Expanding the canon: An inclusive neurobiology of thalamic and subthalamic fear circuits.

Appropriate expression of fear in the face of threats in the environment is essential for survival. The sustained expression of fear in the absence of threat signals is a central pathological feature of trauma- and anxiety-related disorders. Our understanding of the neural circuitry that controls fear inhibition coalesces around the amygdala, hippocampus, and prefrontal cortex. By discussing thalamic and sub-thalamic influences on fear-related learning and expression in this review, we suggest a more inclusive neurobiological framework that expands our canonical view of fear. First, we visit how fear-related learning and expression is influenced by the aforementioned canonical brain regions. Next, we review emerging data that shed light on new roles for thalamic and subthalamic nuclei in fear-related learning and expression. Then, we highlight how these neuroanatomical hubs can modulate fear via integration of sensory and salient stimuli, gating information flow and calibrating behavioral responses, as well as maintaining and updating memory representations. Finally, we propose that the presence of this thalamic and sub-thalamic neuroanatomy in parallel with the tripartite prefrontal cortex-amygdala-hippocampus circuit allows for dynamic modulation of information based on interoceptive and exteroceptive signals. This article is part of the Special Issue on "Fear, Anxiety and PTSD".

Incerto-thalamic modulation of fear via GABA and dopamine.

Fear generalization and deficits in extinction learning are debilitating dimensions of Post-Traumatic Stress Disorder (PTSD). Most understanding of the neurobiology underlying these dimensions comes from studies of cortical and limbic brain regions. While thalamic and subthalamic regions have been implicated in modulating fear, the potential for incerto-thalamic pathways to suppress fear generalization and rescue deficits in extinction recall remains unexplored. We first used patch-clamp electrophysiology to examine functional connections between the subthalamic zona incerta and thalamic reuniens (RE). Optogenetic stimulation of GABAergic ZI → RE cell terminals in vitro induced inhibitory post-synaptic currents (IPSCs) in the RE. We then combined high-intensity discriminative auditory fear conditioning with cell-type-specific and projection-specific optogenetics in mice to assess functional roles of GABAergic ZI → RE cell projections in modulating fear generalization and extinction recall. In addition, we used a similar approach to test the possibility of fear generalization and extinction recall being modulated by a smaller subset of GABAergic ZI → RE cells, the A13 dopaminergic cell population. Optogenetic stimulation of GABAergic ZI → RE cell terminals attenuated fear generalization and enhanced extinction recall. In contrast, optogenetic stimulation of dopaminergic ZI → RE cell terminals had no effect on fear generalization but enhanced extinction recall in a dopamine receptor D1-dependent manner. Our findings shed new light on the neuroanatomy and neurochemistry of ZI-located cells that contribute to adaptive fear by increasing the precision and extinction of learned associations. In so doing, these data reveal novel neuroanatomical substrates that could be therapeutically targeted for treatment of PTSD.