My research focuses on rodent models studying functional neuronal dynamics to challenges of homeostatic control. The study if and how individuals cope with environmental challenges is at the core of my research interests. Challenges that come from the social environment of the individual receive my particularly interest. The study of social interactions and how these can result in adaptation and/or maladaptation in the neural circuitry involved in the regulation of social behavior is very relevant if one considers that psychosocial stressors are frequently the cause of psychopathologies like anxiety and depression in humans. There are many animal models applied to unravel mechanisms involved in successful or failing adaptation to stressors. Stressors that have a high face validity with respect to the stressors that both humans and animals face are ecologically relevant models like the psychosocial stress resulting from social defeat as modeled in the so-called resident-intruder paradigm. Also the study of consequences social interactions in colony-like structures with both males and females housed together resulting in individuals that occupy different positions in the social hierarchy such dominant, subdominant and subordinate are very relevant from a translational point of view.

 Social stress

The Behavioral Physiology unit in Haren has a long-standing reputation in the study of lasting effects of social stress in rodent models and in the study of individual differences in the way rats and mice cope with their environment. The study of neuronal plasticity changes that follow stimuli that threaten homeostasis plays a central role in this research.

The majority of stress stimuli in humans that lead to psychopathology are of social nature. Since many studies have indicated that different types of stress can elicit qualitatively different patterns of behavioral and physiological stress responses, the research on the consequences of social stress in experimental animal models is, therefore, crucial from a translational point of view.

In our laboratory we use rodent social stress models such as the social defeat paradigm and the social colony model (Visible Burrow System: VBS).

Stress of social defeat

In the first, acute and lasting consequences of stressful defeat experiences in social conflicts are studied in experimental male rats. These are introduced into the territory of an aggressive male conspecific. The intruder is rapidly investigated, attacked and defeated by the resident. To ensure the desired outcome of the social conflict, residents have a higher bodyweight and are familiarized with fighting. They belong to the so-called Wildtype Groningen (WTG) strain from which males are selected with relatively high levels of aggression. The WTG rat strain originates from rats caught in the wild and outbred in the laboratory for many generations. Rats from this strain show a large variety in social behaviors and male WTG rats differ widely in their offensive aggression.

Focusing on the consequences of social defeat stress it can be concluded in general that the effects of social defeat on baseline activity of cardiovascular, endocrine and autonomic nervous systems appear to be relatively short-lasting, i.e. not lasting much longer than 24-48 hours after defeat. Long-lasting effects (lasting for several weeks or even months) are reported, however, on behavioral, physiological and neurobiological responses to social and non-social challenges of various nature.

Animal stress models are generally applied in order to gain our understanding of mechanisms involved in human stress-related psychopathologies like anxiety, depression and post-traumatic stress disorders (PTSD). Although it is generally acknowledged that it is practically impossible to distinguish these behaviorally complex and heavily intertwined clinical disorders in animal models, attempts have been made to define the severe and lasting effects in the stress models into terms of these human diseases.

Social behavior in semi-natural mixed-sex social rat colonies: Stress of social subordination

In a social colony, male and female rats are living together in semi-natural conditions. After the development of a social structure dominant and subordinate males are identified. This difference in social status coincides behavioral, neuroendocrine, physiological and neurobiological differences between individuals of these two hierarchy levels. These differences can be studied in stable colonies with male dominants that are capable to constrain their aggressive behavior towards subordinate individuals but also in less stable colonies with dominants that show excessive aggressive or violent behavior. In the latter, subordinates may show behavioral and physiological indications of stress of chronic social subordination.

A good example of studying social behavior in a colony structure is the Visible Burrow System (VBS). The VBS, created 25 years ago by the Blanchard’s, provides a unique experimental paradigm that allows for highly nuanced behavior within a laboratory setting and detailed evidence for a rodent’s psychosocial state, as well as the opportunity to examine the neural and neuroendocrine cascade effects that connect behavior with potential predictive and constructive validity. Basically, the VSB habitat effectively recreates in a lab setting key environmental and behavioral features of rat colonies in the wild.

Social colonies like the VBS also offer possibilities to study the neural substrates underlying these behaviors related to social dominancy like aggression and violent behavior. The social colony can also be considered as an optimal read-out to study if and how behavioral, pharmacological or genetic interventions at various time points in development affect the capacity to successfully integrate and function in complex social structures.

Within the Adaptive Life Program, a substantial amount of money is reserved to study animals in semi-natural environments in the laboratory. We are currently (2016) developing modified VBS’ in which social behavior and its neurobiological and physiological correlates can be studied in rats and mice. In this approach state-of-the-art techniques will be implemented such biotelemetry to monitor blood pressure, heart rate, body temperature and locomotor activity in each individual simultaneously (Stellar). Feeding behavior and body weight will be monitored at feeders and analyzed fully automatically using RFID tags. Furthermore, we are currently developing techniques that allow individual tracking and analysis of social interactions between individuals. The combination of these techniques in the VBS is rather unique and will deliver new insight into the neurocircuitry involved in the regulation of and adaptation to living in social hierarchical structures.   

Stress during adolescence  

More recently I extended my research towards studying how adolescent stress will affect adult physiology and behavior. Adolescence is the transitional phase during which the juvenile develops into an independent adult individual. In this period in particular frontal cortical brain regions and related neural circuitry are structurally remodeled to a relatively high extent resulting in a refined connectivity and functionality of these brain regions in adulthood.

I aim to address the question if a high structural neuronal plasticity during adolescence makes this developmental period particularly vulnerable to lasting detrimental effects of stress. Initial results show a remarkable ability in adolescent rats to recover from a socially adverse condition. This may seem surprising but the data clearly indicate the relatively high resilience of adolescent rats to lastingly develop behavioral and neurobiological stress pathologies. These results may be indicative that the predictive adaptive responses (PAR) as described earlier by Gluckman (Gluckman, Hanson and Beedle; 2007) in perinatal development also exists during adolescent development. It may well be that adaptations occur during adolescent development depending on the environmental conditions that help the individual to function optimally similar conditions during adulthood. This so-called match-mismatch hypothesis was developed mainly to explain how perinatal conditions may play a role in the rapid development of metabolic disease but seem to be valid also for stress-related behavior in other developmental periods. In future studies I plan to study how different social environmental conditions during perinatal and adolescent development will modulate adult brain and behavior.