Increased stress reactivity is associated with cognitive deficits and decreased hippocampal brain-derived neurotrophic factor in a mouse model of affective disorders

Cognitive deficits are a common feature of major depression (MD), with largely unknown biological underpinnings. In addition to the affective and cognitive symptoms of MD, a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is commonly observed in these patients. Increased plasma glucocorticoid levels are known to render the hippocampus susceptible to neuronal damage. This structure is important for learning and memory, creating a potential link between HPA axis dysregulation and cognitive deficits in depression. In order to further elucidate how altered stress responsiveness may contribute to the etiology of MD, three mouse lines with high (HR), intermediate (IR), or low (LR) stress reactivity were generated by selective breeding.The aim of the present study was to investigate whether increased stress reactivity is associated with deficits in hippocampus-dependent memory tests. To this end, we subjected mice from the HR, IR, and LR breeding lines to tests of recognition memory, spatial memory, and depression-like behavior. In addition, measurements of brain-derived neurotrophic factor (BDNF) in the hippocampus and plasma of these animals were conducted.Our results demonstrate that HR mice exhibit hippocampus-dependent memory deficits along with decreased hippocampal, but not plasma, BDNF levels. Thus, the stress reactivity mouse lines are a promising animal model of the cognitive deficits in MD with the unique feature of a genetic predisposition for an altered HPA axis reactivity, which provides the opportunity to explore the progression of the symptoms of MD, predisposing genetic factors as well as new treatment strategies.     

Increased stress reactivity is associated with reduced hippocampal activity and neuronal integrity along with changes in energy metabolism

Patients suffering from major depression have repeatedly been reported to have dysregulations in hypothalamus-pituitary-adrenal (HPA) axis activity along with deficits in cognitive processes related to hippocampal and prefrontal cortex (PFC) malfunction. Here, we utilized three mouse lines selectively bred for high (HR), intermediate, or low (LR) stress reactivity, determined by the corticosterone response to a psychological stressor, probing the behavioral and functional consequences of increased vs. decreased HPA axis reactivity on the hippocampus and PFC. We assessed performance in hippocampus- and PFC-dependent tasks and determined the volume, basal activity, and neuronal integrity of the hippocampus and PFC using in vivo manganese-enhanced magnetic resonance imaging and proton magnetic resonance spectroscopy. The hippocampal proteomes of HR and LR mice were also compared using two-dimensional gel electrophoresis and mass spectrometry. HR mice were found to have deficits in the performance of hippocampus- and PFC-dependent tests and showed decreased N-acetylaspartate levels in the right dorsal hippocampus and PFC. In addition, the basal activity of the hippocampus, as assessed by manganese-enhanced magnetic resonance imaging, was reduced in HR mice. The three mouse lines, however, did not differ in hippocampal volume. Proteomic analysis identified several proteins that were differentially expressed in HR and LR mice. In accordance with the notion that N-acetylaspartate levels, in part, reflect dysfunctional mitochondrial metabolism, these proteins were found to be involved in energy metabolism pathways. Thus, our results provide further support for the involvement of a dysregulated HPA axis and mitochondrial dysfunction in the etiology and pathophysiology of affective disorders.     

Intrahippocampal Corticosterone Response in Mice Selectively Bred for Extremes in Stress Reactivity: A Microdialysis Study

The hypothalamic‐pituitary‐adrenocortical (HPA) axis is one of the major stress hormone systems, and glucocorticoids (GCs) play a pivotal role in homeostatic processes throughout the body and brain. A dysregulation of the HPA axis, leading to an aberrant secretion of GCs, is associated with affective disorders such as major depression. In the present study, three mouse lines selectively bred for high (HR), intermediate (IR) or low (LR) stress reactivity were used to elucidate the temporal dynamics of intrahippocampal corticosterone (CORT) in response to a standardised stressor. In particular, we addressed the question of whether the distinct differences in HPA axis reactivity between the three mouse lines, as determined by plasma CORT measurements, are present in the central nervous system as well, and if the respective endophenotype is brought about by alterations in blood–brain barrier (BBB) functionality. We applied in vivo microdialysis in the hippocampus, demonstrating that the concentrations of CORT released from the adrenals in response to restraint stress are not only distinctly different in the plasma, but can also be found in the central nervous system, although the differences between the three mouse lines were attenuated, particularly between IR and LR animals. Additionally, a time lag of approximately 60 min was observed in all three lines regarding intrahippocampal peak concentrations of CORT after the onset of the stressor. Furthermore, we showed that the penetration and clearance of CORT in the hippocampal tissue was not affected by differences in BBB functionality because the multidrug resistance 1 P‐glycoprotein (Mdr1 Pgp) was equally expressed in HR, IR and LR mice. Furthermore, we could exclude surgical damage of the BBB because peripherally‐injected dexamethasone, which is a high affinity substrate for the Mdr1 Pgp and therefore restricted from entering the brain, could only be detected in the plasma and was virtually absent in the brain.     

Reaction of sleep–wakefulness cycle to stress is related to differences in hypothalamo–pituitary–adrenal axis reactivity in rat

Acute stress is known to modify sleep–wakefulness cycle, although with considerable interindividual differences. The origin of these individual differences remains unknown. One possibility is an involvement of the hypothalamo–pituitary–adrenal axis (HPA), as its reactivity is correlated with an individual's behavioral reactivity to stress, and it is known to influence the sleep–wakefulness cycle. The present study was designed to analyze relationships between natural differences in behavioral reactivity to stress associated with differential HPA reactivity and stress-induced changes in sleep–wakefulness. Adult rats were classified into two sub-groups according to their locomotor reactivity to a mild stress (novel environment): the `low responders (LR)' and the `high responders (HR)' animals exhibited different glucocorticoid secretion in response to stress. We show that immobilization stress induced an increase in wakefulness in LR animals and a decrease in wakefulness in HR animals. On the other hand, paradoxical sleep was increased in both LR and HR animals. Moreover, we observed that LR animals slept more than the HR animals, whereas the two groups had similar levels of paradoxical sleep. These results indicate that the response of the sleep–wakefulness cycle to stress is related to the behavioral reactivity to stress, in turn governed by the individual's reactivity of the HPA axis. The involvement of dopaminergic mechanisms is discussed.     

Pituitary glucocorticoid receptor deletion reduces vulnerability to chronic stress

The incidence of chronic stress is frequently related to the development of psychiatric disorders like depression. The hypothalamic-pituitary-adrenal (HPA) axis is a major physiological system that mediates the stress response. Tight HPA axis regulation through negative feedback mechanisms is essential for health and environmental adaptation. This feedback regulation acts in part through the glucocorticoid receptor (GR) on several organizational levels, including the pituitary, the hypothalamus and the hippocampus. However, the precise role of the different anatomical structures, specifically the pituitary, in HPA axis regulation is yet largely unknown. Here, we show that a conditional pituitary GR knockout is not necessarily detrimental for the animal's ability to cope with chronic stress situations. Mice with a deletion of the GR at the pituitary (GR(POMCCre)) were subjected to 3 weeks of chronic social defeat stress. We analyzed both the behavioral and neuroendocrine phenotype as well as the central nervous system expression of genes involved in HPA axis function in these animals. Our results show a more resilient phenotype of GR(POMCCre) mice with respect to anxiety-related behavior and neuroendocrine parameters compared to stressed wild type animals. In light of the previously reported high corticosterone levels during postnatal development in GR(POMCCre) mice, our findings suggest that adverse early life events may have beneficial developmental effects on the organism to improve stress coping later in life.     

Prenatal stress does not alter innate novelty-seeking behavioral traits, but differentially affects individual differences in neuroendocrine stress responsivity

Exposure to stress during prenatal or early postnatal life can dramatically impact adult behavior and neuroendocrine function. We recently began to selectively breed Sprague-Dawley rats for high (high responder, HR) and low (low responder, LR) novelty-seeking behavior, a trait that predicts a variety of differences in emotional reactivity, including differences in neuroendocrine stress response, fear- and anxiety-like behavior, aggression, and propensity to self-administer drugs of abuse. We evaluated genetic-early environment interactions by exposing HR- and LR-bred animals to prenatal stress (PS) from pregnancy day 3-20, hypothesizing that PS exposure would differentially impact HR versus LR behavior and neuroendocrine reactivity. We evaluated novelty-induced locomotion, anxiety-like behavior, and corticosterone stress response in weanling (25-day-old) and adult HR-LR stressed and control males. Exposure to PS did not alter HR-LR differences in locomotion, but did impact anxiety-like behavior, specifically in LR animals. Surprisingly, LR animals exposed to PS exhibited less anxiety than LR controls. HR rats were not affected by PS, with both stress and control groups showing low levels of anxiety. PS differentially impacted neuroendocrine stress reactivity in young versus adult HR-LR animals, leading to an exaggerated corticosterone response in LR pups compared to LR controls, while HRs pups were unaffected. In contrast, exposure to PS produced an exaggerated stress response in HR adults, compared to HR controls, while LR animals were not significantly affected. These findings highlight how genetic predisposition may shape individual's response to early life stressors, and furthermore, show that a history of early life stress may differentially impact an organism at different points in life. Future work will explore neural mechanisms which underlie the different behavioral and neuroendocrine consequences of PS in HR versus LR animals.     

Stress-related depression: Neuroendocrine,genetic, and therapeutical aspects

Objective. To summarize current concepts on neuroendocrine and genetic principles underlying stress-related depression and to discuss the challenges of personalized treatment in depression. Methods. Review of the literature pertaining to genetic and neuroendocrine basis of stress-related depression including aspects of treatment response with a focus on the hypothalamus-pituitary-adrenal (HPA) axis. Results. There is increasing evidence that genetic polymorphisms and dysregulation of the HPA axis are associated with the pathophysiology of stress-related depression. Individual stress hormone reactivity seems to be determined by a combination of genetic and environmental factors, contributing to both, resilience or vulnerability. Conclusions. Although substantial progress has been made, current knowledge is still limited. Further basic and clinical research is needed to identify specific subgroups and to minimize heterogeneity of the depression phenotype. A better characterization is essential to detect genetic and functional predictors of antidepressant treatment response to follow the vision of personalized therapy in psychiatry.     

Widespread hypothalamic–pituitary–adrenocortical axis‐relevant and mood‐relevant effects of chronic fluoxetine treatment on glucocorticoid receptor gene expression in mice

Tricyclic antidepressants (TCAs) have been used to treat melancholic depression, which has been associated with elevated hypothalamic–pituitary–adrenocortical (HPA) axis activity, whereas patients suffering from atypical depression, which is often associated with decreased HPA axis activity, show preferential responsiveness to monoamine oxidase inhibitors (MAOIs). We previously reported drug‐specific effects of the TCA imipramine and the MAOI phenelzine on HPA axis‐relevant endpoints in mice that may explain differential antidepressant responses in melancholic vs. atypical depression. However, selective serotonin reuptake inhibitors (SSRIs) are reported to be effective in both melancholic and atypical depression. We therefore hypothesized that SSRIs would share HPA axis‐related effects with either TCAs or MAOIs. To test this hypothesis, we measured HPA axis‐relevant gene expression in male C57BL/6 mice treated for 5 weeks with 10 mg/kg/day fluoxetine. To control for potential fluoxetine‐induced changes in glucocorticoid secretion, mice were adrenalectomized and given fixed levels of glucocorticoids. Fluoxetine decreased glucocorticoid receptor (GR) gene expression in the prefrontal cortex, amygdala, locus coeruleus and dorsal raphé nucleus, and increased locus coeruleus tyrosine hydroxylase and dorsal raphé nucleus tryptophan hydroxylase‐2 (TPH2) gene expression. These results resembled those that we previously reported for MAOI treatment, but included decreases in GR and increases in TPH2 gene expression in the dorsal raphé nucleus that were induced by TCAs but not MAOIs. Correlating with inhibitory effects on central amygdala GR gene expression, fluoxetine also decreased amygdala corticotropin‐releasing hormone gene expression, an effect not previously observed with MAOIs or TCAs. These actions may be relevant to the efficacy of SSRIs in treating a range of depression and anxiety disorders.     

Depressive disorders-is it time to endorse different pathophysiologies?

Enhanced activity of the hypothalamic-pituitary-adrenal (HPA) axis, involving elevated secretion of corticotropin-releasing hormone (CRH), is considered a key neurobiological alteration in major depression. Enhanced CRH secretion is also believed to contribute to the typical sleep alterations and the clinical presentation of major depression. While it is acknowledged that HPA overdrive and hypernoradrenergic function is associated with melancholic depression, there is growing evidence that hypoactivity of the HPA axis and afferent noradrenergic pathways is present in patients with atypical features of depression. The clinical relevance of such a differentiation is highlighted by findings which suggest distinct responses to pharmacological treatments. Moreover, it has been reported that female patients respond better to selective serotonin re-uptake inhibitors (SSRI) than tricyclic antidepressants. Interestingly, the female predominance among patients with depression seems to be restricted to the atypical subtype. Besides HPA axis activity, distinct alterations of the serotonergic system may also play a critical role for the melancholic and atypical phenotypes, namely a reduced restrained via 5-HT(1A) autoreceptors in the former and primarily reduced serotonin synthesis in the latter. Moreover, there is evidence for an immune activation in patients with depression, the extent and duration of which may be distinguishable for the melancholic and the atypical subtype. In this regard, lessons can be learned from depressive symptoms in patients with autoimmune disease, associated with different alterations of the HPA axis, and in patients undergoing cytokine therapy. In conclusion, the available data today suggest that clinically relevant differences in the underlying pathophysiology in patients with depression exist. The identification of distinct endophenotypes for major depression will not only improve our understanding of the disease, but will also contribute to more specific treatment strategies.