Effects of maternal separation on baseline sleep and cold stress-induced sleep rebound in adult Wistar rats

STUDY OBJECTIVES: To evaluate the influence of early life environments on basal and cold stress-induced sleep patterns in rats. DESIGN: The design was a 3 (Groups [control, early handling, maternal separation]) x 2 (Situations [basal, poststress]) x 11 (Time-blocks) factorial design. From postnatal days 2 to 14, whole litters were either submitted to early handling (15 minutes per day away from the mother) or maternal separation (180 minutes per day away from the mother). At 75 to 90 days of age, sleep was recorded for 22 hours (beginning at 9:00 AM) before and after 1 hour of cold stress (4 degrees C). SUBJECTS: Wistar male rats (n = 7-10 animals per group). MEASUREMENTS AND RESULTS: Sleep was analyzed in blocks of 2 hours, in 30-second epochs, separately in the daytime and nighttime sleep recordings. Maternally separated rats exhibited more paradoxical sleep at baseline, compared to both control and early-handled rats. In the first 2 hours following the end of cold stress, all groups showed a decrease in paradoxical sleep, whereas slow-wave sleep was reduced only in the control group. The highest corticosterone plasma concentration was observed immediately after stress. Sleep rebound after stress was equally manifested in all groups in the dark part of the light-dark cycle. CONCLUSIONS: Maternal separation during early infancy resulted in permanent changes of the sleep architecture reflected by augmented time spent in paradoxical sleep. Although these findings were not expected in light of the literature, they emphasize the importance of the early familiar environment on future behavior of rats.     

Long-term effects of maternal separation on ethanol intake and brain opioid and dopamine receptors in male Wistar rats

Accumulating evidence indicates that an animal's response to a drug can be profoundly affected by early environmental influences. The brain opioid and dopamine systems may play a critical role in these effects, since various types of stress and drugs of abuse promote alterations in these brain systems. To study this further, we investigated long-term behavioural and neurochemical effects of repeated maternal separation in male Wistar rats. The pups were separated in litters daily from their dams for either 15 min (MS15) or 360 min (MS360) from postnatal days 1-21. Analysis of the kappa- and delta-opioid, dopamine D(1)- and D(2)-like receptors with receptor autoradiography revealed long-term neurochemical changes in several brain areas. D(1)-like receptor binding was affected in the hippocampus and D(2)-like receptor binding in the ventral tegmental area and the periaqueductal gray, whereas minor changes were seen in opioid receptor density after maternal separation. At 10-13 weeks of age, MS15 rats had a lower ethanol intake whereas, the MS360 rats consumed more 8% ethanol solution compared with MS15 and animal facility-reared rats. Ethanol consumption altered kappa-receptor density in several brain areas, for example the amygdala, substantia nigra and the periaqueductal gray. D(1)-like receptor binding was affected in distinct brain areas, including the nucleus accumbens, where also delta-opioid receptor density was changed in addition to the frontal cortex. Ethanol-induced changes were observed in D(2)-like receptor density in the ventral tegmental area in MS360, and in the ventral tegmental area and frontal-parietal cortex in animal facility-reared rats. These findings show that early experiences can induce long-lasting changes in especially brain dopamine receptor density and that ethanol consumption induces alterations in opioid and dopamine receptor density in distinct brain areas. It is also suggested that changes induced by repeated MS15 may provide protection against high voluntary ethanol intake.     

Age-dependent effects of maternal deprivation on oxidative stress in infant rat brain

Developing brain is much more sensitive to all kind of stressors than the developed brain. Early maternal deprivation causes some behavioural and physiological effects on rats. After the birth, there is no endocrinological response to stressors between post-natal 4 and 14th days, which is called stress-hyporesponsive period (SHRP) in rats. This hypo-responsiveness is time- and stressor-specific, as some more severe stressors have been shown to induce a stress response. The present study examined the effects of maternal deprivation on oxidative stress in the hippocampus, prefrontal cortex (PFC) and striatum regions of the brain both during and after SHRP of the infant rats. The results showed that maternal deprivation in SHRP increased antioxidant enzyme activities and reduced lipid peroxidation in infant rat brain. However, by the termination of SHRP, maternal deprivation reduced enzyme activities and increased lipid peroxidation. The results indicated that infant brain might be protected in SHRP from maternal deprivation-induced oxidative stress.     

睡眠剥夺对大鼠学习记忆及脑细胞超微结构的影响及红景天提取物干预研究

目的探讨红景天提取物对睡眠剥夺大鼠学习记忆及脑细胞超微结构的影响。方法采用改良多平台水环境法制作大鼠睡眠剥夺模型,采用迷宫法检测大鼠学习记忆能力,采用透射电子显微镜对脑细胞超微结构进行观察。结果睡眠剥夺前各组学习记忆基本一致,睡眠剥夺组(SD组)随睡眠剥夺时间的增加,出现学习障碍,反应时间较空白对照组(CC组)和环境对照组(TC组)明显增加(p<0.05,相似文献   

Fos expression in arousal and reward areas of the brain in grass rats following induced wakefulness

In the diurnal grass rat nocturnal voluntary wakefulness induces Fos expression in specific cellular populations of arousal and reward areas of the brain. Here, we evaluated whether involuntary wakefulness would result in similar patterns of Fos expression. We assessed this question using male grass rats that were sleep deprived for 6h by gentle stimulation (SD group), starting 2h before lights off (12:12 LD cycle). Then, we examined expression of Fos in cholinergic cells of the basal forebrain (BF), as well as in dopaminergic cells of the reward system, and compared these results to those obtained from an undisturbed control group. Different from previous results with grass rats that were voluntary awake, the BF of SD animals only showed a significant increase in Fos expression in non-cholinergic neurons of the medial septum (MS). These observations differ from reports for nocturnal rodents that are sleep deprived. Thus, our results show that voluntary and induced wakefulness have different effects on neural systems involved in wakefulness and reward, and that the effects of sleep deprivation are different across species. We also investigated whether other arousal promoting regions and circadian and stress related areas responded to sleep deprivation by changing the level of Fos expression. Among these areas, only the lateral hypothalamus (LH) and the ventro lateral preoptic area showed significant effects of sleep deprivation that dissipated after a 2h period of sleep recovery, as it was also the case for the non-cholinergic MS. In addition, we found that Fos expression in the LH was robustly associated with Fos expression in other arousal and reward areas of the brain. This is consistent with the view that the arousal system of the LH modulates neural activity of other arousal regions of the brain, as described for nocturnal rodents.     

Both long and brief maternal separation produces persistent changes in tissue levels of brain monoamines in middle-aged female rats

Adverse experiences early in life are associated with an increased incidence of later psychopathology including depression. Based on evidence that dysfunction of central monoaminergic systems is involved in the pathophysiology of depression, we hypothesize that early adversity could negatively affect these systems. To test this we have investigated the effects of maternal separation, which has been suggested to model early-life stress and the development of a depression-like syndrome in the rat, on brain monoaminergic systems. Since depression is more common in women and the risk of developing this disorder appears to increase with age, we have studied such effects in middle-aged female rats. Rat pups were separated for 180 min (long maternal separation; LMS) or 15 min (brief maternal separation; BMS, often referred to as neonatal handling) twice daily for 2 weeks postpartum. An animal facility-reared (AFR) group was also included. At 15 months of age tissue levels of monoamines and their metabolites in several different brain regions were analyzed. In the LMS females tissue levels of both 5-HT and 5-hydroxyindole acetic acid (5-HIAA) were significantly increased in the dorsal raphe nucleus, and 5-HIAA and homovanillic acid levels were also elevated in the nucleus accumbens as compared with AFR and BMS rats. In the cingulate cortex both LMS and BMS decreased noradrenaline (NA) levels, although this effect was more pronounced in the LMS rats. On the other hand, BMS decreased 5-HT, 5-HIAA, dopamine (DA) as well as NA levels in the amygdala and produced an increase in DA levels in response to acute stress in the hypothalamus, an effect not seen in AFR rats. Our results demonstrate that LMS produced persistent alterations in both serotonergic, noradrenergic and dopaminergic systems in brain regions that have been suggested to be implicated in the pathophysiology of depression. In addition, BMS affected brain monoaminergic levels mainly in the amygdala.     

Parvalbumin immunoreactivity: a reliable marker for the effects of monocular deprivation in the rat visual cortex.

In mammals, monocular deprivation performed during the early stages of postnatal development (critical period) dramatically affects the functional organization of the visual cortex. Since the early work of Hubel and Wiesel, the effects of monocular deprivation are accounted for by the fibers driven by the two eyes competing for the control of cortical territories. In cat and monkey striking structural changes accompany the functional effects of monocular deprivation. Also, in the rat, monocular deprivation causes functional alteration at the level of visual cortex; no structural correlates of these effects, however, have so far been described. Parvalbumin is a calcium binding protein that in the neocortex colocalizes with a subpopulation of GABAergic neurons. Here we report that in the rat monocular deprivation results in a dramatic reduction of parvalbumin-like immunoreactivity in the visual cortex contralateral to the deprived eye. This effect is due to competitive phenomena and not to visual deprivation itself, it is restricted to the binocular portion of the visual cortex and neither binocular deprivation, nor dark rearing can induce it. We conclude that parvalbumin-like immunoreactivity is a useful immunohistochemical marker for the effects of monocular deprivation in the rat visual cortex.     

Effects of neonatal maternal deprivation and postweaning environmental complexity on dendritic morphology of prefrontal pyramidal neurons in the rat

It has been reported that periodic maternal separation in rats leads to a variety of endure behavioral, neurochemical and microstructural sequelae associated with the pathophysiology of anxiety disorders. Since it has been proposed that these changes might be permanent, we examined whether environmental complexity aid to recover the structural dendritic impairment induced by neonatal maternal deprivation in the medial prefrontal cortex of the rat. In addition, the anxiety-like behavior was assessed in the elevated plus-maze. Repeated maternal separation between postnatal days 6-21 (3 hours daily) significantly reduced the dendritic material in layer II/III pyramidal neurons and induced anxiety-like behaviors in the elevated plus maze. Furthermore, environmental stimulation (twice a day, 1 h each) during 12 consecutive days (postnatal days 23-35) failed to recover the neuronal and behavioral disorders induced by neonatal maternal separation. The results demonstrated that (i) neonatal maternal separation severely altered pyramidal dendritic outgrowth in close association with anxiety-like behavior assessed in the elevated plus maze, and (ii) postweaning environmental complexity was unable to recover neither the prefrontocortical neuronal impairment nor the novelty-induced anxiety-like behavior triggered by early maternal deprivation.     

Decreased NaCl sensitivity in zinc-deprived rats.

NaCl thresholds and ability to discriminate between NaCl and sucrose were assessed in rats using an operant discrimination conditioning procedure before and during moderate and severe zinc deprivation and during zinc supplementation. NaCl thresholds were approximately 1 mM before dietary zinc manipulation. They increased in all zinc-deprived rats tested 10 and 17 days after initiation of deprivation but did not change in pair-fed controls maintained on supplemental zinc. Threshold changes were greater for those rats severely zinc deprived than for those only moderately deprived and were greater as the period of deprivation lengthened. Plasma zinc concentrations decreased significantly in deprived rats from values obtained at baseline, values in severely deprived rats being significantly lower than in those only moderately deprived. Although zinc-deprived rats discriminated NaCl from sucrose, they made more discrimination errors than controls. Following 24 days of zinc supplementation, previously deprived rats exhibited no significant improvement in gustatory performance, although their body weight increased and plasma zinc concentrations increased; but these later changes were not significant. These results demonstrate that zinc deprivation induces decreased gustatory sensitivity and confirm a role for zinc in taste.     

Adrenocortical response to stress in fasted and unfasted artificially reared 12-day-old rat pups

Recent studies have compared artificially reared (AR) rats with dam-reared rats on behavioral outcomes but, despite the fact that they are deprived of their mothers during the stress hyporesponsive period (SHRP), little is known about the effects of AR on the development of the stress response. In this study, the corticosterone (CORT) response to a stressor (saline injection ip) on postnatal Day 12 was assessed in rat pups that had been either dam-reared (DR) or artificially reared since Day 5. In the preceding 24 hr, half the pups in the DR group were maternally deprived (DEP). To control for the food deprivation consequent to maternal deprivation in these groups, half the pups in the AR groups also underwent 24-hr food deprivation (DEP). In the nondeprived condition AR pups did not differ from DR pups on untreated CORT levels or on levels at 1-hr poststress (i.e., all rats demonstrated low levels of CORT characteristic of the SHRP). In contrast, both maternally deprived DR pups and food-deprived AR pups exhibited increased untreated CORT levels as well as a significant increase at 30-min poststress, but CORT elevations were lower in the AR groups than in the DR groups. Thus, long-term maternal deprivation through artificial rearing in rats does not affect the reduced CORT levels and reduced CORT responsiveness associated with the SHRP; however, if animals are food deprived, then all show increased basal CORT levels and a greater CORT response to stress, although this response is lower in AR groups than in DR groups. These results suggest that rat pups artificially reared with adequate nutrition will still exhibit the SHRP.     

Protective effect of melatonin against maternal deprivation-induced acute hippocampal damage in infant rats

It is known that maternal deprivation induces hippocampal damage in the developing brains. In the present study, we examined the effects of melatonin on maternal deprivation-induced hippocampal damage both during and after stress-hyporesponsive period (SHRP). Hippocampal damage was examined by cresyl violet staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. The results showed that a single episode of maternal deprivation for 24 h at post-SHRP induced neuronal loss in hippocampus regions of the brain in the infant rats, while it did not influence hippocampal neurons in SHRP. Melatonin prevented maternal deprivation-induced hippocampal damage in the infant rats at post-SHRP. These results suggest that melatonin is a potentially beneficial agent to improve the neurobehavioral outcomes of maternal deprivation in later developmental period.     

Play is indispensable for an adequate development of coping with social challenges in the rat

In this study, young rats were deprived of early social interactions during weeks 4 and 5 of life. Different behavioral tests were conducted in adulthood to study the behavioral responses of rats lacking early social experiences. Juvenile deprivation resulted in decreased social activity and an altered sexual pattern, but did not affect locomotor activity or the performance in the elevated plus maze. Furthermore, behavioral and neuroendocrine responses of juvenile isolated rats were dramatically altered when they were confronted with territorial aggression. Juvenile deprived rats did not readily display a submissive posture in response to the resident and showed no immobility behavior after being returned to the resident's territory, while their plasma corticosterone and adrenaline concentrations were significantly increased compared to nonisolated controls. In contrast, behavioral responses in the shock prod test were not affected by previous isolation. The results suggest that early social experiences are vital for interactions with conspecifics later in life, i.e., aggression, sexual, and social interactions.     

Effects of pre- and postnatal stimulation on developmental,emotional, and cognitive aspects in rodents: a review

Interactions between the organism and its environment, during pregnancy as well as during the postnatal period, can lead to important neurobehavioral changes. We briefly review the literature, and successively present the main results from our laboratory concerning the behavioral effects of prenatal stress, differential rearing conditions, and postnatal handling. We show that submitting primiparous DA/HAN rats to an acute emotional stress (exposure to a cat) at gestational day10, 14, or 19 leads to greatly increased mortality of pups and to decreased body weight of surviving animals. The effects of such a stressor on emotional reactivity are less obvious. Cognitive processes are impaired depending on the learning task. Enriched environments restore abnormal behaviors (emotional reactivity, motor skills, motor and spatial learning) due to brain trauma or genetic deficiencies. In any case, environmental enrichment does prevent or slow down aging effects. The effects of postnatal handling noted when using classical tests of emotional reactivity also are clear when defensive reaction paradigms are used. Furthermore, pregnant females that are early handled are less anxious than nonhandled females. We hypothesize that, when subjected to a stressor, the offspring of early-handled females would be protected from the deleterious effects of this stress compared to pups of nonhandled females.     

Long-term effects on brain opioid and opioid receptor like-1 receptors after short periods of maternal separation in rats

Short periods of maternal separation of neonatal rats are known to induce attenuated behavioural and neuroendocrine responses to stress in adult life. The present study was carried out to evaluate whether 15 min separation from the dam during postnatal days 1-21 (MS15) can induce long-term changes in brain opioid (kappa- and delta-receptors) and opioid receptor-like 1 (ORL1) densities in male Sprague-Dawley rats. Receptor autoradiography indicated that MS15 rats had increased delta-receptor density in the basomedial amygdala compared to animal facility reared rats 2 months after MS15. No differences in brain kappa- or ORL1-receptor density were found. The results indicate that a manipulation early in life can induce persistent neurochemical changes in the delta-opioid receptor system, which suggests involvement of delta-opioid receptors in the altered emotional processing in these rats.     

Short- and long-term effects of intermittent social defeat stress on brain-derived neurotrophic factor expression in mesocorticolimbic brain regions

Social defeat stress is an ethologically salient stressor which activates dopaminergic areas and, when experienced repeatedly, has long-term effects on dopaminergic function and related behavior. The mechanism for these long-lasting consequences remains unclear. A potential candidate for mediating these effects is brain-derived neurotrophic factor (BDNF), a neurotrophin involved in synaptic plasticity and displaying alterations in dopaminergic regions in response to various types of stress. In this study, we sought to determine whether repeated social defeat stress altered BDNF mRNA and protein expression in dopaminergic brain regions either immediately after the last stress exposure or 4 weeks later. Male Sprague–Dawley rats were subjected to social defeat stress consisting of brief confrontation with an aggressive male rat every third day for 10 days; control rats were handled according to the same schedule. Animals were euthanized either 2 h or 28 days after the last stress or handling episode. Our results show that 2 h after stress, BDNF protein and mRNA expression increased in the medial prefrontal cortex. At this time-point, BDNF mRNA increased in the amygdala and protein expression increased in the substantia nigra. Twenty-eight days after stress, BDNF protein and mRNA expression were elevated in the medial amygdala and ventral tegmental area. Given the role of BDNF in neural plasticity, BDNF alterations that are long-lasting may be significant for neural adaptations to social stress. The dynamic nature of BDNF expression in dopaminergic brain regions in response to repeated social stress may therefore have implications for lasting neurochemical and behavioral changes related to dopaminergic function.     

Stress: postulates, analysis in terms of the general theory of functional systems]

Further developing of the general theory of stress, put forward by Selye, the theory of functional systems treats stress, of any origin, as a systemic response of the organism to a conflict situation. The theory of functional systems regards, along with the action of stressors, the conflict behavioral situation in which the subjects are deprived of a possibility to satisfy their main requirements, i. e. attainment of useful adaptation results, as the leading cause of stress. It is the conflict behavioral situation that gives rise to the primary reaction of the organism, viz. psychoemotional stress. Cerebral mechanisms of emotional stress in terms of the theory of functional systems are primary in the pathogenesis of psychomotor disorders in stress. The specific neurochemical changes in the limbico-reticular structures of the brain, certain neurochemical disintegration of the neuronal elements, constituting the limbico-reticular structures of the brain, underlie emotional stress. Our experiments showed that predisposition to emotional stress is accounted for by the decreased level of catecholamines and certain oligopeptides such as substance PI (?), beta-endorphins, peptide, causing delta-sleep in the limbico-reticular structures of the brain.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of undernutrition on morphine analgesia, haloperidol catalepsy and pentobarbitone sodium hypnosis in developing new born rats

In the present study, half of the pups of a litter were undernourished by 12 h daily maternal deprivation from day 5 to day 18 postnatal and were subsequently nutritionally rehabilitated. Responses of CNS-acting drugs (morphine analgesia, pentobarbitone sodium hypnosis, haloperidol catalepsy) were studied at the age of day 9, 12 and 18 in maternally deprived and of day 25 in nutritionally rehabilitated new born rats as compared to that of their nourished littermates. The results showed that the response of these CNS-acting drugs was maximum at the age of day 9 postnatal and progressively decreased thereafter as the age of the animal advanced. The responses of these drugs in maternally deprived animals varied on different days of undernourishment as compared to that of their nourished littermates. The responses were significantly less in first half and were significantly more in second half period of undernourishment. The changes observed in the responses of these CNS-acting drugs were directly related to the changes observed in brain serotonin level in maternally deprived and nutritionally rehabilitated new born rats. The present findings suggest that the nature and degree of undernutrition imposed in suckling rats might only produce temporary effects on the response of CNS-actin drugs and on brain serotonin levels which is reversible if undernourished new born rats were nutritionally rehabilitated on an appropriate time of brain development.     

Plasma catecholamines in fasted and sucrose supplemented rats

Rats were food deprived or given a sucrose supplemented diet for 3 days. Resting plasma catecholamine levels measured remotely from undisturbed rats were not altered by either dietary treatment. However, food deprivation did result in decreases in resting mean arterial blood pressure, heart rate, plasma volume and plasma Na+ concentration. After one minute of intermittent footshock food deprived and sucrose fed rats did not differ from controls with respect to blood pressure, heart rate or plasma catecholamine levels but food deprived rats were less active during footshock and had lower levels of plasma glucose immediately after footshock when compared to controls or sucrose fed rats. Food deprivation and dietary sucrose supplementation have been shown to alter norepinephrine (NE) turnover in specific sympathetic target tissues. Our data indicate that these changes in turnover are not reflected by changes in plasma NE. Therefore, NE turnover rates and plasma NE concentration may not be equivalent indices of sympathetic activity.     

Loss of sensory input increases the intrinsic excitability of layer 5 pyramidal neurons in rat barrel cortex

Development of the cortical map is experience dependent, with different critical periods in different cortical layers. Previous work in rodent barrel cortex indicates that sensory deprivation leads to changes in synaptic transmission and plasticity in layer 2/3 and 4. Here, we studied the impact of sensory deprivation on the intrinsic properties of layer 5 pyramidal neurons located in rat barrel cortex using simultaneous somatic and dendritic recording. Sensory deprivation was achieved by clipping all the whiskers on one side of the snout. Loss of sensory input did not change somatic active and resting membrane properties, and did not influence dendritic action potential (AP) backpropagation. In contrast, sensory deprivation led to an increase in the percentage of layer 5 pyramidal neurons showing burst firing. This was associated with a reduction in the threshold for generation of dendritic calcium spikes during high-frequency AP trains. Cell-attached recordings were used to assess changes in the properties and expression of dendritic HCN channels. These experiments indicated that sensory deprivation caused a decrease in HCN channel density in distal regions of the apical dendrite. To assess the contribution of HCN down-regulation on the observed increase in dendritic excitability following sensory deprivation, we investigated the impact of blocking HCN channels. Block of HCN channels removed differences in dendritic calcium electrogenesis between control and deprived neurons. In conclusion, these observations indicate that sensory loss leads to increased dendritic excitability of cortical layer 5 pyramidal neurons. Furthermore, they suggest that increased dendritic calcium electrogenesis following sensory deprivation is mediated in part via down-regulation of dendritic HCN channels.     

Functional expression of CXCR3 in cultured mouse and human astrocytes and microglia

The aging brain is characterized by selective neurochemical changes involving several neural populations. A deficit in the cholinergic system of the basal forebrain is thought to contribute to the development of cognitive symptoms of dementia. Attempts to prevent age-associated cholinergic vulnerability and deterioration therefore represent a crucial point for pharmacotherapy in the elderly. In this paper we provide evidence for the protective effect of nicergoline (Sermion) on the degeneration of cholinergic neurons induced by nerve growth factor deprivation. Nerve growth factor deprivation was induced by colchicine administration in rats 13 and 18 months old. Colchicine induces a rapid and substantial down-regulation of choline acetyltransferase messenger RNA level in the basal forebrain in untreated adult, middle-aged and old rats. Colchicine failed to cause these effects in old rats treated for 120 days with nicergoline 10 mg/kg/day, orally. Moreover, a concomitant increase of both nerve growth factor and brain-derived neurotrophic factor content was measured in the basal forebrain of old, nicergoline-treated rats. Additionally, the level of messenger RNA for the brain isoform of nitric oxide synthase in neurons of the basal forebrain was also increased in these animals.Based on the present findings, nicergoline proved to be an effective drug for preventing neuronal vulnerability due to experimentally induced nerve growth factor deprivation.