Incerto-thalamic modulation of fear via GABA and dopamine

Abstract

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.

A zona incerta-basomedial amygdala circuit modulates aversive expectation in emotional stress-induced aversive learning deficits

“…Wang et al reported that parvalbumin (PV)-positive neuronal projections from the ZI to the Po (ZI-Po) are critical for promoting nocifensive behaviors . We cannot rule out the possibility that ZI TH + neurons have local connections with GABA neurons that modulate freezing behavior through nocifensive adjustment (Chou et al, 2018;Venkataraman et al, 2021).…”

Throwing open the doors of perception: The role of dopamine in visual processing

“…A13 neurons also project to the paraventricular nucleus of the thalamus (Li et al, 2014;Otake & Ruggiero, 1995), periaqueductal grey (Messanvi et al, 2013) and the mesencephalic locomotor region (Sharma et al, 2018). Although recent evidence has associated the A13 neurons with both conditioned fear through projections to thalamus (Brandao & Coimbra, 2019;Venkataraman et al, 2021) and nociception through projections to periaqueductal grey and central amygdala (Moriya & Kuwaki, 2021), there is a paucity of evidence elucidating the functional role of A13 dopaminergic neurons in SC.…”

“…It is tempting to speculate that input from A13 could represent the source of modulation to the bottom-up information streaming into the SC. Notably, this may involve not only dopaminergic mechanisms because, like midbrain dopamine neurons, A13 neurons have recently been shown to co-release GABA into target areas (Venkataraman et al, 2021). This modulation could act in series with the disinhibition from the caudate, where the visual response is first sensitized to reward prediction in the superficial layers, receiving further top-down modulation via the caudate and cerebral cortex when determining a motor response.…”

Inactivation of Zona Incerta Blocks Social Conditioned Place Aversion and Modulates Post-traumatic Stress Disorder-Like Behaviors in Mice

“…Activation of ZI or targeted stimulation of GABAergic cells in the ZI attenuates fear generalization and enhances extinction recall. Targeted activation of the dopaminergic ZI projection to thalamic reunions has no effect on fear generalization but enhances extinction recall in a dopamine receptor D1-dependent manner (Venkataraman et al, 2019(Venkataraman et al, , 2021. Silencing of ZI or specifically suppression of the ZI PV + neurons blocks fear conditioning memory acquisition and remote retrieval (Zhou et al, 2018).…”