Physiological

Communication

Biosci. Biotech. Res. Comm. 9(3): 341-348 (2016)

Cognitive type susceptibility in ICR mice model of

chronic cerebral hypoperfusion.

Sirilak Somredngan

and Wachiryah Thong-asa

Physiology Division, Department of Zoology, Faculty of Science, Kasetsart University, Bangkok, Thailand.

ABSTRACT

Animal model of chronic cerebral hypoperfusion (CCH) was found to be bene cial as pathophysiological provided

relevance to vascular dementia (VD) and subcortical ischemic vascular dementia (SIVD). There were many evidence

kinds of CCH animal model and all were useful. The present study investigated the pathophysiology of mild CCH in

ICR mice during 2 to 8 weeks of permanent right common carotid artery occlusion Sensorimotor, cognitive abilities

and anxiety-like behavior were assessed in Morris water maze (MWM) and elevated plus maze (EPM), respectively.

Frontal cortex, striatum and hippocampus infarctions were evaluated using 2% 2,3,5-triphenyltetrazolium chloride

(TTC) at 2, 4 and 8 weeks of permanent right common carotid arteryocclusion. Sensorimotor, spatial learning and

memory in the acquisition paradigm of the MWM and anxiety-like behavior assessed in the EPM were not affected

during the experimental period of 2, 4 and 8 weeks of arterial occlusion.Signi cant de cit of learning  exibility and

memory of reverse platform location in the reversal paradigm were found, though reversible of learning  exibility

de cit presented at 8 weeks. Signi cant infarction early appeared in striatum since 4 weeks while the frontal cortex

and hippocampus stated at 8 weeks. The present study suggested that mild CCH induced by permanent right com-

mon carotid artery occlusion in ICR mice induced reversible learning  exibility de cit but not memory of the reverse

platform location in the MWM.

KEY WORDS: CHRONIC CEREBRAL HYPOPERFUSION, ELEVATED PLUS MAZE,LEARNING FLEXIBILITY, SPATIAL LEARNING AND MEMORY.

341

ARTICLE INFORMATION:

*Corresponding Author: fsciwyth@ku.ac.th

Received 20

Aug, 2016

Accepted after revision 7

Sep, 2016

BBRC Print ISSN: 0974-6455

Online ISSN: 2321-4007

Thomson Reuters ISI ESC and Crossref Indexed Journal

NAAS Journal Score 2015: 3.48 Cosmos IF : 4.006

reserved.

Online Contents Available at: http//www.bbrc.in/

INTRODUCTION

Animal model of chronic cerebral hypoperfusion (CCH)

can be induced by permanent ligation of major cerebral

arterial supplies. Severity of pathological appearances

depended on the number of vessel occlusion and persis-

tent of cerebral reduction. CCH study in animal model

is associated with cerebral blood  ow (CBF) reduction,

metabolic insuf cient, oxidative stress, neuroin am-

mation, neurotransmitter system dysfunction, mental

confusion, cognitive decline, white matter and neu-

ronal degeneration. These pathological relevancies of

342 COGNITIVE TYPE SUSCEPTIBILITY IN ICR MICE OF CCH MODEL BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Sirilak Somredngan and Wachiryah Thong-asa

CCH model were variable due to the difference of vessel

occlusion type and animal strain. Among rodent strain,

the difference in susceptibility has been reported, (Reid

et al. 2010). The rapid onset and signi cant pathophysi-

ological appearance clearly revealed in permanent bilat-

eral common carotid artery occlusion (BCCAO) model.

BCCAO model has provided bene cial data of causative

role played by cerebral hypoperfusion in neurodegen-

erative diseases and can be further useful in neuropro-

tective and therapeutic researches, (Farkas et al. 2007

and Du et al. 2016).

Knowing of pathomechanism is relevant to vascu-

lar dementia (VD) and subcortical ischemic vascular

dementia (SIVD) using a milder model of CCH such as

unilateral carotid artery occlusion (UCO) model. There

was frequency used of right common carotid artery

occlusion (rCCAO), and it revealed useful data of CCH

outcome both in rats and mice. Pathological relevance

for instance signi cant reduction of ipsilateral CBF,

activation of pro-in ammatory cytokine (IL-1, TNF-

), inhibition of anti-in ammatory cytokine (IL-4, 10),

downregulation of A1 adenosine receptors, white matter

damage, hippocampal neuronal degeneration,and corre-

lation with cognitive impairments such as spatial learn-

ing and memory (Yoshizaki et al. 2008, Thong-asa et al.

2013, Thong-asa and Tilokskulchai 2014, Cheng et al.

2015, Thong-Asa 2015).

Reversible of cognitive de cit was reported in short-

term but not long-term study of rCCAO without neu-

ronal degeneration correlation (Thong-asa et al. 2013,

Thong-asa and Tilokskulchai 2014, Thong-Asa 2015).

Cognitive ability outcomes from rodent assessed in cog-

nitive tasks might improve by repetitive test, previous

experience and compensatory mechanisms of cerebral

ischemia in CCH model were also suggested. Data com-

paring from rats and mice rCCAO model, focus only on

cognitive which varied due to the difference of maze

paradigm, repetitive test or previous experience and

effect of global ischemia on behavioral measures of

emotion, locomotion as well as habituation(Choy et al.

2006, Coyle and Panzenbeck 1990, Dellu et al. 1997,

Kim et al. 2008). Rats exhibited more susceptibility than

mice as more spatial ability de cits were found since 6

days of rCCAO(Thong-asa et al. 2013) but it was only 4

weeks in mice, (Cheng et al. 2015).

There are reports about global cerebral ischemia

induced hyperactivity, anxiety and locomotion which

might help reversible of cognitive ability de cit as

well(Milot and Plamondon 2009, Plamondon and Khan

2005). It is interesting that strain of rat and mouse used

as CCH model provide differences of pathophysiologi-

cal outcome. It is important to clarify the pathomecha-

nism, susceptibility and neuropathology correlated with

behavioral de cit in each CCH rodent model. Regarding

the importance of basic knowledge, the present study

aimed to investigate the pathophysiologyof CCH induced

by permanent right common carotid artery occlusion

focus on ICR mice strain.

MATERIAL AND METHODS

Animals:

Thirty-six male ICR mice, 40 – 50 grams, were

obtained from the National Laboratory Animal Cen-

tre, Mahidol University, Salaya, Nakornprathom.Mice

were housed under 12h/12h light-dark cycle with well-

controlled temperature (23 ± 2

C), humidity (55 ± 5%)

with appropriated ventilation. Mice were allowed free

access to standard food pellets and RO water. The pre-

sent study was conducted in accordance with interna-

tionally accepted principles for laboratory animal use

and care of the European Community (EEC directive of

1986; 86/609/EEC) and the experimental protocol was

approved by theAnimal Ethics Committee, Kasetsart

University Research and Development Institute (KURDI),

Kasetsart University, Bangkok, Thailand (ID#OACKU

04559).

Experimental protocol:

In brief, mice were randomly

assigned to two main groups of Sham and unilateral

(right) common carotid artery occlusion (UCO). After

fasting, mice were anesthetized by sodium pentobarbi-

tal (45 mg/kg) intraperitoneal injection. After checking

their re exes, a skin incision was made on the midline

ventral neck, right common carotid artery was exposed,

and it was cleared from nerves and surrounding connec-

tive tissues then permanently occluded with silk suture.

After wound sutured, antibiotic was given intramuscular

injection and mice were placed under heat lamps and

blankets in a recovery chamber. Sham and UCO main

groups were further randomly divided into 3 experi-

mental groups based on the period of arterial occlusion

at 2, 4 and 8weeks.Evaluation of sensorimotor, cogni-

tive abilities usingthe Morris water maze (MWM), anx-

iety-like behavior in the elevated plus maze(EPM), and

infarction volume of brain tissues were conducted at

these period as well.

Sensorimotor and cognitive abilities evaluation in the

Morris water maze:

The Morris water maze was a 150

cm diameter plastic pool and 50 cm tall. It was  lled

with 30 cm depth of water (25

C). Prior to the cognitive

tests, the sensorimotor evaluation was done in order to

assess visual and motor abilities. Sensorimotor test was

conducted using the visible platform paradigm (cue test).

Brie y, a visible platform was placed and clearly seen-

above the water surface about 2 cm. Mice were given

four trials to swim, search, climb and sit on the visible

platform. The maximum time for each trail was 120 sec-

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS COGNITIVE TYPE SUSCEPTIBILITY IN ICR MICE OF CCH MODEL 343

Sirilak Somredngan and Wachiryah Thong-asa

onds. The swimming speed of each group was compared

for sensorimotor evaluation. On the following day, spa-

tial learning was tested and continued for  ve consecu-

tive days as the acquisition trial. Brie y, the pool was

divided into four quadrants: northeast (NE), northwest

(NW), southeast (SE), and southwest (SW) on the com-

puter monitorthat was connected to a ceiling camera.

The hidden platform was placed under the water surface

about 2 cm in the center of the NW quadrant (the target

quadrant of acquisition trial).

A variety of visual cues were placed outside and

around the pool. Mice were continuously given four tri-

als a day with 120 minutes maximum timeof each trial.

For ran out time case, mice were guided to the hidden

platform by the experimenter. When the acquisition

trial was completed, the probe trial began in order to

determine spatial memory capacity. The hidden platform

was removed from the target quadrant, and mice were

allowed to swim for 60 seconds, then the time spent in

each quadrant was recorded. The time spent in the target

quadrant was then further converted to percentage of

time spent in the target quadrant and represented as spa-

tial memory capacity. After  nish acquisition trial and

probe, learning  exibility was continuously assessed in

the reversal trial for three consecutive days. The only

difference from the acquisition trial was the switching of

hidden platform to the opposite quadrant (SE). The probe

trial was delivered on the last test day as well in order to

assess memory capacity of reverse platform location. All

data were record by using Smart

3.0.04 (Planlab/Har-

vard Apparatus).

Anxiety-like behavior assessment in the elevated plus

maze:

After  nishing the cognitive tests in the MWM,

the anxiety-like behavior was further evaluated. The

EPM was a cross shape maze comprised of two open

(25x5x0.5cm) and two closed (25x5x16cm) arms with

a central platform (5x5x0.5cm). EPM was placed in dry

circular tank (normally used as the MWM) and about 40

cm above the  oor. The EPM was started at 6.00 pm. by

transferring all mice into the experimental room 30 min

prior to the test. Illumination was maintained at 100 lux

in the experimental room. The testing of anxiety-like

behavior was started when mice were placed on the cen-

tral platform facing to the closed arm. Mice were allowed

to move freely in the EPM for 5 min with continuously

video recording. Arm entries de ned as the center of

mass of the mouse enters the arm.The number of open

arm entries and duration were analyzed and served as

an index of anxiolytic behavior, (Komada et al. 2008).

Infarction area analysis: After  nishing all behav-

ioral tests in each experimental period, all mice were

sacri ced by lethal dose of intraperitoneal injection of

sodium pentobarbital (>60 mg/kg). Brains were quickly

removed after decapitation, and brie y washed in cold

0.9 % normal saline solution (NSS) and cut with surgi-

cal blade to yield 2 mm of thickness. Brain pieces were

stained with 2 % 2, 3, 5-triphenyltetrazolium chloride

(TTC) at 37

C for 10 min. After staining with TTC, brain

pieces were kept in 10 % neutral buffer formalin (NBF)

for 24 h, then images were captured and analyzed.

Infarction area was calculated by using UTHSCSA Image

Tool 3.0by differentiated pale tissue area among reddish

areas. About TTC technique, colorless TTC was reduced

to a deep-red precipitate by dehydrogenases in the pres-

ence of NADH of viable tissue. The lethally damaged

cells do not retain these reactants, nonviable areas were

not stained and appear pale, while viable cells were stain

red(Fishbein et al. 1981).

Statistical analysis:

All data were interpreted as mean

± SEM., spatial learning ability and learning  exibil-

ity (represented by escape latencies) were analyzed by

repeated-measure analysis of variance (ANOVA) fol-

lowed by Fisher’s PLSD post hoc test. Memory capac-

ity (% time spent in the target quadrant), anxiety-like

behavior index (represented by open arm entries and

duration), infarction area (represented by % infarction)

were analyzed by ANOVA followed by Fisher’s PLSD

post hoc test. Statistical signi cance was accepted at

p-value < 0.05.

RESULTS

Sensorimotor evaluation at 2, 4 and 8 weeks: All mice

exhibited normal ability of swimming, seeing and

climbing on the platform during cue test in the MWM.

Results indicated no signi cant difference of the swim-

ming speed (cm/min) at 2 (Sham 2W = 17.18±1.97, UCO

2W = 17.81±1.48, p > 0.05), 4 (Sham 4W = 19.25±0.99,

UCO 4W = 19.87±1.37, p > 0.05) and 8 (Sham 8W =

18.89±1.09, UCO 8W = 19.23±0.81, p > 0.05) weeks after

permanent right common carotid artery occlusion.

Spatial cognitions and learning  exibility at 2, 4 and

8 weeks:

Swimming pathof acquisition and reversal tri-

als, the target selected quadrants, spatial learning abil-

ity, spatial memory capacity, learning  exibility and

memory capacity of reverse platform location at 2, 4

and 8 weeks of right common carotid artery occlusion

showed in Fig.1. Spatial learning ability indicated by

the escape latency was not difference at all period of the

experiment (p > 0.05).Similar to spatial memory capac-

ity indicated by the percentage of time spent in the tar-

get quadrant of the acquisition probe (p > 0.05). These

results imply that the permanent right common carotid

artery occlusion for a period of 2, 4 and 8 weeks did not

induce de cit on spatial learning ability and memory

capacity of ICR mice CCH model.

344 COGNITIVE TYPE SUSCEPTIBILITY IN ICR MICE OF CCH MODEL BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Sirilak Somredngan and Wachiryah Thong-asa

common carotid artery occlusion at 2, 4 and 8 weeks did

not induce difference in anxiety-like behavior (p > 0.05).

Infarction area at 2, 4 and 8 weeks: Percentage of infarc-

tion area in Fig. 3 indicated the signi cant difference

in the frontal cortex and hippocampal areas found at 8

weeks (p < 0.05). Striatum infarction found signi cantly

at 4 and 8 weeks of arterial occlusion (p < 0.05). Infarc-

tion areas from TTC staining in our present study sug-

gested about early appearance of infarction on striatum

in ICR mice CCH model.

DISCUSSION

The present study used ICR mice as CCH model induced

by permanent right common carotid artery occlusion-

and persistent from 2 to 8 weeks. This CCH model did

not induce spatial learning and memory de cits, but

revealed about cognitive type susceptible to CCH that-

was the learning  exibility. The present study also

found reversible of  exibility de cit but not the mem-

ory capacity of new platform location. Mice strain that

used as CCH model induced by permanent right commo n

carotid artery occlusion such as ICR and B57BL/6 gave

such differences of outcome. Using of ICR mice as the

present study revealed about CCH did not induce spa-

tial learning and memory de cits during 2 to 8 weeks,

but B57BL/6 mice the de cit of spatial memory capac-

ity appeared since 2 weeks and spatial learning de cit

found at 4 weeks, (Cheng et al. 2015).

It was not surprise because of B57BL/6 was the most

susceptible to global cerebral ischemia rather than ICR

or other mouse strains, based on neurological signs, his-

tological  ndings, cortical microcirculatory and perfu-

sion patterns(Yang et al. 1997).There were reports about

the differences of pathophysiology and behavioral out-

come among mouse strains(Adams et al. 2002, Brosnan-

Watters et al. 2000). Not only strain difference, sex also

concern especially in the cognitive behavioral tests(Ge et

al. 2013). There was evidence indicated that locomotor

activities such as the basal open- eld activity of the ICR

was greater than that of the C57BL/6, the hippocampal-

dependent learning and memory such as novel object

was lower in the ICR and the strength of memory reten-

tion in the ICR mice was relatively weak (Kim et al.

2008). This evidence correlated with our present study

that the  exibility of learning and memory retention

especially for the new platform location were impaired.

As the differences of brain circuit and mechanism of

cognitions, affected of cognitive functions depended on

location of circuit area andneuronal cell damage.

We suggest that cognitive type speci c factor that

early affected in ICR mice CCH model was the  exibil-

ity.Adaptive behavior associated with prefrontal cortex-

FIGURE 1. Representation of swimming paths,

target quadrants, spatial learning and memory in

the acquisition paradigm, learning  exibility and

memory in the reversal paradigm assessed in Morris

water maze (MWM); spatial learning ability and

learning  exibility represented by escape latencies

(sec); memory capacity represented by the percent-

age of time spent in the target quadrant (%); at 2,

4 and 8 weeks of permanent right common carotid

artery occlusion, * p < 0.05.

The escape latency in the reversal trial(learning  ex-

ibility) signi cantly increased in UCO group at 2 (p <

0.05) and 4 (p < 0.05)but not 8 weeks (p > 0.05) of per-

manent right common carotid artery occlusion which

indicated reversible of learning  exibility de cit at 8

weeks. Memory capacity of the reverse platform loca-

tion in the reversal probe signi cantly decreased in UCO

group at all periods (p < 0.05) with no such the reversible

as found in learning  exibility. Our data revealed about

cognitive type susceptible to CCH that was induced by

permanent right common carotid artery occlusion and it

was the cognitive  exibility.

Anxiety-like behavior at 2, 4 and 8 weeks: Anxiety-like

behavior indicated by the number of open arm entries

and duration at 2, 4 and 8 weeks showed in Fig.2. The

result indicated that CCH induced by permanent right

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS COGNITIVE TYPE SUSCEPTIBILITY IN ICR MICE OF CCH MODEL 345

Sirilak Somredngan and Wachiryah Thong-asa

FIGURE 2. Representation of anxiety-like behavior assessed in the elevated plus maze (EPM).

Data interpreted as open arm entries and duration at 2, 4 and 8 weeks of right common

carotid artery occlusion.

FIGURE 3. Representation of brain tissue stained with 2 % 2, 3, 5-triph-

enyltetrazolium chloride (TTC) of frontal cortex, striatum and hippocampus.

White arrow indicated example of pale TTC area as identi cation of tissue

infarction. Scale bar = 1 cm.

346 COGNITIVE TYPE SUSCEPTIBILITY IN ICR MICE OF CCH MODEL BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS

Sirilak Somredngan and Wachiryah Thong-asa

basal ganglia circuitry, facilitating a shift in strategies

and response pattern(Ragozzino et al. 2009).The present

study found signi cant infarction of striatum since 4

weeks that might correlated with this  exibility de -

cit. However, reversible of learning  exibility de cit did

not correlate with signi cant frontal cortex and stria-

tum infarction at 8 weeks. TTCtechnique use the reac-

tion of dehydrogenase to reduce TTC and turn to red

color in healthy tissue (Fishbein et al. 1981). Tissue lack

of blood perfusion was found to lead to lack of O

and

further NADH in cellular respiration. TTC technique had

high degree identi cation of infarct area and volume

and suitable for producing accurate measurements of

cerebral experimental infarcts as the use of cresyl violet

staining (Tureyen et al. 2004).

The present study identi ed pale area of TTC as not a

pure white, but pink-white, so we got a trend. It might

describe as penumbra area of ischemic tissue, perfu-

sion still present and cells are viable with hypofunc-

tion because of metabolic insuf cient. This area was

destined as delayed cell dead or survive (Heiss and Graf

1994). As we had found in the frontal cortex and stri-

atum, the reversible of learning  exibility de cit at 8

weeks that not correlated with infarction volume might

involve compensatory mechanisms such as vascular

remodeling and improvement of collateral blood sup-

FIGURE 4. Representation of infarction area of frontal cortex, striatum and hippocampus using TTC staining

technique. The infarction area indicated by the percentage of infarction at 2, 4 and 8 weeks of permanent

right common carotid artery occlusion (UCO), * p < 0.05.

BIOSCIENCE BIOTECHNOLOGY RESEARCH COMMUNICATIONS COGNITIVE TYPE SUSCEPTIBILITY IN ICR MICE OF CCH MODEL 347

Sirilak Somredngan and Wachiryah Thong-asa

ply that help survive of cells in this penumbra-like area

in CCH model(Choy et al. 2006, Coyle and Panzenbeck

1990).The ipsilateral cerebral blood reduction in rCCAO

mice returned to normal level with 4 weeks was reported

(Yoshizaki et al. 2008), however, hemispheric perfusion

asymmetry was found in some challenge situation such

as hypercapnia. It was report about progressively less

pronounced with time but a slight asymmetry still per-

sists one month after unilateral carotid occlusion(Ley et

al. 1985). This hemodynamic insuf cient might last long

as the artery was occluded. Early affected of CCH was

on cognitive behavior while pathological appearance

of damaged neuron not signi cantly presented as has

been reported by Thong-asa et al. (2013), Thong-asa and

Tilokskulchai (2014) and Thong-Asa (2015).

Unlike present study, spatial learning and memory in

the acquisition trial and probe did not affected but learn-

ing  exibility. The difference between acquisition and

reversal paradigm in the MWM produced a difference

outcome of stress and lead to difference effect on syn-

aptic density of the hippocampus. The divergent effects

of experiences on CA3 hippocampal synaptic activity,

i.e. stress as a suppressor and learning as a promoter

of synaptic plasticity (Sandi et al. 2003). Susceptibil-

ity of cognition type to CCH found in the present study

might involve stress inducing during reversal paradigm

as well. Learning  exibility associated with prefrontal

cortex-basal ganglia circuitry while spatial acquisition

was hippocampal-dependent cognitive type. It was not

surprising that hippocampus-dependent learning ability

in acquisition trial did not correlate with hippocampus

infarction found in the present study.

The percentage of infarction area in the hippocam-

pus higher than the frontal cortex and striatum but it

was not signi cantly different until 8 weeks. There was

a report suggested that hippocampal-dependent spatial

learning only requires a minislab (down to 26% of total)

of dorsal hippocampal tissue (Moser et al. 1995).

The present study found infarction area not more

than 25% and not all of this area appear dead. It is

interesting that how long after appearance of signi cant

infarction in the hippocampus that the spatial learning

and memory in the acquisition paradigm will appear?

There are reports suggesting about increase of locomo-

tor activity and mental confusion such as anxiety-like

behavior in the ischemic experimental animals(Milot

and Plamondon 2009, Plamondon and Khan 2005) and

these factors might involve facilitation of cognitive abil-

ity in the cognitive tasks. Early after ischemic onset as

24 hours and 1 week, it appeared signi cantly anxiolytic

promoting of ischemia.This anxiolytic promoting disap-

peared in long term as time-dependent effects of global

cerebral ischemia. These reports provided data only

ischemic-reperfusion model unlike in the present study.

We assessed anxiety-like behavior at 2, 4 and 8 weeks of

CCH model and we found only trend that UCO mice had

higher open arm entries and duration than Sham with

no signi cant difference. We  rst report about anxiety-

like behavior in CCH mice model, and it did not involve

or facilitate the cognitive abilities in this study.

In conclusion, the present study suggested that mild

CCH induced by permanent right common carotid artery

occlusion in ICR mice induce reversible learning  ex-

ibility de cit but not memory of the reverse platform

location paradigm of the MWM. Our study imply about

cognitive type susceptible to mild CCH in ICR mice and

it was the learning  exibility.

ACKNOWLEDGEMENTS

We would like to thank Department of Zoology, Fac-

ulty of Science, Kasetsart University for research facility

and assistance. This work was supported by a grant from

Graduate School, Kasetsart University.

Con ict of interest:

None.

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