Richter-Levin G, Müller I, Tripathi K, Stork O. Active resilience in response to traumatic stress. In: Chen A, (ed). Stress Resilience: Molecular and Behavioral Aspects. San Diego: Elsevier Inc./Academic Press, 2020: 95-106. Link
The mechanisms behind individual variability which leads only some individuals to develop stress-related psychopathologies is one of the key questions in stress research today. Here we explore the contribution of one target molecule, the GABA synthetic enzyme glutamic acid decarboxylase (GAD)65, to mechanisms of vulnerability and resilience. GAD65 is critically involved in the activity-dependent regulation of GABAergic inhibition in the central nervous system. It is also required for the maturation of the GABAergic system during adolescence, a phase that is critical for the development of several neuropsychiatric diseases. Mice bearing null mutation of the GAD65 gene develop hyperexcitability of the amygdala and hippocampus, and a phenotype of increased anxiety and pathological fear memory reminiscent of post-traumatic stress disorder. However, GAD65 haplodeficiency, which results in delayed postnatal increase of GABA levels, provides resilience to juvenile-stress induced anxiety to GAD65(+/-) mice.
Results obtained so far clearly indicate that GAD65 functioning is relevant to both stress vulnerability and stress resilience. The variable results regarding stress-related alterations in the expression of GAD65, together with the differences between effects of homozygous GAD65(-/-) knockout and GAD65 haplodeficiency, suggest that the role of GAD65 in stress vulnerability and resilience may differ in different brain regions and between different developmental stages. More temporal- and spatial- specific manipulations of expression are required in order to more accurately describe the role played by this enzyme in coping with stress.
Gad65 is brought here only as an example. Similar caution is required when examining the role of other target molecules in individual difference related to stress vulnerability and stress resilience.
Dr. Ahsan Raza
During our everyday life experiences, we tend to remember events with fine details that occur close in time. However, events that occurred long time ago are remembered with vague details and thus are prone to memory loss. With the passage of time, the fear memory losses its specificity resulting in a generalized fear and inappropriate anxiety, a hallmark of posttraumatic stress disorder (PTSD). In this LSA-CBBS project, neuronal circuits in the dentate gyrus will be investigated which plays important role in discriminating between different stimuli. This project investigates how the activity of neuronal circuits in the dente gyrus and its associated brain regions change over time after a fear experience. For this purpose, suitable genetic mouse model, chemogenetic intervention, behavioral readout and sophisticated electrophysiological techniques will be used to find cellular entry points for a possible intervention to specifically prevent fear generalization. This will not only increase our understanding of basic circuit mechanisms of memory formation but will also help in a longer run to the development of urgently needed new therapeutic methods for PTSD.
Dr. Anil Annamneedi
Tight synaptic connections between neurons are essential for proper brain functioning. Both sides of the synapse, i.e., pre and post synaptic sides composed of complex protein machinery, which are important for normal cognitive performance of brain. Several brain diseased conditions like neuropsychiatry, lead to synaptic protein dysregulation resulting in impaired brain functioning. Mechanisms of such conditions includes changes in GABAergic inhibitory system, with poor knowledge about the presynaptic proteins’ dysfunction. The focus of this CBBS funded LSA project is to understand the presynaptic proteins’ role, using knockout mouse models for a presynaptic Bassoon protein in GABAergic neuronal types. Pharmacological interventions will be performed together with behavioural, immunohistochemical, electrophysiological and transcriptome analyses.
Dr. Gürsel Caliskan: Bottom-up modulation of hippocampal engrams via sustained amygdalar activity, together with Dr. Guilherme Gomez (Leibniz Institute for Neurobiology) and Dr. Anne Stellmacher (Institute for Pharmacology and Toxicology).
The CBBS network project aims to investigate the dynamics of engram formation in the hippocampus during normal and pathological conditions using state-of-the-art technologies that allow circuit intervention. We will perform in vivo/in vitro electrophysiological analysis to investigate oscillatory and metaplastic processes that support engram formation/stability and combine this approach with engram-specific proteomic analysis. Specifically, we will focus on a well-defined circuit (DG-CA3) in the hippocampus that is crucial for pattern separation/completion function and systematically evaluate dynamic changes in hippocampal computation under high amygdalar activity.
A traumatic childhood is among the most important risk factors for developing stressrelated psychopathologies such as posttraumatic stress disorder or depression later in life. However, despite the proven role of astrocytes in regulating transmitter release and synaptic plasticity, the contribution of astrocytic transmitter metabolism to such stress-induced psychopathologies is currently not understood. In rodents, childhood adversity can be modeled by juvenile stress exposure, resulting in increased anxiety, and impaired coping with stress in adulthood. We describe that such juvenile stress in rats, regardless of additional stress in adulthood, leads to reduced synaptic efficacy in the ventral CA1 (vCA1) Schaffer collaterals, but increased long-term potentiation (LTP) of synaptic transmission after high-frequency stimulation. We tested whether the glutamate–glutamine-cycle guides the lasting changes on plasticity observed after juvenile stress by blocking the astrocytic glutamate-degrading enzyme, glutamine synthetase (GS). Indeed, the pharmacological inhibition of GS by methionine sulfoximine in slices from naïve rats mimics the effect of juvenile stress on vCA1-LTP, while supplying glutamine is sufficient to normalize the LTP. Assessing steady-state mRNA levels in the vCA1 stratum radiatum reveals distinct shifts in the expression of GS, astrocytic glutamate, and glutamine transporters after stress in juvenility, adulthood, or combined juvenile/adult stress. While GS mRNA expression levels are lastingly reduced after juvenile stress, GS protein levels are maintained stable. Together our results suggest a critical role for astrocytes and the glutamate–glutamine cycle in mediating long-term effects of juvenile stress on plasticity in the vCA1, a region associated with anxiety and emotional memory processing.
In GeNeRARe we investigate activating mutations of the RAS signalling pathway that lead to different form of a group of rare genetic disorders, so-called RASopathies, including Noonan Syndrome, Costellos Syndrome and others. We are interested in the mechanisms that result in intellectual disabilities in these disturbances and investigate the underlying neuronal dysfunction.