Recurrent stress across life may improve cognitive performance in individual rats, suggesting the induction of resilience

Depressive symptoms are often accompanied by cognitive impairments and recurrent depressive episodes are discussed as a potential risk for dementia. Especially, stressful life events are considered a potent risk factor for depression. Here, we induced recurrent stress-induced depressive episodes over the life span of rats, followed by cognitive assessment in the symptom-free period. Rats exposed to stress-induced depressive episodes learned faster than control rats. A high degree of stress-induced depressive-like behavior early in the paradigm was a predictor of improved cognitive performance, suggesting induction of resilience. Subsequently, exposure to lorazepam prior to stress-induced depressive episodes and cognitive testing in a nonaversive environment prevented the positive effect. This indicates a beneficial effect of the stress-associated situation, with the existence of individual coping abilities. Altogether, stress may in some have a beneficial effect, yet for those individuals unable to tackle these aversive events, consecutive unpleasant episodes may lead to worse cognitive performance later in life

Rats overexpressing the dopamine transporter display behavioral and neurobiological abnormalities with relevance to repetitive disorders

The dopamine transporter (DAT) plays a pivotal role in maintaining optimal dopamine signaling. DAT-overactivity has been linked to various neuropsychiatric disorders yet so far the direct pathological consequences of it has not been fully assessed. We here generated a transgenic rat model that via pronuclear microinjection overexpresses the DAT gene. Our results demonstrate that DAT-overexpression induces multiple neurobiological effects that exceeded the expected alterations in the corticostriatal dopamine system. Furthermore, transgenic rats specifically exhibited behavioral and pharmaco-therapeutic profiles phenotypic of repetitive disorders. Together our findings suggest that the DAT rat model will constitute a valuable tool for further investigations into the pathological influence of DAT overexpression on neural systems relevant to neuropsychiatric disorders

Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia

The notion that schizophrenia is a neurodevelopmental disorder in which neuropathologies evolve gradually over the developmental course indicates a potential therapeutic window during which pathophysiological processes may be modified to halt disease progression or reduce its severity. Here we used a neurodevelopmental maternal immune stimulation (MIS) rat model of schizophrenia to test whether early targeted modulatory intervention would affect schizophrenia’s neurodevelopmental course. We applied deep brain stimulation (DBS) or sham stimulation to the medial prefrontal cortex (mPFC) of adolescent MIS rats and respective controls, and investigated its behavioral, biochemical, brain-structural and -metabolic effects in adulthood. We found that mPFC-DBS successfully prevented the emergence of deficits in sensorimotor gating, attentional selectivity and executive function in adulthood, as well as the enlargement of lateral ventricle volumes and mal-development of dopaminergic and serotonergic transmission. These data suggest that the mPFC may be a valuable target for effective preventive treatments. This may have significant translational value, suggesting that targeting the mPFC before the onset of psychosis via less invasive neuromodulation approaches may be a viable preventive strategy.We thank Renate Winter, Doris Zschaber and Roselies Pickert for excellent technical assistance. This research was conducted under the EraNet Neuron framework (DBS_F20rat) and supported by the BMBF, Germany (B01EW1103, 01EE1403A), Fundación Mapfre, Comunidad de Madrid and the Ministry of Economy and Competitiveness ISCIII-FIS grants (PI14/00860, CPII/00005) co-financed by ERDF (FEDER) Funds from the European Commission, ‘A way of making Europe’, Spain (PI14/00860, CPII/00005, MV1500002), the CSO-MOH, Israel (3-8580) and the Canadian Institutes of Health Research, Canada (CIHR, 110068), and co-financed by the DFG, Germany (WI 2140/1-1/2; WI 2140/2-1).Publicad

Neurobiological substrates of quinpirole induced compulsive checking behavior in rats

Repetitives Verhalten ist Symptom vieler psychiatrischer und neurologischer Erkrankungen. Ein besseres Verständnis der Pathophysiologie von repetitivem Verhalten könnte bei der Aufklärung dieser hoch prävalenten und stark belastenden Krankheiten helfen. Ursächlich scheint eine Desinhibierung von im CSTC-Regelkreis enkodierten Stereotypien zu sein. Klinische Befunde und eine Reihe von Studien legen eine DAerge Dysregulation nahe, konnten bisher aber kein weitreichendes Verständnis der Pathophysiologie erbringen um kausale Therapiestrategien zu entwickeln. Die bisherige Studienlage ist widersprüchlich - sowohl DA-Agonisten als auch -Antagonisten induzieren und reduzieren repetitives Verhalten. Eine mögli-che Erklärung dieser Diskrepanz könnte eine phasisch-tonische DA-Ausschüttung sein, wobei ein dysfunktionales DAT-System ein erhöhtes Angebot an phasischem, einem verminderten Angebot an tonischem DA und einer erhöhten Expression von D2-Rezeptoren bedingen könnte. Die unterschiedliche striatale Verteilung der verschieden wirkenden DA- Rezeptoren würde so zu einer Imbalance im CSTS Regelkreis führen. Zur Überprüfung dieser Hypothese führt diese Arbeit bio- und immunhistochemische Unter-suchungen des DAergen Systems unter besonderer Berücksichtigung des CSTC Regelkrei-ses an einem validierten Zwangsmodell der Ratte durch. Die chronisch-intermittierende Gabe des D2/3-Rezeptor-Agonisten QNP löst hier kontextabhängig (OF Exposition) Zwangähnliches Verhalten aus. Der experimentelle Aufbau hilft darzustellen, welche neurobiologischen Veränderungen von der OF-Exposition, der DAergen Intervention oder beidem resultieren. Die Daten dieser Arbeit zeigen, dass die OF-Exposition zu veränderten Expressionen von IEGs führt, glutamaterge, glutaminerge, GABAerge, 5-HTerge und schließlich DAerge Transmission bedingt und die Proliferation hemmt. Die DAerge Intervention führt zu veränderten Expressionen von IEGs, beeinflusst das 5-HTerge System, inhibiert das glutamaterge und GABAerge System, aktiviert die Proliferation und führt zur erhöhten DA-Synthese bei verrin-gertem DA-Abbau. Die Kombination aus beidem induziert wie erwartet repetitives Verhalten in den Ratten und geht mit erhöhtem DA-Gehalt bei erhöhter Synthese und reduziertem Abbau, veränderter c-Fos-Expression im CPu und erhöhtem 5-HT-Gehalt im LGP einher. Da der erhöhte DA-Gehalt nur nach chronisch-intermittierender QNP-Gabe und OF-Exposition vorliegt, ist dies vermutlich neurobiologisches Korrelat repetitiven Verhaltens. Der Wechsel zwischen verstärkter DA-Wirkung bei Agonisten-Gabe und deren anschließendem Ausbleiben führt wahrscheinlich zur vermehrten DAT-Aktivität, zur Reduktion tonischen DA, zur erhöhten D2-Rezeptor-Dichte, zur Erhöhung der phasischen DA- Ausschüttung und schließlich zu einer Imbalance im CSTC Regelkreis, die zum Phänotyp führt. Die vorliegenden Ergebnisse unterstreichen die hohe funktionelle Relevanz des Neurotransmitters DA im CSTC-Regelkreis in der Pathophysiologie. Ein transgenes Rattenmodell mit überexprimiertem DAT wird zurzeit untersucht, um die bisher am pharmakologischen Modell gewonnen Daten zu erweitern.Repetitive behaviour is a characteristic symptom of a number of psychiatric and neurological disorders. A better understanding of the pathophysiological mechanisms of repetitive behavior is necessary to elucidate the etiology of these highly prevalent and disabling disorders. Repeti-tive behavior seems to be grounded in a disinhibition of stereotypies encoded in the CSTC circuit. Clinical findings and a number of experimental studies suggest that DAergic dysregulation plays a major role, but could not yet give sufficient knowledge to develop therapeutical strategies interfering directly with the pathophysiology of this disorder. Studies are partly contradictory. Both DA- agonists and -antagonists have been shown to induce and reduce repeti-tive behavior. One possible explanation could be a differential effect on phasic vs tonic DA, where a dysfunctional DAT could act to reduce tonic DA in the synaptic cleft, to enhance D2-receptor-density and to increase phasic DA release. The distinct striatal distribution of the different acting DA receptors would then lead to an imbalance in the CSTC circuit causing a thalamic desinhibition and repeated cortical activation. To investigate this hypothesis, the present study examines the DAergic system applying bio- and immunohistochemical analysis with particular reference to the CSTC circuit in the valid QNP rat model of obsessive-compulsive disorder. Chronic intermittent injections of the selec-tive D2/3-receptor agonist QNP are used to induce repetitive behavior in the OF. Several con-trol conditions allow for the attribution of neurobiological alterations to either OF exposure, the DAergic intervention or both. The present results show alterations in expressions of IEGs, glutamatergic, glutaminergic, GABAergic, 5-HTergic and DAergic neurotransmission and reduced proliferation after OF exposure. The DAergic intervention leads to alterations in expressions of IEGs, 5-HTergic transmission, inhibitory impacts on glutamatergic and GABAergic systems, increased prolif-eration and synthesis of DA and reduced DA metabolism. As expected, only the combination of both chronic-intermittent QNP and OF exposure induces repetitive behaviour in the rats and is accompanied by elevated DA contents and reduced metabolism, varied striatal c-Fos-expression and enhanced 5-HT contents in the LGP. As the elevated DA contents only arises by chronic-intermittent QNP and OF exposure, this presumably causes the repetitive behaviour. The switch between enhanced DA action after external application of QNP and the following absence of the agonist quite likely leads to an increased activity of the DAT, thereby to a reduction of tonic DA, an upregulation of D2-receptor density and an enhanced phasic DA release, all contributing to an imbalance in CSTC circuit, inducing the repetitive phenotype. The present results highlight the relevance of the DA system in the CSTC circuit in the pathogenesis of repetitive disorders. A transgenic rat model overexpressing the DAT is currently under investigation to add to the knowledge gen-erated from the pharmacological model in this work

Visual deprivation independent shift of ocular dominance induced by cross-modal plasticity.

There is convincing evidence that the deprivation of one sense can lead to adaptive neuronal changes in spared primary sensory cortices. However, the repercussions of late-onset sensory deprivations on functionality of the remaining sensory cortices are poorly understood. Using repeated intrinsic signal imaging we investigated the effects of whisker or auditory deprivation (WD or AD, respectively) on responsiveness of the binocular primary visual cortex (V1) in fully adult mice. The binocular zone of mice is innervated by both eyes, with the contralateral eye always dominating V1 input over ipsilateral eye input, the normal ocular dominance (OD) ratio. Strikingly, we found that 3 days of WD or AD induced a transient shift of OD, which was mediated by a potentiation of V1 input through the ipsilateral eye. This cross-modal effect was accompanied by strengthening of layer 4 synapses in V1, required visual experience through the ipsilateral eye and was mediated by an increase of the excitation/inhibition ratio in V1. Finally, we demonstrate that both WD and AD induced a long-lasting improvement of visual performance. Our data provide evidence that the deprivation of a non-visual sensory modality cross-modally induces experience dependent V1 plasticity and improves visual behavior, even in adult mice

Medial Forebrain Bundle Deep Brain Stimulation has Symptom-specific Anti-depressant Effects in Rats and as Opposed to Ventromedial Prefrontal Cortex Stimulation Interacts With the Reward System

Background: In recent years, deep brain stimulation (DBS) has emerged as a promising treatment option for patients suffering from treatment-resistant depression (TRD). Several stimulation targets have successfully been tested in clinical settings, including the subgenual cingulum (Cg25) and the medial forebrain bundle (MFB). MFB-DBS has led to remarkable results, surpassing the effect of previous targets in terms of response latency and number of responders. However, the question remains as to which mechanisms underlie this difference. Objective/hypothesis: The aim of the present study was to thoroughly study the anti-depressant effect of MFB-DBS in the Flinders sensitive line (FSL) rat model of depression as well as to investigate whether MFB-DBS and Cg25-DBS operate through the same neurobiological circuits. Methods: FSL and control rats received bilateral high-frequency stimulation to the MFB at the level of the lateral hypothalamus, while being subjected to a variety of depression-and anxiety-related behavioral paradigms. To further compare the effects of MFB-DBS and Cg25-DBS on reward-related behavior, animals were stimulated in either the MFB or ventromedial prefrontal cortex (vmPFC, rodent analog to Cg25), while being tested in the intra-cranial self-stimulation paradigm. Results: A marked symptom-specific anti-depressant effect of MFB-DBS was demonstrated. The ICSS-paradigm revealed that MFB-DBS, as opposed to vmPFC-DBS interacts with the reward system. Conclusion: Our data suggest that MFB-DBS and Cg25-DBS do not operate via the same neurobiological circuits. This differentiation might be of interest when selecting patients for either Cg25- or MFB-DBS. (C) 2015 Elsevier Inc. All rights reserved

Non-invasive modulation reduces repetitive behavior in a rat model through the sensorimotor cortico-striatal circuit

Abstract Involuntary movements as seen in repetitive disorders such as Tourette Syndrome (TS) results from cortical hyperexcitability that arise due to striato-thalamo-cortical circuit (STC) imbalance. Transcranial direct current stimulation (tDCS) is a stimulation procedure that changes cortical excitability, yet its relevance in repetitive disorders such as TS remains largely unexplored. Here, we employed the dopamine transporter-overexpressing (DAT-tg) rat model to investigate behavioral and neurobiological effects of frontal tDCS. The outcome of tDCS was pathology dependent, as anodal tDCS decreased repetitive behavior in the DAT-tg rats yet increased it in wild-type (wt) rats. Extensive deep brain stimulation (DBS) application and computational modeling assigned the response in DAT-tg rats to the sensorimotor pathway. Neurobiological assessment revealed cortical activity changes and increase in striatal inhibitory properties in the DAT-tg rats. Our findings show that tDCS reduces repetitive behavior in the DAT-tg rat through modulation of the sensorimotor STC circuit. This sets the stage for further investigating the usage of tDCS in repetitive disorders such as TS

Age-dependent differences in pulmonary host responses in ARDS: a prospective observational cohort study

Background: Results from preclinical studies suggest that age-dependent differences in host defense and the pulmonary renin–angiotensin system (RAS) are responsible for observed differences in epidemiology of acute respiratory distress syndrome (ARDS) between children and adults. The present study compares biomarkers of host defense and RAS in bronchoalveolar lavage (BAL) fluid from neonates, children, adults, and older adults with ARDS. Methods: In this prospective observational study, we enrolled mechanical ventilated ARDS patients categorized into four age groups: 20 neonates ( 65 years of age). All patients underwent a nondirected BAL within 72 h after intubation. Activities of the two main enzymes of RAS, angiotensin converting enzyme (ACE) and ACE2, and levels of biomarkers of inflammation, endothelial activation, and epithelial damage were determined in BAL fluid. Results: Levels of myeloperoxidase, interleukin (IL)-6, IL-10, and p-selectin were higher with increasing age, whereas intercellular adhesion molecule-1 was higher in neonates. No differences in activity of ACE and ACE2 were seen between the four age groups. Conclusions: Age-dependent differences in the levels of biomarkers in lungs of ARDS patients are present. Especially, higher levels of markers involved in the neutrophil response were found with increasing age. In contrast to preclinical studies, age is not associated with changes in the pulmonary RAS