Gabriele Flügge

Anhedonia and motivational deficits in rats: Impact of chronic social stress

Stress, especially chronic stress, is one of the most important factors responsible for precipitation of affective disorders in humans. The animal models commonly used in the investigation of stress effects are based mainly on powerful physical stressors. In the majority of cases, these models are not relevant to situations that human beings encounter in everyday life. In our study, an animal model for chronic social stress has been developed for rats using a resident-intruder paradigm. This paradigm is considered a model of social defeat or subordination, and therefore may mimic situations occurring in humans. Rats were subjected daily to subordination stress for a period of five weeks and, in parallel, tested with a battery of behavioural tests. Chronically stressed rats showed behavioural changes, including decreased motility and exploratory activity, increased immobility in a forced swim test, and reduced preference for sweet sucrose solution (anhedonia). Reduced locomotor and exploratory activity represents a loss of interest in new stimulating situations, implying a deficit in motivation. Increased immobility in the forced swim test indicates behavioural despair, a characteristic of depressive disorders. Decreased sucrose preference may indicate desensitisation of the brain reward mechanism. Since anhedonia is one of the core symptoms of depression in humans, our findings suggest that the rat chronic social stress model may be an appropriate model for depressive disorders.

Evidence for Estrogen-Receptive GABAergic Neurons in the Preoptic/Anterior Hypothalamic Area of the Rat Brain

Estrogen target neurons are numerous in the medial preoptic/anterior hypothalamic area (MPO/AH) of the female rat brain, and they are thought to play a crucial role in reproductive functions. This brain region is also known to contain high concentrations of the inhibitory transmitter gamma-aminobutyric acid (GABA) and of its synthesizing enzyme glutamate decarboxylase (GAD). Since it is known that GABA is involved in the regulation of gonadotropin release from the pituitary gland it has been proposed that estrogen feedback may be mediated by this transmitter. Here we show, by a combined method of estrogen autoradiography and GAD immunocytochemistry, that estrogen-receptive neurons of GABAergic nature exist in the MPO/AH.

Social stress in tree shrews: Effects on physiology, brain function, and behavior of subordinate individuals

Social stress is known to be involved in the etiology of central nervous disorders such as depression. In recent years, animal models have been developed that use chronic stress to induce neuroendocrine and central nervous changes that might be similar to those occurring in the course of the development of depressive disorders. The present review gives a summary of observations made in the tree shrew chronic social stress model. During periods of daily social stress, male tree shrews develop symptoms that are known from many depressed patients such as persistent hyperactivities of both the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system, disturbances in sleeping patterns, and reduced motor activity. Moreover, various physiological parameters indicate an acceleration of the over all metabolic rate in socially stressed tree shrews. Some of these parameters can be renormalized by antidepressants thus supporting the view of the tree shrew social stress paradigm as model for major depression. In the brains of socially stressed animals, monoamine receptors show dynamic changes that reflect adaptation to the persistent monoaminergic hyperactivity during periods of chronic stress. In addition to the changes in neurotransmitter systems, there are structural changes in neurons, e.g., retraction of the dendrites of hippocampal pyramidal neurons. Together, these processes are suggested as a cause of behavioral alterations that can be counteracted by antidepressants in this naturalistic social stress model.

Immunocytochemical localization of estrogen-binding neurons in the songbird brain

This study used monoclonal antibodies against estrogen receptor for the identification and localization of estrogen-binding cells in the avian brain. The distribution of estrogen-binding neurons in the songbird brain conformed to the general vertebrate pattern with highest labelling in hypothalamus and preoptic area. For the first time, estrogen-binding neurons were found in the song control system: these neurons might provide a substrate for the direct action of estrogen on the song system.

Stress impairs GABAergic network function in the hippocampus by activating nongenomic glucocorticoid receptors and affecting the integrity of the parvalbumin-expressing neuronal network.

Stress facilitates the development of psychiatric disorders in vulnerable individuals. It affects physiological functions of hippocampal excitatory neurons, but little is known about the impact of stress on the GABAergic network. Here, we studied the effects of stress and a synthetic glucocorticoid on hippocampal GABAergic neurotransmission and network function focusing on two perisomatic interneurons, the parvalbumin (PV)- and the cholecystokinin (CCK)-positive neurons. In acute hippocampal slices of rat, application of the potent glucocorticoid receptor (GR) agonist dexamethasone (DEX) caused a rapid increase in spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons. This effect was mediated by a nongenomic GR that evoked nitric oxide (NO) release from pyramidal neurons. Retrograde NO signaling caused the augmentation of GABA release from the interneurons and increased CCK release, which in turn further enhanced the activity of the PV-positive cells. Interestingly, chronic restraint stress also resulted in increased sIPSCs in CA1 pyramidal neurons that were Ca2+-dependent and an additional DEX application elicited no further effect. Concomitantly, chronic stress reduced the number of PV-immunoreactive cells and impaired rhythmic sIPSCs originating from the PV-positive neurons. In contrast, the CCK-positive neurons remained unaffected. We therefore propose that, in addition to the immediate effect, the sustained activation of nongenomic GRs during chronic stress injures the PV neuron network and results in an imbalance in perisomatic inhibition mediated by the PV and CCK interneurons. This stress-induced dysfunctional inhibitory network may in turn impair rhythmic oscillations and thus lead to cognitive deficits that are common in stress-related psychiatric disorders.

Psychosocial stress, glucocorticoids, and structural alterations in the tree shrew hippocampus.

Animal models for chronic stress represent an indispensable preclinical approach to human pathology since clinical data point to a major role of psychological stress experiences, acute and/or chronic, to the development of behavioral and physiological disturbances. Chronic emotional arousal is a consequence of various types of social interactions, and one major neurohumoral accompaniment is the activation of the classic stress circuit, the limbic--hypothalamic--pituitary--adrenocortical (LHPA) axis. The adrenocortical glucocorticoid hormones cortisol and corticosterone are principal effectors within this circuit since they affect neurotransmission and neuroendocrine control, thus having profound effects on mood and behavior. Using the experimental paradigm of chronic psychosocial stress in tree shrews, we investigated the impact of aversive chronic social encounters on hippocampal structure and function. In chronically stressed animals, we observed dendritic atrophy of hippocampal pyramidal neurons and an impairment of neurogenesis in the dentate gyrus. However, a stress-induced loss of hippocampal neurons was not observed in this animal model. This review summarizes our recent results on structural changes occurring during chronic stress in neurons of the hippocampus and their potential influence on learning and memory. We discuss whether these changes are reversible and to what extent glucocorticoids might be responsible for the stress-induced effects.

Stress, glucocorticoids and structural plasticity of the hippocampus

Sustained stress can have numerous pathophysiological effects. Adrenal glucocorticoid hormones are principal effectors in the stress response. They have profound effects on mood and behavior and affect neurochemical transmission and neuroendocrine control. We have used the experimental paradigm of chronic psychosocial stress in tree shrews to investigate the impact of aversive social encounters on brain structures. Chronic stress in male tree shrews which is accompanied by constantly elevated levels of glucocorticoids leads to structural changes in hippocampal neurons. Whereas dendritic atrophy of hippocampal pyramidal neurons and impairment of neurogenesis in the dentate gyrus could be demonstrated in chronically stressed tree shrews, a loss of hippocampal neurons was not observed in this animal model. The present review summarizes recent results on the question which structural changes occur during chronic stress in neurons of the brain and whether glucocorticoids might be responsible for such stress effects. The role of transmitter systems in stress-related neuronal plasticity is also discussed.

Chronic social stress: effects on limbic brain structures

Different types of stressors are known to activate distinct neuronal circuits in the brain. Acute physiological stimuli that are life threatening and require immediate reactions lead to a rapid stimulation of brainstem and hypothalamus to activate efferent visceral pathways. In contrast, psychological stressors activate higher-order brain structures for further interpretations of the perceived endangerment. Common to the later multimodal stressors is that they need cortical processing and, depending on previous experience or ongoing activation, the information is assembled within limbic circuits connecting, e.g., the hippocampus, amygdala and prefrontal cortex to induce neuroendocrine and behavioral responses. In view of the fact that stressful life events often contribute to the etiology of psychopathologies such as depressive episodes, several animal models have been developed to study central nervous mechanisms that are induced by stress. The present review summarizes observations made in the tree shrew chronic psychosocial stress paradigm with particular focus on neurotransmitter systems and structural changes in limbic brain regions.

Chronic psychosocial stress induces morphological alterations in hippocampal pyramidal neurons of the tree shrew.

The effect of sustained psychosocial stress on the morphology of hippocampal pyramidal neurons was analysed in male tree shrews after 14, 20, and 28 days of social confrontation. A variety of physiological changes such as constantly elevated levels of urinary cortisol and norepinephrine and reduced body weight, which are indicative of chronic stress were observed in the subordinate, but not in the dominant males. Light microscopic analysis of Nissl-stained hippocampal sections showed that the staining intensity of the nucleoplasm in the CA1 and CA3 pyramidal neurons was increased after prolonged psychosocial stress, indicating a change in the nuclear chromatin structure. These alterations were observed only in subordinate animals and increased in a time dependent manner in accordance with the length of the stress period. There was, however, neither a reduction in density nor a degeneration of pyramidal neurons in chronically stressed animals. Mechanisms which may possibly account for the observed alterations are discussed.

Modulation of binding sites for corticotropin-releasing hormone by chronic psychosocial stress.

This study was conducted to determine whether long lasting psychosocial stress would affect corticotropin-releasing hormone (CRH) binding sites in the brain, the pituitary, and the adrenal gland. As a model for sustained emotional stress we used chronic psychosocial conflict in male tree shrews. In subordinate tree shrews, repeated confrontation with a dominant conspecific results in constant hyperactivity of the HPA-axis and an elevated neurosympathetic tone. After 24 days of psychosocial conflict, CRH binding sites were quantified by in vitro-autoradiography with 125I-ovine CRH in 23 discrete brain regions, the pituitaries, and the adrenal glands of subordinate and control animals. Chronic stress significantly reduced the number of binding sites (Bmax) in the anterior lobe of the pituitary, the dentate gyrus, the CA1-CA3 areas of the hippocampus, and in both the stratum griseum superficiale and the stratum opticum of the superior colliculus. In cortical area 17, the reduction of Bmax was counterbalanced by an increase in the affinity (Kd) of the radioligand for the binding sites. A significant stress-induced enhancement of Bmax was observed in the frontal cortex, cingulate cortex, claustrocortex, the central and lateral nucleus of the amygdala, and in the choroid plexus. This increase was accompanied by a significant decrease of Kd-values in the frontal and cingulate cortex, the lateral nucleus of the amygdala, and the choroid plexus. These findings represent the first in vivo demonstration of a modulation of extrahypothalamic CRH receptors by a naturally occurring form of stress. The different response patterns of the central CRH binding sites reflect distinct neuroendocrine processes which are presumed to coordinate behavioral, autonomic, endocrine, and immune responses to long-lasting psychosocial conflict.