Activity-regulated cytoskeleton-associated protein (Arc/Arg3.1)-mediated plasticity in the paraventricular thalamic nucleus promotes a fundamental adaptation to stress

BACKGROUNDHabituation is defined as a progressive decline in response to repeated exposure to a familiar and predictable stimulus and is highly conserved across species. Disrupted habituation is a signature of post-traumatic stress disorder (PTSD). In rodents, habituation is observed in neural, neuroendocrine and behavioral responses to repeated exposure to the predictable and moderately intense stress or restraint. We previously demonstrated that lesions to the posterior division of the paraventricular thalamic nucleus (pPVT) impairs habituation. However, the underlying molecular mechanisms and specific neural connections among the pPVT and other brain regions that underlie habituation are unknown. METHODSBehavioral and neuroendocrine habituation was assessed in adult male Sprague-Dawley restraints using the repeated restraint paradigm. Pan neuronal and Cre-dependent Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were used to chemogenetically inhibit the pPVT and the subpopulation of pPVT neurons that project to the medial prefrontal cortex (mPFC), respectively. Activity-regulated cytoskeleton-associated protein (Arc) expression was knocked down in the pPVT using siRNA directed towards Arc. Golgi staining was used to assess structural plasticity of pPVT neurons. Local field potential recordings were used to assess coherent neural activity between the pPVT and mPFC. The attentional set-shifting task was used to assess mPFC-dependent behavior. RESULTSHere, we show that Arc promotes habituation by increasing stress-induced spinogenesis in the pPVT, increasing coherent neural activity with the mPFC, and improving mPFC-mediated cognitive flexibility. CONCLUSIONOur results demonstrate that Arc induction in the pPVT regulates habituation to repeated restraint and mPFC function. One Sentence SummaryWe demonstrate that Arc in the posterior division of the paraventricular thalamic nucleus promotes habituation to repeated stress by increasing dendritic spines.