Learned helplessness: Validity and reliability of depressive-like states in mice

Chourbaji, Sabine; Zacher, Christiane; Sanchis‐Segura, Carles; Dormann, Christof; Vollmayr, Barbara; Gass, Peter

doi:10.1016/j.brainresprot.2005.09.002

Cited by 180 publications

(144 citation statements)

References 23 publications

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“…The learned helplessness paradigm is a depression model in which an animal is exposed to unpredictable and uncontrollable stressors (Chourbaji et al, 2006;Chourbaji et al, 2005). See Supplementary Methods for a detailed description of the experimental procedure.…”

Section: Learned Helplessnessmentioning

confidence: 99%

Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity

Weber

Vogt

Gartside

et al. 2014

Neuropsychopharmacol

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Both the glutamatergic and serotonergic (5-HT) systems are implicated in the modulation of mood and anxiety. Descending cortical glutamatergic neurons regulate 5-HT neuronal activity in the midbrain raphe nuclei through a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors. To analyze the functional role of GLUA1-containing AMPA receptors in serotonergic neurons, we used the Cre-ERT2/loxP-system for the conditional inactivation of the GLUA1-encoding Gria1 gene selectively in 5-HT neurons of adult mice. These Gria1 5-HT À / À mice exhibited a distinct anxiety phenotype but showed no alterations in locomotion, depression-like behavior, or learning and memory. Increased anxiety-related behavior was associated with significant decreases in tryptophan hydroxylase 2 (TPH2) expression and activity, and subsequent reductions in tissue levels of 5-HT, its metabolite 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine in the raphe nuclei. However, TPH2 expression and activity as well as monoamine levels were unchanged in the projection areas of 5-HT neurons. Extracellular electrophysiological recordings of 5-HT neurons revealed that, while a1-adrenoceptor-mediated excitation was unchanged, excitatory responses to AMPA were enhanced and the 5-HT 1A autoreceptor-mediated inhibitory response to 5-HT was attenuated in Gria1 5-HT À / À mice. Our data show that a loss of GLUA1 protein in 5-HT neurons enhances AMPA receptor function and leads to multiple local molecular and neurochemical changes in the raphe nuclei that dysregulate 5-HT neuronal activity and induce anxiety-like behavior.

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Section: Learned Helplessnessmentioning

confidence: 99%

Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity

Weber

Vogt

Gartside

et al. 2014

Neuropsychopharmacol

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“…This subsequently leads to the development of coping deficits in aversive but escapable situations. The experimental procedure was used as previously described (Chourbaji et al, 2005) (see Supplementary section for details).…”

Section: Learned Helplessnessmentioning

confidence: 99%

“…Again, no difference could be observed between mice homozygous for the 1473G and 1473C alleles (Figures 4d-f). Also, mice of both genotype failed to reach criteria for helpless behavior (Chourbaji et al, 2005) (see figure legend for details). Finally, no differences could be found between homozygous 1473G and 1473C mice when tested for anhedonia in a sucrose preference test (Figure 4c).…”

Section: G Micementioning

confidence: 99%

“…Table S1). In both behavioral paradigms, mice of both Tph2 1473 alleles showed no differences in immobility times, which is a measure of behavioral despair, under unstressed conditions (pre-stress) and following a chronic mild stress procedure (CMS; post-stress) (TST: (Chourbaji et al, 2005). (g) Plasma corticosterone concentrations.…”

Section: Pharmacological Treatment Of Elevated Anxiety With Chronic Ementioning

confidence: 99%

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A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

Berger

Weber

Perreau-Lenz

et al. 2012

Neuropsychopharmacol

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The association of single-nucleotide polymorphisms (SNPs) in the human tryptophan hydroxylase 2 (TPH2) gene with anxiety traits and depression has been inconclusive. Observed inconsistencies might result from the fact that TPH2 polymorphisms have been studied in a genetically heterogeneous human population. A defined genetic background, control over environmental factors, and the ability to analyze the molecular and neurochemical consequences of introduced genetic alterations constitute major advantages of investigating SNPs in inbred laboratory mouse strains. To investigate the behavioral and neurochemical consequences of a functional C1473G SNP in the mouse Tph2 gene, we generated congenic C57BL/6N mice homozygous for the Tph2 1473G allele. The Arg 447 substitution in the TPH2 enzyme resulted in a significant reduction of the brain serotonin (5-HT) in vivo synthesis rate. Despite decreased 5-HT synthesis, we could detect neither a reduction of brain region-specific 5-HT concentrations nor changes in baseline and stress-induced 5-HT release using a microdialysis approach. However, using a [ 35 S]GTP-g-S binding assay and 5-HT 1A receptor autoradiography, a functional desensitization of 5-HT 1A autoreceptors could be identified. Furthermore, behavioral analysis revealed a distinct anxiety phenotype in homozygous Tph2 1473G mice, which could be reversed with chronic escitalopram treatment. Alterations in depressive-like behavior could not be detected under baseline conditions or after chronic mild stress. These findings provide evidence for an involvement of functional Tph2 polymorphisms in anxiety-related behaviors, which are likely not caused directly by alterations in 5-HT content or release but are rather due to compensatory changes during development involving functional desensitization of 5-HT 1A autoreceptors.

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“…Animals with LH behavior exhibit impairments of behavioral, biochemical, physiological and hormonal parameters somewhat similar to those observed in patients with depressive disorders for several days. 2,[6][7][8] Interestingly, however, only 10-80% of animals exposed to inescapable shock develop LH behaviors. [9][10][11] The variability of responses in these animals may be due to several factors including procedures and condition of the induction of LH behaviors, the criteria used for defining LH behaviors 11) and also genetic variation.…”

mentioning

confidence: 99%

Possible Involvement of Signal Transducers and Activators of Transcription 3 System on Depression in the Model Mice Brain

Mingmalairak

Tohda

Murakami

et al. 2010

Biological & Pharmaceutical Bulletin

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Although available evidence from neurobiological studies consistently indicates that depression phenotypes are the outcome of a combination of genetic and environmental factors, 1,2) little is known about the pathophysiology of depression. A large number of clinical observations have suggested that stress is a predisposing factor involved in the onset of affective disorders, especially depression. [3][4][5] Most animal models of depression are based on behavioral deficits induced by a variety of stress paradigms. One of the most commonly used animal models of depression is a learned helplessness (LH) paradigm. In this paradigm, animals previously exposed to inescapable shock are subsequently less able to escape from shock than control animals. Animals with LH behavior exhibit impairments of behavioral, biochemical, physiological and hormonal parameters somewhat similar to those observed in patients with depressive disorders for several days.2,6-8) Interestingly, however, only 10-80% of animals exposed to inescapable shock develop LH behaviors. [9][10][11] The variability of responses in these animals may be due to several factors including procedures and condition of the induction of LH behaviors, the criteria used for defining LH behaviors 11) and also genetic variation. When we think about the variation from another viewpoint, clarifying the reason for this may give us information about endogenous factors that are involved in generation of depressive disorders. Therefore, in this article, we divided stressed animals into two groups which presented a symptom of depression and which did not show it, artificially, and examined the gene expression changes between.We previously found that antidepressant drugs and a traditional Chinese and Japanese prescription (Wakan-yaku) with antidepressant-like action enhances expression of BCL2/adenovirus E1B 19kD-interacting protein 3 (BNIP3) mRNA in a cultured cell line NG108-15. Our results suggest that BNIP3 is a candidate intrinsic factor related to antidepressive effects of these drugs.12) We also found that BNIP3 mRNA expression is upregulated by stress exposure and BNIP3 may be involved in imipramine-induced amelioration of depressive state of LH mouse brain.13) Using this model animal brain, it seems possible to find novel depressive factors in addition to BNIP-3.Microarray technology vastly improved brain research when it arrived some years ago and has become a very useful tool for identification of genes and molecular pathways involved in psychiatric disorders. [14][15][16] Further to understand the pathophysiology of depression, accumulation of gene expression analyses based on the phenotypic variability of animals exposed to stress is needed. In the present study, we investigated the expression of genes associated with the pathogenesis of depressive disorders using DNA microarray technique in the LH mice frontal cortex. Genes that were down-regulated or up-regulated were examined in detail by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR...

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Learned helplessness: Validity and reliability of depressive-like states in mice

Cited by 180 publications

References 23 publications

Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity

Adult AMPA GLUA1 Receptor Subunit Loss in 5-HT Neurons Results in a Specific Anxiety-Phenotype with Evidence for Dysregulation of 5-HT Neuronal Activity

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

Possible Involvement of Signal Transducers and Activators of Transcription 3 System on Depression in the Model Mice Brain

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