Cue-inhibited ventrolateral periaqueductal gray neurons signal fear output and threat probability in male rats

Wright, Kristina M; Jhou, Thomas C.; Pimpinelli, Daniel; McDannald, Michael A.

doi:10.7554/elife.50054

Cited by 25 publications

(26 citation statements)

References 25 publications

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“…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 .…”

Section: Resultsmentioning

confidence: 99%

Foot shock facilitates reward seeking in an experience-dependent manner

Strickland

Dileo

Moaddab

et al. 2020

Preprint

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Animals organize reward seeking around aversive events. An abundance of research shows that foot shock, as well as a shock-associated cue, can elicit freezing and suppress reward seeking. Yet, there is evidence that experience can flip the effect of foot shock to facilitate reward seeking. Here we examine cue suppression, foot shock suppression and foot shock facilitation of reward seeking in a single behavioural setting. Male Long Evans rats received fear discrimination consisting of danger, uncertainty and safety cues. Discrimination took place over a baseline of rewarded nose poking. With limited experience, all cues and foot shock strongly suppressed reward seeking. With continued experience, suppression became specific to shock-associated cues and foot shock facilitated reward seeking. Our results provide a means of assessing positive properties of foot shock, and may provide insight into maladaptive behavior around aversive events.

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Section: Resultsmentioning

confidence: 99%

Foot shock facilitates reward seeking in an experience-dependent manner

Strickland

Dileo

Moaddab

et al. 2020

Preprint

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“…The different types of vlPAG responses to the CS that we observed are consistent with previous reports: the fast onset neurons 10, 12, 36, 44 (our cluster 1) likely encode the fear prediction error 42, 44 and shall correspond, at least in part, to dopamine-vGluT2 expressing neurons 42 . Slower excitatory responses (our cluster 3) rather encode threat probability 12, 44 , while neurons with inhibitory responses to the CS (our cluster 2) more likely encode fear expression 10, 45 .…”

Section: Discussionmentioning

confidence: 98%

Bidirectional control of fear memories by the cerebellum through the ventrolateral periaqueductal grey

Frontera

Aissa

Sala

et al. 2020

Preprint

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10Fear conditioning is a form of associative learning that is known to involve brain areas, notably the 11 amygdala, the prefrontal cortex and the periaqueductal grey (PAG). Here, we describe the functional 12 role of pathways that link the cerebellum with the fear network. We found that the cerebellar 13 fastigial nucleus (FN) sends glutamatergic projections to vlPAG that synapse onto glutamatergic and 14 GABAergic vlPAG neurons. Chemogenetic and optogenetic manipulations revealed that the FN-vlPAG 15 pathway controls bi-directionally the strength of the fear memory, indicating a role in the association 16 of the conditioned and unconditioned stimuli, a function consistent with vlPAG encoding of fear 17 prediction error. In addition, we found that a FN -thalamic parafascicular nucleus pathway, which 18 may relay cerebellar influence to the amygdala, is involved in anxiety and fear expression but not in 19 fear memory. Our results reveal the contributions to the emotional system of the cerebellum, which 20 exerts a potent control on the strength of the fear memory through excitatory FN-vlPAG projections. 21 22 23 Keywords: cerebellum; limbic circuits; fear memory, chemogenetics, electrophysiology 24 vermis, in relation to negative emotions (e.g. during recall of self-generated emotional episodes 20 ). 50 Consistent with this, localized cerebellar lesions, principally in the midline vermis, account in large 51 part for the emotional disturbances, inappropriate behavior and changes in affect, which are 52 collectively termed the "cerebellar cognitive affective syndrome" 21 and reported in cerebellar 53 patients. Several studies have shown that the cerebellum has functional connections from fear-54 related areas including the PAG, the amygdala, and the prefrontal cortex [22][23][24][25] . In accordance with the 55 existence of such connections, Pavlovian fear conditioning affects cerebellar plasticity 26 , post-56 conditioning cerebellar inactivation affects memory consolidation 27 , and cerebellar lesions -or 57 inactivation-modulate freezing 24,28 ; however, the pathways by which the cerebellum participates to 58 fear learning or expression remain undefined. 59. The cerebellar vermis, which is most consistently associated with emotional pathologies and fear 60 expression 20,24,29 , projects to the fastigial nucleus (FN), a deep cerebellar nucleus (DCN) which 61 projects to many targets from the spinal cord to the diencephalon 22 . The purpose of the present 62 study is to study the contribution of specific FN output pathways to fear learning. Using 63 neuroanatomical tracings, chemogenetic modulation of the cerebellar input to the vlPAG and to the 64 BLA during fear conditioning, optogenetics and extracellular electrophysiological recordings in awake 65 freely moving animals, we demonstrate the contribution of the cerebellum to fear learning through 66 its inputs to the vlPAG. 67 68 4 69 70Results 71 Neuroanatomical link between the cerebellum and vlPAG 72In order to examine cerebellar projections to areas involve...

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“…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.…”

Section: Cue-excited Neurons Increase Firing To Rewardmentioning

confidence: 89%

“…Regression output was a beta coefficient for each regressor, quantifying the strength (greater distance from 0 = stronger) and direction (>0 = positive and <0 = negative) of the predictive relationship between each regressor and single unit firing. Regression allowed us to determine whether the firing of each VP neuron was better described by the rat's behavior in that session (fear output) or the shock probability associated with each cue (relative threat) 50,51 .…”

Section: Low and Intermediate Firing Neurons Signal Relative Threatmentioning

confidence: 99%

Ventral pallidum neurons signal relative threat

Moaddab

Ray

McDannald

2020

Preprint

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Ventral pallidum (VP) neurons scale firing increases to reward value and decrease firing to aversive cues.Anatomical connectivity suggests a critical role for the VP in threat-related behavior. Here we tested whether firing decreases in VP neurons conform to relative threat by recording single units while male rats discriminated cues predicting unique foot shock probabilities. Rats behavior and VP single unit firing discriminated danger, uncertainty and safety cues. We found that two VP populations (Low firing and Intermediate firing) signaled relative threat, proportionally decreased firing according shock probability: danger < uncertainty < safety. Low firing neurons showed reward firing increases, consistent with a general signal for relative value.Intermediate firing neurons were unresponsive to reward, revealing a specific signal for relative threat. The results suggest an integral role for the VP in threat-related behavior. ResultsMale, Long Evans rats (n = 14) were moderately food-deprived and trained to nose poke in a central port in order to receive a reward (food pellet). Nose poking was reinforced throughout fear discrimination, but poke-reward and cue-shock contingencies were independent. During fear discrimination, three distinct auditory cues predicted unique foot shock probabilities: danger (p=1.00), uncertainty (p=0.25), and safety (p=0.00) (Fig. 1a). Each fear discrimination session consisted of 16 trials: 4 danger, 2 uncertainty-shock, 6 uncertainty-omission, and 4 safety, mean 3.5 min inter-trial interval (ITI). Each trial started with a 20 s baseline period followed by 10 s cue presentation. Foot shock (0.5 mA, 0.5 s) was administered 2 s following cue offset on shock trials (Fig. 1b). Trial order was randomized for each rat, each session. Fear was measured by the suppression of rewarded nose poking. A suppression ratio was calculated by comparing nose poke rates during baseline and cue periods (see methods). After eight discrimination sessions, rats were implanted with drivable microelectrode bundles dorsal to the VP (Fig. 1c). Following recovery, single unit activity was recorded while rats underwent fear discrimination. The microelectrode bundle was advanced through

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Cue-inhibited ventrolateral periaqueductal gray neurons signal fear output and threat probability in male rats

Cited by 25 publications

References 25 publications

Foot shock facilitates reward seeking in an experience-dependent manner

Foot shock facilitates reward seeking in an experience-dependent manner

Bidirectional control of fear memories by the cerebellum through the ventrolateral periaqueductal grey

Ventral pallidum neurons signal relative threat

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