Modulation of fear generalization by the zona incerta

Abstract

Fear expressed toward threat-associated stimuli is an adaptive behavioral response. In contrast, the generalization of fear responses toward nonthreatening cues is a maladaptive and debilitating dimension of trauma-and anxiety-related disorders. Expressing fear to appropriate stimuli and suppressing fear generalization require integration of relevant sensory information and motor output. While thalamic and subthalamic 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 subthalamic 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 designer receptors exclusively activated by designer drugs (DREADDs)-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. trauma | posttraumatic stress disorder | subthalamic | fear inhibition | anxiety E xpressing fear toward cues that have previously been associated with trauma is adaptive (conditioned fear). Equally adaptive is the expression of fear toward stimuli that closely resemble traumatic cues (fear generalization). Such generalization of fear allows the organism to be "better safe than sorry." However, fear generalization can diminish quality of life and is a highly debilitating dimension of trauma-and anxiety-related disorders like posttraumatic stress disorder and generalized anxiety disorder (1-4). Reducing fear generalization, while maintaining adaptive fear responses, will reduce the daily burden experienced by individuals living with these disorders and requires identifying neural circuitry that could modulate fear generalization.Brain regions such as the lateral amygdala (5-7), central amygdala (8,9), prefrontal cortex (10, 11), hippocampus (3, 12), and bed nucleus of the stria terminalis (13, 14) have been implicated in fear generalization. More importantly, these regions play crucial roles in detecting threats and assigning valence to environmental stimuli (15-18). Therefore, while manipulating these regions could potentially reduce fear generalization, doing so might compromise threat detection, conditioned fear, and survival. In this study, we set out to ask whether targeting brain ...

An excitatory ventromedial hypothalamus to paraventricular thalamus circuit that suppresses food intake

“…It is well-demonstrated that PVT serves as a major thalamic interface between hindbrain and hypothalamus, and is also involved in hypothalamic–thalamic–striatal circuitry for integrating appetitive motivation with energy state and feeding 35 , 45 . A recent study shows that PVT receives GABAergic inputs from ZI, a brain region that modulates defense and fear behaviors 46 , 47 , and activation of ZI GABAergic inputs to PVT induces rapid binge-like feeding 38 . In a sharp contrast to the orexigenic feeding effect of GABAergic inputs to PVT, our results show that VMH SF1 neurons project excitatory glutamatergic inputs to PVT to inhibit food intake.…”

Direct visualization and characterization of the human zona incerta and surrounding structures

“…In a perhaps related manner, in rodent studies, the rostral ZI provides inhibitory control over the thalamus during sleep (Llinás & Jahnsen, 1982;Watson et al, 2014), which may also relate to its perceived role in modulating consciousness (Mitrofanis, 2005;Power & Mitrofanis, 2001). Finally, recent evidence, also in rodents, suggests an important role for the ZI in modulating fear generalization (Venkataraman et al, 2019) and appetite (Zhao et al, 2019).…”

Assaying Fear Memory Discrimination and Generalization: Methods and Concepts

“…In this case, the CS− becomes what is known as a "safety signal." This paradigm has been used successfully in both rat (Duvarci, Bauer, & Pare, 2009) and mouse models (Venkataraman et al, 2019).…”

“…Increasing the intensity of the US is one of the most reliable parameters for promoting generalized responding. Numerous studies have shown that increasing the intensity of the US increases generalization (Baldi, Lorenzini, & Bucherelli, 2004;Ghosh & Chattarji, 2015;Venkataraman et al, 2019). For instance in mice, "weak" US intensities from 0.3 to 0.5 mA results in CS+ discrimination, while 0.8-to 1.0-mA US intensity promoted generalization (Ghosh & Chattarji, 2015).…”

“…For these reasons, Pavlovian fear conditioning is currently a leading model for studying circuity thought to be dysregulated in PTSD. Numerous brain systems have been demonstrated to contribute to fear discrimination and generalization processing, including the cingulate cortex (Ortiz et al., ), hippocampus (Besnard & Sahay, ), amygdala (Ciocchi et al., ; Ghosh & Chattarji, ; Grosso, Santoni, Manassero, Renna, & Sacchetti, ), thalamic and subthalamic nuclei (Ferrara, Cullen, Pullins, Rotondo, & Helmstetter, ; Ramanathan, Ressler, Jin, & Maren, ; Venkataraman et al., ; Xu & Sudhof, ), midbrain (Rozeske et al., ), and prefrontal cortices (Fitzgerald et al., ; Pollack et al., ; Rozeske et al., ; Scarlata et al., ). For a review on the neurobiology of fear generalization, see Asok, Kandel, and Rayman () and Sangha, Diehl, Bergstrom, and Drew ().…”