Social and structural housing conditions influence the development of a depressive-like phenotype in the learned helplessness paradigm in male mice.

Structural and social factors are known to play a crucial role in the pathogenesis of depression. Since animal models of depression are a major tool to gain insights into the mechanisms involved in the pathophysiology of this disease it is important not only to exploit but also to be aware of factors that may affect these models. As housing represents a fundamental external factor, which is controversially debated to affect the animals' emotionality, this study aimed to investigate the impact of different social and structural housing conditions on the development of a depressive-like syndrome in the learned helplessness paradigm. Group housing in an impoverished environment led to an increased vulnerability in the learned helplessness paradigm. Groups that were housed enriched, however, were less helpless. Furthermore impoverished conditions did not increase the vulnerability in single housed animals. Regarding emotionality in the animals, basal anxiety was reduced and the exploration was enhanced by group housing and enriched environment. These results suggest that housing conditions significantly influence the outcome of learned helplessness studies.

Mice with genetically altered glucocorticoid receptor expression show altered sensitivity for stress-induced depressive reactions.

Altered glucocorticoid receptor (GR) signaling is a postulated mechanism for the pathogenesis of major depression. To mimic the human situation of altered GR function claimed for depression, we generated mouse strains that underexpress or overexpress GR, but maintain the regulatory genetic context controlling the GR gene. To achieve this goal, we used the following: (1) GR-heterozygous mutant mice (GR+/-) with a 50% GR gene dose reduction, and (2) mice overexpressing GR by a yeast artificial chromosome resulting in a twofold gene dose elevation. GR+/- mice exhibit normal baseline behaviors but demonstrate increased helplessness after stress exposure, a behavioral correlate of depression in mice. Similar to depressed patients, GR+/- mice have a disinhibited hypothalamic-pituitary-adrenal (HPA) system and a pathological dexamethasone/corticotropin-releasing hormone test. Thus, they represent a murine depression model with good face and construct validity. Overexpression of GR in mice evokes reduced helplessness after stress exposure, and an enhanced HPA system feedback regulation. Therefore, they may represent a model for a stress-resistant strain. These mouse models can now be used to study biological changes underlying the pathogenesis of depressive disorders. As a first potential molecular correlate for such changes, we identified a downregulation of BDNF protein content in the hippocampus of GR+/- mice, which is in agreement with the so-called neurotrophin hypothesis of depression.

Mice with a fra-1 knock-in into the c-fos locus show impaired spatial but regular contextual learning and normal LTP.

The immediate early gene c-fos is part of the AP-1 transcription factor complex, which is involved in molecular mechanisms underlying learning and memory. Mice that lack c-Fos in the brain show impairments in spatial reference and contextual learning, and also exhibit a reduced long-term potentiation of synaptic transmission (LTP) at CA3-to-CA1 synapses. In the present study, we investigated mice in which c-fos was deleted and replaced by fra-1 (c-fos(fra-1) mice) to determine whether other members of the c-fos gene family can substitute for the functions of the c-fos gene. In c-fos(fra-1) mice, both CA3-to-CA1 LTP and contextual learning in a Pavlovian fear conditioning task were similar to wild-type littermates, indicating that Fra-1 expression restored the impairments caused by brain-specific c-Fos depletion. However, c-Fos-mediated learning deficits in a reference memory task of the Morris watermaze were also present in c-fos(fra-1) mice. These findings suggest that different c-Fos target genes are involved in LTP, contextual learning, and spatial reference memory formation.

Reduced expression of brain-derived neurotrophic factor in mice deficient for pituitary adenylate cyclase activating polypeptide type-I-receptor.

In vitro pituitary adenylate cyclase activating polypeptide (PACAP) induces the expression of brain-derived neurotrophic factor (BDNF) via its specific receptor PAC1. Since BDNF has been implicated in learning paradigms and mice lacking functional PAC1 have deficits in hippocampus-dependent associative learning, we investigated whether PAC1 mutants show alterations in hippocampal expression of BDNF and its receptor TrkB. Semi-quantitative in situ-hybridization using exon-specific BDNF-probes revealed significantly reduced expression of the exon-III and exon-V-specific transcripts within the hippocampal CA3 region in PAC1-deficient mice. A similar trend was observed for the exon-I-specific transcript. The expression of the exon-III-specific transcript was also reduced within the dentate gyrus, while Trk B-expression did not differ between genotypes. Our data demonstrate that even in vivo PAC1-mediated signaling seems to play a pivotal role for the transcriptional regulation of BDNF.

Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior.

The "neurotrophin hypothesis" of depression predicts that depressive disorders in humans coincide with a decreased activity and/or expression of brain-derived neurotrophic factor (BDNF) in the brain. Therefore, we investigated whether mice with a reduced BDNF expression due to heterozygous gene disruption demonstrate depression-like neurochemical changes or behavioral symptoms. BNDF protein levels of adult BDNF(+/-) mice were reduced to about 60% in several brain areas investigated, including the hippocampus, frontal cortex, striatum, and hypothalamus. The content of monoamines (serotonin, norepinephrine, and dopamine) as well as of serotonin and dopamine degradation products was unchanged in these brain regions. By contrast, choline acetyltransferase activity was significantly reduced by 19% in the hippocampus of BDNF(+/-) mice, indicating that the cholinergic system of the basal forebrain is critically dependent on sufficient endogenous BDNF levels in adulthood. Moreover, BDNF(+/-) mice exhibited normal corticosterone and adrenocorticotropic hormone (ACTH) serum levels under baseline conditions and following immobilization stress. In a panel of behavioral tests investigating locomotor activity, exploration, anxiety, fear-associated learning, and behavioral despair, BDNF(+/-) mice were indistinguishable from wild-type littermates. Thus, a chronic reduction of BDNF protein content in adult mice is not sufficient to induce neurochemical or behavioral alterations that are reminiscent of depressive symptoms in humans.

Forebrain-specific trkB-receptor knockout mice: behaviorally more hyperactive than "depressive".

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 long-term memory and NR2A-type NMDA receptor-dependent synaptic plasticity in mice lacking c-Fos in the CNS.

The immediate early gene c-fos is part of the activator protein-1 transcription factor and has been postulated to participate in the molecular mechanisms of learning and memory. To test this hypothesis in vivo, we generated mice with a nervous system-specific c-fos knock-out using the Cre-loxP system. Adult mice lacking c-Fos in the CNS (c-fosDeltaCNS) showed normal general and emotional behavior but were specifically impaired in hippocampus-dependent spatial and associative learning tasks. These learning deficits correlated with a reduction of long-term potentiation (LTP) in hippocampal CA3-CA1 synapses. The magnitude of LTP was restored by a repeated tetanization procedure, suggesting impaired LTP induction in c-fosDeltaCNS mice. This rescue was blocked by a selective inhibitor of NR2B-type NMDA receptors. This blockade was compensated in wild-type mice by NR2A-type NMDA receptor-activated signaling pathways, thus indicating that these pathways are compromised in c-fosDeltaCNS mice. In summary, our data suggest a role for c-Fos in hippocampus-dependent learning and memory as well as in NMDA receptor-dependent LTP formation.