Neuropharmacology of emotional systems
Prof. Dr. rer. nat. habil. M. Fendt
Emotions are important for the behavior of humans and animals. For example, the emotion fear helps to handle potentially dangerous situations. However, extreme and/or maladaptive emotions can lead to mood and anxiety disorders in humans (e.g., depression, anxiety disorders). However, maladaptive emotions are also behavioral endophenotypes of other neuropsychiatric disorders. Further endophenotypes of these disorders are often impaired cognition and/or deficits in cognitive flexibility.
Goal of our group is to improve our understanding of the neuropharmacological basis of emotions and cognitive flexibility. Currently, our research is focused on the following projects:
- Neuropharmacological mechanisms of event learning
- Orexin’s role in mouse behavioral endophenotypes for neuropsychiatric diseases
- Social transmission of fear & ultrasonic vocalization
- Neuropharmacology of cognitive flexibility
- Role of G-protein coupled receptors in innate and learned fear
More detailed description of the projects:
During fear learning, stimuli which predict an aversive situation are learned. After such kind of learning, the learned stimulus alone is able to induce conditioned fear (which prepares the body for a potential further aversive situation). However, what happens if a stimulus is present at the end of an aversive situation? Recent research suggests that such stimuli elicit behaviors (e.g., approach behavior) indicating “conditioned relief”. A very similar learning phenomenon is safety learning. Here, animals and humans learn that a stimulus predicts the absence of an aversive event.
We investigate these phenomena in rodents. We found that the acoustic startle response is strongly attenuated after relief and safety conditioning. Furthermore, we showed that the nucleus accumbens, a part of the brain reward system, is important for conditioned relief but not for safety learning. We recently found that the infralimbic cortex is involved in conditioned safety.
This research is partly in collaboration with Bertram Gerber (Leibniz-Institute of Neurobiology, Magdeburg) and was funded until 2019 by the DFG/SFB779.
- Judith Kreutzmann, MSc (PhD project)
- Rami El Matine (MD project)
- Ceylan-Scarlett Steinecke (master project)
Bergado Acosta JR, Kahl E, Kogias G, Uzuneser TC & Fendt M (2017) Relief learning requires a coincident activation of dopamine D1 and NMDA receptors within the nucleus accumbens. Neuropharmacology 114: 58-66.
Kreutzmann JC, Khalil R, Köhler JC, Mayer D, Florido A, Nadal R, Andero R & Fendt M (2020) Neuropeptide-S-receptor deficiency affects sex-specific modulation of safety learning by pre-exposure to electric stimuli. Gen Brain Behav 19: e12621.
Mayer D, Kahl E, Uzuneser TC & Fendt M (2018) Role of the mesolimbic dopamine system in relief learning. Neuropsychopharmacology 43: 1651-1659.
The orexin system is mainly known for its important role in mediating feeding and promoting wakefulness. However, the orexin system also projects to brain areas that are not involved in the aforementioned functions implying a more complex role as previously assumed. This idea is supported by animal studies – partly from our group – revealing that the orexin system participates in several other behavioral and physiological processes such as emotions, reward, sociability, and cognition. Human studies in patients with narcolepsy (i.e. with a loss of orexin neurons) or with schizophrenia further indicate connections between the orexin system and several psychiatric symptoms. For example, narcolepsy and schizophrenia share some symptoms such as hallucinations, altered plasma orexin levels are associated with particular symptoms of schizophrenia, and treatment with neuroleptics influences brain orexin levels.
Based on all these findings, we proposed the hypothesis that the orexin system plays a role in behavioral endophenotypes for schizophrenia. Currently, we will address this hypothesis in a DFG-funded project (FE 483/10-1) using genetic, pharmacological and chemogenetic manipulations of the orexin system in mice submitted to different behavioral paradigms.
In collaboration with Michael Koch (University of Bremen), we further investigate orexin’s role in fear and anxiety. This includes paradigms of panic-like anxiety but also social fear conditioning. Last, we also utilize the narcoleptic episodes of orexin-deficient mice to investigate novel pharmacological treatment approaches for the symptoms of narcolepsy.
- Archana Durairaja, MSc (PhD project)
- Nadine Faesel, MSc (PhD project)
- Alexandrina Demidova (master project)
Khalil R & Fendt M (2017) Increased anxiety but normal fear and safety learning in orexin-deficient mice. Behav Brain Res 320: 210-218.
Leibiger J & Fendt M (2014) Behavioral analysis of narcoleptic episodes in orexin-deficient mice. Behav Genet 44: 136-143.
Schmidt C, Leibiger J & Fendt M (2016) The norepinephrine reuptake inhibitor reboxetine is more potent in treating murine narcoleptic episodes than the serotonin reuptake inhibitor escitalopram. Behav Brain Res 308: 205-210.
States of fear can be transmitted from one animal to the other, for example via ultrasonic vocalization or alarm pheromones, but also via observational learning. We are interested in the behavioral characteristics but also neuropharmacological basis of these phenomena.
In collaboration with Yasushi Kiyokawa (University of Tokyo), we investigate the neural mechanisms underlying alarm pheromone-induced defensive behavior in rats. Rats’ alarm pheromone is secreted from perianal glands and emitted in potentially dangerous situations. Our current research is focused on the role of the bed nucleus of the stria terminalis in alarm pheromone-induced defensive behavior.
In collaboration with Markus Wöhr (University of Marburg, University of Southern Denmark), we investigate defensive behavior induced by playbacks of ultrasonic vocalization in rats. Furthermore, we started to study the role of ultrasonic vocalization in observational fear learning.
- Jessica Giese (MD project)
- Vanessa Näck (MD project)
Breitfeld T, Bruning JEA, Inagaki H, Takeuchi Y, Kiyokawa Y & Fendt M (2015) Temporary inactivation of the anterior part of the bed nucleus of the stria terminalis blocks alarm pheromone-induced defensive behavior in rats. Front Neurosci 9: 321.
Fendt M, Brosch M, Wernecke KEA, Willadsen M & Wöhr M (2018) Predator odour but not TMT induces 22-kHz ultrasonic vocalizations in rats that lead to defensive behaviours in conspecifics upon replay. Sci Rep 8: 11041
The attentional set shifting task (ASST) in mice is based on compound discrimination learning and consists of different phases including reversal learning, intra- and extradimensional shift. In the T-maze, reversal learning but also the used learning strategy to solve specific task can be studied. Using the ASST and T-maze learning, we recently started to investigate the neurpharmacological underpinnings of cognitive flexibility. Our focus is on the role of the NMDA receptor and associated signaling pathways.
- Mahmoud Harb (MD project)
- Simon Schumacher (MD project)
- Iman Hassan (master project)
- Ahmet Oguzhan Bicakci (master project)
Clinically established anxiolytic drugs are mainly working via the GABAergic, serotonergic and noradrenergic system. However, these mechanisms of action are connected to side effects and some patients are non-responsive. Therefore, there is a medical need to discover and to investigate new anxiolytic mechanisms of action. During the last decade, metabotropic glutamate receptors (mGluRs), the GABA-B receptor and neuropeptide receptors came in the focus of fear research. Some of these receptors are meanwhile well investigates, others not.
In a DFG-funded project (FE 483/7-1), we explore the role of NPS and its receptor in animal models of pathological fear. In collaboration with groups of Norvay and Poland and funded by HelseNord, Norway, we investigate the role of GABA-B receptor modulators on fear and anxiety
- Małgorzata Kołodziejczyk, MSc (PhD project)
Kolodziejczyk MH & Fendt M (2020) Corticosterone treatment and incubation time after contextual fear conditioning synergistically induce fear memory generalization in neuropeptide S receptor-deficient mice. Front Neurosci 14: 128.
Germer J, Kahl E & Fendt M (2019) Memory generalization after one-trial contextual fear conditioning: effects of gender and neuropeptide S receptor deficiency. Behav Brain Res 361: 159-166.