Chronic stress and impaired glutamate function elicit a depressive-like phenotype and common changes in gene expression in the mouse frontal cortex

Major depression might originate from both environmental and genetic risk factors. The environmental chronic mild stress (CMS) model mimics some environmental factors contributing to human depression and induces anhedonia and helplessness. Mice heterozygous for the synaptic vesicle protein (SVP) vesicular glutamate transporter 1 (VGLUT1) have been proposed as a genetic model of deficient glutamate function linked to depressive-like behaviour. Here, we aimed to identify, in these two experimental models, gene expression changes in the frontal cortex, common to stress and impaired glutamate function. Both VGLUT1+/- and CMS mice showed helpless and anhedonic-like behavior. Microarray studies in VGLUT1+/- mice revealed regulation of genes involved in apoptosis, neurogenesis, synaptic transmission, protein metabolic process or learning and memory. In addition, RT-PCR studies confirmed gene expression changes in several glutamate, GABA, dopamine and serotonin neurotransmitter receptors. On the other hand, CMS affected the regulation of 147 transcripts, some of them involved in response to stress and oxidoreductase activity. Interestingly, 52 genes were similarly regulated in both models. Specifically, a dowregulation in genes that promote cell proliferation (Anapc7), cell growth (CsnK1g1), cell survival (Hdac3), inhibition of apoptosis (Dido1) was observed. Genes linked to cytoskeleton (Hspg2, Invs), psychiatric disorders (Grin1, MapK12) or an antioxidant enzyme (Gpx2) were also downregulated. Moreover, genes that inhibit the MAPK pathways (Dusp14), stimulate oxidative metabolism (Eif4a2) and enhance glutamate transmission (Rab8b) were upregulated. We suggest that these genes could form part of the altered “molecular context” underlying depressive-like behaviour in animal models. The clinical relevance of these findings is discussed

Increased vulnerability to depressive-like behaviour of mice with decreased expression of VGLUT1

Background: Many studies have linked depression to an increase in the excitatory-inhibitory ratio in the forebrain. Presynaptic alterations in a shared pathway of the glutamate/GABA cycle may account for this imbalance. Recent evidence suggests that decreased vesicular glutamate transporter 1 (VGLUT1) levels in the forebrain affects the glutamate/GABA cycle and induces helpless behaviour. Here we studied decreased VGLUT1 as a potencial factor enhancing a depressive-like phenotype in an animal model. Methods: Glutamate and GABA synthesis as well as oxidative metabolism were studied in heterozygous mice for the vesicular glutamate transporter 1 (VGLUT1+/-) and WT. Subsequently, the regulation of neurotransmitter levels, proteins involved in the glutamate/GABA cycle and behaviour by both genotype and chronic mild stress (CMS) was studied. Finally, the effect of chronic imipramine on VGLUT1 control and CMS mice was also studied. Results: VGLUT1+/- mice showed increased neuronal synthesis of glutamate, decreased cortical and hippocampal GABA, VGLUT1 and EAAT1, as well as helplessness and anhedonia. CMS induced an increase of glutamate and a decrease of GABA, VGAT and GAD65 in both areas and led to upregulation EAAT1 in the hippocampus. Moreover, CMS induced anhedonia, helplessness, anxiety and impaired recognition memory. VGLUT1+/- CMS mice showed a combined phenotype (genotype plus stress) and specific alterations, such as an upregulation of VGLUT2 and hyperlocomotion. Moreover, an increased vulnerability to anhedonia and helplessness reversible by chronic imipramine was shown. Conclusions: These studies highlight a crucial role for decreased VGLUT1 in the forebrain as a biological mediator of increased vulnerability to chronic mild stress

Regulation of markers of synaptic function in mouse models of depression: chronic mild stress and decreased expression of VGLUT1

Depression has been linked to failure in synaptic plasticity originating from environmental and/or genetic risk factors. The chronic mild stress (CMS) model regulates the expression of synaptic markers of neurotransmitter function and associated depressive-like behaviour. Moreover, mice heterozygous for the synaptic vesicle protein (SVP) vesicular glutamate transporter 1 (VGLUT1), have been proposed as a genetic model of deficient glutamate function linked to depressive-like behaviour. Here, we aimed to identify, in these two experimental models, mechanisms of failure in synaptic plasticity, common to stress and impaired glutamate function. First, we show that CMS induced a transient decrease of different plasticity markers (VGLUT1, synapsin 1, sinaptophysin, rab3A and activity regulated cytoskeletal protein Arc) but a long-lasting decrease of the brain derived neurotrophic factor (BDNF) as well as depressive-like behaviour. The immediate early gene (IEG) Arc was also downregulated in VGLUT1+/- heterozygous mice. In contrast, an opposite regulation of synapsin 1 was observed. Finally, both models showed a marked increase of cortical Arc response to novelty. Increased Arc response to novelty could be suggested as a molecular mechanism underlying failure to adapt to environmental changes, common to chronic stress and altered glutamate function. Further studies should investigate whether these changes are associated to depressive-like behaviour both in animal models and in depressed patients

Stress, sex, and motivated behaviors

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137361/1/jnr23815.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137361/2/jnr23815_am.pd

Intergenerational accumulation of impairments in maternal behavior following postnatal social stress

Early adversity such as depressed maternal care can have long-term physiological and behavioral effects on offspring and future generations. Exposure to chronic social stress (CSS), an ethologically model of postpartum depression and anxiety, during lactation impairs maternal care and exerts similar effects on the F1 dam offspring of the stressed F0 dams. These changes associate with increased corticosterone and neuroendocrine alterations. CSS F2 offspring further display decreased social behavior as juveniles and adults and decreased basal levels of corticosterone. This current study investigates the intergenerational inheritance of alterations in maternal behavior in F2 CSS dams together with neuroendocrine and immune markers to explore whether aspects of maternal behavior are intergenerationally inherited through immune and neuroendocrine mechanisms. We find that defects in maternal care behavior persist into the F2 generation with F2 dams exhibiting a pervasively depressed maternal care and increased restlessness throughout lactation. This occurs together with reduced basal cortisol (in contrast to an increase in F1 dams), a lack of changes in neuroendocrine gene expression, and reduced serum ICAM-1 (intercellular adhesion molecule-1) levels - a marker for inflammation and blood–brain barrier integrity. The data support the hypothesis that the effects of chronic social stress can accumulate across multiple generations to depress maternal care, increase restlessness and alter basal functioning of the immune system and hypothalamic pituitary adrenal axis

Sistema de façana ventilada lleugera

En la primera part del projecte s’estudien els antecedents històrics del sistema constructiu de façana ventilada lleugera, la seva descripció i definició, la constitució, els diferents tipus de classificacions, el marc normatiu i les exigències funcionals.La segona part consisteix en la resolució de les façanes d’un edifici plurifamiliar a mode d’exemple amb el sistema constructiu estudiat, en aquest cas lafaçana ventilada lleugera. Definint els tipus de materials que s’empraran en cada cas, així com el tipus de sistema que s’utilitzarà, a més de la realització dels càlculs necessaris per garantir les exigències i els requeriments tant en termes d’estabilitat estructural, com de compliment de requeriments tèrmics i acústic

Estudio conductual y neurobiológico del estrés crónico social en ratón

Major depression is a mental disorder often preceded by exposure to chronic stress or stressful life events. Recently, animal models based on social conflict such as chronic social defeat stress (CSDS) are proposed to be more relevant to stress-induced human psychopathology compared to environmental models like the chronic mild stress (CMS). Although CSDS has been proposed as a model of depression, most CSDS studies rely only on analysis of stress-induced social avoidance. Moreover, the predictive validity of the model has been poorly analyzed let alone the possible alterations in dendritic and synaptic structures of brain regions involved in emotional processing. Therefore, the aims of this work were to study comparatively social versus environmental stress using the CMS and CSDS models. Secondly we have fully characterized the validity of the CSDS model as a possible model of depression. Comparing both stress models we observed that CMS induced a clear depressive-like profile including anhedonia, helplessness and memory impairment. CSDS induced anhedonia, hyperactivity, anxiety, social avoidance and freezing, signs also common to anxiety and posttraumatic stress disorders. Both models disrupted the excitatory inhibitory balance in the prefrontal cortex. Moreover, CSDS decreased dopamine in the prefrontal cortex and brainstem. We suggests that while depressive-like behaviours might be associated to altered aminoacid neurotransmission in cortical areas, CSDS induced anxiety behaviours might be linked to specific alteration of dopaminergic pathways involved in rewarding processes. We next explored the predictive validity of the CSDS model using different classes of antidepressants and we observed that this validity was limited. Firstly, repeated venlafaxine showed antidepressant-like activity and both venlafaxine and tianeptine behaved as effective anxiolytics. However CSDS-induced social avoidance was only partially reverted by tianeptine. On the other hand, fluoxetine failed to revert most of the behavioral alterations. In addition, defeated mice showed a downregulation of VGLUT1 mRNA in amygdale and VGLUT1+/- mice showed an enhanced vulnerability to stress-induced social avoidance. However, unlike the environmental model of CMS, these mice did not show enhanced vulnerability to depressive behaviour when exposed to CSDS. Moreover, CSDS induced an opposite regulation of the spine density and different synaptic plasticity markers in the prefrontal cortex and the amygdale. Specifically while in the prefrontal cortex spine density, GluR1 AMPA receptor subunit, PSD95 and Synaptophysin were increased, a decrease was found in the amygdale. In addition, in the amygdale a downregulation of NR1 NMDA subunit, mGlur4, brain derived neurotrophic factor (BDNF) and CREB was also found. In addition, stressed mice exposed to the social interaction test with a dominant mouse experienced marked freezing and showed increased in pCREB/CREB ratio, proBDNF and mature BDNF in the amygdale. Taken together these results suggest that CSDS is not a pure model of depression. Indeed it addresses relevant aspects of anxiety-related disorders. Firstly, CSDS induced anhedonia and social avoidance is not associated in this model. Moreover, CSDS might be affecting brain areas mainly involved in the processing of social behaviour, such as the amygdale, where glutamatergic mechanism could play a key role. In addition, these results suggest a persistent maladaptive function of the prefrontal cortex and amygdale of socially defeated mice. Moreover, this would be the first evidence that late reencounter with an aversive social stimuli can triggers fear conditioning in socially defeated mice and support the validity of CSDS to model clinical aspects of post-traumatic stress disorders

Estudio conductual y neurobiológico del estrés crónico social en ratón

Major depression is a mental disorder often preceded by exposure to chronic stress or stressful life events. Recently, animal models based on social conflict such as chronic social defeat stress (CSDS) are proposed to be more relevant to stress-induced human psychopathology compared to environmental models like the chronic mild stress (CMS). Although CSDS has been proposed as a model of depression, most CSDS studies rely only on analysis of stress-induced social avoidance. Moreover, the predictive validity of the model has been poorly analyzed let alone the possible alterations in dendritic and synaptic structures of brain regions involved in emotional processing. Therefore, the aims of this work were to study comparatively social versus environmental stress using the CMS and CSDS models. Secondly we have fully characterized the validity of the CSDS model as a possible model of depression. Comparing both stress models we observed that CMS induced a clear depressive-like profile including anhedonia, helplessness and memory impairment. CSDS induced anhedonia, hyperactivity, anxiety, social avoidance and freezing, signs also common to anxiety and posttraumatic stress disorders. Both models disrupted the excitatory inhibitory balance in the prefrontal cortex. Moreover, CSDS decreased dopamine in the prefrontal cortex and brainstem. We suggests that while depressive-like behaviours might be associated to altered aminoacid neurotransmission in cortical areas, CSDS induced anxiety behaviours might be linked to specific alteration of dopaminergic pathways involved in rewarding processes. We next explored the predictive validity of the CSDS model using different classes of antidepressants and we observed that this validity was limited. Firstly, repeated venlafaxine showed antidepressant-like activity and both venlafaxine and tianeptine behaved as effective anxiolytics. However CSDS-induced social avoidance was only partially reverted by tianeptine. On the other hand, fluoxetine failed to revert most of the behavioral alterations. In addition, defeated mice showed a downregulation of VGLUT1 mRNA in amygdale and VGLUT1+/- mice showed an enhanced vulnerability to stress-induced social avoidance. However, unlike the environmental model of CMS, these mice did not show enhanced vulnerability to depressive behaviour when exposed to CSDS. Moreover, CSDS induced an opposite regulation of the spine density and different synaptic plasticity markers in the prefrontal cortex and the amygdale. Specifically while in the prefrontal cortex spine density, GluR1 AMPA receptor subunit, PSD95 and Synaptophysin were increased, a decrease was found in the amygdale. In addition, in the amygdale a downregulation of NR1 NMDA subunit, mGlur4, brain derived neurotrophic factor (BDNF) and CREB was also found. In addition, stressed mice exposed to the social interaction test with a dominant mouse experienced marked freezing and showed increased in pCREB/CREB ratio, proBDNF and mature BDNF in the amygdale. Taken together these results suggest that CSDS is not a pure model of depression. Indeed it addresses relevant aspects of anxiety-related disorders. Firstly, CSDS induced anhedonia and social avoidance is not associated in this model. Moreover, CSDS might be affecting brain areas mainly involved in the processing of social behaviour, such as the amygdale, where glutamatergic mechanism could play a key role. In addition, these results suggest a persistent maladaptive function of the prefrontal cortex and amygdale of socially defeated mice. Moreover, this would be the first evidence that late reencounter with an aversive social stimuli can triggers fear conditioning in socially defeated mice and support the validity of CSDS to model clinical aspects of post-traumatic stress disorders