The nucleus accumbens core is necessary to scale fear to degree of threat

Abstract

<jats:title>Abstract</jats:title><jats:p>Fear is adaptive when the level of the response rapidly scales to degree of threat. Using a discrimination procedure consisting of danger, uncertainty and safety cues, we have found rapid fear scaling (within two seconds of cue presentation) in male rats. Here we examined a possible role for the nucleus accumbens core (NAcc) in the acquisition and expression of fear scaling. In experiment 1, male Long Evans rats received bilateral sham or neurotoxic NAcc lesions, recovered and underwent fear discrimination. NAcc-lesioned rats were generally impaired in scaling fear to degree of threat, and specifically impaired in rapid uncertainty-safety discrimination. In experiment 2, male Long Evans rats received NAcc transduction with halorhodopsin or a control fluorophore. After fear scaling was established, the NAcc was illuminated during cue or control periods. NAcc-halorhodopsin rats receiving cue illumination were specifically impaired in rapid uncertainty-safety discrimination. The results reveal a general role for the NAcc in scaling fear to degree of threat, and a specific role in rapid discrimination of uncertain threat and safety.</jats:p><jats:sec><jats:title>Significance Statement</jats:title><jats:p>Rapidly discriminating cues for threat and safety is essential for survival and impaired threat-safety discrimination is a hallmark of stress and anxiety disorders. In two experiments, we induced nucleus accumbens core (NAcc) dysfunction in rats receiving fear discrimination consisting of cues for danger, uncertainty and safety. Permanent NAcc dysfunction, via neurotoxic lesion, generally disrupted the ability to scale fear to degree of threat, and specifically impaired one component of scaling: rapid discrimination of uncertain threat and safety. Reversible NAcc dysfunction, via optogenetic inhibition, specifically impaired rapid discrimination of uncertain threat and safety. The results reveal that the NAcc is essential to scale fear to degree of threat, and is a plausible source of dysfunction in stress and anxiety disorders.</jats:p></jats:sec>

Retrorubral field is a hub for diverse threat and aversive outcome signals

“…27,28 The RRF is anatomically poised to interact with a larger threat network. RRF neurons, including A8 dopamine, directly project to regions essential to fear, including medullary/pontine regions, 29 the central amygdala, 1,3 nucleus accumbens core, 30,31 ventral pallidum, 32,33 bed nucleus of the stria terminalis, 34,35 and hippocampus. 36,37 Indeed, RRF neuron-type composition and connectivity have led to previous proposals for a role in fear.…”

Foot shock facilitates reward seeking in an experience-dependent manner

“…Our laboratory has observed robust danger, uncertainty, and safety discrimination using suppression ratios calcluated from rates of rewarded nose poking 31,32,[35][36][37] . Classic studies examining defensive behaviour have reported robust post shock freezing 18,25,38 .…”

“…This work is underway in our laboratory and we speculate that female rats show foot shock facilitation of reward seeking. This is based on our observation that female rats readily acquire fear discrimination 37 . Further, manipulating shock-related prediction error activity -although a distinct behavioural mechanism from facilitationhas an equivalent effect on male and female fear behaviour 34 .…”

Ventral pallidum neurons signal relative threat

“…So far, no differences in VP activity/function have been found in studies that examined biological sex 18,39,55 . Our laboratory has observed complete and comparable fear discrimination in male and female rats 11,51,56,57 . We predict that equivalent relative threat signaling will be observed in female and male VP neurons.…”

“…Brain regions essential to fear, most notably the central amygdala [1][2][3] and basolateral amygdala (BLA) [4][5][6][7][8] , must be necessary to signal and utilize relative threat. At the same time, threat learning and behavior is the product of a larger neural network 9,10 that includes regions traditionally implicated in reward [11][12][13][14] .…”