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Myocardial infarction (MI) with subsequent depression is associated with increased cardiac mortality. Impaired central mineralocorticoid (MR) and glucocorticoid receptor (GR) equilibrium has been suggested as a key mechanism in the pathogenesis of human depression. Here, we investigate if deficient central MR/GR signaling is causative for a poor outcome after MI in mice. Mice with an inducible forebrain-specific MR/GR knockout (MR/GR-KO) underwent baseline and follow-up echocardiography every 2 weeks after MI or sham operation. Behavioral testing at 4 weeks confirmed significant depressive-like behavior and, strikingly, a higher mortality after MI, while cardiac function and myocardial damage remained unaffected. Telemetry revealed cardiac autonomic imbalance with marked bradycardia and ventricular tachycardia (VT) upon MI in MR/GR-KO. Mechanistically, we found a higher responsiveness to atropine, pointing to impaired parasympathetic tone of 'depressive' mice after MI. Serum corticosterone levels were increased but-in line with the higher vagal tone-plasma and cardiac catecholamines were decreased. MR/GR deficiency in the forebrain led to significant depressive-like behavior and a higher mortality after MI. This was accompanied by increased vagal tone, depleted catecholaminergic compensatory capacity and VTs. Thus, limbic MR/GR disequilibrium may contribute to the impaired outcome of depressive patients after MI and possibly explain the lack of anti-depressive treatment benefit., (© 2022. The Author(s).)

Rapid-acting antidepressants disprove the dogma that antidepressants need several weeks to become clinically effective. Ketamine, the prototype of a rapid-acting antidepressant, is an N‑methyl-D-aspartate (NMDA) receptor blocking agent. A single i.v. application of ketamine induces rapid changes in glutamatergic neurotransmitter systems, leading to preferential activation of glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. This evokes the activation of brain-derived neurotrophic factor (BDNF), causing plastic changes in the central nervous system within 24 h. In the prefrontal cortex ketamine leads to a regeneration of synaptic contacts, which have been damaged by chronic stress. This regeneration correlates with improvement of depression-like behavioral changes in rodent models. Classical monoaminergic antidepressants can cause similar changes but with considerably longer latency periods. For clinical application a nasal spray of esketamine has been developed, since this enantiomer has the highest affinity for NMDA receptors; however, since R‑ketamine and certain ketamine metabolites also have antidepressant effects in preclinical models, these are currently being tested in clinical studies. Moreover, there are many other glutamatergic substances under clinical investigation for antidepressant effects without ketamine-like adverse effects. In addition, there are also several promising rapid-acting antidepressants that do not primarily act via the glutamate system, such as the gamma-aminobutyric acid (GABA) receptor modulator brexanolone or the serotonin receptor agonist psilocybin., (© 2021. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The molecular background of depression is intensively studied in terms of alterations of inhibitory circuits, mediated by gamma aminobutyric acid (GABA) signalization. We investigated the effects of chronic social isolation (CSIS) and chronic fluoxetine (Flx) treatment (15 mg/kg/day) (3 weeks), on Parvalbumin (PV) and GAD67 expression in a layer-specific manner in rat dorsal hippocampal subregions. CSIS-induced depressive- and anxiety-like behaviours were confirmed with decrease in sucrose preference and increase in marble burying during behavioural testing, while Flx antagonized these effects. CSIS altered PV expression in stratum pyramidale (SP) of dorsal cornu ammonis 1 (dCA1) and stratum radiatum (SR) of dCA3. Flx antagonized this effect, and boosted PV expression in SP of the entire dCA and the dorsal dentate gyrus (dDG), as well as in the SR of dCA1/CA3. CSIS showed no significant effects on GAD67 expression, while Flx boosted its expression within the SR of the entire CA and SO of the dCA3. A correlation between SP of dCA1 and SR of dCA3 with regard to PV changes, implicates their possible role in the inhibitory circuit alterations. Flx-induced increase in GAD67 expression, specifically in SR of the entire dHIPP, may impose its involvement in the cell metabolic processes. Strong negative correlation between GAD67 and sucrose preference following Flx-treatment of CSIS rats was revealed. PV + cells of the SP layer of dCA1 and CA2 could be a potential target for the antidepressant action of Flx, while strong effect of Flx on GAD67 expression in the SR should be more extensively studied., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Tianeptine (Tian) has been widely used in treating mood and anxiety disorders, and recently as a nootropic to improve cognitive performance. However, its mechanisms of action are insufficiently clear. We used a comparative proteomic approach to identify sub-proteome changes in hippocampal cytosol and non-synaptic mitochondria (NSM) following chronic Tian treatment (3 weeks, 10 mg/kg/day) of adult male Wistar rats and rats exposed to chronic social isolation stress (CSIS) (6 weeks), an animal model of depression. Behavioural assessment of depressive and anxiety-like behaviours was based on sucrose preference, forced swim test and marble burying. Selected differently expressed proteins were validated by Western blot and/or immunohistochemical analysis. Tian normalized the behavioural alternations induced by CSIS, indicating its antidepressant and anxiolytic efficacy. Proteomic data showed that Tian increased the expression of proteasome system elements and redox system enzymes, enhanced energy metabolism and increased glyceraldehyde-3-phosphate dehydrogenase expression bound to NSM in control rats. Tian-treatment of CSIS-stressed rats resulted in a minor suppression of the increase in proteasome elements and antioxidative enzymes, except for an increase in Cu-Zn superoxide dismutase, and increased the level of Lactate dehydrogenase. Our results indicate on an increased NSM functionality in controls and suppression of the CSIS-induced impairment of NSM functionality by Tian treatment as well as on the CSIS-caused discrepancy in Tian effects relative to controls., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

Animal models in psychiatric research are indispensable for insights into mechanisms of behaviour and mental disorders. Distress is an important aetiological factor in psychiatric diseases, especially depression, and is often used to mimic the human condition. Modern bioethics requires balancing scientific progress with animal welfare concerns. Therefore, scientifically based severity assessment of procedures is a prerequisite for choosing the least compromising paradigm according to the 3Rs principle. Evidence-based severity assessment in psychiatric animal models is scarce, particularly in depression research. Here, we assessed severity in a cognitive depression model by analysing indicators of stress and well-being, including physiological (body weight and corticosterone metabolite concentrations) and behavioural (nesting and burrowing behaviour) parameters. Additionally, a novel approach for objective individualised severity grading was employed using clustering of voluntary wheel running (VWR) behaviour. Exposure to the paradigm evoked a transient elevation of corticosterone, but neither affected body weight, nesting or burrowing behaviour. However, the performance in VWR was impaired after recurrent stress exposure, and the individual severity level increased, indicating that this method is more sensitive in detecting compromised welfare. Interestingly, the direct comparison to a somatic, chemically induced colitis model indicates less distress in the depression model. Further objective severity assessment studies are needed to classify the severity of psychiatric animal models in order to balance validity and welfare, reduce the stress load and thus promote refinement.

Aims: Myocardial infarction (MI) and heart failure (HF) are risk factors for the development of depression, additionally worsening the quality of life and patient outcome. How HF causes depression and how depression promotes HF remain mechanistically unclear, which is at least partly caused by the difficulty of in vivo modelling of psychosomatic co-morbidity. We aimed to study the potential sequence of events with respect to different depression aspects upon HF., Methods and Results: Male C57BL6 mice underwent MI, followed by behavioural and echocardiographic characterization. Motility, exploration, and anxiety-like behaviour were unaffected in mice after MI. We did not observe increased depressive-like behaviour in the sucrose preference, tail suspension, or Porsolt forced swim test. Mice did not display signs of learned helplessness (LH) when compared to sham. Accordingly, cluster analysis revealed only a slightly higher quota of LH in HF (38%) vs. sham mice (32%). But strikingly, three-group cluster analysis revealed an additional intermediate subpopulation at risk for LH after HF (29%). Interestingly, this population featured elevated cardiac expression of nr4a1., Conclusions: The LH paradigm uncovered a subtle predisposition to depressive-like behaviour after MI, whereas testing for anhedonia and despair was insufficient to show a behavioural shift in mice. Therefore, we suggest an accumulating risk profile and a multiple-hits hypothesis regarding the pathogenesis of co-morbid depression after MI. Symptoms of LH may present a marker of subclinical depression after MI, the impact of which remains to be investigated. The proposed sequence of behavioural testing enables the mechanistic dissection of cardio-psychogenic signalling in the future., (© 2019 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Exposure of an organism to chronic social isolation (CSIS) has been shown to have an important role in depression. Fluoxetine (Flx) is a first-line treatment for depression; however, its downstream mechanisms of action beyond serotonergic signaling remain ill-defined. We investigated the effect of 3 weeks of Flx (15 mg/kg/day) treatment on behavioral changes and protein expression/activity of the GSH-dependent defense system, including reduced glutathione (GSH), glutathione peroxidase (GPx), glutathione reductase (GLR), and glutathione S-transferase (GST), as well as catalase (CAT), in the hippocampus of rats exposed to 6 weeks of CSIS. The subcellular distributions of nuclear factor-κB (NF-κB), as well as, cytosolic IL-1β and IL-6 protein expression, were also determined. CSIS induced depressive- and anxiety-like behaviors, evidenced by a decrease in sucrose preference and an increase in the number of buried marbles. Moreover, CSIS compromised redox homeostasis, targeting enzymes such as GPx, CAT, GST, and caused NF-κB nuclear translocation with a concomitant increase in IL-6 protein expression, without an effect on IL-1β. Flx treatment reversed CSIS-induced depressive- and anxiety-like behaviors, modulated GSH-dependent defense by increasing GLR and GST activity, and suppressed NF-κB activation and cytosolic IL-6 protein expression in socially isolated rats. The present study suggests that changes in the GSH-dependent defense system, NF-κB activation and increased IL-6 protein expression may have a role in social isolation-induced changes in a rat model of depression and anxiety, and contributes to our understanding of the mechanisms that underlie the antidepressant and anti-inflammatory activity of Flx in socially isolated rats.

Morc1 gene has recently been identified by a DNA methylation and genome-wide association study as a candidate gene for major depressive disorder related to early life stress in rodents, primates and humans. So far, no transgenic animal model has been established to validate these findings on a behavioral level. In the present study, we examined the effects of a Morc1 loss of function mutation in female C57BL/6N mice on behavioral correlates of mood disorders like the Forced Swim Test, the Learned Helplessness Paradigm, O-Maze and Dark-Light-Box. We could show that Morc1(-/-) mice display increased depressive-like behavior whereas no behavioral abnormalities regarding locomotor activity or anxiety-like behavior were detectable. CORT plasma levels did not differ significantly between Morc1(-/-) mice and their wildtype littermates, yet - surprisingly - total Bdnf mRNA-levels in the hippocampus were up-regulated in Morc1(-/-) animals. Although further work would be clarifying, Morc1(-/-) mice seem to be a promising epigenetically validated mouse model for depression associated with early life stress., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Increasing paternal age is known to be associated with a great variety of psychiatric disorders such as schizophrenia or autism. Hence the factor "age" may be taken as strategic tool to analyse specific scientific hypotheses. Additionally, this finding also needs to be addressed in rather pragmatically performed breeding protocols of model organisms, since otherwise artefacts may challenge the validity of the results. Our study was performed to investigate influences of advanced age of mouse dams (30 vs. 16weeks) on maternal- and offspring behaviour. Adult offspring of both sexes was analysed in a test battery comprising paradigms for exploration, anxiety and depressive-like behaviours. Final blood sampling was conducted for stressphysiological analysis. Interestingly, advanced age of the mothers was associated with increased nest-building quality while maternal activity was unaffected. Moreover "maternal (mice) age" (MA) affected emotionality in the offspring, which became apparent in the dark-light box and the social recognition paradigm. These findings not only emphasize MA to model a potent risk factor with regard to emotional stability, but also underscore the vast necessity to include information about breeding protocols into the methods section of any animal study., (Copyright © 2015. Published by Elsevier Inc.)

The concept of learned helplessness defines an escape or avoidance deficit after uncontrollable stress and is regarded as a depression-like coping deficit in aversive but avoidable situations. Based on a psychological construct, it ideally complements other stress-induced or genetic animal models for major depression. Because of excellent face, construct, and predictive validity, it has contributed to the elaboration of several pathophysiological concepts and has brought forward new treatment targets. Whereas learned helplessness can be modeled not only in a broad variety of mammals, but also in fish and Drosophila, we will focus here on the use of this model in rats and mice, which are today the most common species for preclinical in vivo research in psychiatry.

The incidence of major depression is known to be influenced by both genetic and environmental factors. In the current study, we therefore set out to investigate depressive-like behavior and its modification by environmental enrichment using rats bred for 'learned helplessness'. 45 males of congenitally helpless (cLH, n=22) and non-helpless (cNLH, n=23) rats of two different generations were used to systematically investigate differential effects of environmental enrichment on learned helpless behavior, anhedonic-like behavior (sweetened condensed milk consumption) and spontaneous behavior in the home cage. While enrichment was found to reduce learned helpless behavior in 14 weeks old, but not 28 weeks old cLH rats, it did not affect the consumption of sweetened condensed milk. Regarding the home cage behavior, no consistent changes between rats of different strains, housing conditions, and ages were observed. We could thus demonstrate that a genetic predisposition for learned helplessness may interact with environmental conditions in mediating some, but not all depressive-like symptoms in congenitally learned helpless rats. However, future efforts are needed to isolate the differential benefits of environmental factors in mediating the different depression-related symptoms., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The glutamate system is thought to play an important role in modulating mood and anxiety. Ionotropic NMDA receptors critically influence neuronal circuits regulating emotional behaviour. Their pharmacological blockade triggers fast antidepressant and anxiolytic effects. In line with this concept, ablation of the GluN2A subunit of NMDA receptors induces antidepressant and anxiolytic effects. However, it is not known if absence of the GluN2A-containing NMDA channel or of the GluN2A-mediated intracellular signalling is responsible for these effects. To further investigate the contribution of the GluN2A-containing NMDA receptors in mood disorders we analysed mice lacking the intracellular C-terminus of the GluN2A subunit (GluN2AΔC/ΔC) in tests relevant for anxiety and depression. Interestingly, GluN2AΔC/ΔC mice showed decreased anxiety, but no anti-depressive-like phenotype, indicating a predominant role of the intracellular signalling of the GluN2A subunit in anxiety. These data suggest distinct roles of the GluN2A subunit as whole vs. its intracellular domain in modulating anxiety and depression-like symptoms and reveal differential molecular targets for the therapy of mood and anxiety disorders., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Disturbances in cognitive functioning are among the most debilitating problems experienced by patients with major depression. Investigations of these deficits in animals help to extend and refine our understanding of human emotional disorder, while at the same time providing valid tools to study higher executive functions in animals. We employ the "learned helplessness" genetic rat model of depression in studying working memory using an eight arm radial maze procedure with temporal delay. This so-called delayed spatial win-shift task consists of three phases, training, delay and test, requiring rats to hold information on-line across a retention interval and making choices based on this information in the test phase. According to a 2×2 factorial design, working memory performance of thirty-one congenitally helpless (cLH) and non-helpless (cNLH) rats was tested on eighteen trials, additionally imposing two different delay durations, 30 s and 15 min, respectively. While not observing a general cognitive deficit in cLH rats, the delay length greatly influenced maze performance. Notably, performance was most impaired in cLH rats tested with the shorter 30 s delay, suggesting a stress-related disruption of attentional processes in rats that are more sensitive to stress. Our study provides direct animal homologues of clinically important measures in human research, and contributes to the non-invasive assessment of cognitive deficits associated with depression.

Investigations of cognitive biases in animals are conceptually and translationally valuable because they contribute to animal welfare research and help to extend and refine our understanding of human emotional disorders, where biased information processing is a critical causal and maintenance factor. We employed the "learned helplessness" genetic rat model of depression in studying cognitive bias and its modification by environmental manipulations. Using a spatial judgment task, responses to ambiguous spatial cues were assessed before and after environmental enrichment to test whether this manipulation would cause an optimistic shift in emotional state. Twenty-four congenitally helpless and nonhelpless male rats were trained to discriminate two different locations, "rewarded" versus "aversive." After successful acquisition of this spatial discrimination, cognitive bias was probed by measuring responses to three ambiguous locations. Latencies to "reach" and to actively "choose" a goal pot were recorded alongside exploratory behaviors. An overall strain difference was observed, with helpless rats displaying longer "reach" latencies than nonhelpless rats. This implies a "pessimistic" response bias in helpless rats, underscoring their depressive-like phenotype. No strain differences were observed regarding other behavioral measures. Half of the animals were then transferred to enriched cages and retested. Environmental enrichment resulted in reduced "choose" latencies in both rat strains, associating enrichment with more optimistic interpretations of ambiguous cues. Our results emphasize the suitability of cognitive bias measurement for animal emotion assessment. They extend the methodological repertoire for characterizing complex phenotypes and bear implications for animal welfare research and for the use of animal models in preclinical research.

Objectives: Recent evidence suggests that alterations in hippocampal glutamate and γ-aminobutyric acid (GABA) are associated with the pathomechanism of depression and treatment effects of electroconvulsive therapy (ECT). Thus, proton magnetic resonance spectroscopy (¹H MRS) at a 9.4 T animal system seems a promising tool to study underlying mechanisms since it allows for an accurate quantification of metabolites with distinction of glutamate, GABA and glutamine, as well as separation of taurine from choline., Methods: A well-validated animal model of treatment resistant depression (congenital learned helpless rats = cLH) was investigated by hippocampal in vivo ¹H MRS with and without a 1-week course of electroconvulsive shocks (ECS), an animal model of ECT, and compared to wild type (WT) animals, while saline and clomipramine injections served as additional controls., Results: Untreated cLH rats showed significantly lower glucose and higher taurine concentrations compared to WT animals. Besides alterations on these metabolites, ECS increased glutamate in WT and cLH and choline in cLH rats. Moreover, correlations between glutamate and GABA concentrations with learned helpless behaviour were revealed., Conclusions: These findings support the idea of disordered hippocampal metabolism in an animal model of treatment resistant depression and suggest an early impact of ECS on MR-detectable hippocampal metabolites.

Background: Although poststroke depression (PSD) is a frequent chronic complication of stroke with high relevance for outcome and survival, underlying pathomechanisms remain inadequately understood. This may be because suitable animal models are largely lacking and existing models are poorly characterized., Methods: Male 129/SV mice were subjected to 30-min middle cerebral artery occlusion (MCAo)/reperfusion and serial magnetic resonance imaging scans. A subset of animals received selective serotonin reuptake inhibitor citalopram starting 7 days after MCAo. Behavioral assessment was performed at 14 weeks. To identify biological correlates of PSD, we quantified corticosterone levels in serum and brain-derived neurotrophic factor levels in brain. The integrity of the mesolimbic dopaminergic system was assessed using tyrosine hydroxylase and dynorphin in situ hybridizations as well as dopamine transporter autoradiography., Results: Left, but not right, MCAo, elicited anhedonia and increased anxiety and despair. This depression-like syndrome was associated with alterations in the mesolimbic reward system. MCAo resulted in delayed degeneration of dopaminergic neurons in ipsilateral midbrain, which was accompanied by reduced dopamine concentrations and decreased levels of dopamine transporter density along with increased brain-derived neurotrophic factor protein levels in ischemic striatum and increased dynorphin messenger RNA expression in nucleus accumbens. Chronic antidepressant treatment initiated as late as 7 days after stroke reversed the behavioral phenotype, prevented degeneration of dopaminergic midbrain neurons, and attenuated striatal atrophy at 4 months., Conclusions: Our results highlight the importance of the dopaminergic system for the development of PSD. Prevention of secondary neurodegeneration by antidepressants may provide a novel target for subacute stroke therapy., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The dopamine D(2)/D(3) receptor agonist pramipexole exerts antidepressive capacities in patients with Parkinson's disease with little evidence for patients with affective diseases only. Little is known about the neurobiological basis of these antidepressive effects. In this study, C57BL/6N mice received acute or chronic (3 weeks) treatment with pramipexole in different dosages (0.1, 0.3, 1, and 3mg/kg b.w.) and imipramine or saline serving as positive and negative controls. To characterize antidepressant-like effects mice underwent behavioral characterization. In a second experiment dosages of pramipexole shown to be effective were used and candidate brain regions including hippocampus, frontal cortex and striatum were analyzed for levels of 5-hydroxytryptamine (5-HT), noradrenaline and dopamine and their metabolites as well as brain-derived neurotrophic factor (BDNF) to investigate possible neurochemical correlates of behavioral changes. Whereas acute treatment with pramipexole resulted in antidepressive-like effects in the Porsolt Forced Swim Test, Novel Cage Test, Openfield Test and Dark-light-Box Test and a tendency but insignificant effect in the Tail Suspension Test, chronic treatment did not show significant effects in any of the behavioral analyses. Neurochemical analyses revealed a highly significant effect on dopaminergic metabolites in the striatum as well as a moderate transient modulation of the serotonergic system in the hippocampus. BDNF levels were not affected by any dosage and treatment regime in any brain region investigated. In conclusion, the present data substantiate antidepressive effects of pramipexole and indicate a contribution of the dopaminergic and serotonergic metabolism in these effects, but argue against an eminent role of BDNF., (Copyright © 2011 Elsevier B.V. All rights reserved.)

According to the "neurotrophin hypothesis", brain-derived neurotrophic factor (BDNF) is an important candidate gene in depression. Moreover, environmental stress is known to represent a risk factor in the pathophysiology and treatment of this disease. To elucidate, whether changes of BDNF availability signify cause or consequence of depressive-like alterations, it is essential to look for endophenotypes under distinct genetic conditions (e.g. altered BDNF expression). Furthermore it is crucial to examine environment-driven BDNF regulation and its effect on depressive-linked features. Consequently, gene × environment studies investigating prospective genetic mouse models of depression in different environmental contexts become increasingly important. The present review summarizes recent findings in BDNF-mutant mice, which have been controversially discussed as models of depression and anxiety. It furthermore illustrates the potential of environment to serve as naturalistic stressor with the potential to modulate the phenotype in wildtype and mutant mice. Moreover, environment may exert protective effects by regulating BDNF levels as attributed to "environmental enrichment". The effect of this beneficial condition will also be discussed with regard to probable "curative/therapeutic" approaches., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

5-alpha-reductase is involved as a rate-imitating enzyme in the metabolism of steroids. Several 5-alpha-reduced steroids such as dihydrotestosterone, allopregnanolone or tetrahydrocorticosterone have neurotrophic, neuroprotective, and anxiolytic properties. Reduced 5-alpha-reductase activity has been observed during depressive illness in humans. Finasteride inhibits 5-alpha-reductase and can robustly induce anxious and depressive behaviors in rodents. In humans finasteride treatment has been linked to an increase of depressive symptoms. A recent study reported that finasteride treatment inhibits hippocampal neurogenesis in mice. As hippocampal neurogenesis has been linked to emotional behavior, this could be of possible relevance for the pathophysiology of affective disorders. Further studies are needed to evaluate potential neuropsychiatric side effects of finasteride treatment in humans., (© 2010 Wiley Periodicals, Inc.)

Behavioural studies using transgenic techniques in mice usually require extensive backcrossing to a defined background strain, e.g. to C57BL/6. In this study we investigated whether backcrossing can be replaced by using the 129SvEv strain from which the embryonic stem cells are generally obtained for gene targeting strategies to analyze e.g. depression-like behaviour. For that purpose we subjected male and female 129SvEv mice to two frequently used depression tests and compared them with commonly used C57BL/6 mice. 129SvEv and C57BL/6 mice exhibited differing profiles with regard to locomotion and pain sensitivity. However, in the learned helplessness paradigm, a procedure, which represents a valid method to detect depressive-like behaviour, 129SvEv animals develop a similar level of helplessness as C57BL/6 mice. One great advantage of the 129SvEv animals though, is the fact that in this strain even females develop helplessness, which could not be produced in C57BL/6 mice. In the tail suspension test, both genders of 129SvEv exhibited more despair behaviour than C57BL/6 animals. We therefore suggest that this strain may be utilized in the establishment of new test procedures for affective diseases, since costly and time-consuming backcrossing can be prevented, depressive-like behaviour may be analyzed effectively, and gender-specific topics could be addressed in an adequate way., (Copyright 2010 Elsevier B.V. All rights reserved.)

Epidemiological studies have revealed a strong genetic contribution to the risk for depression. Both reduced hippocampal serotonin neurotransmission and brain-derived neurotrophic factor (BDNF) levels have been associated with increased depression vulnerability and are also regulated during aging. Brains from young (5 months old) and old (13 months old) congenital Learned Helplessness rats (cLH), and congenital Non Learned Helplessness rats (cNLH) were immunohistochemically stained for the serotonin transporter and subsequently stereologically quantified for estimating hippocampal serotonin fiber density. Hippocampal BDNF protein levels were measured by ELISA. An exacerbated age-related loss of serotonin fiber density specific for the CA1 area was observed in the cLH animals, whereas reduced hippocampal BDNF levels were seen in young and old cLH when compared with age-matched cNLH controls. These observations indicate that aging should be taken into account when studying the neurobiological factors behind the vulnerability for depression and that understanding the effect of aging on genetically predisposed individuals may contribute to a better understanding of the pathophysiology behind depression, particularly in the elderly.

Increasing evidence suggests that depression is characterised by impaired brain plasticity that might originate from the interaction between genetic and environmental risk factors. Hence, the aim of this study was to investigate changes in neuroplasticity following exposure to stress, an environmental condition highly relevant to psychiatric disorders, in glucocorticoid receptor-deficient mice (GR(+/-)), a genetic model of predisposition to depression. Specifically, we have analysed the neurotrophin brain-derived neurotrophic factor (BDNF) and the immediate-early gene activity-regulated cytoskeletal-associated protein (Arc), two closely related molecules that can contribute to neuroplastic and morphological changes observed in depression. We found a region-specific influence of the GR-genotype on BDNF levels both under basal and stress conditions. Steady-state levels of BDNF mRNA were unchanged in hippocampus while up-regulated in frontal lobe of GR(+/-) mice. Following exposure to an acute stress, increased processing from pro- to mature BDNF was observed in hippocampal synaptosomes of wild-type mice, but not in GR mutants. Furthermore, the stress-dependent modulation of Arc was impaired in the hippocampus of GR(+/-) mice. These results indicate that GR(+/-) mice show overt differences in the stress-induced modulation of neuroplastic proteins, which may contribute to pathologic conditions that may originate following gene x environment interaction.

Negative cognitive bias-the tendency to interpret ambiguous situations pessimistically-is a central feature of stress-related disorders such as depression. The underlying neurobiology of this bias, however, remains unclear, not least because of a lack of translational tools. We established a new ambiguous-cue interpretation paradigm and, with respect to the etiology of depression, evaluated if environmental and genetic factors contribute to a negative bias. Rats were trained to press a lever to receive a food reward contingent to one tone and to press another lever in response to a different tone to avoid punishment by electric foot-shock. In the ambiguous-cue test, the lever-press responses to tones with frequencies intermediate to the trained tones were taken as indicators for the rats' expectation of a positive or negative event. A negative response bias because of decreased positive and increased negative responding was found in congenitally helpless rats, a genetic animal model of depression. Moreover, treatment with a combined noradrenergic-glucocorticoid challenge, mimicking stress-related changes in endogenous neuromodulation, biased rats away from positive responding. This response shift was accompanied by neuronal activation in dentate gyrus and amygdala. Thus, environmental and genetic risk factors for depression induce a response bias, which resembles the pessimistic bias of patients suffering from depression. The behavioral paradigm described constitutes a useful tool to study the neuronal basis of decision making under ambiguous conditions and may promote innovative pharmaco- and psychotherapy for depression.

Glucocorticoid receptor (GR) heterozygous mice (GR(+/- )) represent a valuable animal model for major depression. GR(+/- ) mice show a depression-related phenotype characterized by increased learned helplessness on the behavioral level and neuroendocrine alterations with hypothalamo-pituitary-adrenal (HPA) axis overdrive characteristic of depression. Hippocampal brain-derived neurotrophic factor (BDNF) levels have also been shown to be reduced in GR(+/- ) animals. Because adult hippocampal neurogenesis has been implicated in the pathophysiology of affective disorders, we studied here the effects of the GR(+/- ) genotype on neurogenesis in vivo. In a 2 x 2 design, GR(+/- ) mice and GR(+/+) littermate controls were either subjected to 1 h of restraint stress or left undisturbed in their home cages after intraperitoneal injection of BrdU. Stress exposure and BrdU injections were performed once daily for 7 days and neurogenesis analyzed 4 weeks later. BrdU cell counts were significantly reduced as an effect of GR(+/- ) genotype and as an effect of stress. Majority of the BrdU+ cells showed co-labeling with mature neuronal marker NeuN or astrocytic marker S100beta with no further significant effect of either experimental condition or of genotype. In sum, this results in reduced neurogenesis in GR(+/- ) mice which is further repressed by restraint stress. Our results, thus, reinforce the link between reduced neurogenesis, stress, neurotrophins, and behavioral symptoms of and susceptibility to depression.

Affymetrix chips were used to perform a hypothesis-free large-scale screening of transcripts in the hippocampus of olfactory bulbectomized mice, an established animal model of depression. Because only 11 transcripts were significantly changed, the statistically subsequent 25 transcripts below the significance level were additionally included in a first round of qRT-PCR evaluations. Furthermore, all 36 genes were then tested for mutual interactions or interactions with other molecules in a physiological context using PathwayArchitect software. Thirty of them were displayed in a network interacting with at least one partner molecule from the list or with other partner molecules known from the literature. All partner molecules from the most prominent 10 molecules of this network were then identified and put together into a new list. On those grounds, the hypothesis was made that metabolic network components of the insulin signaling pathway are perturbed in the disease. This pathway was subsequently tested by a second round of qRT-PCR, adding also a few additional candidate molecules belonging to this pathway. It turned out that the key target -- FABP7 -- fell into the group of transcripts not significantly regulated within the chip data, and another key target -- IRS1 -- did not show up in the chip experiments at all. In conclusion, our data reveal a problem with adhering to statistical significances in microarray experiments, insofar as molecules important for the disease may fall into the range of statistical noise. This approach may also be useful to find new targets for pharmacotherapy in affective disorders., ((c) 2008 Wiley-Liss, Inc.)

Hippocampal neurogenesis has been implicated in the pathogenesis of and recovery from depression. However, most of the underlying studies were endpoint investigations in experimental animals yielding conflicting results, and it has been under debate to which extent these results could be transferred to human patients. Now, researchers have developed a powerful new tool to address these questions by a non-invasive method in humans and animals in vivo, using magnetic resonance spectroscopy to detect a biomarker for proliferating progenitor cells that give rise to new neurons. This makes it possible to study the role of neural progenitor cells in a wide variety of human brain disorders.

In the era of mutant mice generated as molecular in vivo models for complex pathogenetic and therapeutic aspects of particular human diseases, glucocorticoid receptor transgenic mice represent an interesting and promising tool. Animals carrying mutations of this receptor show alterations in the hypothalamic-pituitary-adrenal (HPA)-system, which are comparable to those observed in depressed patients. Furthermore, similarities that may model the human disease have been described on the behavioral and pharmacological level, which increase the impact of such mutants. In this review we summarize different approaches used to alter or eliminate glucocorticoid receptor expression and function, and discuss their relevance as models for depression.

Test batteries are an essential and broadly used tool for behavioural phenotyping, especially with regard to mouse models of particular diseases, such as depression. Facing the problem of an often limited number of mutant animals, it therefore seems crucial to develop and optimise such test batteries in terms of an ideal throughput of subjects. This study aimed to characterize several common stressors, which are used for the investigation of depressive-like features with regard to their capability of each of them to affect performance in a subsequent behavioural test. Here we investigated swim-, restraint- and footshock-stress in male C57/BL6 mice, focusing on post-stress corticosterone elevations as well as potential effects on the behavioural level. The stressors increased circulating corticosterone levels when assessed 1 h after exposure. On the behavioural level, no test interactions could be detected, which suggests, that in general, combining these test conditions in experiments with a restricted availability of animals seems to be rather unproblematic.

Activation of the transcription factor CREB by Ser142 phosphorylation is implicated in synchronizing circadian rhythmicity, which is disturbed in many depressive patients. Hence, one could assume that emotional behaviour and neuroendocrinological markers would be altered in CREB(S142A) mice, in which serine 142 is replaced by alanine, preventing phosphorylation at this residue. Moreover, associations of CREB Ser142 and seasonal affective disorder (SAD) might be detectable by the analysis of single-nucleotide polymorphisms (SNPs) in the CREB gene close to the Ser142 residue in SAD patients. However, neither CREB(S142A) mice demonstrate features of depression, nor there is evidence for an association of SAD with the CREB genotypes. Nevertheless, in humans there is an association of a global seasonality score and circadian rhythmicity with the CREB genotypes in healthy control probands, but not SAD patients. This parallels the phenotype of CREB(S142A) mice, presenting alterations of circadian rhythm and light-induced entrainment. Thus it is reasonable to assume that CREB Ser142 represents a molecular switch in mice and men, which is responsible for the (dys)regulation of circadian rhythms.

The neurotrophin and serotonin (5-HT) hypotheses of depression were studied in a mouse model of reduced glucocorticoid receptor (GR) function (GR(+/-) mice), which recently has been proven as a murine model of predisposition for depressive behaviour under stressful conditions. In this model we studied diurnal changes in neurotrophins and serotonergic function in candidate brain regions mediating depressive behaviour. Morning and evening levels of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) were analyzed in representative brain regions of GR(+/-) and wildtype mice. The diurnal variation of hippocampal BDNF in wildtypes with higher levels in the morning was absent in GR(+/-) mice. Hypothalamus and parietal cortex displayed enhanced BDNF levels in GR(+/-) mice. In the frontal cortex, striatum and hypothalamus NGF increased from morning to evening in both genotypes, with an exaggeration in GR(+/-) mice. The diurnal variation of 5-HT levels and turnover did not differ significantly between genotypes. It was only in the hypothalamus that the evening level of 5-HIAA was lower in GR(+/-) mice than in wildtype mice. In conclusion, the present data indicate a contribution of altered BDNF and NGF protein levels to the predisposition for depressive behaviour in the GR(+/-) mouse model of depression, but argue against an eminent role of the serotonergic system.

The olfactory bulbectomy in rodents has been proposed as an animal model for depression. According to the neurotrophin and monoamine hypotheses of depression, the present study examined neurotrophin and monoamine (serotonin, norepinephrine, dopamine) levels in several depression-related brain regions of mice subjected to olfactory bulbectomy. As expected, bulbectomized animals revealed behavioral alterations such as locomotor hyperactivity and reduced gain of bodyweight, regarded as correlates of a depressive-like state. Compared to sham-operated animals, bulbectomized mice demonstrated significantly increased brain-derived neurotrophic factor (BDNF), but regular nerve growth factor (NGF), protein levels in hippocampus (+108%) and frontal cortex (+48%) 16 days after olfactory bulbectomy. In these brain regions as well as in the hypothalamus, bulbectomy also caused a reduction of the molar ratio of 5-hydroxyindoleacetic acid to serotonin (5-HT) indicating a decrease in 5-HT turnover. Similarly, a hypofunction of the dopamine (DA) turnover was evident only in the hypothalamus in response to olfactory bulbectomy, presenting a decrease in the ratio 3,4 dihydroxyphenylacetic acid/DA with increased levels of DA. In all other brain areas investigated the levels of DA, its metabolite DOPAC and norepinephrine remained unaltered. Thus, olfactory bulbectomy seems to be a valid animal model also in mice related to serotonergic dysfunctions resembling bulbectomized rats that are a well-known model of hyposerotoninergic agitated depression. With respect to the common BDNF hypothesis of depression--predicting decreased BDNF expression in depression-related brain areas--the novel and challenging conclusions concern the increased BDNF protein levels in target regions of the cholinergic basal forebrain system in bulbectomized mice.

Depression is a multifactorial and multigenetic disease. At present, three main theories try to conceptualize its molecular and biochemical mechanisms, namely the monoamine-, the hypothalamus-pituitary-adrenal- (HPA-) system- and the neurotrophin-hypotheses. One way to explore, validate or falsify these hypotheses is to alter the expression of genes that are involved in these systems and study their respective role in animal behavior and neuroendocrinological parameters. Following an introduction in which we briefly describe each hypothesis, we review here the different mouse lines generated to study the respective molecular pathways. Among the many mutant lines generated, only a few can be regarded as genetic depression models or as models of predisposition for a depressive syndrome after stress exposure. However, this is likely to reflect the human situation where depressive syndromes are complex, can vary to a great extent with respect to their symptomatology, and may be influenced by a variety of environmental factors. Mice with mutations of candidate genes showing depression-like features on behavioral or neurochemical levels may help to define a complex molecular framework underlying depressive syndromes. Because it is conceivable that manipulation of one single genetic function may be necessary but not sufficient to cause complex behavioral alterations, strategies for improving genetic modeling of depression-like syndromes in animals possibly require a simultaneous targeted dysregulation of several genes involved in the pathogenesis of depression. This approach would correspond to the new concept of 'endophenotypes' in human depression research trying to identify behavioral traits which are thought to be encoded by a limited set of genes.

In order to develop a model for a depression-like syndrome in mice, we subjected male C57BL/6 mice to a 4-week-long chronic stress procedure, consisting of rat exposure, restraint stress, and tail suspension. This protocol resulted in a strong decrease in sucrose preference, a putative indicator of anhedonia in rodents. Interestingly, predisposition for stress-induced anhedonia was indicated by submissive behavior in a resident-intruder test. In contrast, most mice with nonsubmissive behavior did not develop a decrease in sucrose preference and were regarded as nonanhedonic. These animals were used as an internal control for stress-induced behavioral features not associated with the anhedonic state, since they were exposed to the same stressors as the anhedonic mice. Using a battery of behavioral tests after termination of the stress procedure, we found that anhedonia, but not chronic stress per se, is associated with key analogues of depressive symptoms, such as increased floating during forced swimming and decreased exploration of novelty. On the other hand, increased anxiety, altered locomotor activity, and loss of body weight were consequences of chronic stress, which occurred independently from anhedonia. Thus, behavioral correlates of stress-induced anhedonia and of chronic stress alone can be separated in the present model.

Background: According to the neurotrophin hypothesis of depression, decreased activity of brain-derived neurotrophic factor (BDNF) contributes to behavioral and plasticity-related alterations in depressed patients. We investigated the hypothesis that mice with a forebrain-specific knockout of the trkB receptor, the main mediator of BDNF signaling, represent a genetic animal model for depression., Methods: Using the CRE-loxP system, we bred trkB(CaMKII-CRE) mice with a trkB-receptor disruption in the forebrain. We subjected trkB-mutant mice to a battery of behavioral tests, comprising open field, elevated zero maze, emergence test, novel object test, and forced swim. Additionally, we investigated the hypothalamic-pituitary-adrenal (HPA) axis immunohistochemically and by plasma analyses., Results: trkB(CaMKII-CRE) mice showed a stereotyped hyper-locomotion with reduced explorative activity, and impulsive reactions to novel stimuli. The trkB-mutant mice did not exhibit depressionlike behaviors such as increased "despair" in the forced swim test, increased anxiety in the elevated zero maze, or neophobia in the novel object test. Furthermore, no HPA dysregulation was observed under normal and stressful conditions., Conclusions: trkB(CaMKII-CRE) mice cannot be regarded as a genetic mouse model of depression. Instead, the behavioral symptoms of trkB(CaMKII-CRE) mice, comprising hyper-locomotion, stereotyped behaviors, and cognitive impairments, are similar to those postulated for mouse models of attention-deficit disorder.

Impaired corticosteroid receptor signaling is a key mechanism in the pathogenesis of stress-related psychiatric disorders such as depression and anxiety. Since in vivo expression and functional studies of corticosteroid receptors are not feasible in the human central nervous system, such analyses have to be done in animal models. Transgenic mice with mutations of corticosteroid receptors are promising tools, which allow us to investigate the role of these proteins in the pathogenesis of symptoms characteristic for depression and anxiety. This review summarizes the neuroendocrinological and behavioral findings that have been obtained in six different mouse strains with specific mutations that influence the expression or the function of the glucocorticoid or the mineralocorticoid receptor (MR). The analyses of these mice helped to define molecular concepts of how corticosteroid receptors regulate the activity of the hypothalamic-pituitary-adrenal (HPA) system. Furthermore, some of these mutant mice exhibited characteristic alterations in behavioral tests for anxiety and despair. However, so far, none of the mouse strains described here can be viewed as an animal model of a specific psychiatric disease defined by common diagnostic criteria. Using high throughput technologies for the identification of genes regulated by glucocorticoid receptor (GR) and MR in brain areas responsible for specific symptoms of stress-related disorders will yield potential new drug targets for the treatment of depression and anxiety.

Abstract Aims Myocardial infarction (MI) and heart failure (HF) are risk factors for the development of depression, additionally worsening the quality of life and patient outcome. How HF causes depression and how depression promotes HF remain mechanistically unclear, which is at least partly caused by the difficulty of in vivo modelling of psychosomatic co‐morbidity. We aimed to study the potential sequence of events with respect to different depression aspects upon HF. Methods and results Male C57BL6 mice underwent MI, followed by behavioural and echocardiographic characterization. Motility, exploration, and anxiety‐like behaviour were unaffected in mice after MI. We did not observe increased depressive‐like behaviour in the sucrose preference, tail suspension, or Porsolt forced swim test. Mice did not display signs of learned helplessness (LH) when compared to sham. Accordingly, cluster analysis revealed only a slightly higher quota of LH in HF (38%) vs. sham mice (32%). But strikingly, three‐group cluster analysis revealed an additional intermediate subpopulation at risk for LH after HF (29%). Interestingly, this population featured elevated cardiac expression of nr4a1. Conclusions The LH paradigm uncovered a subtle predisposition to depressive‐like behaviour after MI, whereas testing for anhedonia and despair was insufficient to show a behavioural shift in mice. Therefore, we suggest an accumulating risk profile and a multiple‐hits hypothesis regarding the pathogenesis of co‐morbid depression after MI. Symptoms of LH may present a marker of subclinical depression after MI, the impact of which remains to be investigated. The proposed sequence of behavioural testing enables the mechanistic dissection of cardio‐psychogenic signalling in the future.

Andrei-Nicolae Vasilescu,1,* Nina Schweinfurth,2,* Stefan Borgwardt,2,* Peter Gass,1 Undine E Lang,2,* Dragos Inta,1,2,* Sarah Eckart2,* 1Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany; 2Department of Psychiatry (Universitäre Psychiatrische Kliniken), University of Basel, Basel, Switzerland *These authors contributed equally to this work Abstract: Classical monoaminergic antidepressants show several disadvantages, such as protracted onset of therapeutic action. Conversely, the fast and sustained antidepressant effect of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine raises vast interest in understanding the role of the glutamate system in mood disorders. Indeed, numerous data support the existence of glutamatergic dysfunction in major depressive disorder (MDD). Drawback to this short-latency therapy is its side effect profile, especially the psychotomimetic action, which seriously hampers the common and widespread clinical use of ketamine. Therefore, there is a substantial need for alternative glutamatergic antidepressants with milder side effects. In this article, we review evidence that implicates NMDARs in the prospective treatment of MDD with focus on rapastinel (formerly known as GLYX-13), a novel synthetic NMDAR modulator with fast antidepressant effect, which acts by enhancing NMDAR function as opposed to blocking it. We summarize and discuss current clinical and animal studies regarding the therapeutic potential of rapastinel not only in MDD but also in other psychiatric disorders, such as obsessive–compulsive disorder and posttraumatic stress disorder. Additionally, we discuss current data concerning the molecular mechanisms underlying the antidepressant effect of rapastinel, highlighting common aspects as well as differences to ketamine. In 2016, rapastinel received the Breakthrough Therapy designation for the treatment of MDD from the US Food and Drug Administration, representing one of the most promising alternative antidepressants under current investigation. Keywords: depression, glutamate, NMDARs, rapastinel, ketamine

The olfactory bulbectomy in rodents has been proposed as an animal model for depression. According to the neurotrophin and monoamine hypotheses of depression, the present study examined neurotrophin and monoamine (serotonin, norepinephrine, dopamine) levels in several depression-related brain regions of mice subjected to olfactory bulbectomy. As expected, bulbectomized animals revealed behavioral alterations such as locomotor hyperactivity and reduced gain of bodyweight, regarded as correlates of a depressive-like state. Compared to sham-operated animals, bulbectomized mice demonstrated significantly increased brain-derived neurotrophic factor (BDNF), but regular nerve growth factor (NGF), protein levels in hippocampus (+108%) and frontal cortex (+48%) 16 days after olfactory bulbectomy. In these brain regions as well as in the hypothalamus, bulbectomy also caused a reduction of the molar ratio of 5-hydroxyindoleacetic acid to serotonin (5-HT) indicating a decrease in 5-HT turnover. Similarly, a hypofunction of the dopamine (DA) turnover was evident only in the hypothalamus in response to olfactory bulbectomy, presenting a decrease in the ratio 3,4 dihydroxyphenylacetic acid/DA with increased levels of DA. In all other brain areas investigated the levels of DA, its metabolite DOPAC and norepinephrine remained unaltered. Thus, olfactory bulbectomy seems to be a valid animal model also in mice related to serotonergic dysfunctions resembling bulbectomized rats that are a well-known model of hyposerotoninergic agitated depression. With respect to the common BDNF hypothesis of depression – predicting decreased BDNF expression in depression-related brain areas – the novel and challenging conclusions concern the increased BDNF protein levels in target regions of the cholinergic basal forebrain system in bulbectomized mice.

Cytokine-dependent mechanisms in the CNS have been implicated in the pathogenesis of depression. Interleukin-6 is upregulated in depressed patients and dowregulated by antidepressants. It is, however, unknown whether IL-6 is involved in the pathogenesis of depression.We subjected IL-6-deficient mice (IL-6−/−) to depression-related tests (learned helplessness, forced swimming, tail suspension, sucrose preference). We also investigated IL-6 in the hippocampus of stressed wild-type mice.IL-6−/− mice showed reduced despair in the forced swim, and tail suspension test, and enhanced hedonic behavior. Moreover, IL-6−/− mice exhibited resistance to helplessness. This resistance may be caused by the lack of IL-6, because stress increased IL-6 expression in wild-type hippocampi.This suggests that IL-6 is a component in molecular mechanisms in the pathogenesis of depression. IL-6−/− mice represent tools to study IL-6-dependent signaling pathways in the pathophysiology of depression in vivo. Moreover, these mice may support the screening of compounds for depression by altering cytokine-mediated signaling.