Projects

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.

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.

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.

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.