Amygdaloid pERK1/2 in corticotropin-releasing hormone overexpressing mice under basal and acute stress conditions

Corticotropin-releasing hormone (CRH) coordinates neuroendocrine and behavioral adaptations to stress. Acute CRH administration in vivo activates extracellular signal-regulated kinase 1/2 (ERK1/2) in limbic brain areas, acting through the CRH receptor type 1 (CRH-R1). In the present study, we used CRH-COE-Cam mice that overexpress CRH in limbic-restricted areas, to analyze the effect of chronic CRH overexpression on ERK1/2 activation. By immunohistochemistry and confocal microscopy analysis we found that pERK1/2 levels in the basolateral amygdala (BLA) were similar in control and CRH overexpressing mice under basal conditions. Acute stress caused comparably increased levels of corticosterone in both control (CRH-COE^con-Cam) and CRH overexpressing (CRH-COE^hom-Cam) animals. CRH-COE^hom-Cam mice after stress showed reduced pERK1/2 immunoreactivity in the BLA compared to CRH-COE^hom-Cam animals under basal conditions. Radioligand binding and in situ hybridization revealed higher density of CRH-R1 in the amygdala of CRH-COE^hom mice under basal conditions compared to control littermates. A significant reduction of the receptor levels was observed in this area after acute stress, suggesting that stress may trigger CRH-R1 internalization/downregulation in these CRH overexpressing mice. Chronic CRH overexpression leads to reduced ERK1/2 activation in response to acute stress in the BLA.     

Effects of repeated maternal separations on the adrenocortical response to stress of preweanling rats.

Previous data indicate that the infant rat shows a marked increase in adrenocortical responsiveness to stress immediately following prolonged maternal separation. In Experiment 1 we studied the immediate effects of repeated maternal deprivation. Our results indicate that the increase in basal as well as stress-induced corticosterone levels is a direct function of the length of the deprivation period immediately preceding testing, and is not cumulative. In Experiment 2 we examined the long-term consequences of maternal deprivation on adrenal responsivity. Four days following a single 24-h period of maternal deprivation, pups remained hyperresponsive to stress, although their basal levels of corticosterone had returned to control values. Shorter periods of deprivation (which did result in increased responsivity immediately following deprivation) did not have persistent effects. Our data suggest: 1) short periods of deprivation do not have a cumulative effect, and 2) there is a critical length of deprivation beyond which persistent changes in adrenocortical responsivity ensue.     

Prenatal stress and neonatal rat brain development

Chronic or repeated stress during human fetal brain development has been associated with various learning, behavioral, and/or mood disorders, including depression in later life. The mechanisms accounting for these effects of prenatal stress are not fully understood. The aim of this study was to investigate the effects of prenatal stress on early postnatal brain development, a disturbance of which may contribute to this increased vulnerability to psychopathology. We studied the effects of prenatal stress on fetal growth, stress-induced corticosterone secretion, brain cell proliferation, caspase-3-like activity and brain-derived neurotrophic factor protein content in newborn Fischer 344 rats. In addition to a slight reduction in birth weight, prenatal stress was associated with elevated corticosterone levels (33.8%) after 1 h of maternal deprivation on postnatal day 1, whereas by postnatal day 8 this pattern was reversed (-46.5%). Further, prenatal stress resulted in an approximately 50% decrease in brain cell proliferation just after birth in both genders with a concomitant increase in caspase-3-like activity within the hippocampus at postnatal day 1 (36.1%) and at postnatal day 5 (females only; 20.1%). Finally, brain-derived neurotrophic factor protein content was reduced in both the olfactory bulbs (-24.6%) and hippocampus (-28.2%) of prenatally stressed male offspring at postnatal days 1 and 5, respectively. These detrimental central changes observed may partly explain the increased susceptibility of prenatally stressed subjects to mood disorders including depression in later life.     

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.     

Glucocorticoid receptor-dependent desensitization of 5-HT1A autoreceptors by sleep deprivation: studies in GR-i transgenic mice

Sleep deprivation for one night induces mood improvement in depressed patients, an action that probably involves the serotonergic (5-HT) system. In animals, sleep deprivation and pharmacologic treatment with antidepressants exert similar effects on 5-HT neurotransmission, notably functional desensitization of 5-HT1A autoreceptors located on 5-HT neurons in the dorsal raphe nucleus (DRN). However, in stressful conditions, corticosterone can also induce a desensitization of these autoreceptors. STUDY OBJECTIVES: To investigate the mechanisms of this adaptation during sleep deprivation and the possible involvement of corticosterone, we studied the effects of an 18-hour sleep deprivation, by forced locomotion, on 5-HT1A receptor-mediated firing response of DRN 5-HT neurons in transgenic mice with impaired glucocorticoid-receptor expression (GR-i) and in wild-type animals. We also examined the effects of chronic treatment with the antidepressant drug fluoxetine in the same paradigm. MEASUREMENTS AND RESULTS: In both wild-type and GR-i mice, the 18-hour sleep deprivation or fluoxetine treatment had no effect on the spontaneous firing of 5-HT neurons recorded under anesthesia. However, sleep deprivation decreased the potency of the 5-HT1A agonist 8-OH-DPAT to inhibit 5-HT neuronal firing in wild-type mice, whereas it had no effect in GR-i animals. Conversely, after chronic fluoxetine treatment, the induced reduction of this 5-HT1A autoreceptor-driven response was of larger amplitude in GR-i than in wild-type mice. CONCLUSIONS: These data suggest that glucocorticoid-receptor activation by corticosterone participates in the antidepressant-like adaptive changes in 5-HT1A autoreceptors in sleep-deprived mice. On the other hand, GR-i animals exhibited enhanced 5-HT1A autoreceptor desensitization induced by fluoxetine, in line with data in other animal models of depression.     

Repeated immobilization stress in the early postnatal period increases stress response in adult rats

Repeated immobilization stress tests in the early postnatal period were performed to determine the effects on the growth of developing rats as well as the response of the HPA axis to subsequent novel stress in adulthood. In addition, effects of maternal deprivation (MD) with the same period of the exposure to immobilization stress were also examined. We used 2 different types of immobilization stress and 2 different types of MD: immobilization stress for 30 min/day from postnatal day 7 (P7) to P13 (IS7-13 group); immobilization stress for 30 min on P7 (IS7 group); MD for 30 min/day from P7 to P13 (MD7-13 group); and MD for 30 min on P7 (MD7 group). Body weights were lower in the IS7-13 group than in the control group from P10 to P50, although body weight gain in the MD7-13 group was only transiently affected. Stress-induced corticosterone levels in the IS7-13 group were higher than in the control group and did not return to baseline levels until at least 120 min after the termination of stress, whereas temporal variations of stress-induced corticosterone levels did not differ between the IS, MD7-13, MD7, and control groups. Repeated immobilization stress in the early postnatal period induced long-term effects on the growth of developing rats and stress response of the HPA axis to the novel stress in adulthood, although a single immobilization stress, periodic MD, or a single MD had little effect.     

Central Deficiency of Corticotropin-Releasing Hormone Receptor Type 1 (CRH-R1) Abolishes Effects of CRH on NREM But Not on REM Sleep in Mice

Study Objectives:

Corticotropin-releasing hormone (CRH) is the major activator of the hypothalamic-pituitary-adrenocortical (HPA) system and orchestrates the neuroendocrine, autonomous as well as behavioral responses to stress. Many studies suggest an influence of CRH on sleep-wake regulation even in the absence of stressors. However, none of these studies yet clearly distinguished between central and peripheral effects of CRH. Therefore, we investigated in CNS-specific CRH receptor type 1 deficient mice whether centrally administered CRH could induce its sleep-wake modulatory effects without peripheral induction of HPA activity.

Design:

Male mice (C57BL/6J, CNS-specific CRH-R1 knockout [CKO] mice and their control littermates [CL]) were intracerebroventricularily (i.c.v.) injected with vehicle or 3 different doses of CRH shortly before the beginning of the light period. Electroencephalogram (EEG) and electromyogram (EMG) were monitored to compare the effects of CRH on vigilance states with or without presence of central CRH-R1. To quantify HPA-axis reactivity to CRH injections in CKO and CL animals, blood samples were analyzed to determine plasma corticosterone concentrations.

Results:

I.c.v. injections of CRH promoted wakefulness while decreasing NREMS in C57BL/6J and CRH-R1 CL animals, whereas such changes were not exerted in CKO mice. However, REMS suppression after CRH application persisted in all animals. I.c.v. injected CRH increased plasma corticosterone levels in both CL and CKO mice.

Conclusions:

The results demonstrated that CRH has a major impact on wake and NREMS regulation which is predominantly mediated through central CRH-R1. Peripheral actions of CRH, i.e., elevated HPA activity, may interfere with its central effects on REMS but not on NREMS suppression.

Citation:

Romanowski CPN; Fenzl T; Flachskamm C; Wurst W; Holsboer F; Deussing JM; Kimura M. Central deficiency of corticotropin-releasing hormone receptor type 1 (CRH-R1) abolishes effects of CRH on NREM but not on REM sleep in mice.SLEEP 2010;33(4):427-436.     

Local corticotropin releasing hormone (CRH) signals to its receptor CRHR1 during postnatal development of the mouse olfactory bulb

Neuropeptides play important physiological functions during distinct behaviors such as arousal, learning, memory, and reproduction. However, the role of local, extrahypothalamic neuropeptide signaling in shaping synapse formation and neuronal plasticity in the brain is not well understood. Here, we characterize the spatiotemporal expression profile of the neuropeptide corticotropin-releasing hormone (CRH) and its receptor CRHR1 in the mouse OB throughout development. We found that CRH-expressing interneurons are present in the external plexiform layer, that its cognate receptor is expressed by granule cells, and show that both CRH and CRHR1 expression enriches in the postnatal period when olfaction becomes important towards olfactory-related behaviors. Further, we provide electrophysiological evidence that CRHR1-expressing granule cells functionally respond to CRH ligand, and that the physiological circuitry of CRHR1 knockout mice is abnormal, leading to impaired olfactory behaviors. Together, these data suggest a physiologically relevant role for local CRH signaling towards shaping the neuronal circuitry within the mouse OB.     

Hypothalamus-pituitary-adrenal modifications consequent to chronic stress exposure in an experimental model of depression in rats

The modifications in the hypothalamus-pituitary-adrenal (HPA) axis function induced by repeated unavoidable stress exposure, according to a standardized procedure used for inducing an experimental model of depression, were studied. Rats exposed to this procedure show hyporeactivity to both pleasurable and aversive stimuli and this condition is antagonized by the repeated administration of classical antidepressant drugs. We also studied whether imipramine administration during stress exposure would interfere with the possible modifications in the HPA axis. Rats were exposed to a 4-week stress procedure with and without imipramine treatment and then tested for escape, as compared with non-stressed control animals. Twenty-four hours later all rats were bled through a tail nick for plasma corticosterone measurement before and after dexamethasone (10 microg/kg) or corticotropin-releasing hormone (CRH, 1 microg/kg) administration. Rats were then killed, adrenals and thymus weighed, brain areas dissected out and frozen for glucocorticoid receptors (GRs) and corticotropin-releasing hormone receptor 1 (CRHR1) immunoblotting and for the assessment of hypothalamic corticotropin-releasing hormone levels. RESULTS: Rats exposed to a 4-week unavoidable stress showed escape deficit and their basal plasma corticosterone levels were higher than those of control animals. Moreover, they had decreased response to dexamethasone administration, adrenal hypertrophy, and decreased GR expression in the hippocampus, hypothalamus, medial prefrontal cortex and pituitary. No significant modifications in CRHR1 expression were observed in the pituitary nor in different discrete brain areas. CRH levels in the hypothalamus and the plasma corticosterone response to CRH administration were found to be higher in stressed rats than in controls. Imipramine treatment offset all the behavioral and neurochemical stress-induced modifications. In conclusion, the present results strengthen the assumption that the escape/avoidance behavioral deficit induced by inescapable stress exposure is accompanied by steadily increased HPA activity, and that imipramine effect is strongly related to a normalization of HPA axis activity.     

Blockage of glucocorticoid, but not mineralocorticoid receptors prevents the persistent increase in circulating basal corticosterone concentrations following stress in the rat

Exposure to a single session of intense inescapable stressors results in elevations of plasma corticosterone levels selective to the trough of the circadian rhythm that last for several days after stressor cessation. In the present study, we examined whether this stress-induced alteration in the regulation of the circadian trough is dependent upon glucocorticoid and/or mineralocorticoid receptor activation during stress. Pre-treatment with the mineralocorticoid receptor (MR) antagonist, spironolactone (RU-28318; 50 mg/kg, s.c.), and/or the glucocorticoid receptor (GR) antagonist, mifepristone (RU-38486; 50 mg/kg, s.c.) 1 h before inescapable stress (40, 2.0-mA tail-shocks delivered over a 1 h period) had no effect on the acute plasma corticosterone response to inescapable stress. Treatment with the MR antagonist alone did not affect the appearance of basal corticosterone elevations in stressed rats. However, the elevated trough plasma corticosterone levels were no longer evident in rats treated previously with the GR antagonist either alone or in combination with the MR antagonist. GR activation during stressor exposure appears to be necessary for the development of subsequent basal corticosterone elevations.     

Long lasting alteration in REM sleep of female rats submitted to long maternal separation

Early adverse experiences represent risk factors for the development of anxiety and mood disorders. Maternal separation can induce biobehavioral alterations in male rodents similar to those seen in depressed humans, such as hyperresponsiveness to stress and sleep disturbances. Nonetheless, no study has yet explored the effects of early life events on the relationship between stress and sleep in female rats. Whole litters of Wistar rats were submitted to brief- or long maternal separations (15 [BMS] or 180 min/day [LMS], from postnatal days 2-14) or kept undisturbed with their mothers (CTL). When adults, female rats were sleep-recorded for 22 h before (baseline) and after a 1 h exposure to cold stress (post-stress). Additional subsets of animals were sacrificed before, 1 or 3 h after the stressor for plasma corticosterone determination. No differences in baseline sleep were observed among the groups. Female rats submitted to LMS exhibited a significant increase of REM sleep on the night following a 1 h exposure to cold stress, whereas the sleep of BMS rats was barely altered by stress. All groups exhibited similar basal and stress-induced corticosterone levels. The present results are compared to a previous study performed in male rats, and corroborate that manipulations applied during infancy modify the expression of stress-induced sleep rebound.     

Cross-fostering Effects on Weight,Exploratory Activity,Acoustic Startle Reflex and Corticosterone Stress Response in Norway Gray Rats Selected for Elimination and for Enhancement of Aggressiveness Towards Human

Two rat lines, one tame, the other aggressive, differing by many behavioral features and stress reactivity were developed by long-term selection of wild gray rats for elimination and enhancement of aggressiveness towards humans. The aim of this work was to study the role of the maternal environment in the expression of these differences between the two rat lines using the cross-fostering paradigm. Fostering of tame rats of both sexes by aggressive mothers and aggressive females by tame mothers was without effect on behavior score towards humans, but the cross-fostered aggressive males had a small, yet significant, increase in aggressiveness score. Cross-fostering revealed that exploratory behavior in the hole-board test and the acoustic startle amplitude were weakly affected by maternal interactions, although there was an effect on body weight and on the stress corticosterone response. Body weight was decreased in tame males fostered by aggressive mothers only and it was increased in cross-fostered aggressive rats of both sexes. Fostering of tame males and females by an aggressive mother enhanced almost twofold the corticosterone response immediately after stress, while fostering of aggressive ratlings of both sexes by a tame mother was without effect. The current results demonstrated that the maternal postnatal environment had no substantial effect on the behavioral responses of both tame and aggressive rats, but it possibly contributed to the development of the corticosterone response to restraint stress in the tame, and not the aggressive rats, i.e. these effects of cross-fostering were dependent on ratling genotype. Edited by Tamara Phillips.     

Changes in anxiety-related behaviors and hypothalamic-pituitary-adrenal activity in mice lacking the 5-HT-3A receptor

The serotonin-3 (5-HT-3A) receptor has been localized in limbic and brainstem structures that regulate anxiety-related behavior and hypothalamic-pituitary-adrenal (HPA) activity, but its role in regulating anxiety-related behaviors is equivocal, and evidence for its role in regulating HPA activity is limited. Therefore, we used 5-HT-3A receptor knockout (KO) mice to further study these issues. Behavior in the elevated plus maze, open field, light-dark box and after Pavlovian fear conditioning was examined in addition to HPA activity under basal and acute stress conditions. Compared to age-matched adult male wild-type (WT) controls, adult male KO mice exhibited increased distance traveled in the open arms of the elevated plus maze, consistent with decreased measures of anxiety. There were no differences between the two genotypes in exploratory behavior in the open field or light-dark test. KO mice displayed enhanced fear conditioning indexed by fear-induced freezing behavior. KO mice displayed lower adrenocorticotropin (ACTH) responses to restraint or lipopolysaccharide (LPS). In addition, lower vasopressin mRNA in the paraventricular nucleus of the hypothalamus (PVN) and higher corticotropin-releasing hormone (CRH) mRNA in the central amygdala were observed in KO compared to WT mice. Therefore, deletion of the 5-HT-3A receptor revealed an important role for this receptor in regulating HPA responses to acute stress and a potential interaction between the 5-HT-3A receptor and CRH in the amygdala. Together, these data suggest that the 5-HT-3A receptor does not have a unitary role in the regulation of anxiety- and fear-related behaviors but has a potentially substantial role in the regulation of HPA activity.     

Behavioral, neuroendocrine and thermoregulatory actions of apelin-13

As the distribution of apelinergic neurons in the brain suggests an important role of apelin-13 in the regulation of neuroendocrine processes, in the present experiments the effects of this recently identified neuropeptide on the open-field activity, the hypothalamo-pituitary-adrenal (HPA) system and the body temperature were investigated. I.c.v. administration of apelin-13 (1-10 microg) to rats caused significant increases in square crossing, rearing, plasma corticosterone release and core temperature, whereas it did not influence the spontaneous motor activity during telemetric observation. To determine the mediation of the actions of apelin, a corticotropin-releasing hormone (CRH) antagonist, the nonselective dopamine antagonist haloperidol, the selective dopamine D1 receptor antagonist SCH-23390 and the nitric oxide synthase inhibitor Nomega-nitro-L-arginine-methyl ester (L-NAME) were administered to the rats. The apelin-evoked HPA activation was diminished by preadministration of the CRH antagonist, while the dopamine antagonist and L-NAME attenuated only the square crossing and rearing induced by apelin-13. To characterize the transmission of the thermoregulatory action of apelin, animals were pretreated either with L-NAME, the CRH antagonist or with the cyclooxygenase inhibitor noraminophenazone. L-NAME and the CRH antagonist did not cause significant inhibition of the apelin-evoked increase in core temperature, while the cyclooxygenase inhibitor, applied 30 min before peptide treatment, did not prove effective in preventing the apelin-evoked thermoregulatory response, whereas when it was administered 2 h after the peptide treatment, it transiently and significantly reduced the hyperthermic response. The present data suggest that apelin-13 plays an important role in the regulation of behavioral, endocrine and homeostatic responses in the CNS, and dopamine, nitric oxide and prostaglandins seem to take part in the mediation of its effects. Since the corticosterone response could be blocked by the CRH antagonist, it is likely to be mediated through the activation of the CRH neurons.     

Postnatal microbial colonization programs the hypothalamic–pituitary–adrenal system for stress response in mice

Indigenous microbiota have several beneficial effects on host physiological functions; however, little is known about whether or not postnatal microbial colonization can affect the development of brain plasticity and a subsequent physiological system response. To test the idea that such microbes may affect the development of neural systems that govern the endocrine response to stress, we investigated hypothalamic–pituitary–adrenal (HPA) reaction to stress by comparing germfree (GF), specific pathogen free (SPF) and gnotobiotic mice. Plasma ACTH and corticosterone elevation in response to restraint stress was substantially higher in GF mice than in SPF mice, but not in response to stimulation with ether. Moreover, GF mice also exhibited reduced brain-derived neurotrophic factor expression levels in the cortex and hippocampus relative to SPF mice. The exaggerated HPA stress response by GF mice was reversed by reconstitution with Bifidobacterium infantis . In contrast, monoassociation with enteropathogenic Escherichia coli , but not with its mutant strain devoid of the translocated intimin receptor gene, enhanced the response to stress. Importantly, the enhanced HPA response of GF mice was partly corrected by reconstitution with SPF faeces at an early stage, but not by any reconstitution exerted at a later stage, which therefore indicates that exposure to microbes at an early developmental stage is required for the HPA system to become fully susceptible to inhibitory neural regulation. These results suggest that commensal microbiota can affect the postnatal development of the HPA stress response in mice.     

Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress

Corticotropin-releasing hormone (CRH) is centrally involved in coordinating responses to a variety of stress-associated stimuli. Recent clinical data implicate CRH in the pathophysiology of human affective disorders. To differentiate the CNS pathways involving CRH and CRH receptor 1 (Crhr1) that modulate behavior from those that regulate neuroendocrine function, we generated a conditional knockout mouse line (Crhr1(loxP/loxP)Camk2a-cre) in which Crhr1 function is inactivated postnatally in anterior forebrain and limbic brain structures, but not in the pituitary. This leaves the hypothalamic-pituitary-adrenocortical (HPA) system intact. Crhr1(loxP/loxP)Camk2a-cre mutants showed reduced anxiety, and the basal activity of their HPA system was normal. In contrast to Crhr1 null mutants, conditional mutants were hypersensitive to stress corticotropin and corticosterone levels remained significantly elevated after stress. Our data clearly show that limbic Crhr1 modulates anxiety-related behavior and that this effect is independent of HPA system function. Furthermore, we provide evidence for a new role of limbic Crhr1 in neuroendocrine adaptation to stress.     

Behavioral and hormonal responses to stress in the newborn mouse: Effects of maternal deprivation and chlordiazepoxide

These studies investigated behavioral and hormonal responses to stress in developing mice. Experiment 1 examined the effects of 24-hr maternal deprivation on corticosterone (CORT) secretion and ultrasonic vocalization (UVZ) rate in 4-, 8-, and 12-day-old mice. At these ages, exposure to a novel environment resulted in minimal changes in CORT secretion. Maternal deprivation increased pups′ CORT secretion in an age-dependent fashion but did not affect their UVZ rate. The aim of experiment 2 was to test the effects of cholordiazepoxide (CDP), an anxyolytic compound, on CORT secretion and UVZ in both normally reared and in maternally deprived 8-day-old mice. CDP administration elevated CORT increases in deprived (DEP) animals. CDP affected UVZ only in nondcprived (NDEP) animals: UVZ ratewas decreased by high CDP doses Overall, these findings demonstrate that the infant mouse shows a period of stress hyp9oresponsiveness similar to the rat and that maternal presence contributes to inhibit adrenocorticalactivity. CDP administration, butnot novelty exposure, increased CORT secretion in 8-day- old normally reared mice suggesting that during the stress hyporesponsive period, the HPA axis is capable of responding only to specific stimuli. Changes in HPA axis activity and UVZ rateresulting from maternal deprivation and/or CDP challenge do not seem to be directly related. ©1994 John Wiley & Sons, Inc.     

Early-life stress induces motor coordination dysfunction in adult mice

Although child abuse has become a serious social problem in most countries, the neural mechanisms by which it induces adulthood mental disorders is not yet fully understood. Mice exposed to early-life stresses, such as maternal deprivation (MD) during lactation, are a good model for studying the effects of neglect of humans in early life. Early-life stress induces structural/functional changes of neurons in the hippocampus, prefrontal cortex, and amygdala, and causes mental disorders in adulthood. In this study, we found motor coordination dysfunction in male MD mice. We also found that the expression levels of the aminomethylphosphonic acid receptor subunits GluA1 and GluA3 were high in the cerebellum of male MD mice. The basal activity of the cerebellum detected by field-potential analysis was higher in male MD mice than in male control mice. Caloric stimulation increased the activity of the cerebellum of control mice, but it did not significantly increase the activity of the cerebellum in male MD mice. We concluded that early-life stress induced a functional change in the cerebellum of MD mice and that this change induced motor coordination dysfunctions.     

Time course of the effect of maternal deprivation on the hypothalamic-pituitary-adrenal axis in the infant rat.

Prolonged (i.e., 24-hr) maternal deprivation leads to a marked disinhibition of the infant rat's adrenocortical response to stress and/or ACTH. In the following study we examined the time course over which these effects develop. Pups were maternally deprived for varying lengths of time (i.e., 0, 2, 4, 8, & 24 hr); at the end of this period, corticosterone (CORT) secretion in response to stress (novelty or novelty plus saline injection) and ACTH injection was measured. Basal levels of CORT increased progressively over time in 7- and 11- (but not 3-) day-old pups. CORT release in response to stress followed a similar pattern. In contrast, ACTH injection resulted in marked increases in CORT levels regardless of the length of maternal deprivation in 3-day-old animals; at older ages, however, 24 hr of deprivation led to a much larger increase. These findings support the hypothesis that the hypothalamic-pituitary-adrenal axis of the neonatal rat is subject to maternal regulation.