Category Archives: Papers

Our new paper is online: Region-specific involvement of interneuron subpopulations in trauma-related pathology and resilience

Region-specific involvement of interneuron subpopulations in trauma-related pathology and resilience.  Tsur SR, Demiray YE, Tripathi K, Stork O, Richter-Levin G, Albrecht A.Neurobiol Dis. 2020 Jun 16:104974.

Abstract

Only a minority of trauma-exposed individuals develops Posttraumatic stress disorder (PTSD) and active processes may support trauma resilience. Individual behavioral profiling allows investigating neurobiological alterations related to resilience or pathology in animal models of PTSD and is utilized here to examine the activation of different interneuron subpopulations of the dentate gyrus-amygdala system associated with trauma resilience or pathology. To model PTSD, rats were exposed to juvenile stress combined with underwater trauma (UWT) in adulthood. Four weeks later, individual anxiety levels were assessed in the elevated plus maze test for classifying rats as highly anxious ‘affected’ vs. ‘non-affected’, i.e. behaving as control animals. Analyzing the activation of specific interneuron subpopulations in the dorsal and ventral dentate gyrus (DG), the basolateral (BLA) and central amygdala by immunohistochemical double-labeling for cFos and different interneuron markers, revealed an increased activation of cholecystokinin (CCK)-positive interneurons in the ventral DG, together with increased activation of parvalbumin- and CCK-positive interneurons in the BLA of affected trauma-exposed rats. By contrast, increased activation of neuropeptide Y (NPY)-positive interneurons was observed in the dorsal DG of trauma-exposed, but non-affected rats. To test for a direct contribution of NPY in the dorsal DG to trauma resilience, a local shRNA-mediated knock down was performed after UWT. Such a treatment significantly reduced the prevalence of resilient animals. Our results suggest that distinct interneuron populations are associated with resilience or pathology in PTSD with high regional specificity. NPY within the dorsal DG was found to significantly contribute to trauma resilience.

Keywords: Behavioral profiling; Cholecystokinin; Dentate gyrus; Interneurons; Neuropeptide Y; Neuropeptides; PTSD; Pathology; Rat; Resilience.

Our new publication is online:  Active resilience in response to traumatic stress.

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

 

Abstract

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. 

We welcome the new LSA Fellows Dr. Syed Ahsan Raza and Dr. Anil Annamneedi, who started their projects in our lab in January 2020.

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.

 

The new CBBS Network “CBBS circuits” led by Dr. Gürsel Caliskan started in January 2020.

 

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.