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PD Dr. Miriam Schneider

Spanagel R, Schneider M. DFG - Deutsche Forschungsgemeinschaft KFO 256, 2nd funding period: TP 07 Neurobiological Consequences and Mechanisms of Early Social Rejection Experiences. 08/2015-07/2018.

1 Results of the first funding period The major aim of the present proposal is to further elucidate the molecular consequences and mechanisms of social rejection or ostracism in a rodent model with relevance to borderline personality disorder (BPD). The experience of social rejection by others is a major source of distress in humans and has been implicated in the development of various psychiatric disorders including BPD. BPD patients often report experiences of neglect and rejection during childhood and adolescence, and display a heightened sensitivity toward social rejection in adulthood. During the first funding period of our associated project (AP1) we accomplished the establishment of an innovative animal model for the long-term consequences of early adverse social experiences in laboratory rats. By manipulation of social requirements during childhood and/or adolescence we were able to evoke persistent behavioral changes in adult female rats that resemble core aspects BPD, such as disturbed social interaction and recognition memory and decreased pain sensitivity. In addition to these behavioral changes, our initial findings show alterations in the endocannabinoid system (ECS) as a long-term consequence to rejection experiences. In particular, adolescent social rejection was found to enhance levels of the endocannabinod anandamide (AEA) on the long-term. Related to our findings, a recent study reported alterations of peripheral endocannabinoid levels in BPD patients, which is in support of a relevant role of the ECS not only in our animal model but also in BPD patients that may led to an improved understanding and new therapeutic approach to BPD. 2 New questions and work schedule Although it is well established that social rejection plays a major role in BPD, the neurobiological consequences and mechanisms linked to social rejection are largely unknown. We here aim to further examine these neurobiological processes by investigating the consequences of alterations in social requirements in adolescent rats - alone, and in combination with early modulations of mother-infant interaction. Our investigations will be focused on neurochemical systems involved in the modulation of social behavior and pain processing. Aside from our initial findings on alterations in the ECS we here aim to extend our analysis to the central oxytocin and the endogenous opioid system. These three neurochemical systems have been identified by our CRU as the most promising candidate systems for medication development and are also studied in the context context of the other IPs. Here we plan to utilize inter alia imaging techniques such as positron emission tomography (PET) and molecular (Western blot, autoradiography) and neurochemical analysis (e.g. liquid chromatography/ tandem mass spectrometry (LC/MS-MS)). Alterations in thermal pain reactivity will be used as behavioral readout. Based on our previous findings we now also intend to monitor the time course of neurobiological consequences of social rejection experiences throughout adolescence and early adulthood at different time points more closely, in order to shed light on the timing of the mechanistic processes mediating the persistent behavioral and neurobiological changes in adulthood. Furthermore, in order to gain a causal link of a given molecular change and a specific BPD-like behavioral feature we will use a regional viral-mediated gene transfer approach in an additional rescue experiment. A first target will be the normalization of enhanced amygdalar AEA levels and the hereby expected normalization of pain perception. Other identified persistent molecular changes will be also selectively targeted by viral-mediated gene transfer. This approach will not only provide a mechanistical inside for BPD but will also deliver new intervention strategies for our CRU.

Bundesverwaltungsamt, Köln : CaPRis - Cannabis: Potential und Risiken. Eine wissenschaftliche Analyse - Nichtmedizinischer und medizinischer Cannabiskonsum. 10/2015-03/2017.

Hintergrund: Eine rasante Weiterentwicklung der wissenschaftlichen Erkenntnisse zu Cannabinoiden, den Inhaltsstoffen von Cannabis, erfordert einen ständigen Abgleich des aktuellen Forschungsstandes zur Bewertung möglicher Risiken sowie des therapeutischen Potentials. Ziel: Es soll eine objektive, valide und an der besten wissenschaftlichen Evidenz orientierte Bewertung 1.) der kurz- und langfristigen psychischen, organischen und sozialen Folgen des Konsums von pflanzlichen und synthetischen Cannabisprodukten zum Freizeitgebrauch sowie 2.) der Indikation/Kontraindikation bzw. der kurz- und langfristigen Wirksamkeit (positiv, fehlend, unerwünscht) von Cannabisarzneimitteln und dem Kenntnisstand zur Selbstmedikation erfolgen. Methode: Ein systematisches Review der internationalen Literatur soll nach den höchsten wissenschaftlichen Standards durchgeführt werden. Für die zu bearbeitenden Themenbereiche werden klinische Fragen formuliert, systematische Literaturrecherchen durchgeführt, eingeschlossen Studien methodisch und inhaltlich bewertet sowie Evidenz- und Konfidenzgrade vergeben. Abschießend erfolgt, auf der Synopsis der Evidenz basierend, die Beantwortung der klinischen Fragen. Ergebnisse: Der aktuellste Forschungsstand wird dargestellt. Für den Freizeitgebrauch von Cannabinoiden wird ein Risoko-Profil für spezifische Konsumentengruppen erstellt. Für den Gebrauch von Cannabisarzneimitteln wird ein Nutzen-Risiko-Profil für spezifische Patientengruppen erarbeitet. Motive, Erwartungen und Folgen eines nicht-ärztlich verordneten Cannabisgebrauchs werden beschrieben.

Schneider M, Friemel CM, Spanagel R. MWK - Ministerium für Wissenschaft Forschung und Kunst Baden-Württemberg : Neurobiologische Untersuchungen zu der altersabhängigen reduzierten Empfindlichkeit gegenüber natürlichen Verstärkern und Drogenverstärkern. 01/2014-12/2015.

Motivational factors and reward processing have a great impact on key symptoms of frailty. Thus, appetite loss, apathy, and exhaustion are a result, at least in part, of altered reward processing in elderly people. Reward processes involve complex behavioral patterns, including appetitive and hedonic activities which all remain essential as we age. However, the interactions of rewards with an aged brain are only poorly understood. The present project is therefore aiming to investigate age-related changes in the reward system and the behavioral consequences. The main focus will be based on the measurement of the development of sensitivity for food reward during aging and also on the influence of the dopaminergic (DA) and endocannabinoid (ECB) system on this process.

Schneider M, Spanagel R, Schneider P. : KFO 256 AP 1: Modulationen der Mutter-Kind Beziehung und soziale Zurückweisung bei juvenilen Ratten als Tiermodell zur Erzeugung einer BP-ähnlichen Symptomatik . 01/2012-12/2014.

Schneider M, Friemel CM. FOR 926 (SP9) : Impact of the developing endocannabinoid system in rats on the modulatory influence of stress on adolescent ethanol intake . 07/2011-06/2014.

The endocannabinoid (ECB) system plays a key role in determining the reinforcing effects of alcohol and this appears to be especially true for the pubertal period, where the ECB system has been shown to be overactive. Stress is an important factor that is contributing to an individual’s vulnerability to various neuropsychological dysfunctions, including drug abuse. Growing evidence indicates that pubertal organisms react differentially, both physiologically and behaviorally, to a stressor compared to adults, however, the underlying mechanisms have not been clarified. Finally, a close interaction between the ECB system and stress is already well established. With our project we are therefore aiming to shed light on the mechanisms underlying the heightened influence of stress on the initiation of ethanol intake during puberty/adolescence in rats and investigate the developmental impact of different stressors on ECB functioning.

Schneider M, Friemel CM. DFG - Deutsche Forschungsgemeinschaft : FG 926, TP SP 09, Physiologie und Pathophysiologie des Endocannabinoidsystems, Effekte von Stress auf den Alkoholkonsum in der Adoleszenz: modulatorischer Einfluß des reifenden endocannabinoiden Systems. 07/2011-06/2014.

Die Pubertät ist ein äußerst sensibler Entwicklungsabschnitt für den experimentellen Gebrauch von Drogen. Die Initiierung des Drogenkonsums (z.B. Alkohol) während dieser Entwicklungsphase birgt erwiesenermaßen ein hohes Risiko für die spätere Entwicklung von Suchterkrankungen. Das endocannabinoide (ECB) System spielt eine wichtige modulatorische Rolle bei der Vermittlung von Belohnungsprozessen (z.B. Alkohol). Dies gilt insbesondere für die Pubertät, da hier das ECB System eine erhöhte Aktivität aufweist. Stress ist ein wichtiger Vulnerabilitätsfaktor für verschiedene neuropsychiatrische Erkrankungen, wie z.B. Alkoholismus. Da Suchterkrankungen oftmals in der Pubertät ihren Ursprung haben, ist es von größter Wichtigkeit den negativen Einfluß von Stress während der Entwicklung besser zu verstehen. Es ist bekannt dass Jugendliche eine andere Stressreaktivität zeigen als Erwachsene, jedoch sind die genauen Mechanismen unklar. Eine enge Verbindung zwischen dem ECB System und Stress-Systemen ist zudem außreichend in der Literatur belegt. Mit dem vorliegenden Antrag wollen wir daher den entwicklungsabhängigen Einfluß von Stress auf Alkoholkonsum und das ECB System während der Adoleszenz untersuchen.

Schneider M, Goepfrich A. : CIMH Award: Der Einfluß kortikaler Reifungsprozesse im endocannabinoiden System auf die kognitive und soziale Entwicklung in der Adoleszenz. 04/2011-03/2014.

A major aspect in cognitive development is the ability to suppress inappropriate thoughts and actions in favor of goal-directed behaviors, and these necessary impulse control mechanisms appear to mature during adolescence. Additionally, the prefrontal cortex (PFC) may not be as efficient at regulating social and emotional responses during adolescence compared with earlier and later timepoints in life. We are planning to examine the detailed development of cognitive and social abilities during adolescence. One common denominator in many of these developmental processes is the endocannabinoid (ECB) system which undergoes profound developmental changes during puberty. This modulatory system is not only a major player in mediating cognitive processing and neuroplasticity, but is also strongly involved in social behavior. We will therefore examine a possible correlation between cognitive and social development and maturation of the ECB system, as well as the impact of the developing ECB system on neurodevelopmental alterations (e.g myelination) in the PFC. A third section of the project will focus on risks and consequences of exposure to cognitive enhancers during adolescence, as well as their interaction with the ECB system.

Schneider M, Friemel CM. DFG - Deutsche Forschungsgemeinschaft SCHN 958/3-1: Die Bedeutung der Pubertät bei Aspekten der Suchtentwicklung. 09/2009-08/2012.

Puberty is a highly susceptible developmental period during which the organization of the brain is completed. A variety of species typically tend to seek out new stimuli during puberty and show increases in consummatory behavior for appetitive rewards such as food, and importantly, this may extend to drugs of abuse as well. It is during adolescence that most drinkers initiate alcohol intake, and therefore a major goal of the present project will be the examination and characterization of the special sensitivity of pubertal animals to alcohol and non-alcoholic sweetened beverages in comparison to adulthood. Moreover, we are interested in the role of the endocannabinoid system in modulating the primary motivational and rewarding properties of appetitive drug and non-drug related stimuli. The project will be mainly based on pharmacological behavioral experiments, in combination with the use of innovative genetic models of enhanced endocannabinoid signaling. Three different operational measures of appetitive reward/reinforcement efficacy will be used: the progressive ratio schedule, the conditioned place preference test, as well as the newly developed paradigm of conditioned odor attenuation of the startle response, a pioneering animal model for the measurement of hedonic emotional states.


Zentralinstitut für Seelische Gesundheit (ZI) - https://www.zi-mannheim.de