Differential anxiety-like behavior, HPA responsiveness, and host-resistance in mice with different circling preference

Accepted Manuscript Differential anxiety-like behavior, HPA responsiveness, and hostresistance in mice with different circling preference

Dongsoo Kim, Kicheol Cheon PII: DOI: Reference:

S0165-5728(17)30413-7 doi:10.1016/j.jneuroim.2017.12.022 JNI 476694

To appear in:

Journal of Neuroimmunology

Received date: Revised date: Accepted date:

13 September 2017 14 December 2017 27 December 2017

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Differential anxiety-like behavior, HPA responsiveness, and hostresistance in mice with different circling preference Dongsoo Kim1 , Kicheol Cheon2

Department of Basic Science, Korea Air Force Academy, 635 Danjaero, Cheongju, Chungbuk, Republic of Korea 28187

5th R&D Institute, Korean Agency for Defense Development, PO Box 35, Yuseong, Daejeon,

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Republic of Korea 34186

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Address correspondence to: Dongsoo Kim, Current affiliation: Department of Basic Science, Air Force Academy, Republic of Korea Address: 635 Danjaero, Cheongju, Chungbuk, 28187, Republic of Korea, Tel: +82-43-290-6453 Fax: +82-43-298-0922 E-mail: [email protected]

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Funding information

The current study was supported by the grant from the Korean Agency for Defense Development (ADD-13-01-06-18).

Conflict of interest The authors declare no conflict of interest, financial or otherwise.

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Abstract Relationships between behavioral sidedness and immune responses were different

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depending on behavior tests and severity of biological stress in mice. It was necessary to elucidate the psychophysiological mediators that connect behavioral sidedness and

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immune responses. This study investigated interrelationships among anxiety- like

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behavior, the HPA axis responsiveness, and host-resistance to bacterial infection. Mice

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that preferred clockwise circling had lower locomotor activities, higher anxiety- like

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behavior, and faster activation of the HPA axis than mice that preferred counterclockwise circling. A fast activation of the HPA axis was associated with a

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higher host-resistance to low dose bacterial infection.

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Keywords: Behavioral sidedness; stress; host-resistance; anxiety; locomotor activity

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Introduction Novelty-seeking behavior is one of the stable individual traits in human and animals (Pawlak et al., 2008; Rosario and Abercrombie, 1999). Individual differences in locomotor activity in a novel environment were associated with differences in stress

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responses, which were then linked to differences in immune responses (Clinton et al.,

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2008; Duclot et al., 2011; Macri et al., 2007). Rats with higher rates of locomotor

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activity and sustained exploration in a novel environments (HR rats) have higher HPA activities and anti-SRBC (Sheep Red Blood Cell) antibody production compared to rats

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that showed lower rates of locomotor activity (LR rats) (Kabbaj et al., 2000; Sandi et al., 1992). Individual differences in locomotor activities in a novel environments were also

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associated with differences in drug-seeking behaviors and sensitivity to psychoactive drugs. HR rats were more sensitive to morphine when used as a locomotor stimulant

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than LR rats (Bevins and Peterson, 2004; Kabbaj, 2006; White et al., 2004). Healthy men who seek novelty more often were also observed to have higher psychoactive drug-

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seeking behaviors (Bardo et al., 1996; Leyton et al., 2002). Individual differences in adaptation to novel environments can be partially explained by differences in novelty-

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seeking behaviors, which are associated with drug-seeking behavior as well as the induction of stress and immune responses. Handedness is also a common individual traits (Geschwind and Behan, 1982; O’Connor et al., 2005; Perelle and Ehrman, 1994). There are several studies suggesting that hand or paw preference in humans and animals are associated with individual differences in immune function (Geschwind and Behan, 1982; Kim et al., 1999; Neveu, 1992). Right paw-preferred mice (RP mice) had higher immune responses than left paw-preferred mice (LP mice), while the degree of imbalance in paw use, regardless of dominance,

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was negatively correlated with immune function (Betancur, 1991; Fride et al., 1990a). There was also an observed genetic variation in the association between handedness and immune function (Fride et al., 1990b). On the contrary, right-turning preference mice (RT mice), who match to LP mice, presented with higher antigen-specific antibody

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production and host-resistance to bacterial infection than left-turning preference mice

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(LT mice) (Kim et al., 1999). However, in cases with a high degree of biological stress

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from bacterial infection, there was no difference in the immune reactivity between RT and LT mice, and inorganic lead (Pb) intoxication prior to bacterial infection resulted in

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relatively lower host-resistance in RT mice compared with LT mice (Kim et al., 2001; Kim and Lawrence, 2000). LP mice were higher responders in plasma corticosterone

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secretion in response to restraint stress or LPS inoculation than RP mice (Neveu and Moya, 1997). There are some mediators that associate handedness with immune

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responses, one of which may be the hypothalamic-pituitary-adrenal (HPA) axis responsiveness.

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In previous studies, interpersonal differences in novelty-seeking behavior were dependent on the rate of exploration in an open-field, but the relevance of novelty-

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seeking behaviors and sidedness behaviors remains unclear. These two behavioral traits can be associated with one another as both are evident when exposed to stress. LP mice exposed to restraint stress had higher corticosterone levels than RP mice (Neveu and Moya, 1997). LT mice showed no difference in corticosterone levels to RT mice before stress exposure, but corticosterone levels of LT mice were higher than those of RT mice after bacterial infection, which serves as a form of biological stress (Kim et al., 1999). The levels of stress hormones measured at specific times after infection is certainly associated with ongoing infection levels as a result of host resistance, and interpreting it

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as differences in stress responsiveness can lead to systemic errors. LP mice matched to RT mice represented lower immune responses than RP mice, who conversely matched to LT mice; however, RT mice showed higher immune responses than LT mice. LP mice secreted more plasma corticosterone in response to restraint stress or LPS

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inoculation than RP mice (Neveu and Moya, 1997). Inversely, LT mice had higher

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serum corticosterone levels than RT mice at three days post- infection. To date, the

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contradictions of both studies in immune responses have not been clearly elucidated. We hypothesize that serum corticosterone levels measured through an anti-bacterial

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process may reflect the severity of infection, but may not explain neuro- immune interactions in the early stages of infection. In addition, if there are differences in stress

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responsiveness in the early stages of infection between LT and RT mice, the cause of contradictory observations between paw-preference and circling-preference studies can

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be explained.

The specific aims of this study are to investigate whether circling behavior correlates

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with novelty-seeking behavior, as well as examine whether anxiety- like behavior and the HPA axis responsiveness is related to differential host-resistance in mice with

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different circling preference.

Methods Animals

8 week-old BALB/cByJ male mice were obtained from Daehan Biolink (Eumseong, Chungbuk, Republic of Korea). Mice were tail- marked and rehoused in the same cage after each experiment to minimize psychosocial disturbance. All experimental animals were maintained in a 12 h light/dark cycle and were seronegative for known background

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viral agents. They were allowed free access to food and water. The roo m was maintained at 21±2℃ and RH = 40±20%. The experimental study was approved by the Institutional Animal Care and Use Committee of Catholic University of Daegu (IACUC-2015-046); all procedures were performed in accordance with the study

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protocol. Mice were randomly grouped and tail- marked, after which they were

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acclimated for one week prior to the start of the study. The experimental animals were

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placed in a standard cage (262113 cm), housing four animals each, in a specific

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pathogen free environment. The timeline of experiments is displayed in Figure 1.

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Fig. 1. The timeline of experiments

Circling behavior test Circling behavior of mice were measured in the cylindrical Plexiglas chamber. To prevent behavioral disturbances due to exposure to unfamiliar environments, experimental animals were transferred to a behavioral test laboratory 1 h prior to the circling behavior test. Spontaneous circling behavior measured in a cylindrical arena during nocturnal period (16:30 PM~08:30AM), and the behavior test laboratory was

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kept dark (0 lux). Mice allowed free access to water and food during nocturnal circling test. Circling behavior was recorded using the EthoVision XT system (Noldus, Wageningen, Netherlands). In a cylindrical arena, 360 degrees of activity was automatically counted by one circling. Spontaneous circling behavior was measured

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twice with a week interval. The criteria of spontaneous circling preference was same as

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previously described (Kim et al., 1999). Two groups were created by selecting mice that

counterclockwise circling (CCW mice, n=14).

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Open field test

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exhibited over 60% predominance in clockwise circling (CW mice, n=15) or

The locomotor activity of mice were measured in the square open field. To prevent

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behavioral disturbances due to exposure to unfamiliar environments, experimental animals were transferred to a behavioral test laboratory 1 h prior to the open field test,

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and the behavior test laboratory was kept dark (0 lux). The degree of locomotor activity was recorded using the EthoVision XT system (Noldus, Wageningen, Netherlands).

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Mice were placed in a square arena (303030 cm) for 30 min during the diurnal period to measure locomotor activity. Behavioral tests were conducted between 08:00 and

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12:00 daily in the dark laboratory (0 lux). The arena was divided into a center (1515 cm) and four periphery sectors. Mice were placed into the center and allowed to explore the arena for 5 minutes. To assess the process of adaptation in a novel environment, mice were exposed to the open field for 5 minutes on 3 consecutive days (Leussis and Bolivar, 2006). Whenever a mouse was replaced, the arena was wiped with 70% alcohol and dried. Elevated Zero Maze

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The maze is a black circular track divided into four open and closed quadrants. Two open quadrants or two closed quadrants with equal lengths face each other on opposite sides. The circular track has 5 cm wide, 40 cm in diameter (inner diameter 30 cm), and elevated 110 cm off from the floor (Scitech Korea Inc., Seoul, Republic of Korea). The

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closed quadrants are enclosed by black acrylic walls that are 28.5 cm in height. The

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open quadrants have a 1 cm high clear lip to prevent animals from falling down. The

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behavior test laboratory was kept dark (0 lux). The animal was placed in the center of a closed quadrant and its activity was recorded for 5 min using the EthoVision XT system

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(Noldus, Wageningen, Netherlands). Total time spent in open and closed quadrants

Serum corticosterone levels

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were recorded.

Mice in each cage were anesthetized with CO 2 , and cardiac blood samples were

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collected consistently at approximately 12:00 AM, and then centrifuged at 4,000 rpm and 4°C for 30 min. Corticosterone ELISA kits (Abcam, Cambridge, UK) were used;

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and measurements followed the manufacturer’s protocol. Standards and samples were added to a 96 well plate at 25 L each well, after which 25 L of biotinylated

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corticosterone was added. Plates were then incubated for 2 h at room temperature, washed four times with washing buffer, after which 50 L of enzyme (Avidin- BiotinPeroxidase) conjugate was added to each well. Plates were then incubated for 30 min at room temperature, washed four times with washing buffer, and then 50 L chromogen/substrate was added to each well. Plates were then incubated until the optimal blue color developed at room temperature, at which point 50 L of stop solution was added. Serum corticosterone levels were quantified using an Epoch Microplate Spectrophotometer (BioTek Instruments Inc., Winooski, VT).

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In Vivo host-defense against Listeria monocytogenes (LM) infection Viable LM (1104 cfu) was injected intravenously to each mouse. Mice were then sacrificed at 6h, 24h, and 72 h after infection. LM is an intracellular bacterium, whose major target organs are liver and spleen. The LM model is useful to assess a measure of

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innate immunity. The spleen was aseptically removed and homogenized in 1 ml saline

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with a glass homogenizer. The homogenates were sequentially diluted and the diluted

37°C, after which colonies of LM were counted.

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Statistical analysis

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homogenates were plated onto blood agar plates. Plates were incubated overnight at

All data are presented as meanstandard error of the mean (SEM). Inter-group

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comparison was made using one-way ANOVA test. Pearson correlation was used for correlation analysis. Statistical analyses were performed with SYSTAT ver.13.0 (Systat

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Results

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software Inc., St Jose, CA, USA), and p<0.05 was considered statistically significant.

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Differential locomotor activity was associated with behavioral sidedness. The spontaneous locomotor activity of BALB/c mice was analyzed in an open field, which serve as a novel environment. The spontaneous locomotor activity of mice (n=48) showed a significant negative correlation with the percent of CW circling preference (Fig. 2A, p<0.006). CW mice showed significantly lower locomotor activity than CCW mice in an unfamiliar open field (Fig. 2B; F=14.30, p<0.001). However, correlation between locomotor activity and circling preference was diminished according to repeated exposure. The correlation coeffic ient for the second exposure was

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0.166 (p=0.33) and 0.08 (p=0.62) on the third day. Spontaneous nocturnal circling

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preference is associated in part with novelty-seeking behavior

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Fig. 2. Correlation between behavioral sidedness and locomotor activity Total distance moved in an open field (n=48) correlated negatively to the percent of CW circling preference (Fig. 2A). Mice that preferred clockwise circling (CW mice, n=15)

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showed significantly lower locomotor activity than mice preferred counterclockwise

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circling (CCW mice, n=14) in an open field (Fig. 2B). Error bars represent standard errors of the mean (SEM). **p < 0.001.

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Association of spontaneous locomotive activity with explorative behavior Higher locomotive activity in a novel environment was associated with the explorative activity of mice. CCW mice demonstrated significantly longer duration of locomotor activity in the central section of the arena until the second day of open field exposure compared to CW mice (Fig 3A; F=6.53, p=0.02 for day1; F=4.83, p=0.04 for day2). However, differences between the two groups gradually decreased, and eventually disappeared on day 3 (Fig 3A). In the elevated zero- maze test, the time spent by CW mice in the closed quadrants was significantly longer than CCW mice (Fig. 3B; F=8.40,

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p<0.01). CW mice demonstrated lower explorative activity in a novelty and higher

Fig. 3. Anxiety- like behavior

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anxiety- like behavior compared to CCW mice.

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CCW mice (n=14) demonstrated significantly higher explorative activity until their second exposure to the open field over 2 consecutive days, compared to CCW mice

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(n=15) (Fig 3A). CW mice spent a significantly longer time in the closed quadrants of the zero- maze (Fig 3B). Error bars represent standard errors of the mean (SEM).

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*p < 0.05.

Differential hypothalamic-pituitary-adrenal axis responsiveness and host-defense In order to investigate whether spontaneous behavioral traits are related to stress resistance, biological stress from relatively low doses of Listeria monocytogenes (LM) infection was loaded, after which host resistance was measured. HPA axis responses to bacterial infection was measured through serum corticosterone levels at 6, 24, and 72 h after bacterial infection. The HPA axis responses of CW mice were rapidly induced at

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the early stage of infection, while that of CCW mice were delayed (Fig. 4). Serum corticosterone levels of CW mice at 24 h after infection were significantly higher than those of CCW mice (F=9.99, p<0.02). Host-defense levels against bacterial infection was measured through viable LM counts at 6, 24, and 72 h after bacterial infection in

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the spleen, which is the target organ of LM. LM was not detected at 6 h after LM

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infection, but was later observed at 24 h post- infection; there was no observed

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difference between CW and CCW mice. However, the bacterial burden of CW mice was significantly lower than that of CCW mice at 72 h after infection (F=11.23, p <0.01)

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(Fig. 5). Spontaneous anxiety- like behaviors of CW mice were associated with faster activation of the HPA axis, and was in turn related to higher host-resistance to LM

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infection.

Fig. 4. Induction of serum corticosterone after infection Serum corticosterone levels were measured at 6 (CW mice, n=5; CCW mice, n=4), 24 (n=5, each), and 72 hours (n=5, each) after bacterial infection. The HPA response of CW mice was rapidly induced at the early stages of infection, while serum corticosterone levels of CW mice at 24 h after infection were significantly higher than those of CCW

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mice. Error bars represent standard errors of the mean (SEM). *p < 0.05.

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Fig. 5. Bacterial burden in the spleen after infection

Viable LM in the spleen were measured at 6 (CW mice, n=5; CCW mice, n=4), 24 (n=5,

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each), and 72 hours (n=5, each) after bacterial infection. The bacterial burden of CW mice was significantly lower than that of CCW mice at 72 h after infection. The

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bacterial burden was not detectable at 6 h after infection. Error bars represent standard errors of the mean (SEM). *p < 0.05.

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Correlation between behaviors and corticosterone levels Correlation coefficients between behaviors and basal serum corticosterone levels are presented in Table 1. The percent CW circling correlated negatively with total distance traveled in the open field. The percent of CW circling correlated negatively with duration in the center of the open field (r=-0.42, p<0.004), and positively with duration in the closed quadrants of the zero- maze (r=0.49, p<0.002). Total distance traveled correlated positively with time spent in the center of the open field (r=0.59, p<0.001). Duration spent in the center of the open field correlated negatively with duration in the

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closed quadrants of the zero- maze (r=-0.34, p<0.03). High percentage of CW circling was associated with low locomotor activity in a novel environment, and high anxietylike behavior. Basal serum corticosterone levels did not correlate significantly with any behaviors tested. However, CW mice exhibited higher anxiety-like behavior than CCW

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mice, showing fast activation of the HPA axis. High anxiety- like behavior may be

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associated with fast induction of the HPA axis to biological stress exposure.

4. 5.

Total Dis (n=48) CTR Time (n=48) Time-closed (n=48) Basal CORT (n=29)

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-0.39* -0.42*

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3.

-

(n=48)

0.59**

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%CW

0.49*

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2*

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1**

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Table 1. Correlation between behaviors and corticosterone levels

-0.30*

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-0.19**

-0.34*

0.12**

-0.21*

-0.26*

Note. Peason’s correlation. *p<0.05, **p<0.001.

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CTR stands for center. CORT stands for corticosterone.

Discussion The locomotor activity of mice in a novel environment varied according to their nocturnal circling preferences. The locomotor activity in a novel environment of mice showed a significant negative correlation with CW circling preference. CW mice showed lower locomotor activity than CCW mice. The CW circling preference can be

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interpreted as a left paw preference, while the CCW circling preference can be interpreted as a right paw preference (Mohr et al., 2003; Nielsen et al., 1997). Finally, novelty-seeking behavior is related to paw preference. This study suggests that RP mice may exhibit higher novelty-seeking behavior compared to LP mice.

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The spontaneous nocturnal circling preference of mice was related to anxiety- like

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behavior. CW mice spent a significantly shorter time in the open quadrants of zero- maze

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compared to CCW mice, and exhibited significantly lower locomotor activity in the center zone of the open field after two exposure over consecutive days. Total distance

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traveled in the open field correlated positively with explorative activity in the center zone of the open field, and explorative activity in the center zone correlated negatively

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with time spent in the closed quadrants of zero-maze. In the open field, the difference in anxiety- like behavior between CW and CCW mice disappeared at the third consecutive

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exposure. This is a normal adaptation to unfamiliar environment after repeated exposure. Meanwhile, Anxiety- like behaviors were not associated with basal corticosterone levels.

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However, high anxiety- like behavior associated with rapid induction of the HPA axis response. In conclusion, spontaneous lower locomotor activity in a novel environment,

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which are different among individuals, may be interpreted as a behavioral trait that represents tension and concentration in the early response to unfamiliar environment, although it is within the criteria of anxiety- like behavior caused by exposure to stress. This behavioral trait was a dominant trait of CW mice compared to CCW mice. Locomotor activity of BALB/cByJ mice in the open field decreases with intensity of light (McReynolds et al., 1967) Behavioral tests except circling preference test was conducted without light to keep spontaneous locomotion and to reduce confounding influence from the test room and researcher during diurnal period. However,

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disturbance in light-dark cycle of mice could induce non-specific physiological responses. To minimize influence of light-dark cycle disturbance on behaviors and many physiological variables, the test room’s lighting, temperature and noise levels were kept consistently for all subjects, and blood was collected a week after the end of

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behavior tests.

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Behavioral sidedness was associated with differences in the HPA axis responsiveness.

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There was no significant difference in basal corticosterone levels between CW and CCW mice before exposure to stress. However, there was a significant difference in

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response to biological stress caused by relatively low dose of LM infection.

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Corticosterone levels of CW mice were significantly higher than that of CCW mice at 24 h after infection. CW mice showed a rapid HPA response whereas the HPA axis

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responses of CCW mice were delayed. As a result, spontaneous anxiety- like behaviors may be associated with rapid activation of the HPA axis. Spontaneous anxiety- like

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behavior, which can be initiated by stress responses, indicate the maintenance of attention and alertness for a certain period of time (Derakshan et al., 2007; Ducottet et

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al., 2004).

On the other hand, the rapid activation of the HPA axis was positively associated with the clearance of LM. Glucocorticoids increased the expression of interferon receptors early in the immune response and promoted the migration of immune cells into the peripheral organs (Dhabhar, 2009; Dhabhar et al., 1995; Ruzek et al., 1999). In the adaptation process against biological stress, it is clear that activation of the HPA axis has been considered an urgent signal in the early stages of the immune response and has a positive effect on host-resistance. CW mice infected with relatively low doses of LM exhibited faster HPA axis responses

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and LM clearance at 72 h after infection than CCW mice. However, it is necessary to distinguish between sensitivity to stress and resistance to severe and extended stress. While handedness represents a behavioral trait among individuals and can induce a difference in immune response, relationships between handedness and life span remain

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unclear (Halpern and Coren, 1991). LT mice showed higher resistance to low dose

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infection (Kim et al., 2001; Kim and Lawrence, 2000).

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infection than RT mice, but in contrast had relatively lower resistance to high dose

This study suggests that spontaneous novelty-seeking behaviors may either be an

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inherent anxiety- like response to unfamiliar environment exposure, and these can be distinguished by cognitive behavioral tests such as habituation patterns and measuring

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basal stress hormone levels. In addition, this study also suggests that individuals exhibiting spontaneous anxiety to unfamiliar environments, without activation of the

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HPA axis, are more sensitive to stress exposure, which may be beneficial in coping to

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Neurosci. Biobehav. Rev. doi:10.1016/j.neubiorev.2008.06.007 Perelle, I.B., Ehrman, L., 1994. An international study of human handedness: The data. Behav. Genet. 24, 217–227. doi:10.1007/BF01067189 Rosario, L.A., Abercrombie, E.D., 1999. Individual differences in behavioral reactivity:

9230(99)00040-4 Ruzek, M.C., Pearce, B.D., Miller,

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Correlation with stress-induced norepinephrine efflux in the hippocampus of Sprague-Dawley rats. Brain Res. Bull. 48, 595–602. doi:10.1016/S0361a H., Biron, C. a, 1999. Endogenous

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glucocorticoids protect against cytokine-mediated lethality during viral infection. J.

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Immunol. 162, 3527–3533. Sandi, C., Borrell, J., Guaza, C., 1992. Behavioral factors in stress-induced immunomodulation. Behav. Brain Res. 48, 95–98. doi:10.1016/S0166-

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4328(05)80144-5 White, D.A., Kalinichev, M., Holtzman, S.G., 2004. Individual differences in locomotor reactivity to a novel environment and sensitivity to opioid drugs in the rat. II.

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Agonist-induced antinociception and antagonist- induced suppression of fluid consumption. Psychopharmacology (Berl). 177, 68–78. doi:10.1007/s00213-004-

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Graphical abstract

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Highlights

 Correlation between behavioral sidedness and novelty-seeking behavior is

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proposed.

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 The HPA axis responsiveness is different depending on mice with different

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circling preference.

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 Spontaneous anxiety-like behavior in a novel environment can be a form of

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vigilance.

 A fast activation of the HPA axis was associated with a higher host-resistance to

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low dose bacterial infection.