Adult neuroplasticity: more than 40 years of research.

Within the last four decades, our view of the mature vertebrate brain has changed significantly. Today it is generally accepted that the adult brain is far from being fixed. A number of factors such as stress, adrenal and gonadal hormones, neurotransmitters, growth factors, certain drugs, environmental stimulation, learning, and aging change neuronal structures and functions. The processes that these factors may induce are morphological alterations in brain areas, changes in neuron morphology, network alterations including changes in neuronal connectivity, the generation of new neurons (neurogenesis), and neurobiochemical changes. Here we review several aspects of neuroplasticity and discuss the functional implications of the neuroplastic capacities of the adult and differentiated brain with reference to the history of their discovery.

NDRG2 as a marker protein for brain astrocytes.

The protein NDRG2 (N-myc downregulated gene 2) is expressed in astrocytes. We show here that NDRG2 is located in the cytosol of protoplasmic and fibrous astrocytes throughout the mammalian brain, including Bergmann glia as observed in mouse, rat, tree shrew, marmoset and human. NDRG2 immunoreactivity is detectable in the astrocytic cell bodies and excrescencies including fine distal processes. Glutamatergic and GABAergic nerve terminals are associated with NDRG2 immunopositive astrocytic processes. Müller glia in the retina displays no NDRG2 immunoreactivity. NDRG2 positive astrocytes are more abundant and more evenly distributed in the brain than GFAP (glial fibrillary acidic protein) immunoreactive cells. Some regions with very little GFAP such as the caudate nucleus show pronounced NDRG2 immunoreactivity. In white matter areas, NDRG2 is less strong than GFAP labeling. Most NDRG2 positive somata are immunoreactive for S100ß but not all S100ß cells express NDRG2. NDRG2 positive astrocytes do not express nestin and NG2 (chondroitin sulfate proteoglycan 4). The localization of NDRG2 overlaps only partially with that of aquaporin 4, the membrane-bound water channel that is concentrated in the astrocytic endfeet. Reactive astrocytes at a cortical lesion display very little NDRG2, which indicates that expression of the protein is reduced in reactive astrocytes. In conclusion, our data show that NDRG2 is a specific marker for a large population of mature, non-reactive brain astrocytes. Visualization of NDRG2 immunoreactive structures may serve as a reliable tool for quantitative studies on numbers of astrocytes in distinct brain regions and for high-resolution microscopy studies on distal astrocytic processes.

Agomelatine in the tree shrew model of depression: effects on stress-induced nocturnal hyperthermia and hormonal status.

The antidepressive drug agomelatine combines the properties of an agonist of melatonergic receptors 1 and 2 with an antagonist of the 5-HT2C receptor. We analyzed the effects of agomelatine in psychosocially stressed male tree shrews, an established preclinical model of depression. Tree shrews experienced daily social stress for a period of 5 weeks and were concomitantly treated with different drugs daily for 4 weeks. The effects of agomelatine (40 mg/kg/day) were compared with those of the agonist melatonin (40 mg/kg/day), the inverse 5-HT2C antagonist S32006 (10mg/kg/day), and the SSRI fluoxetine (15 mg/kg/day). Nocturnal core body temperature (CBT) was recorded by telemetry, and urinary norepinephrine and cortisol concentrations were measured. Chronic social stress induced nocturnal hyperthermia. Agomelatine normalized the CBT in the fourth week of the treatment (T4), whereas the other drugs did not significantly counteract the stress-induced hyperthermia. Agomelatine also reversed the stress-induced reduction in locomotor activity. Norepinephrine concentration was elevated by the stress indicating sympathetic hyperactivity, and was normalized in the stressed animals treated with agomelatine or fluoxetine but not in those treated with melatonin or S32006. Cortisol concentration was elevated by stress but returned to basal levels by T4 in all animals, irrespective of the treatment. These observations show that agomelatine has positive effects to counteract stress-induced physiological processes and to restore the normal rhythm of nocturnal CBT. The data underpin the antidepressant properties of agomelatine and are consistent with a distinctive profile compared to its constituent pharmacological components and other conventional agents.

Altered glial plasticity in animal models for mood disorders.

Numerous clinical evidences support the notion that glial changes in fronto-limbic brain areas could contribute to the pathophysiology of mood disorders. Glial alterations have been reported not only in patients, but also in various kinds of animal models for depression. Molecular and cellular data suggest that all the major classes of glial cells are affected in these conditions, including astrocytes, oligodendrocytes, NG2-positive cells and microglia. The aim of this review was to summarize the currently available experimental results demonstrating alterations in glial morphology and functioning in animal models for mood disorders. Better understanding of these glial changes affecting neuronal activity could help us to identify novel targets for the development of antidepressant drugs.

Chronic psychosocial stress and citalopram modulate the expression of the glial proteins GFAP and NDRG2 in the hippocampus.

RATIONALE: It has been suggested that there are causal relationships between alterations in brain glia and major depression. OBJECTIVES: To investigate whether a depressive-like state induces changes in brain astrocytes, we used chronic social stress in male rats, an established preclinical model of depression. Expression of two astrocytic proteins, the intermediate filament component glial fibrillary acidic protein (GFAP) and the cytoplasmic protein N-myc downregulated gene 2 (NDRG2), was analyzed in the hippocampus. For comparison, expression of the neuronal protein syntaxin-1A was also determined. METHODS: Adult male rats were subjected to daily social defeat for 5 weeks and were concomitantly treated with citalopram (30 mg/kg/day, via the drinking water) for 4 weeks. RESULTS: Western blot analysis showed that the chronic stress downregulated GFAP but upregulated NDRG2 protein. Citalopram did not prevent these stress effects, but the antidepressant per se downregulated GFAP and upregulated NDRG2 in nonstressed rats. In contrast, citalopram prevented the stress-induced upregulation of the neuronal protein syntaxin-1A. CONCLUSIONS: These data suggest that chronic stress and citalopram differentially affect expression of astrocytic genes while the antidepressant drug does not prevent the stress effects. The inverse regulation of the cytoskeletal protein GFAP and the cytoplasmic protein NDRG2 indicates that the cells undergo profound metabolic changes during stress and citalopram treatment. Furthermore, the present findings indicate that a 4-week treatment with citalopram does not restore normal glial function in the hippocampus, although the behavior of the animals was normalized within this treatment period, as reported previously.

Restraint Stress Intensifies Interstitial K(+) Accumulation during Severe Hypoxia.

Chronic stress affects neuronal networks by inducing dendritic retraction, modifying neuronal excitability and plasticity, and modulating glial cells. To elucidate the functional consequences of chronic stress for the hippocampal network, we submitted adult rats to daily restraint stress for 3 weeks (6 h/day). In acute hippocampal tissue slices of stressed rats, basal synaptic function and short-term plasticity at Schaffer collateral/CA1 neuron synapses were unchanged while long-term potentiation was markedly impaired. The spatiotemporal propagation pattern of hypoxia-induced spreading depression episodes was indistinguishable among control and stress slices. However, the duration of the extracellular direct current potential shift was shortened after stress. Moreover, K(+) fluxes early during hypoxia were more intense, and the postsynaptic recoveries of interstitial K(+) levels and synaptic function were slower. Morphometric analysis of immunohistochemically stained sections suggested hippocampal shrinkage in stressed rats, and the number of cells that are immunoreactive for glial fibrillary acidic protein was increased in the CA1 subfield indicating activation of astrocytes. Western blots showed a marked downregulation of the inwardly rectifying K(+) channel Kir4.1 in stressed rats. Yet, resting membrane potentials, input resistance, and K(+)-induced inward currents in CA1 astrocytes were indistinguishable from controls. These data indicate an intensified interstitial K(+) accumulation during hypoxia in the hippocampus of chronically stressed rats which seems to arise from a reduced interstitial volume fraction rather than impaired glial K(+) buffering. One may speculate that chronic stress aggravates hypoxia-induced pathophysiological processes in the hippocampal network and that this has implications for the ischemic brain.

Nocturnal hyperthermia induced by social stress in male tree shrews: relation to low testosterone and effects of age.

Stress is known to elevate core body temperature (CBT). We recorded CBT in a diurnal animal, the male tree shrew, during a one-week control period and a one-week period of social stress using a telemetric system. During the stress period, when animals were confronted with a dominant male for about 1h daily, CBT was increased throughout the day. We analyzed CBT during the night when animals were left undisturbed and displayed no locomotor activity. To determine whether nocturnal hyperthermia may be related to stress-induced changes in hormonal status, we measured testosterone, noradrenalin and cortisol in the animals' morning urine. The daily social stress increased the mean nocturnal temperature by 0.37 °C. Urinary testosterone was reduced during the stress period, and there was a significant negative correlation between testosterone and the area under the curve (AUC) of the nocturnal CBT. This means that stress-induced hyperthermia was strongest in the animals with the lowest testosterone concentrations. As expected, urinary noradrenalin was elevated during the stress week but a positive correlation with the AUC data was only found for animals younger than 12 months. Cortisol was also increased during the stress week but there were no correlations with nocturnal hyperthermia. However, the stress-induced increases in noradrenalin and cortisol correlated with each other. Furthermore, there were no correlations between the stress-induced increase in nocturnal CBT and body weight reduction or locomotor activity during the light phase. Interestingly, the extent of nocturnal hyperthermia depended on the animals' ages: In animals younger than 12 months, stress increased the AUC by 48%, in animals aged between 12 and 24 months, stress increased the AUC by 36%, and older animals showed only a 7% increase. However, testosterone was not significantly reduced in the older animals. The present data reveal an interrelation between the extent of stress-induced nocturnal hyperthermia, the animals' gonadal hormone status and their ages. The negative correlation between hyperthermia and testosterone indicates that this hormone in particular plays an important role in the regulation of body temperature in male tree shrews.

Chronic restraint stress impairs endocannabinoid mediated suppression of GABAergic signaling in the hippocampus of adult male rats.

Chronic stress, a risk factor for the development of psychiatric disorders, is known to induce alterations in neuronal networks in many brain areas. Previous studies have shown that chronic stress changes the expression of the cannabinoid receptor 1 (CB1) in the brains of adult rats, but neurophysiological consequences of these changes remained unclear. Here we demonstrate that chronic restraint stress causes a dysfunction in CB1 mediated modulation of GABAergic transmission in the hippocampus. Using an established protocol, adult male Sprague Dawley rats were daily restrained for 21 days and whole-cell voltage clamp was performed at CA1 pyramidal neurons. When recording carbachol-evoked inhibitory postsynaptic currents (IPSCs) which presumably originate from CB1 expressing cholecystokinin (CCK) interneurons, we found that depolarization-induced suppression of inhibition (DSI) was impaired by the stress. DSI is a form of short-term plasticity at GABAergic synapses that is known to be CB1 mediated and has been suggested to be involved in hippocampal information encoding. Chronic stress attenuated the depolarization-induced suppression of the frequency of carbachol-evoked IPSCs. Incubation with a CB1 receptor antagonist prevented this DSI effect in control but not in chronically stressed animals. The stress-induced impairment of CB1-mediated short-term plasticity at GABAergic synapses may underlie cognitive deficits which are commonly observed in animal models of stress as well as in patients with stress-related psychiatric disorders.

Activity-dependent regulation of MHC class I expression in the developing primary visual cortex of the common marmoset monkey.

BACKGROUND: Several recent studies have highlighted the important role of immunity-related molecules in synaptic plasticity processes in the developing and adult mammalian brains. It has been suggested that neuronal MHCI (major histocompatibility complex class I) genes play a role in the refinement and pruning of synapses in the developing visual system. As a fast evolutionary rate may generate distinct properties of molecules in different mammalian species, we studied the expression of MHCI molecules in a nonhuman primate, the common marmoset monkey (Callithrix jacchus). METHODS AND RESULTS: Analysis of expression levels of MHCI molecules in the developing visual cortex of the common marmoset monkeys revealed a distinct spatio-temporal pattern. High levels of expression were detected very early in postnatal development, at a stage when synaptogenesis takes place and ocular dominance columns are formed. To determine whether the expression of MHCI molecules is regulated by retinal activity, animals were subjected to monocular enucleation. Levels of MHCI heavy chain subunit transcripts in the visual cortex were found to be elevated in response to monocular enucleation. Furthermore, MHCI heavy chain immunoreactivity revealed a banded pattern in layer IV of the visual cortex in enucleated animals, which was not observed in control animals. This pattern of immunoreactivity indicated that higher expression levels were associated with retinal activity coming from the intact eye. CONCLUSIONS: These data demonstrate that, in the nonhuman primate brain, expression of MHCI molecules is regulated by neuronal activity. Moreover, this study extends previous findings by suggesting a role for neuronal MHCI molecules during synaptogenesis in the visual cortex.

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 Ca(2+)-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.

Neuronal MHC class I molecules are involved in excitatory synaptic transmission at the hippocampal mossy fiber synapses of marmoset monkeys.

Several recent studies suggested a role for neuronal major histocompatibility complex class I (MHCI) molecules in certain forms of synaptic plasticity in the hippocampus of rodents. Here, we report for the first time on the expression pattern and functional properties of MHCI molecules in the hippocampus of a nonhuman primate, the common marmoset monkey (Callithrix jacchus). We detected a presynaptic, mossy fiber-specific localization of MHCI proteins within the marmoset hippocampus. MHCI molecules were present in the large, VGlut1-positive, mossy fiber terminals, which provide input to CA3 pyramidal neurons. Furthermore, whole-cell recordings of CA3 pyramidal neurons in acute hippocampal slices of the common marmoset demonstrated that application of antibodies which specifically block MHCI proteins caused a significant decrease in the frequency, and a transient increase in the amplitude, of spontaneous excitatory postsynaptic currents (sEPSCs) in CA3 pyramidal neurons. These findings add to previous studies on neuronal MHCI molecules by describing their expression and localization in the primate hippocampus and by implicating them in plasticity-related processes at the mossy fiber-CA3 synapses. In addition, our results suggest significant interspecies differences in the localization of neuronal MHCI molecules in the hippocampus of mice and marmosets, as well as in their potential function in these species.

Diurnal rhythm and stress regulate dendritic architecture and spine density of pyramidal neurons in the rat infralimbic cortex.

The medial prefrontal cortex (mPFC) participates in several higher order cognitive functions and is involved in the regulation of the stress response. The infralimbic cortex (ILC), the most ventral part of the mPFC, receives a strong afferent input from the master circadian pacemaker, the suprachiasmatic nucleus. This fact raises the possibility that, similarly to stress, the diurnal rhythm may affect structural plasticity of neurons in the ILC. Here we investigated, whether diurnal changes in combination with immobilization stress have any impact on the dendritic morphology of layer III pyramidal neurons in the ILC. Prefrontal cortices were collected from control rats at two different time points of the diurnal cycle (12h apart), and from rats exposed to 1-week of daily restraint stress either during their active or resting period. Dendritic architecture and spine density of Golgi-Cox stained neurons were digitally reconstructed and analyzed. We found that in control rats during the active period, the basilar dendrites were always longer and more complex, and had more spines than during the resting period. Similar although less pronounced diurnal differences exist in the apical dendrites. Stress affected dendritic architecture in a way that the diurnal differences either disappeared or became reduced in their magnitude. Our findings indicate that the diurnal rhythm has a unique impact on the structural plasticity of pyramidal cells in the ILC and that stress interferes with this form of neuroplasticity.

Hemispheric differences in basilar dendrites and spines of pyramidal neurons in the rat prelimbic cortex: activity- and stress-induced changes.

Pyramidal neurons of the rat medial prefrontal cortex have been shown to react to chronic stress by retracting their apical dendrites and by spine loss. We extended these findings by focusing on the basilar dendritic tree of layer III pyramidal neurons in both hemispheres of the rat prelimbic cortex. Animals were subjected to daily restraint stress for 1 week (6 h/day), during either the resting or the activity period. The morphology of basilar dendrites and spines of Golgi-Cox-stained neurons in the left and right hemispheres was digitally reconstructed and analyzed. We observed the following: (i) there was an inherent hemispheric asymmetry in control rats during the resting period: the number of spines on proximal dendrites was higher in the left than in the right hemisphere; (ii) basal dendrites in controls displayed a diurnal variation: there was more dendritic material during the resting period than in the activity period; (iii) chronic stress reduced the length of basal dendrites in only the right prelimbic cortex; (iv) chronic stress reduced spine density on proximal basal dendrites; (v) restraint stress during the activity period had more pronounced effects on the physiological stress parameters than restraint stress during the resting period. Our results show dynamic hemisphere-dependent structural changes in pyramidal neurons of the rat prelimbic cortex that are tightly linked to periods of resting and activity. These morphological alterations reflect the capacity of the neurons to react to external stimuli and mirror presumptive changes in neuronal communication.

Expression of the axonal membrane glycoprotein M6a is regulated by chronic stress.

It has been repeatedly shown that chronic stress changes dendrites, spines and modulates expression of synaptic molecules. These effects all may impair information transfer between neurons. The present study shows that chronic stress also regulates expression of M6a, a glycoprotein which is localised in axonal membranes. We have previously demonstrated that M6a is a component of glutamatergic axons. The present data reveal that it is the splice variant M6a-Ib, not M6a-Ia, which is strongly expressed in the brain. Chronic stress in male rats (3 weeks daily restraint) has regional effects: quantitative in situ hybridization demonstrated that M6a-Ib mRNA in dentate gyrus granule neurons and in CA3 pyramidal neurons is downregulated, whereas M6a-Ib mRNA in the medial prefrontal cortex is upregulated by chronic stress. This is the first study showing that expression of an axonal membrane molecule is differentially affected by stress in a region-dependent manner. Therefore, one may speculate that diminished expression of the glycoprotein in the hippocampus leads to altered output in the corresponding cortical projection areas. Enhanced M6a-Ib expression in the medial prefrontal cortex (in areas prelimbic and infralimbic cortex) might be interpreted as a compensatory mechanism in response to changes in axonal projections from the hippocampus. Our findings provide evidence that in addition to alterations in dendrites and spines chronic stress also changes the integrity of axons and may thus impair information transfer even between distant brain regions.

Pharmacological validation of a chronic social stress model of depression in rats: effects of reboxetine, haloperidol and diazepam.

Chronic social stress is one of the most important factors responsible for precipitation of depressive disorder in humans. In recent years, the impact of social stress on the development of psychopathologies has been thoroughly investigated in preclinical animal studies. We have shown recently that behavioural effects of chronic social stress in rats can be reversed by citalopram and fluoxetine. This study has been designed for further pharmacological validation of the chronic social stress paradigm as a model of depressive symptoms in rats. For this, rats were subjected to 5 weeks of daily social defeat and were in parallel treatment for a clinically relevant period of 4 weeks with the antidepressant drug reboxetine (40 mg/kg/day) and the neuroleptic drug haloperidol (2 mg/kg/day). The anxiolytic diazepam (1 mg/kg) was administered acutely at the end of the stress period. Stress caused decreased locomotor and exploratory behaviours, decreased sucrose preference and increased immobility in the forced swim test, but did not affect behaviour in the elevated plus maze. Four weeks of oral treatment with reboxetine ameliorated the adverse effects of social stress and normalized behaviours related to motivation and reward sensitivity. The treatment with haloperidol worsened the adverse effects of chronic social stress having effects similar to stress on reward and motivation-related behaviours. Diazepam reduced anxiety-related behaviours as measured in elevated plus maze in control animals having no effects on socially stressed individuals. Neither sucrose preference nor performance in forced swim test was affected by diazepam. The effectiveness and selectivity of the treatment with the antidepressant reboxetine in ameliorating socially induced behavioural disturbances supports the validity of the chronic social stress as a model of depressive-like symptoms in rats.

Chronic stress-induced cellular changes in the medial prefrontal cortex and their potential clinical implications: does hemisphere location matter?

The prefrontal cortex (PFC) is implicated in a number of higher cognitive functions as well as processing emotions and regulation of stress responses. Hemispheric specialization of the PFC in humans in emotional processing is well documented, and there is evidence that a similar functional lateralization is present in all mammals. Recent findings suggest the possibility of an intrinsic structural hemispheric asymmetry in the rat medial PFC (mPFC). Specifically, interhemispheric differences have been found in the architecture of pyramidal cell apical dendritic trees together with hemispheric asymmetry in cell proliferation including gliogenesis. It is now well established that chronic stress has a profound impact on neural plasticity in a number of corticolimbic structures and affects the etiology, pathophysiology, and therapeutic outcome of most psychiatric disorders. We summarize recent experimental data documenting pronounced dendritic remodeling of pyramidal cells and suppressed gliogenesis in the mPFC of rats subjected to chronic stress or to artificially elevated glucocorticoid levels. The stress affect on these structural elements seems to be hemispheric specific, often abolishing or even reversing natural asymmetries seen at the cellular level. We discuss these preclinical observations with respect to clinical findings that show impaired function, altered lateralization and histopathological changes in the PFC in psychiatric patients. We argue that it is important to define the kinds of structural changes that result from long-term stress exposure because this knowledge will improve the identification of cellular endophenotypes in various psychiatric disorders.

Glycoprotein M6a is present in glutamatergic axons in adult rat forebrain and cerebellum.

Glycoprotein M6a is a neuronally expressed member of the proteolipid protein (PLP) family of tetraspans. In vitro studies suggested a potential role in neurite outgrowth and spine formation and previous investigations have identified M6a as a stress-regulated gene. To investigate whether the distribution of M6a correlates with neuronal structures susceptible to alterations in response to stress, we localized M6a expression in neurons of hippocampal formation, prefrontal cortex and cerebellum using in situ hybridization and confocal immunofluorescence microscopy. In situ hybridization confirmed that M6a is expressed in dentate gyrus and cerebellar granule neurons and in hippocampal and cortical pyramidal neurons. Confocal microscopy localized M6a immunoreactivity to distinct sites within axonal membranes, but not in dendrites or neuronal somata. Moreover, M6a colocalized with synaptic markers of glutamatergic, but not GABAergic nerve terminals. M6a expression in the adult brain is particularly strong in unmyelinated axonal fibers, i.e. cerebellar parallel and hippocampal mossy fibers. In contrast, myelinated axons exhibit only minimal M6a immunoreactivity localized exclusively to terminal regions. The present neuroanatomical data demonstrate that M6a is an axonal component of glutamatergic neurons and that it is localized to distinct sites of the axonal plasma membrane of pyramidal and granule cells.

Stress upregulates TPH1 but not TPH2 mRNA in the rat dorsal raphe nucleus: identification of two TPH2 mRNA splice variants.

Serotonin is implicated in stress-related psychopathologies. Two isoforms of the rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase, TPH1 and TPH2, are known. We show here that in the rat dorsal raphe nucleus (DRN), the nucleus that contains the highest number of 5-HT neurons in the brain, TPH1 mRNA reveals a low level of expression but is detectable both by quantitative real-time PCR and in situ hybridization whereas in the pineal gland (PiG), TPH1 mRNA is strongly expressed. To examine effects of stress on TPH expression we exposed male Wistar rats to daily restraint stress for 1 week. As shown by quantitative real-time PCR, TPH1 mRNA is 2.5-fold upregulated by the stress in DRN but not in PiG. Using 3'-RACE, we identified two TPH2 mRNA splice variants in the rat DRN which differ in the length of their 3'-untranslated regions (UTRs). TPH2b (with a short 3'-UTR) is the predominant variant in the DRN, whereas TPH2a (with a longer 3'-UTR) shows a low abundance in this nucleus. In the PiG, only TPH2b is detectable revealing a low level of expression. Expression of both TPH2 splice variants is not affected by stress, neither in DRN nor in the PiG. These data indicate that TPH1 in the serotonergic neurons of the DRN might be relevant for stress-induced psychopathologies.

CRE/CREB-driven up-regulation of gene expression by chronic social stress in CRE-luciferase transgenic mice: reversal by antidepressant treatment.

BACKGROUND: It has been suggested that stress provokes neuropathological changes and may thus contribute to the precipitation of affective disorders such as depression. Likewise, the pharmacological therapy of depression requires chronic treatment and is thought to induce a positive neuronal adaptation, presumably based on changes in gene transcription. The transcription factor cAMP-responsive element binding protein (CREB) and its binding site (CRE) have been suggested to play a major role in both the development of depression and antidepressive therapy. METHODOLOGY/PRINCIPLE FINDINGS: To investigate the impact of stress and antidepressant treatment on CRE/CREB transcriptional activity, we generated a transgenic mouse line in which expression of the luciferase reporter gene is controlled by four copies of CRE. In this transgene, luciferase enzyme activity and protein were detected throughout the brain, e.g., in the hippocampal formation. Chronic social stress significantly increased (by 45 to 120%) CRE/CREB-driven gene expression measured as luciferase activity in several brain regions. This was also reflected by increased CREB-phosphorylation determined by immunoblotting. Treatment of the stressed mice with the antidepressant imipramine normalized luciferase expression to control levels in all brain regions and likewise reduced CREB-phosphorylation. In non-stressed animals, chronic (21 d) but not acute (24 h) treatment with imipramine (2x10 mg/kg/d) reduced luciferase expression in the hippocampus by 40-50%. CONCLUSIONS/SIGNIFICANCE: Our results emphasize a role of CREB in stress-regulated gene expression and support the view that the therapeutic actions of antidepressants are mediated via CRE/CREB-directed transcription.

Morphology of pyramidal neurons in the rat prefrontal cortex: lateralized dendritic remodeling by chronic stress.

The prefrontal cortex (PFC) plays an important role in the stress response. We filled pyramidal neurons in PFC layer III with neurobiotin and analyzed dendrites in rats submitted to chronic restraint stress and in controls. In the right prelimbic cortex (PL) of controls, apical and distal dendrites were longer than in the left PL. Stress reduced the total length of apical dendrites in right PL and abolished the hemispheric difference. In right infralimbic cortex (IL) of controls, proximal apical dendrites were longer than in left IL, and stress eliminated this hemispheric difference. No hemispheric difference was detected in anterior cingulate cortex (ACx) of controls, but stress reduced apical dendritic length in left ACx. These data demonstrate interhemispheric differences in the morphology of pyramidal neurons in PL and IL of control rats and selective effects of stress on the right hemisphere. In contrast, stress reduced dendritic length in the left ACx.