brain Res 283:147-155, 1983
Speiser Z, Korczyn AD, Teplitzky I, et al: Hyperactivity in
rats following postnatal anoxia. Behav Brain Res 7:379382, 1983
Dell’ Anna ME, Calzolari S, Molinari M, et al: Neonatal
anoxia induces transitory hyperactivity, permanent spatial memory deficits and CA1 cell density reduction in
developing rats. Behav Brain Res 45:125-134, 1991
Iuvone L, Geloso MC, Dell⬘Anna E: Changes in open
field behavior, spatial memory, and hippocampal
parvalbumin immunoreactivity following enrichment
in rats exposed to neonatal anoxia. Exp Neurol 139:
25-33, 1996
46. Loidl CF, Gavilanes AW, Van Dijk EH, et al: Effects of
hypothermia and gender on survival and behavior after
perinatal asphyxia in rats. Physiol Behav 68:263-269,
2000
47. Young R, Kolonich J, Woods C, et al: Behavioral performance of rats following neonatal hypoxia-ischemia.
Stroke 17:1313-1316, 1986
48. Weitzdoerfer R, Gerstl N, Pollak D, et al: Long-term
influence of perinatal asphyxia on the social behavior in
the aging rat. Gerontology 50(4):200-205, 2004