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Plasticity of a prefrontal microcircuit during social defeat

Marrone, Livia

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The prefrontal cortex (PFC) is a critical brain area for behavioral flexibility and plays an important role in moderating social behavior and decision making in response to a changing environment. Our lab recently demonstrated that inhibition of projections from the PFC to the dorsal periaqueductal grey (dPAG), a structure involved in defensive behavior, elicits social avoidance in mice. Furthermore, in the PFC of animals which underwent social defeat, the amplitude of the synaptic response to mediodorsal thalamus (MDT) stimulation is significantly decreased (Franklin et al, 2017). The aim of this study was to investigate the molecular mechanisms underlying the weakening of the PFC and the acquisition of social avoidance after the defeat. Using translating ribosome affinity purification (TRAP), we demonstrated that social defeat induces differential changes in excitatory and inhibitory neuronal subpopulations of the PFC. No significant gene expression changes were detected in glutamatergic (Camk2a+) neurons. Pvalb+ interneurons, instead, showed decreased expression of genes related to presynaptic release and neuronal excitability and Sst+ interneurons showed increased expression of genes related to cytoskeleton and axonal growth. Using reporter mice expressing green fluorescent protein (GFP) exclusively in Sst+ neuronal boutons, we confirmed that these neurons make increased presynaptic contacts in PFC layer I after social defeat, consistent with the observed gene expression changes. In the meantime, we investigated postsynaptic plasticity in glutamatergic PFC-dPAG neurons using a novel tool that exploits SNAP-tag technology to label surface α - amino - 3 - hydroxy - 5 - methyl - 4 - isoxazolepropionic acid receptors (AMPARs) in vivo after behavior . Using this tool we found that PFC - d PAG neurons of defeated mice downregulate surface AMPARs at layer I excitatory inputs, the precise region where Sst + neurons show increas ed inhibitory contacts . Selective p harmacogenetic inhibition of Sst+ neurons during social defeat was sufficient to impair the acquis ition of social avoidance , arguing for a potential role of Sst+ inputs in facilitating layer I PFC excitatory synaptic plasticity. In conclusion, we examined transcriptional, structural, and synaptic plasticity mechanisms occurring in the PFC in response to social defeat and identified an essential role for Sst+ neurons in the acquisition of social avoidance behavior. Furthermore, we established a novel technique to image synaptic plasticity by in vivo labeling of surface AMPA receptors that will have broad application in behavioral circuit neuroscience research.

Item Type: Dissertation
Supervisor: Heppenstall, Dr. Paul
Date of thesis defense: 28 November 2017
Date Deposited: 21 Aug 2018 08:57
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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