Effects of Early Maternal Separation on Subsequent Reproductive and Behavioral Outcomes in Male Rats

To investigate effects of maternal separation on reproductive and behavioral outcomes, male Wistar rats were separated from their mothers daily for 3 hr (maternal separation; MS) or 0 hr (control) from postnatal day (PND) 1 to 14. Timing of puberty, reproductive parameters, hormone levels, and aggressive behaviors in juvenile and adult rats were examined. Contrary to expectations, there was no effect of maternal separation on any measure of aggression. However, maternal separation altered peripubertal testosterone secretion and increased mean day of preputial separation. In addition, adult MS males demonstrated less total sexual behavior. There was no difference in sperm counts or testosterone levels at necropsy on PND 56 or in adulthood, but seminal vesicle weights were increased in adult MS rats. These results suggest that early life stress may influence hypothalamic-pituitary-gonadal axis development in males, at least during peripuberty.     

Memory impairments and hippocampal modifications in adult rats with neonatal isolation stress experience

Early life events have profound consequences. Our research demonstrates that the early life stress of neonatal isolation (1-h individual isolation on postnatal days 2-9) in rats has immediate and enduring neural and behavioral effects. Recently, we showed neonatal isolation impaired hippocampal-dependent context conditioned fear in adult rats. We now expand upon this finding to test whether neonatal isolation impairs performance in inhibitory avoidance and in the non-aversive, hippocampal-dependent object recognition task. In addition to assessments of hippocampal-dependent memory, we examined if neonatal isolation results in cellular alterations in the adult hippocampus. This was measured with antibodies that selectively label calpain-mediated spectrin breakdown product (BDP), a marker of cytoskeletal modification that can have neuronal consequences. Neonatally isolated male and female rats showed impaired performance in both memory tasks as well as elevated BDP levels in hippocampal immunoblot samples. In tissue sections stained for BDP, the cytoskeletal fragmentation was localized to pyramidal neurons and their proximal dendrites. Interestingly, the hippocampal samples also exhibited reduced staining for the postsynaptic marker, GluR1. Neonatal isolation may render those neurons involved in memory encoding to be vulnerable to calpain deregulation and synaptic compromise as shown previously with brain injury. Together with our prior research showing enhanced striatal-dependent learning and neurochemical responsivity, these results indicate that the early experience of neonatal isolation causes enduring yet opposing region-specific neural and behavioral alterations.     

The impact of emotional stress early in life on adult voluntary ethanol intake-results of maternal separation in rats

The combination of genetic and environmental factors determines the individual vulnerability for excessive ethanol intake, possibly leading to dependence. The environmental influences early in life represent examples of determinant factors for adult behaviour and can be protective as well as risk factors. Maternal separation is one model to examine the long-term consequences of early environmental experiences on neurochemistry and behaviour, including drug-taking behaviour in experimental animals. In the present review, findings from studies using repeated short and prolonged periods of maternal separation, with emphasis on effects on voluntary ethanol intake in rats with or without a genetic predisposition for high voluntary ethanol intake, are summarized. Despite some contradictory results, the general picture emerging shows that short periods of maternal separation during the postnatal period result in a lower adult voluntary ethanol intake in male rats. Prolonged periods of maternal separation were found to induce a high voluntary ethanol intake in male rats, including rats with a genetic predisposition for high ethanol intake. Results from the literature also show that changes were not just related to time of separation but were also related to the degree of handling. Interestingly, in terms of voluntary ethanol intake, female rats were generally not affected by postnatal maternal separation. The reasons for these sex differences need further investigation. In terms of neurobiological consequences of maternal separation, conclusive data are sparse and one of the future challenges will, therefore, be to identify and characterize underlying neurobiological mechanisms, especially in the individual animal.     

Combined effect of early life stress and acute stress on colonic sensory and motor responses through serotonin pathways: differences between proximal and distal colon in rats

Clinically, adults who have experienced stresses in childhood present with episodes of serious symptoms of irritable bowel syndrome that are associated with acute stress, but the mechanism is not well understood. This study aimed to investigate the colonic sensory/motor responses to acute water avoidance stress (WAS) in male adult rats subjected to neonatal maternal separation (NMS), and the underlying mechanism of sensory/motor responses. Effects of the combined acute and early life stress on visceral sensation, colonic motility, and the tissue and luminal content of serotonin (5-hydroxytryptamine, 5-HT) in the proximal and distal colon were evaluated using the abdominal withdrawal reflex test, faecal pellet output measurement and capillary electrophoresis analysis, respectively. Results showed that WAS significantly increased not only visceral sensitivity but also colonic motility in NMS rats compared to the normal rats. These alterations were accompanied by significant increase in 5-HT content in the proximal but not the distal colonic tissues; these alterations were also associated with increased density of enterochromaffin (EC) cells in the proximal segment. In contrast, the faecal content of 5-HT increased similarly in both segments. Consecutive administration of parachlorophenylalanine to NMS rats was more potent at 500 mg kg?1 day?1 than at 150 mg kg?1 day?1 in suppressing colonic sensory/motor responses to WAS, corresponding to the greater reduction of the tissue and faecal content of 5-HT and of EC cell density in the colon. These data indicate that combined early life stress and acute stress effectively induce visceral hyperalgesia and motility disorder through 5-HT pathways in the colon of rats, and the proximal and distal colon have different responses towards the combined stressors.     

Early maternal separation has mild effects on cardiac autonomic balance and heart structure in adult male rats

Early life adverse experiences have long-term physiologic and behavioral effects and enhance stress sensitivity. This study examined the effects of maternal separation (MS) on cardiac stress responsivity and structure in adulthood. Male Wistar rats were separated from the dams for 3?h per day from postnatal days 2 through 15. When exposed to 5-day intermittent restraint stress (IRS) as adults, MS, and control rats showed similar acute modifications of cardiac sympathovagal balance, quantified via heart rate variability analysis. In addition, MS had no effect on cardiac pacemaker intrinsic activity (as revealed by autonomic blockade with scopolamine and atenolol) and did not affect the circadian rhythmicity of heart rate, neither before nor after IRS. However, MS differed from control rats in cardiac parasympathetic drive following IRS, which was heightened in the latter but remained unchanged in the former, both during the light and dark phases of the daily rhythm. The evaluation of adult cardiac structure indicated that stress experienced during a crucial developmental period induced only modest changes, involving cardiomyocyte hypertrophy, increased density of vascular structures, and myocardial fibrosis. The mildness of these functional-structural effects questions the validity of MS as a model for early stress-induced cardiac disease in humans.     

Effects of early seizures on later behavior and epileptogenicity

Both clinical and laboratory studies demonstrate that seizures early in life can result in permanent behavioral abnormalities and enhance epileptogenicity. Understanding the critical periods of vulnerability of the developing nervous system to seizure-induced changes may provide insights into parallel or divergent processes in the development of autism. In experimental rodent models, the consequences of seizures are dependent on age, etiology, seizure duration, and frequency. Recurring seizures in immature rats result in long-term adverse effects on learning and memory. These behavioral changes are paralleled by changes in brain connectivity, changes in excitatory neurotransmitter receptor distribution, and decreased neurogenesis. These changes occur in the absence of cell loss. Although impaired cognitive function and brain changes have been well-documented following early-onset seizures, the mechanisms of seizure-induced dysfunction remain unclear.     

Viral vector mediated overexpression of human alpha-synuclein in the nigrostriatal dopaminergic neurons: a new model for Parkinson's disease

Parkinson's disease is predominantly a dopamine deficiency syndrome, which is produced in the brain by the loss of cells located in a small area in the ventral midbrain called the substantia nigra. Complete unilateral dopamine lesions, based on the administration of toxic substances (ie, 6-hydroxy-dopamine in rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice and primates) have been extremely useful in testing strategies of replacement. For example, the functional and biochemical impact of the transplanted ventral mesencephalic dopaminergic progenitors has been characterized to a large extent, using the complete lesion model in rats. Over the last decade, however, studies addressing the ability of neurotrophic factors to protect injured dopamine cells prompted researchers to make available partial and progressive lesion models to allow a window of opportunity to interfere the disease progression. Recent findings relating alpha-synuclein with Parkinson's disease pathology have opened new possibilities to develop alternative models based on the overexpression of this protein using recombinant adeno-associated viral vectors, which is valuable not only for helping to better understand its involvement in the disease process, but also to more closely resemble the neurodegeneration found in Parkinson's disease.     

Long-term consequences of early experience on adult avoidance learning in female rats: role of the dopaminergic system

Following our hypothesis that juvenile emotional and/or cognitive experience should affect learning performance at preweaning age as well as adulthood, the present study in female Wistar rats aimed to examine the impact of (i) avoidance training at preweaning age, (ii) exposure to repeated maternal separation, (iii) the combination of both, and (iv) the blockade of dopaminergic neurotransmission on adult two-way active avoidance learning in rats. We found that preweaning, i.e. three week old, rats were less capable of avoidance learning compared to adults. Our main findings revealed that preweaning avoidance training alone improved avoidance learning in adulthood. Furthermore, maternal separation alone also improved avoidance learning in preweaning and in adult rats, but this effect of maternal separation did not add up to the beneficial effect of preweaning avoidance training on adult learning. In addition, the pharmacological blockade of dopamine receptors during preweaning avoidance training via systemic application of haloperidol impaired preweaning avoidance performance in a dose-dependent manner. Testing the haloperidol-treated preweaning presumed "non-learners" as adults revealed that they still showed improved learning as adults. Taken together, our results strongly support the hypothesis that emotional as well as cognitive experience at preweaning age leaves an enduring "memory trace," which can facilitate learning in adulthood. Our pharmaco-behavioral studies suggest that unlike the adult brain, preweaning learning and memory formation is less dependent on dopaminergic mechanisms, which raises the intriguing question of possible alternative pathways.     

The role of the anterodorsal thalami nuclei in the regulation of adrenal medullary function, beta-adrenergic cardiac receptors and anxiety responses in maternally deprived rats under stressful conditions

Maternal separation can interfere with growth and development of the brain and represents a significant risk factor for adult psychopathology. In rodents, prolonged separation from the mother affects the behavioral and endocrine responses to stress for the lifetime of the animal. Limbic structures such as the anterodorsal thalamic nuclei (ADTN) play an important role in the control of neuroendocrine and sympathetic-adrenal function. In view of these findings we hypothesized that the function of the ADTN may be affected in an animal model of maternal deprivation. To test this hypothesis female rats were isolated 4.5 h daily, during the first 3 weeks of life and tested as adults. We evaluated plasma epinephrine (E) and norepinephrine (NE), cardiac adrenoreceptors and anxiety responses after maternal deprivation and variable chronic stress (VCS) in ADTN-lesioned rats. Thirty days after ADTN lesion, in non-maternally deprived rats basal plasma NE concentration was greater and cardiac beta-adrenoreceptor density was lower than that in the sham-lesioned group. Maternal deprivation induced a significant increase in basal plasma NE concentration, which was greater in lesioned rats, and cardiac beta-adrenoreceptor density was decreased in lesioned rats. After VCS plasma catecholamine concentration was much greater in non-maternally deprived rats than in maternally-deprived rats; cardiac beta-adrenoreceptor density was decreased by VCS in both maternally-deprived and non-deprived rats, but more so in non-deprived rats, and further decreased by the ADTN lesion. In the plus maze test, the number of open arm entries was greater in the maternally deprived and in the stressed rats. Thus, sympathetic-adrenal medullary activation produced by VCS was much greater in non-deprived rats, and was linked to a down regulation of myocardial beta-adrenoceptors. The ADTN are not responsible for the reduced catecholamine responses to stress in maternally-deprived rats. Maternal deprivation or chronic stress also induced a long term anxiolytic effect, which was also not affected by ADTN lesion.     

Is the unilateral lesion of the left substantia nigra pars compacta sufficient to induce working memory impairment in rats?

Adult male Wistar rats with a substantia nigra pars compacta (SNc) lesion induced by intranigral administration of 1 micromol 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were used as a model of early phase Parkinson's disease (PD). This lesion caused a partial depletion of striatal dopamine (DA). The animals were submitted to a spatial working memory version of the water maze task in which they had to find a hidden (submersed) platform using online-maintained information that the platform remains in the same place during four consecutive trials, but that it is moved to another place every training day. Left, but not right SNc-lesioned rats were impaired in finding the platform in the second trial. This result suggests that the left SNc plays a key role in spatial working memory. Control experiments ruled out the possibility that motor impairment, sensory neglect, and/or impairment in the mental representation of the contralateral spatial environment had affected performance of the SNc-lesioned rats.     

儿童早期的母亲生活压力对其5岁行为问题的预测效应：链式中介分析

通过对107名幼儿及其母亲历时5年的5次追踪测量, 考察了儿童早期(9~38个月)母亲生活压力对5岁时儿童行为问题的预测效应及其作用机制。结果发现, 在儿童早期, 母亲生活压力具有相对的稳定性, 但引起母亲生活压力的主要生活事件排序有所变化; 儿童早期母亲生活压力对儿童行为问题的作用机制有两种方式：一方面表现为母亲生活压力对儿童5岁时的情绪症状和品行问题的直接效应; 另一方面表现为通过减少母亲积极养育行为进一步影响儿童情绪症状和同伴问题的间接效应; 此外, 儿童早期母亲生活压力还通过积极养育和儿童努力控制的链式中介作用对儿童过度活跃和亲社会行为产生影响。结论:母亲生活压力对儿童行为问题具有预测效应, 这种效应的机制包括母亲生活压力的直接效应以及通过积极养育、努力控制的间接效应。     

Unpredictable chronic stress in juvenile or adult rats has opposite effects, respectively, promoting and impairing resilience

We evaluated the effects of early maternal deprivation (MD; age 7-14 days) alone or in combination with unpredictable chronic stress (UCS; MDUN; 28-84 days) on anxiety and learning in 90 days old adult rats. We hypothesized that exposure to both stressors (MDUN) would be more detrimental than exposure to one or neither. Unexpectedly, adult rats from the MDUN group did not differ from control animals, whereas adult MD animals exhibited impaired avoidance learning. We next investigated the effect of juvenile-onset (30-90 days) versus adult-onset (60-90 days) stress on avoidance learning in adulthood (90 days). We found that adult-onset chronic stress impaired avoidance learning and memory whereas juvenile-onset stress did not. Thus, the results again indicate that juvenile exposure to UCS induces resilience rather than impairment.     

Maternal separation in early life impairs tumor immunity in adulthood in the F344 rat

Neonatal stress alters the hypothalamic-pituitary-adrenal (HPA) axis in rodents, such that, when these animals are exposed to stress as adults they hypersecrete corticosterone. Given that glucocorticoids are immunosuppressive, we examined the impact of maternal separation on HPA axis reactivity, natural killer (NK) cytotoxicity, and tumor growth in Fischer 344 rats following chronic restraint stress in adulthood. Pups underwent a chronic stress protocol whereby they were separated from their dams for 3 h on postnatal days 1-21. In adulthood, corticosterone responses were assessed following exposure to chronic (6 days for 10 h) restraint stress. Rats allocated to the chronic stress condition were inoculated with MADB106 tumor cells on day 4 of the restraint protocol. Blood was assessed for NK cytotoxicity on the final day of the chronic restraint protocol, and tumor colonization was assessed 3 weeks thereafter. Maternal separation impaired developmental weight gain (P < 0.05), depressed NK cytotoxicity (P < 0.05), and increased tumor colonization in the presence of chronic restraint stress in adulthood (P < 0.00 l). These findings occurred independently of circulating plasma corticosterone as only adult stress exposure potentiated corticosterone responses (P < 0.05). Our findings indicate that maternal separation and chronic stress can impair NK cytotoxicity and hence tumor immunity, but these effects are not directly mediated by perturbations in HPA axis function.     

Chronic exposure to a novel odor increases pups' vocalizations, maternal care, and alters dopaminergic functioning in developing mice

This study was designed to assess the stress effect of manipulation of the olfactory environment in developing mice. In a first experiment it was found that mouse pups could be stressed (as measured by an increase in ultrasonic calls) by removing the litter from the dam for 15 min/day for the first 14 days of life and exposing them to a novel odor (clean bedding). This stress procedure also produced a long-term modification in maternal behavior. The stress response (ultrasounds) and the modification of maternal behavior were prevented by providing the litter with home cage bedding during maternal separation. In a second experiment it was demonstrated that early stress influenced apomorphine-induced wall climbing behavior in 15-day-old mice, suggesting stress-induced alterations in the dopaminergic system. Pups exposed to clean bedding during infancy exhibited more wall climbing behavior than pups never separated from the mother. Moreover, preventing the early stress response during mother-offspring separation, by providing pups with home cage bedding, eliminated the increase in apomorphine-induced wall climbing. Taken together these results suggest that olfactory cues are decisive in characterizing stressful situations inducing both immediate and long-lasting effects in mouse pups.     

Effect of neonatal handling on adult rat spatial learning and memory following acute stress

Brief neonatal handling permanently alters hypothalamic-pituitary-adrenal axis function resulting in increased ability to cope with stress. Since stress is known to affect cognitive abilities, in the present study we investigated the effect of brief (15 min) handling on learning and memory in the Morris water maze, following exposure to an acute restraint stress either before training or recall. Exposure of non-handled rats to the acute stress prior to training resulted in quicker learning of the task, than in the absence of the stressor. When acute stress preceded acquisition, male handled rats showed an overall better learning performance, and both sexes of handled animals were less impaired in the subsequent memory trial, compared to the respective non-handled. In addition, the number of neurons immunoreactive for GR was higher in all areas of Ammon's horn of the handled rats during the recall. In contrast, the number of neurons immunoreactive for MR was higher in the CA1 and CA2 areas of the non-handled males. When the acute restraint stress was applied prior to the memory test, neonatal handling was not effective in preventing mnemonic impairment, as all animal groups showed a similar deficit in recall. In this case, no difference between handled and non-handled rats was observed in the number of GR positive neurons in the CA2 and CA3 hippocampal areas during the memory test. These results indicate that early experience interacts with sex and acute stress exposure in adulthood to affect performance in the water maze. Hippocampal corticosterone receptors may play a role in determining the final outcome.     

Object alternation and orbitofrontal system dysfunction in Alzheimer's and Parkinson's disease

Previous performance on measures of frontal system function have suggested prominent orbitofrontal system damage in Alzheimer's disease, but not in Parkinson's dementia. Object alternation (OA), a task sensitive to orbitofrontal system dysfunction in non-human animals, was therefore administered to determine whether this measure would distinguish Alzheimer's from Parkinson's dementia. OA was significantly impaired in Alzheimer's disease compared to Parkinson's dementia, even though both groups were equated for severity of dementia. Although the patients with Parkinson's dementia also showed impairment on OA compared to normals, an error analysis revealed that the performance of the Alzheimer's patients, but not the Parkinson's patients, was characterized by abnormal response perseveration. The marked perseverative deficit in Alzheimer's disease may reflect orbitofrontal system dysfunction whereas the milder, and qualitatively different, deficits in Parkinson's disease may reflect dorsolateral frontal system involvement.     

The Rorschach and traumatic loss: can the presence of traumatic loss be detected from the Rorschach?

Loss, an expected part of everyone's life, can be a catalyst promoting significant growth. But all losses are not the same or affect everyone in like manner. Some losses are of such magnitude and intensity that individuals cannot cope, and, therefore, they keep reliving them (posttraumatic stress syndrome) as if through repeated attempts (Freud, 1923-1922/1961) they might master what had been initially so overwhelming. This study, using an inpatient hospital sample, examines the Rorschach protocols of individuals who had experienced traumatic loss in childhood or early adolescence and compares them with a control group of individuals who appear to have no such history. Our hypotheses that victims of early trauma have a distinguishing Rorschach profile was validated in the exploratory study. Further study is needed to clarify whether factors other than traumatic loss may be contributing to this profile.     

The Rorschach and Traumatic Loss: Can the Presence of Traumatic Loss Be Detected From the Rorschach?

Loss, an expected part of everyone's life, can be a catalyst promoting significant growth. But all losses are not the same or affect everyone in like manner. Some losses are of such magnitude and intensity that individuals cannot cope, and, therefore, they keep reliving them (posttraumatic stress syndrome) as if through repeated attempts (Freud, 1923-1922/1961) they might master what had been initially so overwhelming. This study, using an inpatient hospital sample, examines the Rorschach protocols of individuals who had experienced traumatic loss in childhood or early adolescence and compares them with a control group of individuals who appear to have no such history. Our hypotheses that victims of early trauma have a distinguishing Rorschach profile was validated in the exploratory study. Further study is needed to clarify whether factors other than traumatic loss may be contributing to this profile.     

Contributions of Neuroscience to Our Understanding of Cognitive Development

ABSTRACT— One major contribution of neuroscience to understanding cognitive development has been in demonstrating that biology is not destiny—that is, demonstrating the remarkable role of experience in shaping the mind, brain, and body. Only rarely has neuroscience provided wholly new insights into cognitive development, but often it has provided evidence of mechanisms by which observations of developmental psychologists could be explained. Behavioral findings have often remained controversial until an underlying biological mechanism for them was offered. Neuroscience has demonstrated promise for detecting cognitive problems before they are behaviorally observable—and, hence, promise for early intervention. In this article, we discuss examples drawn from imitation and mirror neurons, phenylketonuria (PKU) and prefrontal dopamine, maternal touch and stress reactivity, and nongenetic (behavioral) intergenerational transmission of biological characteristics.     

Parvalbumin阳性中间神经元缺陷在精神分裂症病理机制中的作用

精神分裂症是一种多发于青壮年的重性精神病, 其原因尚不明确。经典的多巴胺缺陷理论假说在某些方面欠缺解释力; 与此同时, 关于Parvalbumin阳性的中间神经元(后简称PV+神经元)缺陷在精神分裂症病理机制中的作用逐渐明晰, 并引起了越来越多的关注。PV+神经元在绝大部分脑区中是一种快速放电的抑制性神经元, 参与了突触可塑性的调节, 兴奋/抑制平衡的维持和神经发生等。而在精神分裂症中, PV+神经元的异常在患者和动物研究中都被普遍证实, 并发现与 NMDA受体缺陷、gamma波异常和氧化应激存在某些关联。