M. Egeland

Molecular mechanisms in the regulation of adult neurogenesis during stress.

Coping with stress is fundamental for mental health, but understanding of the molecular neurobiology of stress is still in its infancy. Adult neurogenesis is well known to be regulated by stress, and conversely adult neurogenesis regulates stress responses. Recent studies in neurogenic cells indicate that molecular pathways activated by glucocorticoids, the main stress hormones, are modulated by crosstalk with other stress-relevant mechanisms, including inflammatory mediators, neurotrophic factors and morphogen signalling pathways. This Review discusses the pathways that are involved in this crosstalk and thus regulate this complex relationship between adult neurogenesis and stress.

Neurogenic Effects of Fluoxetine Are Attenuated in p11 (S100A10) Knockout Mice

BACKGROUND Chronic but not acute treatment with antidepressants increases hippocampal neurogenesis. Because chronic treatment with antidepressants also upregulates p11, we hypothesized that p11 might regulate effects of antidepressants on aspects of neurogenesis. METHODS Fluoxetine was administered chronically to wild-type (WT) and p11 knockout (KO) mice. In the neurogenic subgranular zone of hippocampus, the effects of fluoxetine on cell survival were examined with bromodeoxyuridine immunohistochemistry, whereas in the same brains cell proliferation was measured with Ki-67 immunohistochemistry, neurogenesis was measured with doublecortin immunohistochemistry, and apoptosis was measured with activated caspase-3. The behavioral action of fluoxetine was assessed in the novelty suppressed feeding test, which is considered neurogenesis-dependent. The localization of p11 in the dentate gyrus was studied with immunohistochemistry. RESULTS Vehicle-treated p11 KO mice have increased levels of markers for immature neuronal cell survival and neurogenesis relative to WT mice. In response to fluoxetine, p11 KO mice have reduced cell proliferation, neurogenesis, cell survival, and cell apoptosis in the subgranular zone of hippocampus when compared with WT littermates. P11 was not expressed in neurogenic cells but in different subtypes of neighboring gamma-aminobutyric acid (GABA)ergic interneurons, which also express serotonin 1B and serotonin 4 receptors. The behavioral effects of fluoxetine in the novelty suppressed feeding test were abolished in p11 KO mice. CONCLUSIONS P11 is abundantly expressed in hippocampal GABAergic interneurons. The p11 KO mice have increased levels of markers for immature neuronal cell survival and neurogenesis and an attenuated response to fluoxetine in measures of neurogenesis and in a neurogenesis-dependent behavioral test.

S33138 [N-[4-[2-[(3aS,9bR)-8-Cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], a Preferential Dopamine D3 versus D2 Receptor Antagonist and Potential Antipsychotic Agent. II. A Neurochemical, Electrophysiological and Behavioral Characterization in Vivo

The novel benzopyranopyrrolidine, S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], is a preferential antagonist of cloned human D3 versus D2L and D2S receptors. In mice, S33138 (0.04–2.5 mg/kg i.p.) increased levels of mRNA encoding c-fos in D3 receptor-rich Isles of Calleja and nucleus accumbens more potently than in D2 receptor-rich striatum. Furthermore, chronic (3 weeks) administration of S33138 to rats reduced the number of spontaneously active dopaminergic neurones in the ventral tegmental area (0.16–10.0 p.o.) more potently than in the substantia nigra (10.0). In primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, antiparkinson actions of the D3/D2 agonist, ropinirole, were potentiated by low doses of S33138 (0.01–0.16 p.o.) but diminished by a high dose (2.5). Consistent with antagonism of postsynaptic D3/D2 sites, S33138 attenuated hypothermia and yawns elicited by the D3/D2 agonist 7-OH-DPAT [(+)-7-dihydroxy-2-(di-n-propylamino)-tetralin] in rats, and it blocked (0.01–0.63, s.c.) discriminative properties of PD128,907 [(+)-(4aR,10bR)-3,4, 4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol; trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide]. Suggesting antagonist properties at D3/D2 autoreceptors, S33138 prevented (0.16–2.5 s.c.) the inhibitory influence of PD128,907 upon dopamine release in frontal cortex, nucleus accumbens, and striatum and abolished (0.004–0.25 i.v.) its inhibition of ventral tegmental dopaminergic neuron firing. At higher doses, antagonist actions of S33138 (0.5–4.0 i.v.) at α2C-adrenoceptors were revealed by an increased firing rate of adrenergic perikarya. Finally, antagonism of 5-hydroxytryptamine (5-HT2A and 5-HT7) receptors was shown by blockade of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane-induced head twitches (0.63–10.0 s.c.) and 5-carboxytryptamine-induced hypothermia (2.5–20.0 i.p.), respectively. In conclusion, S33138 displays modest antagonist properties at central α2C-adrenoceptors, 5-HT2A and 5-HT7 receptors. Furthermore, in line with its in vitro actions, it more potently blocks cerebral populations of D3 versus D2 receptors.

Co-expression of serotonin 5-HT1B and 5-HT4 receptors in p11 containing cells in cerebral cortex, hippocampus, caudate-putamen and cerebellum

p11 is an adaptor protein which binds to serotonin 5-HT(1B) receptors and 5-HT(4) receptors and regulates their localization at the cell surface. In the present study, we examined to what extent p11 containing neurons co-expressed 5-HT(1B)R and/or 5-HT(4)R in cerebral cortex, hippocampus, cerebellum and caudate-putamen. A triple-labeling immunohistochemical approach was taken using antibodies to detect native p11 and 5-HT(1B)R combined with visualization of EGFP driven under the 5-HT(4)R promoter in BAC-transgenic mice. In the caudate-putamen, the hippocampal pyramidal cell layer of CA1 and the hippocampal granule cell layer of dentate gyrus, most p11 containing cells co-expressed both 5-HT(1B)R and 5-HT(4)R. In the cingulate cortex, stratum radiatum/oriens of CA1, hilus of the dentate gyrus and cerebellar cortex, many cells co-expressed p11 and 5-HT(1B)R, but not 5-HT(4)R. In the studied brain regions, few cells solely expressed p11 without any significant expression of 5-HT(1B)R or 5-HT(4)R. It can be concluded that p11 is anatomically positioned to modulate serotonin neurotransmission, via 5-HT(1B)R and 5-HT(4)R, in brain regions important for emotionality, cognition and locomotion.

Modulation of Adult Hippocampal Neurogenesis by Early-Life Environmental Challenges Triggering Immune Activation

The immune system plays an important role in the communication between the human body and the environment, in early development as well as in adulthood. Per se, research has shown that factors such as maternal stress and nutrition as well as maternal infections can activate the immune system in the infant. A rising number of research studies have shown that activation of the immune system in early life can augment the risk of some psychiatric disorders in adulthood, such as schizophrenia and depression. The mechanisms of such a developmental programming effect are unknown; however some preliminary evidence is emerging in the literature, which suggests that adult hippocampal neurogenesis may be involved. A growing number of studies have shown that pre- and postnatal exposure to an inflammatory stimulus can modulate the number of proliferating and differentiating neural progenitors in the adult hippocampus, and this can have an effect on behaviours of relevance to psychiatric disorders. This review provides a summary of these studies and highlights the evidence supporting a neurogenic hypothesis of immune developmental programming.

Antidepressant-like properties of sarizotan in experimental Parkinsonism

RationaleDepression and anxiety are common symptoms in Parkinsons disease for which there are no optimal treatments. Sarizotan, an agonist at serotonin receptors and partial agonist at dopamine D2-like receptors, has shown antidyskinetic effects in Parkinsons disease. Based on its pharmacological profile, we hypothesized that sarizotan could also have antidepressant-like properties.ObjectivesExamine effects of sarizotan on behavioral and histological measures known to be regulated by established antidepressants in normal and unilaterally 6-hydroxydopamine-lesioned rats.ResultsSarizotan was found to significantly reduce immobility in the modified forced swim test, a measure of antidepressant-like activity, but had no effects on thigmotaxis or corner time, measures of anxiety-like behavior, in the unilaterally 6-hydroxydopamine-lesioned rats. At the same dose, sarizotan counteracted l-DOPA/benserazide-induced supersentitized rotational behavior and dyskinesias without significantly affecting l-DOPA/benserazide-induced locomotion. At the histological level, sarizotan alone or in combination with l-DOPA/benserazide stimulated cell proliferation, measured by bromodeoxyuridine incorporation or Ki-67 staining, both in the subgranular zone of the dentate gyrus and in the subventricular zone of the striatum in the 6-hydroxydopamine-lesioned hemisphere. Likewise, combined sarizotan and l-DOPA/benserazide treatment stimulated doublecortin levels in the subgranular zone of the dentate gyrus.ConclusionsThese significant effects of sarizotan in the modified forced swim test and on cell proliferation are reminiscent of those found after various antidepressant therapies. These data suggest that sarizotan may have some antidepressant-like and restorative properties in Parkinsonism.

Pharmacological or genetic blockade of the dopamine D3 receptor increases cell proliferation in the hippocampus of adult mice.

Dopamine plays an important role in cellular processes controlling the functional and structural plasticity of neurons, as well as their generation and proliferation, both in the developing and the adult brain. The precise roles of individual dopamine receptors subtypes in adult neurogenesis remain poorly defined, although D3 receptors are known to be involved in neurogenesis in the subventricular zone. By contrast, very few studies have addressed the influence of dopamine and D3 receptors upon neurogenesis in the subgranular zone of the hippocampus, an issue addressed herein employing constitutive D3 receptor knockout mice, or chronic exposure to the preferential D3 receptor antagonist, S33138. D3 receptor knockout mice revealed increased baseline levels of cell proliferation and ongoing neurogenesis, as measured both using Ki‐67 and doublecortin, whereas there was no difference in cell survival as measured by BrdU (5‐bromo‐2′‐deoxyuridine). Chronic administration of S33138 was shown to be functionally active in enhancing levels of the plasticity‐related molecule, delta‐FosB, in the D3 receptor‐rich nucleus accumbens. In accordance with the stimulated neurogenesis seen in D3 receptor knockout mice, S33138 increased proliferation in wild‐type mice. These observations suggest that D3 receptors exert a tonic, constitutive inhibitory influence upon adult hippocampal neurogenesis.

Depletion of adult neurogenesis using the chemotherapy drug Temozolomide in mice induces behavioural and biological changes relevant to depression

Numerous studies have examined links between postnatal neurogenesis and depression using a range of experimental methods to deplete neurogenesis. The antimitotic drug temozolomide (TMZ) has previously been used successfully as an experimental tool in animals to deplete adult neurogenesis and is used regularly on human patients as a standard chemotherapy for brain cancer. In this study, we wanted to evaluate whether TMZ as a model for chemotherapy treatment could affect parameters related to depression in an animal model. Prevalence rates of depression in patients is thought to be highly underdiagnosed, with some studies reporting rates as high as 90%. Results from this study in mice, treated with a regimen of TMZ similar to humans, exhibited behavioural and biochemical changes that have relevance to the development of depression. In particular, behavioural results demonstrated robust deficits in processing novelty and a significant increase in the corticosterone response. Quantification of neurogenesis using a novel sectioning method, which clearly evaluates dorsal and ventral neurogenesis separately, showed a significant correlation between the level of ventral neurogenesis and the corticosterone response. Depression is a complex disorder with discoveries regarding its neurobiology and how it relates to behaviour being only in their infancy. The findings presented in this study demonstrate that chemotherapy-induced decreases in neurogenesis results in previously unreported behavioural and biochemical consequences. These results, we argue, are indicative of a biological mechanism, which may contribute to the development of depression in patients being treated with chemotherapy and is separate from the mental distress resulting from a cancer diagnosis.

Repeated lipopolysaccharide exposure modifies immune and sickness behaviour response in an animal model of chronic inflammation

Repeated lipopolysaccharide exposure is often used in longitudinal preclinical models of depression. However, the potential phenotypic differences from acute depression-mimicking effects are rarely described. This study compared chronic lipopolysaccharide administration of doses previously used in depression research to a new mode of escalating dose injections. Adult male BALB/c mice (n=8/group) were injected intraperitoneally with either a single 0.83 mg/kg dose, a repeated 0.1 mg/kg lipopolysaccharide dose or a dose which escalated weekly from 0.33 to 0.83 mg/kg lipopolysaccharide for six weeks. The escalating lipopolysaccharide group demonstrated most features of sickness behaviour such as weight loss and reduction in food intake every week, whilst this effect was not sustained in other groups. Moreover, only in the escalating lipopolysaccharide group did most peripheral plasma cytokines levels, measured using Luminex multiplex technology, such as interleukin-6, tumour necrosis factor α and interleukin-2 remain over three-fold elevated on the sixth week. In addition, exposure to escalating doses led to a reduction of neuroblast maturation in the dentate gyrus relevant for depression neurobiology. Therefore, this mode of injections might be useful in the studies attempting to replicate neurobiological aspects of the chronic inflammatory state observed in mood disorders.

Abstract # 1728 Physical versus psychosocial stress: Distinctive stressors result in differential behavioural and biological phenotypes

Chronic stress can alter the immune system, stress reactivity, and induce anxiety-and depressive-like behaviour in rodents. However, no study to date has discriminated between the effect(s) of different types of stress. Previous research in our laboratory has shown that physical stress, modelled by daily intraperitoneal injection, induces an anxiety-like behavioural phenotype, while psychosocial stress, modelled by permanent social isolation, induces a depressive-like behavioural phenotype. To determine whether a distinct biological profile corresponds to each of these behavioural phenotypes, we assessed stress responsivity and immune system functioning in our animals exposed to social isolation and/or chronic injection. Here, we show how chronic injection significantly increased stress responsivity, and decreased plasma levels of tumour necrosis factor (TNF)- α in adult male BALB/cAnCrl mice. In contrast, permanent social isolation significantly decreased stress responsivity, and resulted in multiple immunological changes, specifically increasing plasma levels of TNF- α , and decreasing levels of interleukin (IL)-12, IL-10, and vascular endothelial growth factor (VEGF). Interestingly, animals exposed to both stressors had a stress response similar to control animals, and had significantly decreased levels of VEGF. Our data show how two different types of stress, which lead to distinct behavioural phenotypes, results in divergent biological outcomes. Moreover, there appears to be no additive effect of combining physical and psychosocial stress on animal physiology. Indeed, combining distinctive stressors may be masking the effect of individual stressors.