Decreased Anxiety Behavior Research Articles

Pre-mating administration of theophylline could prevent the transgenerational effects of maternal morphine dependence on offspring anxiety behavior: The role of dopamine receptors

Opioid addiction causes some molecular alterations in the brain reward pathway, such as changes in gene expression that may be transferred to the next generation via epigenetic mechanisms such as histone acetylation. This study aimed to evaluate the effect of theophylline as an HDAC (Histone deacetylases) activator on D1 and D2 dopamine receptor expression in the nucleus accumbens (NAc) and anxiety behavior in the offspring of morphine-dependent female rats. Female rats were exposed to escalating doses of morphine for six days and were then treated with theophylline (20 mg/kg) or saline for 10 days before mating with normal male rats. Male and female offspring were tested for anxiety behavior using an elevated plus maze apparatus. Besides, the expression of D1 and D2 dopamine receptors in the NAc was evaluated by real-time PCR (polymerase chain reaction). Results showed that offspring of morphine-dependent female rats had increased expression of both D1 and D2 receptors in the NAc, as well as decreased anxiety behavior, compared to control offspring. However, the mentioned effects were returned to normal levels in the offspring whose morphine-dependent mothers had received theophylline for 10 days before mating. It is concluded that theophylline may be therapeutically effective in minimizing the adverse consequences of maternal morphine dependence on offspring behavior by restoring normal dopamine receptor expression levels and modulating anxiety. To completely comprehend the underlying mechanisms of this phenomenon, more research is required.

The Effect of Forced Exercise on Striatal and Serum Serotonin Levels in a Parkinson’s Mouse Model

Objective: The general treatment approach for Parkinson's disease (PD) is L-dopa administration. While L-dopa only relieves dopaminergic deficiency, it has no effect on the serotonergic system, which is thought to be impaired in the disease. The limitations of current treatment methods have made it necessary to discover new approaches to the treatment of the disease. Studies conducted in recent years report that different types of exercises applied lead to improvement in the symptoms of PD. Exercising decreases serotonin levels and increases dopamine levels. However, the effect of exercise on serotonin levels together with dopamine in PD and its effect on non-motor symptoms such as anxiety and depression are unknown.
 Methods: PD is created using MPTP. The exercise groups were given challenging treadmill exercises for 6 weeks. Serotonin and dopamine levels were measured in the striatum and serum. Parkinson's symptoms were examined with pole test and behavioral tests.
 Results: Exercise significantly reduced bradykinesia, increased motor activity, and decreased anxiety behaviors in the exercise groups. While exercise increased striatal dopamine levels in all exercise groups, there was no difference in striatal serotonin levels. However, the serotonin serum level was decreased in the PD model group. While treadmill exercise increased striatal dopamine levels in the Parkinson's mouse model, it did not cause any change in striatal serotonin levels. However, the decrease in serum serotonin level was determined only in the MPTP group.
 Conclusion: The fact that the decrease in serotonin level was only in the disease group and the lower level of anxiety observed in behavioral experiments suggested that regular treadmill exercise was the reason. However, this improvement was not observed in cases where the anxiety level was very high.

Ablation of the Presynaptic Protein Mover Impairs Learning Performance and Decreases Anxiety Behavior in Mice.

The presynaptic protein Mover/TPRGL/SVAP30 is absent in Drosophila and C. elegans and differentially expressed in synapses in the rodent brain, suggesting that it confers specific functions to subtypes of presynaptic terminals. In order to investigate how the absence of this protein affects behavior and learning, Mover knockout mice (KO) were subjected to a series of established learning tests. To determine possible behavioral and cognitive alterations, male and female 8-week-old KO and C57Bl/6J wildtype (WT) control mice were tested in a battery of memory and anxiety tests. Testing included the cross maze, novel object recognition test (NOR), the Morris water maze (MWM), the elevated plus maze (EPM), and the open field test (OF). Mover KO mice showed impaired recognition memory in the NOR test, and decreased anxiety behavior in the OF and the EPM. Mover KO did not lead to changes in working memory in the cross maze or spatial reference memory in the MWM. However, a detailed analysis of the swimming strategies demonstrated allocentric-specific memory deficits in male KO mice. Our data indicate that Mover appears to control synaptic properties associated with specific forms of memory formation and behavior, suggesting that it has a modulatory role in synaptic transmission.

Whisker trimming induces anti-anxiety like status via activation of dorsomedial hypothalamus nucleus in mice

Whiskers are highly developed tactile organs in mice. Here, we showed that mice with whisker trimming had a decreased anxiety behavior and activation of dorsomedial hypothalamus compared to control mice. Inhibition or damage of dorsomedial hypothalamus reversed the decrease of anxiety level induced by whisker trimming. These results expand the role of whiskers in regulating mouse behaviors to anxiety and suggest a novel function of dorsomedial hypothalamus. These findings indicate importance of normal sensory functions in modulating animal behavior.

Manipulation of vocal communication and anxiety through pharmacologic modulation of norepinephrine in the Pink1-/- rat model of Parkinson disease

Vocal deficits and anxiety are common, co-occurring, and interacting signs of Parkinson Disease (PD) that have a devastating impact on quality of life. Both manifest early in the disease process. Unlike hallmark motor signs of PD, neither respond adequately to dopamine replacement therapies, suggesting that their disease-specific mechanisms are at least partially extra-dopaminergic. Because noradrenergic dysfunction is also a defining feature of PD, especially early in the disease progression, drug therapies targeting norepinephrine are being trialed for treatment of motor and non-motor impairments in PD. Research assessing the effects of noradrenergic manipulation on anxiety and vocal impairment in PD, however, is sparse. In this pre-clinical study, we quantified the influence of pharmacologic manipulation of norepinephrine on vocal impairment and anxiety in Pink1-/- rats, a translational model of PD that demonstrates both vocal deficits and anxiety. Ultrasonic vocalization acoustics, anxiety behavior, and limb motor activity were tested twice for each rat: after injection of saline and after one of three drugs. We hypothesized that norepinephrine reuptake inhibitors (atomoxetine and reboxetine) and a β receptor antagonist (propranolol) would decrease vocal impairment and anxiety compared to saline, without affecting spontaneous motor activity. Our results demonstrated that atomoxetine and reboxetine decreased anxiety behavior. Atomoxetine also modulated ultrasonic vocalization acoustics, including an increase in vocal intensity, which is almost always reduced in animal models and patients with PD. Propranolol did not affect anxiety or vocalization. Drug condition did not influence spontaneous motor activity. These studies demonstrate relationships among vocal impairment, anxiety, and noradrenergic systems in the Pink1-/- rat model of PD.

동물모델에서 柴胡加龍骨牡蠣湯의 수면유도 및 항불안 효과

Shihogayonggolmoryo-tang (ST) is a Korean medical herb cocktail which has been used to treat anxiety induced insomnia. In this study, we will examine sleep-promoting and anti-anxiety effects of ST, and investigate its mechanism. ICR mice were divided into three groups for the first examination : control group (n=11), ST50 group (50 mg/kg, po, n=11), ST200 group (200 mg/kg, po, n=11). Sleep-promoting effect was confirmed by measuring the sleeping duration time and sleeping onset time after thiopental sodium treatment (50 mg/kg, ip). ICR mice were divided into five groups for the second examination : control group (n=11), ST200 group (200 mg/kg, po, n=11), ST200+Flumazenil group (ST 200 mg/kg, po, flumazenil 0.3 mg/kg, ip, n=11), diazepam group (1 mg/kg, ip, n=11), diazepam+flumazenil group (diazepam 1 mg/kg, ip, Flumazenil 0.3 mg/kg, ip, n=11). Anxiety behavior and sleep-promoting effect was confirmed by open field test and measuring the sleeping duration time and sleeping onset time. Expression levels of c-fos in tuberomammillary nucleus (TMN) and ventrolateral preoptic nucleus (VLPO) were analyzed by immunohistochemistry. ST treated group showed significantly decreased anxiety behavior and enhanced sleeping duration time and sleeping onset time concentration dependently. The expression of c-fos was significantly upregulated in VLPO as sleep-inducing center and TMN as downregulated in arousal center by ST treatment. In addition, all effects of ST were reversed by flumazenil. Our results suggest that ST has sleep-promoting and anti-anxiety effects through regulating arousal center (TMN) and sleep-inducing center (VLPO).

Detection of a High-Turnover Serotonin Circuit in the Mouse Brain Using Mass Spectrometry Imaging.

SummaryMonoamine neurotransmitters are released by specialized neurons regulating behavioral, motor, and cognitive functions. Although the localization of monoaminergic neurons in the brain is well known, the distribution and kinetics of monoamines remain unclear. Here, we generated a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels using mass spectrometry imaging (MSI). We found several nuclei rich in both 5-HT and a catecholamine (DA or NE) and identified the paraventricular nucleus of the thalamus (PVT), where 5-HT and NE are co-localized. The analysis of 5-HT fluctuations in response to acute tryptophan depletion and infusion of isotope-labeled tryptophan in vivo revealed a close kinetic association between the raphe nuclei, PVT, and amygdala but not the other nuclei. Our findings imply the existence of a highly dynamic 5-HT-mediated raphe to PVT pathway that likely plays a role in the brain monoamine system.

Non-motor Behavioral Alterations of PGC-1α-Deficient Mice - A Peculiar Phenotype With Slight Male Preponderance and No Apparent Progression.

Dysfunction of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α) has been linked to various neurodegenerative and neuropsychiatric disorders; however, reports on psychic behavioral alterations on PGC-1α-deficient animals are sparse. The present study revisited prior observations of anxiety-related, depression-related, and hippocampal memory-related observations having been made on different PGC-1α-deficient murine strains, in a large-scale analysis on whole-body full-length (FL-)PGC-1α-deficient mice. The examinations were performed on animals covering a wide age range enrolled from both sexes, and included paradigms such as the open-field, elevated plus maze, light-dark box, tail suspension test, and spatial recognition two-trial Y-maze. The findings revealed no signs of previously reported anxiety-like behavior, but revealed an unexpected phenotype with decreased anxiety behavior consistent throughout different paradigms, with slight male preponderance. This was associated with despair-like anhedonic behavior, consistent with that reported previously, but did not associate with either peripheral or brain alterations in kynurenic acid synthesis, which was previously proposed. Though male FL-PGC-1α-deficient mice tended to perform poorer in the hippocampus-based spatial learning paradigm, the genotype overall was not associated with impairment in spatial memory, contradicting with prior observations. None of the observed alterations deteriorated with age, similarly to motor alterations as reported previously. The most likely contributors of this peculiar phenotype are discussed, with clinicopathological correlations drawn. Being the first to address these behavioral domains within the same PGC-1α-deficient strain, our findings extend the knowledge about the complex in vivo effect of PGC-1α dysfunction and add important notes to research in the field of PGC-1α in connection with neuropsychiatric disorders.

Preliminary Data on Some Behavioral Changes Induced by Short-Term Intraperitoneal Oxytocin Administration in Aged Rats.

Oxytocin (OT) is a well-known neuropeptides which together with vasopressin, melatonin, insulin and other hormones can alter both behavior and physiological or neuronal functions. This growing interest on OT roles is also based on the demonstrated beneficial effects as a stress reliever and a social bonding agent. The association between old age and OT was only vaguely studied. Little or few is known on the effect of the OT hormone on the old body. Hereby, we present our preliminary results in the research on behavioral changes regarding the intraperitoneal administration of OT in aged rats. OT was administered for 8 days in Wistar aged rats in parallel with saline administration for control group. Behavioral markers were assessed in some specific behavioral tasks, such as the Y-Maze test for short-term working memory, Open Field test, Elevated Plus Maze, and Forced Swim test for anxious and depressive behavior assessment, and Three-chambered Maze test for sociability assessment. Increased mobility and decreased anxiety behaviors were reported for the aged intraperitoneal OT-treated animals, as compared with controls, during FST and OFT, and respectively FST, EPM, and OFT. Also, decreased depressive-like behaviors were observed in the same animal group during FST and ST. Moreover, a decrease in anxiolytic behavior was observed as exposed to stressful stimuli (such as grooming behavior in OFT, and forced grooming behavior in ST), and as exposed to social stimuli (such as grooming behavior in TCT). Similarly, significant differences were obtained regarding the social behavior of the intraperitoneal OT-treated animal as compared to control group, the animals showing increased sociability and social preference for the stranger animal in TCT. However, no significant effects on the working memory (assessed as spontaneous alternation in YMT) were observed. Intraperitoneal administration of OT in aged rats has clear effects on anxious and depressive behavior, but no significant effects on the working memory. Also, several beneficial effects of OT on social preferences and sociability were observed.

Long-Term Cognitive Deficits After Subarachnoid Hemorrhage in Rats

Cognitive dysfunction can be a long-term complication following subarachnoid hemorrhage (SAH). Preclinical models have been variously characterized to emulate this disorder. This study was designed to directly compare long-term cognitive deficits in the context of similar levels of insult severity in the cisterna magna double-blood (DB) injection versus prechiasmatic blood (PB) injection SAH models. Pilot work identified blood injectate volumes necessary to provide similar mortality rates (20-25%). Rats were then randomly assigned to DB or PB insults. Saline injection and naïve rats were used as controls. Functional and cognitive outcome was assessed over 35days. DB and PB caused similar transient rotarod deficits. PB rats exhibited decreased anxiety behavior on the elevated plus maze, while anxiety was increased in DB. DB and PB caused differential deficits in the novel object recognition and novel object location tasks. Morris water maze performance was similarly altered in both models (decreased escape latency and increased swimming speed). SAH caused histologic damage in the medial prefrontal cortex, perirhinal cortex, and hippocampal CA1, although severity of injury in the respective regions differed between DB and PB. Both SAH models caused long-term cognitive deficits in the context of similar insult severity. Cognitive deficits differed between the two models, as did distribution of histologic injury. Each model offers unique properties and both models may be useful for study of SAH-induced cognitive deficits.

Effects of the anti-multiple sclerosis immunomodulator laquinimod on anxiety and depression in rodent behavioral models.

Laquinimod is a novel oral immunomodulatory drug for the treatment of multiple sclerosis (MS). Considering the frequent co-morbidity of MS with anxiety and depression, we sought to assess the antidepressant and anxiolytic effects of laquinimod in mouse models. Laquinimod (0.5-25 mg/kg), fluoxetine (10 mg/kg) or vehicle were administered for 4-14 days to adult Balb/c mice, followed by behavioral tests and brain BDNF analysis. Following a 4-day administration of laquinimod (5 and 25 mg/kg), an increase in motivated behavior was observed in the forced swim test (p < 0.01 vs. controls). In the open field test, laquinimod (0.5-5 mg/kg), but not fluoxetine, significantly increased motility (p < 0.05), whereas both decreased anxiety behavior (p < 0.01), evident only for laquinimod (5 mg/kg) in the elevated plus maze (p < 0.05). Following 7 days of administration, both drugs decreased anxiety behavior in the elevated plus maze and marble burying tests (p < 0.001 and p < 0.02, respectively). After 14 days, only laquinimod (5 mg/kg) demonstrated anxiolytic efficacy in the open field test (p < 0.05), with evidence of increased BDNF in response to 5-25 mg/kg in the hippocampus, but not frontal cortex (p < 0.05). In conclusion, laquinimod may possess anxiolytic and antidepressant effects, possibly associated with hippocampal BDNF increase, offering promise for MS patients suffering from psychiatric co-morbidity.

Maternal high-fat diet alters anxiety behavior and glucocorticoid signaling in adolescent offspring

Maternal obesity and overconsumption of saturated fats during pregnancy have profound effects on offspring health, ranging from metabolic to behavioral disorders in later life. The influence of high-fat diet (HFD) exposure on the development of brain regions implicated in anxiety behavior is not well understood. We previously found that maternal HFD exposure is associated with an increase in anxiety behavior and alterations in the expression of several genes involved in inflammation via the glucocorticoid signaling pathway in adult rat offspring. During adolescence, the maturation of feedback systems mediating corticosteroid sensitivity is incomplete, and therefore distinct from adulthood. In this study, we examined the influence of maternal HFD on several measures of anxiety behavior and gene expression in adolescent offspring. We examined the expression of corticosteroid receptors and related inflammatory processes, as corticosteroid receptors are known to regulate circulating corticosterone levels during basal and stress conditions in addition to influencing inflammatory processes in the hippocampus and amygdala. We found that adolescent animals perinatally exposed to HFD generally showed decreased anxiety behavior accompanied by a selective alteration in the expression of the glucocorticoid receptor and several downstream inflammatory genes in the hippocampus and amygdala. These data suggest that adolescence constitutes an additional period when the effects of developmental programming may modify mental health trajectories.

Intrathecal Baclofen (ITB) Treatment in a Rodent Model of TBI-induced Spasticity

Intrathecal Baclofen (ITB) Treatment in a Rodent Model of TBI-induced Spasticity

A Genetically Defined Morphologically and Functionally Unique Subset of 5-HT Neurons in the Mouse Raphe Nuclei

Heterogeneity of central serotonin (5-HT) raphe neurons is suggested by numerous lines of evidence, but its genetic basis remains elusive. The transcription factor Pet1 is required for the acquisition of serotonergic identity in a majority of neurons in the raphe nuclei. Nevertheless, a subset of 5-HT neurons differentiates in Pet1 knock-out mice. We show here that these residual 5-HT neurons outline a unique subpopulation of raphe neurons with highly selective anatomical targets and characteristic synaptic differentiations. In Pet1 knock-out mice, 5-HT innervation strikingly outlines the brain areas involved in stress responses with dense innervation to the basolateral amygdala, the paraventricular nucleus of the hypothalamus, and the intralaminar thalamic nuclei. In these regions, 5-HT terminals establish asymmetric synaptic junctions. This target selectivity could not be related to altered growth of the remaining 5-HT neurons, as indicated by axon tracing and cell culture analyses. The residual 5-HT axon terminals are functional with maintained release properties in vitro and in vivo. The functional consequence of this uneven distribution of 5-HT innervation on behavior was characterized. Pet1 knock-out mice showed decreased anxiety behavior in novelty exploration and increased fear responses to conditioned aversive cues. Overall, our findings lead us to propose the existence of Pet1-dependent and Pet1-resistant 5-HT neurons targeting different brain centers that might delineate the anatomical basis for a dual serotonergic control on stress responses.

Differential regional distribution of phosphorylated tau and synapse loss in the nucleus accumbens in tauopathy model mice

Tauopathies differ in terms of the brain regions that are affected. In Alzheimer's disease, basal forebrain and hippocampus are mainly involved, while frontotemporal lobar degeneration affects the frontal and temporal lobes and subcortical nuclei including striatum. Over 90% of human cases of tauopathies are sporadic, although the majority of established tau-transgenic mice have had mutations. This prompted us to establish transgenic mice expressing wild-type human tau (Tg601). Old (>14months old) Tg601 mice displayed decreased anxiety in the elevated plus maze test and impaired place learning in the Morris water maze test. Immunoblotting of brain tissue identified that soluble tau multimer was increased with aging even though insoluble tau was not observed. In the striatum of old Tg601, the level of AT8- or AT180-positive tau was decreased compared with that of other regions, while PHF-1-positive tau levels remained equal. Phosphorylated tau-positive axonal dilations were present mainly in layers V and VI of the prefrontal cortex. Loss of synaptic dendritic spine and decreased immunohistochemical level of synaptic markers were observed in the nucleus accumbens. In vivo 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography analysis also showed decreased activity exclusively in the nucleus accumbens of living Tg601 mice. In Tg601 mice, the axonal transport defect in the prefrontal cortex–nucleus accumbens pathway may lead to decreased anxiety behavior. Differential distribution of hyperphosphorylated tau may cause region-specific neurodegeneration.

Hyperactivity and Enhanced Curiosity of Mice Expressing PKB/SGK-resistant Glycogen Synthase Kinase-3 (GSK-3)

Background: Mounting evidence suggests that bipolar disorder symptoms could be favorably influenced by modification of glycogen synthase kinase-3 (GSK-3) activity. Specifically, the well known antimanic and mood stabilizing medications lithium, valproate, olanzapine and clozapine have been shown to inhibit GSK-3 activity. GSK-3 is phosphorylated and thus inhibited by protein kinase B (PKB/Akt) and serum and glucocorticoid inducible kinase (SGK) isoforms. The present study explored, whether PKB/SGK-dependent GSK-3 regulation influences the behavior of mice. Methods: Gene-targeted knockin mice with mutated and thus PKB/SGK-resistant GSK-3Α, Β (gsk-3^KI) were compared to corresponding wild type mice (gsk-3^WT). The mice were analyzed by open-field, light-dark (LD-) box, O-maze, emergence test, object exploration test and forced swimming test (FST). Results: In open-field, LD-box and O-maze, gsk-3^KI mice displayed a hyperactive and more curious phenotype when compared to wild type mice. Speed and total distance moved as well as rearings were significantly increased in gsk-3^KI compared to gsk-3^WT mice. In the O-maze, gsk-3^KI mice tended to travel a larger distance in the open, unprotected area thangsk-3^WT mice, and performed significantly more unprotected head dips suggesting decreased anxiety behavior. In the forced swimming test, the immobility time was significantly decreased in gsk-3^KI mice indicating a phenotype less prone to depression. Moreover, gsk-3^KImice were less sensitive to the application of chronic mild stress and showed a decreased HPA axis activity. Conclusions: The present observations disclose a significant role of PKB/SGK-dependent regulation of GSK-3 in the control of activity, anxiety and proneness to depression. Accordingly, mice expressing SGK/PKB resistant GSK-3 may be a valuable model of hyperactivity and mania.

Reduced anxiety in the mice expressing mutant (N141I) presenilin 2

Alzheimer's disease (AD) is characterized by progressive cognitive impairment. The effect of presenilin 1 (PS1) and PS2 mutation on cognition has been well characterized in a variety of transgenic mice. However, noncognitive behaviors have not been considered in these mice. In the present study, we found that transgenic mice expressing mutant PS2 (N141I) displayed decreased anxiety behavior determined by the elevated plus maze test and the light dark box test. However, these mice showed biphasic ambulatory activity (hyperactivity followed by hypoactivity) in an open field test. Correlated well with the reduced anxiety, expression of GABA(A)alpha(1) receptor was higher whereas c-Fos was lower in the cortex, hippocampus, and amygdala of the mice expressing PS2 mutation than those of the wild-type PS2 or nontransgenic control mice. These data indicate that PS2 mutation causes reduction of anxiety, and this effect may be related to the change of the expression of GABA(A)alpha(1) receptor and c-Fos. These findings could be useful in the understanding and the treatment of AD patients.

Progesterone’s effects to reduce anxiety behavior of aged mice do not require actions via intracellular progestin receptors

Aging is associated with reduced secretion of, and down-regulation of receptors for, progesterone (P); yet, P's effects when administered to younger and older animals have not been systematically investigated. Some of P's antianxiety effects may be due to its conversion to 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) and its subsequent actions as a positive modulator at GABAA receptor complexes (GBRs). We investigated whether P administration can decrease anxiety behavior of progestin receptor (PR) knockout (PRKO) or wild-type control mice. P (10 mg/kg) or vehicle (propylene glycol) were administered subcutaneously to intact, female or male wild-type or PRKO mice that were either 9-12 or 18-24 months of age. Behavior in tasks that assess spontaneous activity (activity monitor and roto-rod), free exploration of a novel environment (open field, elevated plus maze, and elevated zero maze), and conflict behavior (mirror chamber, dark-light transition, and punished drinking) were examined 1 h after injection. P significantly decreased anxiety behavior of both PRKO and wild-type mice. P did not alter motor behavior but increased central entries in the open field, time in the open quadrants of the elevated zero maze, time in the mirrored chamber, time in the light compartment of the dark-light transition, and punished drinking in young and old mice. P-administered mice had higher levels of hippocampal 3alpha,5alpha-THP and GABA-stimulated chloride flux than did vehicle-administered PRKO or wild-type mice. The effects of P to decrease anxiety behavior of younger and older mice do not require classic PRs and may involve actions of 3alpha,5alpha-THP at GBRs.

Differential early rearing environments can accentuate or attenuate the responses to stress in male C57BL/6 mice

This study investigated the effects of neonatal handling and maternal separation on the development of anxiety behavior and the hypothalamic–pituitary–adrenal axis of C57BL/6 mice. We hypothesized short periods of neonatal handling would diminish anxiety and secretion of corticosterone, while longer periods of maternal separation would elevate anxiety and plasma corticosterone compared to a nonhandled group. Mice were bred and reared as follows. After birth, each litter was assigned to one of four groups: mother and pups removed from the home cage for 10 min (group 1) or 180 min a day (group 2); mother only removed from home cage 180 min a day (group 3); and no handling until weaning (group 4). All separation occurred on the first 10 days of life. Juvenile males that experienced 10 min of separation/day exhibited decreased anxiety behavior compared to all other mice. A second group of litters were bred and reared according to groups 1, 2, and 4 as described above. Upon adulthood, anxiety behavior was assessed in males, and the corticosterone response to an acoustic stressor was quantified. No effect of differential rearing was observed on behavior, but there was a marked effect on plasma corticosterone secretion between the groups. Adult male mice neonatally handled for 10 min/day exhibited a blunted corticosterone response, and mice that experienced 180 min of maternal separation exhibited a prolonged corticosterone response to the acoustic stimulus compared to the nonhandled group. These results demonstrate the development of the mouse's hypothalamic–pituitary–adrenal axis can be modified by neonatal rearing conditions, and suggest that the mouse could be a viable animal model to determine the genetic–environmental interactions governing brain development.