General / Projects

The Center for Behavioral Neuroscience is interested in the neurophysiological underpinnings of normal and pathological behavior. To this end, we apply several rodent models of menatl diseases and normal brain functioning.

Extinction-induced despair: a new animal model of depression

Hopelessness is a major factor in environmentally caused depression in humans that is determined by the absence or omission of anticipated reward. Behavior that is under control of positive or negative reinforcement diminishes or undergoes extinction if the anticipated reward is withhold. Although such mechanisms display a well-known phenomenon for the practising clinician, there is a notable lack of appropriate animal models in this context to date. We started validating such an animal model of extinction induced despair (EID) with respect to extinction of negatively reinforced behavior, more precisely, the withdrawal of a safety platform in a water-maze. As a measure of behavioral despair, we applied the amount of immobility exhibited, reflecting a termination in the seek for safety, indicating a form of learned helplessness. This measure was shown to be sensitive to antidepressant treatment and covaried with the amount of diverse neurotransmitters and neurotrophins, as well as with several markers of the hypothalamic–pituitary–adrenal axis in respective areas of the brain. In this project, we intend to expand and refine this model of EID. The experiments carried out aim at

  1. the assessment of behavioral markers of EID after the extinction of positively reinforced/rewarded behavior (e.g. by food delivery) and the investigation of effects of several classes of antidepressant treatment on this behavior in adult and aged rats.

  2. assessment of putative neurochemical correlates of EID by means of in-vivo microdialysis with respect to serotonergic and dopaminergic mechanisms in respective brain areas (Hippocampus, amygdala, frontal cortex, Ncl. accumbens) in adult and aged rats.

  3. the evaluation of the relationship between EID and the 'Forced Swim Test', a widely applied paradigm in the assessment of depression, in order to investigate possible additive effects. Furthermore, this may shed light in the context of translational models and vulnerability in the expression of depressive beahvior.

  4. investigating the EID model in rats selectively bred to display a high or low level phenotype for learned helplessness behaviors

  5. possible interactions of aging and neurochemical alterations in diverse brain areas in EID in the water-maze

These studies may generate a prominent contribution to further validate an animal model of EID and may significatnly improve our understanding of age-related alterations in neurphysiological parameters relevant in this context.

 

Cognitive deficits in aged and adult rats: Relationship to multiple neurotransmitter receptor systems in the brain

This project is planned to assess age-related differences in the interplay between the different neurotransmitters in diverse brain areas, in relation to age-related differences in cognitive functions (episodic-like memory, spatial memory) and emotionality (anxiety, depression). In the hippocampus of aged rats, we found changes in the pattern of neurotransmitter receptor densities (NMDA, 5-HT1A and α-adrenergic receptor densities) using quantitative receptor autoradiography, that were related to impaired spatial retention memory. Using subgroup correlation analysis, we found that relationships between various HPA-axis markers depend on age as well as learning capacity, reflecting adaptations to the environment as well as an age-independent determination of learning ability. Furthermore, neurotransmitter contents in various brain areas following extinction-induced despair, and, thus depression, revealed a number of age-, despair and age x despair dependent interactions indicating that the neurodynamics underlying depressive-like behavior in the aged may be dependent on biological aging processes, per se, as well as on interaction with the propensity to develop despair.

We wish to extend these findings and assess possible age-related differences in the interaction between multiple neurotransmitter systems and behavioral functions related to cognition and emotionality.

For this purpose, the behavior of aged and adult rodents will be examined using the water maze, episodic-like memory task, extinction-induced despair model, open field, black-white box and/or elevated plus-maze. Physiological methods used to asses the state of various neurotransmittersystems in relevant brain areas will include quantitative receptor autoradiography, in vivo microdialysis and immunohistochemistry.

Behavioral and neurochemical functions of the NK-receptor

Neurokinins are neuropeptides belonging to the tachykinin family. A prominent representative of this class of transmitter is substance P that has been investigated with respect to its behavioral effects in the department for over 20 years. So far, three receptors for neurokinins have identified: the NK1-, NK2- and NK3-receptor. Substance P displays some affinity to all of these receptors, but the greatest affinity for the NK1-receptor. Our previous studies demonstrated a participation of subsance P in the mediation of learning, memory and reinforcement processes in the rat, as well as in non-human primates. Little is known which exact NK-receptors mediate these effects and what other major transmitter systems are involved. The aim of the project is to characterize the role of NK1-, NK2- and NK3-receptors governing learning and memory processes and to assess neurochemical alterations in the cholinergic system of the basal forebrain within the frontal cortex, amygdala, and the hippocampus. To this end, in-vivo microdialysis in the anaesthetized animal will be carried out and analyzed by means of HPLC-EC. The experiments will enhance our understanding of the role of NK-receptors in the mediation of learning and memory processes.

 

Responsible for the content: E-MailProf. Joseph P. Huston PhD