Increase In Depression-like Behavior Research Articles

Mirtazapine modulates Glutamate and GABA levels in the animal model of maternal depression. MRI and 1H MRS study in female rats

We aimed to determine, using in vivo magnetic resonance, whether maternal depression induced by chronic unpredictable stress (CUS) in the pre-gestational period in female rats would be evidenced by structural or neurometabolic changes in the hippocampal region of the brain. At the same time, appropriate behavioral tests were also administered after a relatively long two-month period of a stress paradigm. The objective of the study was not only to study an animal model of CUS using magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS) focused on the hippocampus, but also to use this technique to verify the effectiveness of mirtazapine antidepressant treatment. In the group with CUS, we found a significant decrease in the relative concentration of γ-aminobutyric acid (GABA/tCr) and glutamate+glutamine (Glx/tCr) compared to the control group, while we did not observe any statistically significant change in hippocampal volumes. Moreover, the forced swim test revealed an increase in depression-like behavior. The most important finding was the return of GABA/tCr and Glx/tCr levels to control levels during mirtazapine treatment; however, behavioral tests did not demonstrate any effects from mirtazapine treatment. In vivo1H MRS confirmed mirtazapine modulation of CUS in an animal model more robustly than behavioral tests.

REPEATED COLLECTION OF VAGINAL SMEAR CAUSES STRESS IN MICE

Women are more likely to be misdiagnosed in many neuropsychiatric disorders than men. One of the possible underlying reasons for this disparity may be more frequent use of male mice than female mice in neuroscience studies. With the increasing realization of the shortcomings of this approach in understanding the neurobiological basis of these disorders, many funding agencies mandate the inclusion of both male and female subjects in study design. As the behaviors vary with the stage of the estrous cycle, the collection of vaginal smears to identify the estrous stage becomes a widely used procedure. Here we tested whether vaginal smear collection causes similar effects to that of stress by evaluating an increase in depression-like behavior and impairment in memory. Vaginal smear was collected from Swiss albino mice twice a day for 10 days. In order to test depression-like behavior tail suspension, sucrose preference and splash tests were conducted. Novel object recognition and novel object location tests were performed 1 hour and 24 hours after training to evaluate short-and long-term memory respectively. The female mice whose vaginal smears were collected demonstrated increased behavioral despair and anhedonia. Vaginal smear group showed deficits in both short-term and long-term memory when compared to the control group. Our results indicate that the collection of vaginal smear not only increased depression-like behaviors in mice, but also impaired short-term and long-term memory, indicating that the procedure of vaginal smear collection was stressful. We recommend to consider other ways of estrous cycle staging when studying behavior.

Baicalin regulates depression behavior in mice exposed to chronic mild stress via the Rac/LIMK/cofilin pathway

BackgroundDepression is a common disease that endangers people’s physical and mental health. Traditional Chinese medicine has advantages in treating the emotional and cognitive symptoms of depressive disorders. ObjectiveTo study the effects of baicalin on the behavior and to clarify the underlying mechanism through evaluation of the Rac1-LIMK1-cofilin pathway. MethodsA chronic mild stress (CMS) model of depression was used. Baicalin was administered to the mice for the intervention, and the positive control group was treated with fluoxetine. Behavioral tests were conducted to observe the degree of depressive disorders. Synaptophysin (SYP), postsynaptic density protein-95 (PSD95), brain-derived neurotrophic factor (BDNF), tyrosine kinase receptors (TrkB), Rac1 and cofilin expression was determined using Western blot analysis, and mRNA was quantified using real-time PCR. ResultsMice in the CMS group showed an increase in depression-like behavior (p < 0.01), while mice in the baicalin and fluoxetine groups showed a decrease in depression-like behavior (p < 0.01), compared with the control group. Electron microscopy showed ultrastructural changes in the hippocampal CA3 area of the CMS group, which were alleviated by baicalin treatment. SYP, PSD95, BDNF, TrkB, Rac1 and cofilin protein expression levels were decreased in the CMS group compared with the control group, while these levels were increased in the baicalin and fluoxetine groups (p < 0.01). There was no significant difference among the baicalin and fluoxetine groups (p > 0.05). ConclusionBaicalin markedly alleviated depression-like behavioral changes, exerted effects on SYP, PSD95, BDNF, and TrkB expression, activated the Rac1-cofilin pathway, and subsequently improve synaptic plasticity.

Embryonic Exposure to Dexamethasone Affects Nonneuronal Cells in the Adult Paraventricular Nucleus of the Hypothalamus.

Neurons in the paraventricular nucleus of the hypothalamus (PVN) integrate peripheral signals and coordinate responses that maintain numerous homeostatic functions. An excess of glucocorticoids during fetal development results in long-lasting consequences tied to disrupted PVN development. The PVN contains a distinct neuronal population and a threefold greater vascular density than the surrounding brain regions that prepubertally is reduced in offspring exposed to excess glucocorticoids in utero. This study expands the examination of sex-specific nonneuronal PVN composition by examining astrocytes, astrocytic endfeet, and pericytes. Blood-brain barrier (BBB) competency and composition were examined along with depressive-like behavior and hypothalamic-pituitary-adrenal function in male and female mice. For PVN vasculature, female offspring of vehicle (veh)-treated mothers had significantly more astrocytes and pericytes than male offspring from the same litters. Female offspring from dexamethasone (dex)-treated mothers had significantly lower levels of astrocytes than female offspring from veh-treated mothers, whereas male offspring from dex-treated mothers had greater levels of pericytes compared with veh-treated male offspring. Using the tail-suspension test, male and female offspring from dex-treated mothers had significantly shorter latencies to immobility, indicating an increase in depression-like behavior, and showed greater plasma corticosterone after restraint stress, which was significantly greater in female offspring from dex-treated mothers even after recovery. Therefore, in addition to long-term sex differences in cellular components of the BBB in the PVN that were differentially regulated by fetal glucocorticoid exposure, there were behavioral differences observed into early adulthood in a sex-specific manner.

Depressive symptoms as a side effect of Interferon-α therapy induced by induction of indoleamine 2,3-dioxygenase 1.

Depression is known to occur frequently in chronic hepatitis C viral (HCV) patients receiving interferon (IFN)-α therapy. In this study, we investigated whether indoleamine 2,3-dioxygenase1 (IDO1)-mediated tryptophan (TRP) metabolism plays a critical role in depression occurring as a side effect of IFN-α therapy. Increases in serum kynurenine (KYN) and 3-hydroxykynurenine (3-HK) concentrations and in the ratios of KYN/TRP and 3-HK/kynurenic acid (KA) were much larger in depressive HCV patients than in non-depressed patients following therapy. Furthermore, transfection of a plasmid continuously expressing murine IFN-γ into normal mice significantly increased depression-like behavior. IFN-γ gene transfer also resulted in a decrease in serum TRP levels in the mice while KYN and 3-HK levels were significantly increased in both serum and frontal cortex. Genetic deletion of IDO1 in mice abrogated both the increase in depression-like behavior and the elevation in TRP metabolites’ levels, and the turnover of serotonin in the frontal cortex after IFN-γ gene transfer. These results indicate that the KYN pathway of IDO1-mediated TRP metabolism plays a critical role in depressive symptoms associated with IFN-α therapy.

Hypothalamic dopaminergic neurons in an animal model of seasonal affective disorder

Light has profound effects on mood regulation as exemplified in seasonal affective disorder (SAD) and the therapeutic benefits of light therapy. However, the underlying neural pathways through which light regulates mood are not well understood. Our previous work has developed the diurnal grass rat, Arvicanthis niloticus, as an animal model of SAD. Following housing conditions of either 12:12h dim light:dark (DLD) or 8:16h short photoperiod (SP), which mimic the lower light intensity or short day-length of winter, respectively, grass rats exhibit an increase in depression-like behavior compared to those housed in a 12:12h bright light:dark (BLD) condition. Furthermore, we have shown that the orexinergic system is involved in mediating the effects of light on mood and anxiety. To explore other potential neural substrates involved in the depressive phenotype, the present study examined hypothalamic dopaminergic (DA) and somatostatin (SST) neurons in the brains of grass rats housed in DLD, SP and BLD. Using immunostaining for tyrosine hydroxylase (TH) and SST, we found that the number of TH- and SST-ir cells in the hypothalamus was significantly lower in the DLD and SP groups compared to the BLD group. We also found that treating BLD animals with a selective orexin receptor 1 (OX1R) antagonist SB-334867 significantly reduced the number of hypothalamic TH-ir cells. The present study suggests that the hypothalamic DA neurons are sensitive to daytime light deficiency and are regulated by an orexinergic pathway. The results support the hypothesis that the orexinergic pathways mediate the effects of light on other neuronal systems that collectively contribute to light-dependent changes in the affective state.

Exercise ameliorates depression-like behavior and increases hippocampal BDNF level in ovariectomized rats

The aims of the present study were to investigate whether exercise can improve the depression-like behavior caused by estrogen deficiency. Given that decreased level of brain-derived neurotrophic factor (BDNF) in many brain areas including hippocampus and prefrontal cortex is associated with estrogen deficiency-induced depression-like behavior, we also determined whether exercise affects the levels of BDNF and its receptor in hippocampus and prefrontal cortex (PFC). It was found that ovariectomy (OVX) caused an increase in depression-like behavior in rats and a decrease in BDNF level in hippocampus but not in PFC. The expression of TrkB, a high affinity BDNF receptor in hippocampus and PFC was not affected by OVX. 17β-estradiol (E2) treatment ameliorated depression-like behavior and increased BDNF level in hippocampus in OVX rats. Serum E2 level inversely correlated to depression-like behavior and positively correlated to BDNF level in hippocampus. Exercise ameliorated depression-like behavior, increased serum E2 level and BDNF level in hippocampus in OVX rats. The increased E2 level did not correlate to BDNF level but correlated with some of the behaviors in the rats subjected to exercise. Our results suggested that E2 maintains BDNF in hippocampus, thereby ameliorating depression-like behavior. Exercise amelioration of depression-like behavior in OVX rats is partly due to increased serum E2 level.

Su2073 Neonatal Colonic Irritation Produces Persistent Visceral Hypersensitivity and Altered Affective Behavior in a Mouse Model of Irritable Bowel Syndrome (IBS)

Introduction: A major theme in functional bowel disorders (FBD) such as irritable bowel syndrome (IBS) is that psychological/psychiatric problems have a pathogenic role, based both on the observation that patients with FBD are more anxious and depressed than healthy control, as well as research linking stress and depression to altered gastrointestinal sensory and motor function. However, recent experimental and epidemiological studies suggest that primary visceral disturbances can lead secondarily to persistent behavioral and emotional abnormalities. The aims of the present study were to test the hypothesis that mild chemical irritation of the colon of neonatal mice can produce changes in visceral hypersensitivity and psychological behaviors that persist into adulthood. Methods: Ten-day old C57BL/6 mouse pups received an intracolonic infusion of 20 μl of 0.5% acetic acid (IBS) or saline (control) to mimic a previously validated model of IBS in rats based on neonatal visceral irritation. Psychological behaviors and pain sensitivity of the colon were assessed when these mice were 8-14 weeks of age. Anxiety-like behaviors were tested using elevated plus maze and open field tests. Depression-like behavior was tested by the forced swim test. Colonic hypersensitivity to graded colorectal balloon distension (15, 30, 50 and 70mmHg) was determined by visceromotor responses (VMR) measured by electromyography of external oblique muscle. Resutls: Neonatal colorectal infusion of acetic acid but not saline significantly increased electromyographic activity in response to all of pressure colorectal distension in adults, suggesting the persistence of colonic hypersensitivity. In the elevated plus maze and open field tests, IBS mice showed a significant reduction in time spent in the open arms of elevated plus maze (control: 73.04±5.26s vs IBS: 53.54±6.53s, p<0.05) and in the center of the open field (control: 73.99±6.42s vs IBS: 37.32±4.62s, p<0.05), suggesting an anxietylike phenotype. IBS mice also showed a significant increase in immobility in the forced swim test (control: 90.05±12.08s vs IBS: 140.43±20.06s, p<0.05), suggesting an increase in depression-like behavior. Conclusion: The present results demonstrate that transient colonic irritation in the neonatal period can induce long-lasting depression-like and anxietylike behaviors. These findings provide a new paradigm for the psychological co-morbidity in functional bowel disorders.

Su2074 The Effects of Adenosine A3 Receptor Agonist on Visceral Hypersensitivity of Neonatal Maternally Separated Rat Models

Introduction: A major theme in functional bowel disorders (FBD) such as irritable bowel syndrome (IBS) is that psychological/psychiatric problems have a pathogenic role, based both on the observation that patients with FBD are more anxious and depressed than healthy control, as well as research linking stress and depression to altered gastrointestinal sensory and motor function. However, recent experimental and epidemiological studies suggest that primary visceral disturbances can lead secondarily to persistent behavioral and emotional abnormalities. The aims of the present study were to test the hypothesis that mild chemical irritation of the colon of neonatal mice can produce changes in visceral hypersensitivity and psychological behaviors that persist into adulthood. Methods: Ten-day old C57BL/6 mouse pups received an intracolonic infusion of 20 μl of 0.5% acetic acid (IBS) or saline (control) to mimic a previously validated model of IBS in rats based on neonatal visceral irritation. Psychological behaviors and pain sensitivity of the colon were assessed when these mice were 8-14 weeks of age. Anxiety-like behaviors were tested using elevated plus maze and open field tests. Depression-like behavior was tested by the forced swim test. Colonic hypersensitivity to graded colorectal balloon distension (15, 30, 50 and 70mmHg) was determined by visceromotor responses (VMR) measured by electromyography of external oblique muscle. Resutls: Neonatal colorectal infusion of acetic acid but not saline significantly increased electromyographic activity in response to all of pressure colorectal distension in adults, suggesting the persistence of colonic hypersensitivity. In the elevated plus maze and open field tests, IBS mice showed a significant reduction in time spent in the open arms of elevated plus maze (control: 73.04±5.26s vs IBS: 53.54±6.53s, p<0.05) and in the center of the open field (control: 73.99±6.42s vs IBS: 37.32±4.62s, p<0.05), suggesting an anxietylike phenotype. IBS mice also showed a significant increase in immobility in the forced swim test (control: 90.05±12.08s vs IBS: 140.43±20.06s, p<0.05), suggesting an increase in depression-like behavior. Conclusion: The present results demonstrate that transient colonic irritation in the neonatal period can induce long-lasting depression-like and anxietylike behaviors. These findings provide a new paradigm for the psychological co-morbidity in functional bowel disorders.

Comprehensive behavioral analysis of ENU-induced Disc1-Q31L and -L100P mutant mice

BackgroundDisrupted-in-Schizophrenia 1 (DISC1) is considered to be a candidate susceptibility gene for psychiatric disorders, including schizophrenia, bipolar disorder, and major depression. A recent study reported that N-ethyl-N-nitrosourea (ENU)-induced mutations in exon 2 of the mouse Disc1 gene, which resulted in the amino acid exchange of Q31L and L100P, caused an increase in depression-like behavior in 31 L mutant mice and schizophrenia-like behavior in 100P mutant mice; thus, these are potential animal models of psychiatric disorders. However, remaining heterozygous mutations that possibly occur in flanking genes other than Disc1 itself might induce behavioral abnormalities in the mutant mice. Here, to confirm the effects of Disc1-Q31L and Disc1-L100P mutations on behavioral phenotypes and to investigate the behaviors of the mutant mice in more detail, the mutant lines were backcrossed to C57BL/6JJcl through an additional two generations and the behaviors were analyzed using a comprehensive behavioral test battery.ResultsContrary to expectations, 31 L mutant mice showed no significant behavioral differences when compared with wild-type control mice in any of the behavioral tests, including the Porsolt forced swim and tail suspension tests, commonly used tests for depression-like behavior. Also, 100P mutant mice exhibited no differences in almost all of the behavioral tests, including the prepulse inhibition test for measuring sensorimotor gating, which is known to be impaired in schizophrenia patients; however, 100P mutant mice showed higher locomotor activity compared with wild-type control mice in the light/dark transition test.ConclusionsAlthough these results are partially consistent with the previous study in that there was hyperactivity in 100P mutant mice, the vast majority of the results are inconsistent with those of the previous study; this discrepancy may be explained by differences in the genetic background of the mice, the laboratory environment, experimental protocols, and more. Further behavioral studies under various experimental conditions are necessary to determine whether these Disc1 mutant mouse lines are suitable animal models of schizophrenia and major depression.

Significance of serum glucocorticoid and chelatable zinc in depression and cognition in zinc deficiency

Dietary zinc deficiency elicits neuropsychological symptoms and cognitive dysfunction. To pursue the mechanisms of these symptoms, in the present study, the relationship among serum glucocorticoid, chelatable zinc in the synaptic cleft and brain function based on behavior was examined in young rats fed a zinc-deficient diet for 4 weeks. Serum glucocorticoid level was significantly increased in zinc-deficient rats. However, the induction of in vivo dentate gyrus LTP and object recognition memory were not affected in zinc-deficient rats. Chelatable zinc levels were decreased in the stratum lucidum of the hippocampal CA3, but not in the molecular layer of the dentate gyrus. It is reported that dentate gyrus LTP and object recognition memory are affected in clioquinol (30 mg/kg)-administered rats, in which chelatable zinc is significantly decreased in the molecular layer of the dentate gyrus. Thus, the significant decrease in chelatable zinc in the molecular layer of the dentate gyrus may be required for object recognition memory deficit in zinc deficiency. On the other hand, the time of grooming in the open-field test was decreased in zinc-deficient rats. Immobility time in the forced swim test was increased in zinc-deficient rats, but not in clioquinol-administered rats, in which chelatable zinc was more markedly decreased than in zinc-deficient rats, suggesting that the lack of chelatable zinc does not increase depression-like behavior. These results suggest that the chronic increase in serum glucocorticoid level is involved in the increase in depression-like behavior rather than the decrease in chelatable zinc after 4-week zinc deficiency.

Profiling Trait Anxiety: Transcriptome Analysis Reveals Cathepsin B (Ctsb) as a Novel Candidate Gene for Emotionality in Mice

Behavioral endophenotypes are determined by a multitude of counteracting but precisely balanced molecular and physiological mechanisms. In this study, we aim to identify potential novel molecular targets that contribute to the multigenic trait “anxiety”. We used microarrays to investigate the gene expression profiles of different brain regions within the limbic system of mice which were selectively bred for either high (HAB) or low (LAB) anxiety-related behavior, and also show signs of comorbid depression-like behavior.We identified and confirmed sex-independent differences in the basal expression of 13 candidate genes, using tissue from the entire brain, including coronin 7 (Coro7), cathepsin B (Ctsb), muscleblind-like 1 (Mbnl1), metallothionein 1 (Mt1), solute carrier family 25 member 17 (Slc25a17), tribbles homolog 2 (Trib2), zinc finger protein 672 (Zfp672), syntaxin 3 (Stx3), ATP-binding cassette, sub-family A member 2 (Abca2), ectonucleotide pyrophosphatase/phosphodiesterase 5 (Enpp5), high mobility group nucleosomal binding domain 3 (Hmgn3) and pyruvate dehydrogenase beta (Pdhb). Additionally, we confirmed brain region-specific differences in the expression of synaptotagmin 4 (Syt4).Our identification of about 90 polymorphisms in Ctsb suggested that this gene might play a critical role in shaping our mouse model's behavioral endophenotypes. Indeed, the assessment of anxiety-related and depression-like behaviors of Ctsb knock-out mice revealed an increase in depression-like behavior in females.Altogether, our results suggest that Ctsb has significant effects on emotionality, irrespective of the tested mouse strain, making it a promising target for future pharmacotherapy.

Prolonged Depression-Like Behavior Caused by Immune Challenge: Influence of Mouse Strain and Social Environment

Immune challenge by bacterial lipopolysaccharide (LPS) causes short-term behavioral changes indicative of depression. The present study sought to explore whether LPS is able to induce long-term changes in depression-related behavior and whether such an effect depends on mouse strain and social context. LPS (0.83 mg/kg) or vehicle was administered intraperitoneally to female CD1 and C57BL/6 mice that were housed singly or in groups of 4. Depression-like behavior was assessed with the forced swim test (FST) 1 and 28 days post-treatment. Group-housed CD1 mice exhibited depression-like behavior 1 day post-LPS, an effect that leveled off during the subsequent 28 days, while the behavior of singly housed CD1 mice was little affected. In contrast, singly housed C57BL/6 mice responded to LPS with an increase in depression-like behavior that was maintained for 4 weeks post-treatment and confirmed by the sucrose preference test. Group-housed C57BL/6 mice likewise displayed an increased depression-like behavior 4 weeks post-treatment. The behavioral changes induced by LPS in C57BL/6 mice were associated with a particularly pronounced rise of interleukin-6 in blood plasma within 1 day post-treatment and with changes in the dynamics of the corticosterone response to the FST. The current data demonstrate that immune challenge with LPS is able to induce prolonged depression-like behavior, an effect that depends on genetic background (strain). The discovery of an experimental model of long-term depression-like behavior after acute immune challenge is of relevance to the analysis of the epigenetic and pathophysiologic mechanisms of immune system-related affective disorders.

Kinin B1 receptors mediate depression-like behavior response in stressed mice treated with systemic E. coli lipopolysaccharide.

BackgroundKinin B1 receptors are inducible molecules up-regulated after inflammatory stimuli. This study evaluated the relevance of kinin B1 receptors in a mouse depression behavior model.MethodsMice were exposed to a 5-min swimming session, and 30 min later they were injected with E. coli lipopolysaccharide (LPS). Depression-like behavior was assessed by determining immobility time in a tail suspension test. Different brain structures were collected for molecular and immunohistochemical studies. Anhedonia was assessed by means of a sucrose intake test.ResultsOur protocol elicited an increase in depression-like behavior in CF1 mice, as assessed by the tail-suspension test, at 24 h. This behavior was significantly reduced by treatment with the selective B1 receptor antagonists R-715 and SSR240612. Administration of SSR240612 also prevented an increase in number of activated microglial cells in mouse hippocampus, but did not affect a reduction in expression of mRNA for brain-derived neurotrophic factor. The increased immobility time following LPS treatment was preceded by an enhancement of hippocampal and cortical B1 receptor mRNA expression (which were maximal at 1 h), and a marked production of TNFα in serum, brain and cerebrospinal fluid (between 1 and 6 h). The depression-like behavior was virtually abolished in TNFα p55 receptor-knockout mice, and increased B1 receptor mRNA expression was completely absent in this mouse strain. Furthermore, treatment with SSR240612 was also effective in preventing anhedonia in LPS-treated mice, as assessed using a sucrose preference test.ConclusionOur data show, for the first time, involvement of kinin B1 receptors in depressive behavioral responses, in a process likely associated with microglial activation and TNFα production. Thus, selective and orally active B1 receptor antagonists might well represent promising pharmacological tools for depression therapy.

Knockdown of Clock in the Ventral Tegmental Area Through RNA Interference Results in a Mixed State of Mania and Depression-Like Behavior

Circadian rhythm abnormalities are strongly associated with bipolar disorder; however the role of circadian genes in mood regulation is unclear. Previously, we reported that mice with a mutation in the Clock gene (ClockDelta19) display a behavioral profile that is strikingly similar to bipolar patients in the manic state. Here, we used RNA interference and viral-mediated gene transfer to knock down Clock expression specifically in the ventral tegmental area (VTA) of mice. We then performed a variety of behavioral, molecular, and physiological measures. We found that knockdown of Clock, specifically in the VTA, results in hyperactivity and a reduction in anxiety-related behavior, which is similar to the phenotype of the ClockDelta19 mice. However, VTA-specific knockdown also results in a substantial increase in depression-like behavior, creating an overall mixed manic state. Surprisingly, VTA knockdown of Clock also altered circadian period and amplitude, suggesting a role for Clock in the VTA in the regulation of circadian rhythms. Furthermore, VTA dopaminergic neurons expressing the Clock short hairpin RNA have increased activity compared with control neurons, and this knockdown alters the expression of multiple ion channels and dopamine-related genes in the VTA that could be responsible for the physiological and behavioral changes in these mice. Taken together, these results suggest an important role for Clock in the VTA in the regulation of dopaminergic activity, manic and depressive-like behavior, and circadian rhythms.

Repeated social defeat stress induces chronic hyperthermia in rats

Psychological stressors are known to increase core body temperature ( T c) in laboratory animals. Such single stress-induced hyperthermic responses are typically monophasic, as T c returns to baseline within several hours. However, studies on the effects of repeated psychological stress on T c are limited. Therefore, we measured T c changes in male Wistar rats after they were subjected to 4 social defeat periods (each period consisting of 7 daily 1 h stress exposures during the light cycle followed by a stress-free day). We also assessed affective-like behavioral changes by elevated plus maze and forced swim tests. In the stressed rats, the first social defeat experience induced a robust increase in T c (+ 1.3 °C). However, the T c of these rats was not different from control animals during the subsequent dark period. In comparison, after 4 periods of social defeat, stressed rats showed a small but significantly higher (+ 0.2–0.3 °C) T c versus control rats during both light and dark periods. Stressed rats did not show increased anxiety-like behavior versus control rats as assessed by the elevated plus maze test. However, in the forced swim test, the immobility time of stressed rats was significantly longer versus control rats, suggesting an increase in depression-like behavior. Furthermore, hyperthermia and depression-like behavior were still observed 8 days after cessation of the final social defeat session. These results suggest that repeated social defeat stress induces a chronic hyperthermia in rats that is associated with behavior resembling depression but not anxiety.

Reduction in hippocampal neurogenesis and increase in depression-like behavior in zinc-deficient young rats

Reduction in hippocampal neurogenesis and increase in depression-like behavior in zinc-deficient young rats

Susceptibility to stress in young rats after 2-week zinc deprivation

Dietary zinc deficiency elicits abnormal behavior in stressful environment. It is possible that abnormal corticosterone secretion in zinc deficiency is linked to abnormal behavior. To understand the increase in depression-like behavior in zinc deficiency, in the present study, serum corticosterone concentration was checked in young rats fed a zinc-deficient diet for 2 weeks after exposure to acute stress. Serum corticosterone concentration was higher in zinc-deficient rats after exposure to water-immersed and forced swim stress. Immobility time in the forced swim test was significantly increased in zinc-deficient rats, but not in pair-fed rats, suggesting that the increase in depression-like behavior is due to zinc deficiency rather than decreased food intake. The increase in immobility time in zinc deficiency was restored to the control level by feeding of the control diet. In dexamethasone suppression test, serum corticosterone concentration was markedly decreased in both the control and zinc-deficient rats. These results suggest that excessive corticosterone secretion after exposure to stress is linked to the increase in depression-like behavior in zinc deficiency. It has been reported that exposure to stress and glucocorticoids facilitates the increase in extracellular glutamate in the hippocampus. When the hippocampus was stimulated with 100mM KCl, the concentration of extracellular glutamate was more increased in zinc-deficient rats. In hippocampal slices from zinc-deficient rats, the decrease in FM4-64 fluorescence (exocytosis) was more facilitated. It is likely that zinc deficiency excessively excites glutamatergic neurons in the hippocampus after exposure to acute stress. This excessive excitation seems to contribute to susceptibility to stress after 2-week zinc deprivation and its related behavior such as the increase in depression-like behavior.

Abstinence following Alcohol Drinking Produces Depression-Like Behavior and Reduced Hippocampal Neurogenesis in Mice

Alcoholism and depression show high degrees of comorbidity. Clinical evidence also indicates that depression that emerges during abstinence from chronic alcohol use has a greater negative impact on relapse than pre-existing depression. Although no single neurobiological mechanism can account for the behavioral pathologies associated with these devastating disorders, converging evidence suggests that aspects of both alcoholism and depression are linked to reductions in hippocampal neurogenesis. Here, we report results from a novel preclinical behavioral model showing that abstinence from voluntary alcohol drinking leads to the emergence of depression-like behavior and reductions in neurogenesis. C57BL/6J mice were allowed to self-administer ethanol (10% v/v) vs H(2)O in the home cage for 28 days. Alcohol was then removed for 1 or 14 days, and mice were tested in the forced swim test to measure depression-like behavior. After 14 days, but not 1 day of abstinence from alcohol drinking, mice showed a significant increase in depression-like behavior. The significant increase in depression-like behavior during abstinence was associated with a reduction in proliferating cell nuclear antigen (PCNA) and doublecortin (DCX) immunoreactivity in the dentate gyrus of the hippocampus indicating that both the number of proliferating neural progenitor cells (NPC) and immature neurons were reduced, respectively. The number of NPCs that were labeled with bromo-deoxyuridine (BrdU) at the beginning of alcohol exposure was not altered indicating that survival of NPCs is not linked to abstinence-induced depression. Chronic treatment (14 days) with the antidepressant desipramine during abstinence prevented both the emergence of depression-like behavior and the reduction in hippocampal neurogenesis indicating that abstinence-induced depression is associated with structural plasticity in the hippocampus. Overall, the results of this study support the conclusion that profound functional (i.e. behavioral) and structural changes occur during abstinence from alcohol use and suggest that antidepressant treatment may alleviate some of these pathological neurobehavioral adaptations.

Brain-Derived Neurotrophic Factor Conditional Knockouts Show Gender Differences in Depression-Related Behaviors

Indirect evidence suggests that loss of brain-derived neurotrophic factor (BDNF) from forebrain regions contributes to an individual's vulnerability for depression, whereas upregulation of BDNF in these regions is suggested to mediate the therapeutic effect of antidepressants. We have tested this hypothesis by generating two independent lines of conditional BDNF knockout mice in which the BDNF gene is deleted selectively in forebrain. We show that male conditional knockouts exhibit hyperactivity but normal depression-related behaviors. In contrast, female conditional knockouts display normal locomotor activity but a striking increase in depression-like behavior. We also demonstrate that loss of BDNF in both male and female mice attenuates the actions of the antidepressant desipramine in the forced swim test. These gender differences in depression-related behaviors in BDNF conditional knockout mice provide direct evidence for a role of BDNF in depression. The results also support the view that forebrain BDNF may be essential in mediating antidepressant efficacy.