Ventral Pallidum GABA Neuron Inhibition Augments Context-Appropriate Defensive Responses to Learned Threat Cues

Abstract

The ventral pallidum (VP) is embedded within the brain circuits controlling motivated behavior, which are heavily implicated in addiction and other psychiatric disorders. Prior work showed that VP GABAergic neurons (VPGABA) promote reward approach and seeking, while the intermixed population of VP glutamate neurons instead promote avoidance and aversion. Some have thus suggested a functional dichotomy between these VP subpopulations in reward versus threat. We test this hypothesis by asking how inhibiting VPGABA impacts active and passive defensive responses to learned threat cues in the absence of rewards. We taught GAD1:Cre rats with inhibitory VPGABA DREADDs (or control rats) that a metal probe delivers shock, or that a 20sec auditory cue precedes footshocks. These stimuli thereafter elicit active defensive burying, or passive freezing responses, respectively. We found that VPGABA inhibition with CNO markedly increased stimulus-appropriate defensive responses to both types of learned threats, but failed to consistently alter new learning about them--suggesting VPGABA mediates aversive motivation but not memory formation. VPGABA inhibition also altered threat-related c-Fos expression within VP cell populations, and in their efferent target lateral habenula, but not mediodorsal thalamus--pointing to potential underlying circuit mechanisms of defensive responses. Results indicate that VPGABA neurons not only promote reward seeking as previously reported, but that they may also actively inhibit defensive responses to threats that might otherwise compete with reward seeking. This refines our understanding of subcortical valanced motivation circuits, and may suggest new targets for intervening in disorders like addiction and depression. Highlights-Inhibiting VPGABA increases defenses against threatening stimuli -Both active (burying) and passive (freezing) responses were enhanced -Inhibiting VPGABA excites other VP cells, and neurons in downstream LHb -VP subpopulations may interact to bidirectionally modulate circuits and adaptive behaviors Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/672918v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1978f03org.highwire.dtl.DTLVardef@12e4d59org.highwire.dtl.DTLVardef@d81bfforg.highwire.dtl.DTLVardef@164261_HPS_FORMAT_FIGEXP M_FIG C_FIG