Observation of Distressed Conspecific as a Model of Emotional Trauma Generates Silent Synapses in the Prefrontal-Amygdala Pathway and Enhances Fear Learning, but Ketamine Abolishes those Effects

Abstract

Witnessing pain and distress in others can cause psychological trauma and increase odds of developing PTSD in the future, on exposure to another stressful event. However, the underlying synaptic process remains unknown. Here we report that mice exposed to a conspecific receiving electrical footshocks exhibited enhanced passive avoidance (PA) learning when trained 24 h after the exposure. The exposure activated neurons in the dorsomedial prefrontal cortex (dmPFC) and basolateral amygdala (BLA) and altered synaptic transmission from dmPFC to BLA. It increased amplitude, slowed decay of NMDA receptor-mediated currents, and generated silent synapses. Administration of sub-anesthetic ketamine immediately after the exposure prevented the enhancement of PA learning and silent synapse formation. These findings suggest that ketamine can prevent pathophysiological consequences of psychological trauma.

Behavioral and mechanistic insight into rodent empathy

“…Furthermore, an ACC-restricted deletion of Cav1.2 Ca 2+ channels in mice impaired social fear learning and reduced behavioral pain responses, demonstrating the functional involvement of the affective pain system and Cav1.2 channels of the ACC in observational social fear (Jeon et al, 2010). Observational fear learning has also been shown to activate the dorsomedial prefrontal cortex-basolateral amygdala pathway by increasing the amplitude and slowing the decay of NMDA receptor-mediated currents as well as generating silent synapses (Ito et al, 2015).…”

GABAb Receptor Mediates Opposing Adaptations of GABA Release From Two Types of Prefrontal Interneurons After Observational Fear

“…This study, however, does not rule out a possibility of such changes on exposure to other stressors. Furthermore, it remains to be determined whether the observed changes could be attributed to the contextual learning during OF (Jeon et al, 2010) or to the effect of trauma on future learning in the PA paradigm (Ito et al, 2015).…”

“…Male pups were housed two littermates per cage (Allentown, NJ) since weaning as detailed in Ito et al (2015). All experiments were approved by Virginia Tech IACUC and followed the NIH Guide for the Care and Use of Laboratory Animals.…”

“…Heterozygous male Pvalb tm1(cre)Arbr (Hippenmeyer et al, 2005) or Sst tm2.1(cre)Zjh (Taniguchi et al, 2011) transgenic mice were injected bilaterally with 0.5 μl of the viral solution (10 8 viral particles) per hemisphere in dmPFC at 1.3 mm anterior, 0.4 mm lateral from the bregma, and 1.3 mm ventral from brain surface, as described (Ito et al, 2015). Previous studies have demonstrated specific expression of ChR2 in SOM-INs and PV interneurons (PVINs) of dmPFC using these lines and AAV vector (Kim et al, 2016;Sohal et al, 2009).…”

“…The distress signals act as an unconditional stimulus and lead to memorization of the associated cues and context (Chen et al, 2009;Jeon et al, 2010;Yusufishaq and Rosenkranz, 2013). We have recently shown that OF also enhances future learning in the passive avoidance (PA) task and causes the formation of silent synapses in the input from the dorso-medial prefrontal cortex (dmPFC) to the basolateral amygdala (Ito et al, 2015).…”