Maternal deprivation in neonatal rats of different conditions affects growth rate, circadian clock, and stress responsiveness differentially
Introduction
Maternal deprivation (MD) in the early postnatal period is known to induce a variety of endocrinological and behavioural changes in the grown-up rats [10], [28], [36]. Among them, the responsiveness of the hypothalamus–pituitary–adrenocortical (HPA) axis to noxious stimuli was reported to alter in rats subjected to MD, and the mechanism of these long-term effects of MD has been extensively studied [3], [4], [5], [8], [10], [11], [12], [45]. However, the effects of MD on the HPA axis are not consistent among studies and even controversial [3]. For example, rats exposed to MD for 5 h daily from the postnatal day 2 (P2) to day 6 (P6) increased the stress-induced as well as the basal levels of plasma corticosterone in adult rats [12]. In contrast, rats subjected to MD for 4.5 h daily during the first 3 weeks of life showed a reduced corticosterone response to restraint stress [33]. As for plasma ACTH levels, MD decreased [11], did not affect [10], [22], or increased hormone levels [37], [38]. In some studies, the effects of MD on growth were reported to be transient [10], [12], [23], [38], but in others, the effects persisted until adulthood [4]. A similar discrepancy is detected in the MD effects on behaviors [21]. These findings suggest that subtle differences in the conditions of MD influence the long-term effects of MD.
On the other hand, MD is known to reset the circadian clock of neonatal rats in the absence of light information [7], [13], [44], [48]. The circadian clock in mammals is located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus, and controls the circadian rhythms in physiology and behaviors [16], [43]. The circadian clock in the SCN entrains to the light–dark cycle through the retinohypothalamic tract, which begins to function as early as the postnatal day 6 [24]. Until this developmental stage, the circadian clock entrains to the periodicity of their pregnant and nursing mothers, which is termed as maternal entrainment [17], [24]. Daily MD for 12 h during the light period from P1 to P6 phase-reversed the circadian rhythms in serotonin N-acetyltransferase of the pineal grand [6], [13], in plasma corticosterone [1], in spontaneous locomotor activity [7], [44], and in clock gene expressions in the SCN [7] in rats deprived of light information.
In humans, similar persisting effects of early experiences into adolescence are known as deprivation syndrome [25], [26], [29] or institutional syndrome [9]. Disruption in the relationship between an infant and a primary caregiver would result in impaired growth, cognitive development failure, and characterized behavioral and emotional consequences [9]. However, the biological backgrounds of these symptoms are just beginning to be understood, and for example, impaired growth does not seem to be necessarily due to insufficient quantity and quality of available food [9].
The mechanism of long-term effects of MD on rat pups is not known. Expressed symptoms are likely triggered by a lack of specific conditions associated with maternal nursing which include tactile, olfactory, thermal, nutritional and auditory stimuli [25]. As for the MD effects on the HPA axis, compensatory rich nursing was suggested to enhance a negative feedback regulation through glucocorticoid receptors in the hippocampus [39]. In the present study, in order to have better insights into the mechanism of MD, several aspects of MD were examined for their contributions to long-term effects of MD. We focused on the length of MD, the times of day when MD was imposed and the ambient temperature during MD. We assessed effects of changes in these conditions on body weight gain, stress-induced as well as basal levels of plasma corticosterone in adulthood, and several parameters of spontaneous locomotor rhythm at weaning. We exposed grown-up pups to novel environments (novelty exposure) as a stressor, by transferring them to a new cage with fresh wood chips. Here we demonstrated the differential effects of MD on different functions and critical factors associated with MD.
Section snippets
Animals
Rats of Wistar strain were born and reared in our animal quarters where environmental conditions were controlled: temperature (22 ± 1 °C), humidity (60 ± 5%) and a 12-h light/12-h dark cycle (LD; lights on from 06:00 to 18:00 h). Light intensity at the surface of the cages was about 100 lx. They were fed commercial chow (MF, Oriental Yeast Co., Tokyo, Japan) and water available all the time. The sexual cycles of female rats were examined with vaginal smear, and the rats were mated overnight on
Experiment 1-1
Forty-eight neonatal rats (24 males and 24 females) were blinded by bilateral eye enucleation under cold anesthesia. The operation was performed within 12 h after birth. They were divided into 8 groups (3 males, 3 females per group), which were designated as follows: MD12 in which MD was done between 6 h and 18 h (06:00–18:00 h), MD6am (MD for 6 h in the morning; 06:00–12:00 h), MD6pm (MD in the afternoon; 12:00–18:00 h), MD3Eam (3 h MD in the first quarter of the light phase; early am;
Effects of MD on body weights
There was no significant difference in body weight between males and females until weaning (data not shown), therefore the results from both sexes were mixed. Table 1 represents the body weights of pups subjected to different MD conditions (Experiment 1-1). At the end of MD period (P7), the body weights of the MD12, MD6am and MD6pm were significantly reduced (p < 0.01, p < 0.01, p < 0.05, respectively), while those in the four groups of MD3 were not different from the control. At weaning the body
Discussion
In the present study, maternal deprivation (MD) in neonatal rats is clearly demonstrated to differentially affect the physiological variables in adulthood. MD for 12 h (MD12) decreased the body weight of pups at P7. The body weight in these pups did not catch up with the control until at least 10 weeks old. These rats showed increased basal and stress-induced corticosterone levels in plasma, and their circadian rhythms were phase-reversed in the absence of light. However, the persistent changes
Acknowledgment
The present study was financially supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (13073-2125-14).
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2012, Neuroscience and Biobehavioral ReviewsCitation Excerpt :After MD for 12 h (MD12) from postnatal day 1 to day 7, pups showed increased basal and stress-induced corticosterone levels in plasma. At weaning, their circadian rhythms were phase-reversed in the absence of light (Yamazaki et al., 2005). These authors showed that the effects of MD on the circadian clock depended on the length of MD.
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2012, Brain and DevelopmentMaternal deprivation has sexually dimorphic long-term effects on hypothalamic cell-turnover, body weight and circulating hormone levels
2010, Hormones and BehaviorCitation Excerpt :Moreover, hypothalamic levels of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF)-1, are modified during MD and this is associated with changes in markers of cell proliferation and maturation, with males and females being differently affected (Viveros et al., 2010). Although, it is clear that MD during the critical period of hypothalamic development has long-term effects on systemic growth (Yamazaki et al., 2005; Matsumoto et al., 2006; Ellenbroek et al., 2005; Llorente et al., 2007) and reduces leptin levels at least during early postnatal life (Salzmann et al., 2004; Viveros et al., 2009), how long these modifications persist, as well as how hypothalamic development and endocrine physiology in the adult animal are affected remains largely unknown. Leptin, as well as adiponectin, is an important adipose tissue hormone involved in energy homeostasis (Coll et al., 2007), promoting lipid storage in adipose tissue and fatty acid oxidation in other peripheral tissues.