Research reportNeonatal tactile stimulation reverses the effect of neonatal isolation on open-field and anxiety-like behavior, and pain sensitivity in male and female adult Sprague–Dawley rats
Introduction
It is well known that early experiences induce long-lasting psychophysiological and psychobiological changes in later life. Numerous studies have demonstrated that early adverse experiences such as maternal separation (MS) or neonatal isolation (NI), which interrupt dam–pup interactions, affect the development of the central nervous system and subsequently lead to enhanced susceptibility to stress in adulthood, both behaviorally and endocrinologically [8], [10], [12], [14], [17], [37]. NI and MS differ with respect to isolation of individual offspring. With most MS procedures, only the dams are removed to separate cages, while the pups remain in their home cage. With NI procedures, pups are isolated and placed individually into containers separately from their dams and littermates. In contrast, the protective or therapeutic effects of early intervention on the development of stress vulnerability during the interruption of the dam–pup relationship has not been as thoroughly examined. For example, brief handling of neonatal rats during maternal separation was reported to induce resistance of the hypothalamo-pituitary-adrenal (HPA) axis to stress in adult rats [17]. Several studies have demonstrated that adult rats subjected to neonatal handling exhibited less anxiety-like behaviors in the elevated plus maze as compared with nonhandled rats [19], [27].
Another type of neonatal handling, neonatal tactile stimulation (NTS), also has a distinct effect on the development of stress reactivity. Rats subjected to NTS show increased curiosity and problem-solving ability, and exhibit less emotionality in stressful situations [16]. NTS prevents the rise of serum corticosterone levels typically associated with maternal deprivation stress and causes elevated corticosterone levels to return to normal [25]. NTS also protects against maternal deprivation-induced shortening of hot-plate latencies [35]. Furthermore, it has been reported that NTS alleviates the reduction of hippocampal volume in rats subjected to neonatal hypoxia–ischemia [29]. These findings indicate that subjecting animals to NTS can facilitate their ability to cope with stressful environmental conditions, decrease the enhanced HPA axis in response to stress in adulthood, and protect against brain damage induced by neonatal manipulation.
Postnatal handling, which involves only a brief period (15 min) of mother–pup separation, dampens HPA responses to stress [15], [20], [21]. In contrast, postnatal MS (3 h/day; PN days 2–14) or (6 h/day; PN days 2–10) enhances HPA responses to stressors [18], [28]. In addition, 1 h-neonatal isolation on postnatal days 2–9 also enhances HPA responses to stressors [3]. It has also been shown that early adverse experiences have sex-specific effects on the development of HPA-axis reactivity [4], [36]. Similarly, gender differences exist with respect to the effects of neonatal isolation and neonatal handling on the development of anxiety-like behavior in the elevated plus maze [8], [19] and the conditioned fear test [1], [11]. Although there was no significant sex differences in anxiety-like behavior between rats subjected to neonatal handling and neonatal handling with tactile stimulation [32], it is unclear whether sex differences exist with respect to the ability of NTS to prevent or reverse the enhancement of susceptibility to environmental stimuli in response to early adversities.
In this context, the present study was undertaken to assess whether NTS can prevent or reverse the enhanced susceptibility to environmental stimuli due to NI in adult rats. We compared the effect of NI with the effect of NTS during NI on body weights, locomotor activities in the open-field test, anxiety-like behavior in the elevated plus maze test, pain sensitivity in the hot-plate test, and the fear responses in a contextual fear test on postnatal day 60. We also examined sex-specific effects of NI and NTS on these behavioral tests.
Section snippets
Animals
Pregnant female Sprague–Dawley rats were purchased from Charles River (Yokohama, Japan). The rats were housed individually in the breeding colony at constant room temperature (23 ± 2 °C) and humidity (60%) with a 12/12 h light–dark cycle (lights on at 08:00). Food (Rodent Lab Diet EQ 5L37, Japan SLC Inc.) and water, conforming to the Water Quality Standard required by the Japanese Waterworks Law, were provided ad libitum. Male (n = 153) and female (n = 151) SD rats were used, and no more than two pups
Body weight
Mean body weights of the groups on PN day 22 (weaning day), PN day 40, and PN day 60 are presented in Table 1. While two-way ANOVA revealed a significant effect of gender [F(1, 144) = 8.799, p < 0.05], [F(1, 144) = 1300.440, p < 0.0001], [F(1, 144) = 2150.624, p < 0.001], on PN days 22, 40, and 60, respectively, there was no significant effect of neonatal treatment nor an interaction between neonatal treatment and gender. On weaning day, the mean body weight of females was significantly greater than that
Discussion
In the present study, we examined how two different types of neonatal manipulations (NI as an adverse experience versus NTS as an intervention for adverse experience) in rats affect development, locomotor and exploratory behavior, anxiety-like behavior, pain sensitivity, and contextual fear in adulthood. Furthermore, we examined the sex-specific effect of neonatal manipulations on the susceptibility to environmental stimuli in adulthood. This study had three major findings: (1) Neither NI nor
Acknowledgments
This study was supported by a grant-in-aid for general scientific research from the Ministry of Education, Science, and Culture of Japan, a Health Science Research Grant for Research on Brain Science from the Ministry of Health and Welfare of Japan. The authors thank Drs. T. Takahashi, Y. Iwamoto, T. Watanabe, for helpful advice.
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