PT  - JOURNAL ARTICLE
AU  - Archana Venkataraman
AU  - Natalia Brody
AU  - Preethi Reddi
AU  - Jidong Guo
AU  - Donald Rainnie
AU  - Brian George Dias
TI  - Modulation of fear generalization by the zona incerta
AID  - 10.1101/485250
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 485250
4099  - http://biorxiv.org/content/early/2018/12/03/485250.short
4100  - http://biorxiv.org/content/early/2018/12/03/485250.full
AB  - Fear expressed towards threat-associated stimuli is an adaptive behavioral response. In contrast, the generalization of fear responses toward non-threatening cues is maladaptive and a debilitating dimension of trauma- and anxiety-related disorders. Expressing fear to appropriate stimuli and suppressing fear generalization requires integration of relevant sensory information and motor output. While thalamic and sub-thalamic brain regions play important roles in sensorimotor integration, very little is known about the contribution of these regions to the phenomenon of fear generalization. In this study, we sought to determine whether fear generalization could be modulated by the zona incerta (ZI), a sub-thalamic brain region that influences sensory discrimination, defensive responses, and retrieval of fear memories. To do so, we combined differential intensity-based auditory fear conditioning protocols in mice with C-FOS immunohistochemistry and DREADD-based manipulation of neuronal activity in the ZI. C-FOS immunohistochemistry revealed an inverse relationship between ZI activation and fear generalization – the ZI was less active in animals that generalized fear. In agreement with this relationship, chemogenetic inhibition of the ZI resulted in fear generalization, while chemogenetic activation of the ZI suppressed fear generalization. Furthermore, targeted stimulation of GABAergic cells in the ZI reduced fear generalization. To conclude, our data suggest that stimulation of the ZI could be used to treat fear generalization in the context of trauma- and anxiety-related disorders.