Ventral pallidal modulation of aversion processing

Wulff, Andreas B.; Tooley, Jessica; Marconi, Lauren; Creed, Meaghan C.

doi:10.1016/j.brainres.2018.10.010

Cited by 57 publications

(49 citation statements)

References 78 publications

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“…In addition to the prominent BF vGluT2+ projection to VTA, some of the strongest fiber labeling was evident in the lateral habenula, which plays a crucial role in negative reward predictions (Tian and Uchida, 2015;Baker et al, 2016) and depressive behavior Browne et al, 2018). Recent studies have suggested that VP glutamatergic projections to the lateral habenula and VTA may promote behavioral response to stress or punishment avoidance (Tooley et al, 2018;Wulff et al, 2019), consistent with the response we observed here in vivo.…”

Section: Bf Vglut2+ Neurons Project To Multiple Regions Involved In Psupporting

confidence: 87%

Characterization of basal forebrain glutamate neurons suggests a role in control of arousal and avoidance behavior

Mckenna

Yang

Bellio

et al. 2020

Preprint

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The basal forebrain (BF) is involved in arousal, attention, and reward processing but the role of individual BF subtypes is still being uncovered. Glutamatergic neurons are the least wellunderstood of the three major BF neurotransmitter phenotypes. Here we analyzed the distribution, size, calcium-binding protein content and projections of the major group of BF glutamate neurons expressing the vesicular glutamate transporter subtype 2 (vGluT2) and tested the functional effect of activating them. Mice expressing Cre recombinase under control of the vGluT2 promoter were crossed with a reporter strain expressing the red fluorescent protein, tdTomato, to generate vGluT2-cre-tdTomato mice. Immunohistochemical staining for choline acetyltransferase and a cross with mice expressing green fluorescent protein selectively in GABAergic neurons confirmed cholinergic, GABAergic and vGluT2+ neurons represent separate BF subpopulations. Subsets of BF vGluT2+ neurons expressed the calcium binding proteins calbindin or calretinin, suggesting that multiple subtypes of BF vGluT2+ neurons exist.Anterograde tracing using adeno-associated viral vectors expressing channelrhodopsin2enhanced yellow fluorescent fusion proteins revealed major projections of BF vGluT2+ neurons to neighboring BF cholinergic and parvalbumin neurons, as well as to extra-BF areas involved in the control of arousal and regions responding to aversive or rewarding stimuli such as the lateral habenula and ventral tegmental area. Optogenetic activation of BF vGluT2 neurons in a place preference paradigm elicited a striking avoidance of the area where stimulation was given.Together with previous optogenetic findings suggesting an arousal-promoting role, our findings suggest BF vGluT2 neurons play a dual role in promoting wakefulness and avoidance behavior.

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Section: Bf Vglut2+ Neurons Project To Multiple Regions Involved In Psupporting

confidence: 87%

Characterization of basal forebrain glutamate neurons suggests a role in control of arousal and avoidance behavior

Mckenna

Yang

Bellio

et al. 2020

Preprint

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“…In control mice, activation of the central pain pathway by the STN is limited; thus, inhibition of STN neurons in these mice may not lead to reductions in the activity level in central pain pathways, resulting in only minor effects on pain thresholds. The SNr, GPi, and VP are involved in the perception of multiple types of nociceptive stimuli (10,18,42). We found that SNr, GPi, and VP neurons receiving STN projections differentially regulate mechanical and thermal pain thresholds in both control and parkinsonian mice, suggesting that subpopulations of STN projection neurons may be effective therapeutic targets for the treatment of diverse pain symptoms in PD.…”

Section: Discussionmentioning

confidence: 82%

“…The involvement of the STN-GPi pathway in the perception of mechanical sensory stimulation provides an explanation for clinical observations that either pallidotomy or pallidal DBS, which may disrupt STN-GPi transmission, relieves pain symptoms in PD, including dyskinetic, dystonic, and musculoskeletal pain (43,44). Although it has been shown that both SNr and VP neurons respond to painful stimuli (2,10,18,42), our results are among the first to hint at the critical roles of these two nuclei in parkinsonian pain hypersensitivity. The fact that STN DBS mitigates musculoskeletal and dystonic pain better than central and radicular/neuropathic pain (28) further suggests that the STN may regulate the perception of distinct types of pain stimuli.…”

Section: Discussionmentioning

confidence: 99%

Reversal of hyperactive subthalamic circuits differentially mitigates pain hypersensitivity phenotypes in parkinsonian mice

Luan

Tang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Although pain is a prevalent nonmotor symptom in Parkinson’s disease (PD), it is undertreated, in part because of our limited understanding of the underlying mechanisms. Considering that the basal ganglia are implicated in pain sensation, and that their synaptic outputs are controlled by the subthalamic nucleus (STN), we hypothesized that the STN might play a critical role in parkinsonian pain hypersensitivity. To test this hypothesis, we established a unilateral parkinsonian mouse model with moderate lesions of dopaminergic neurons in the substantia nigra. The mice displayed pain hypersensitivity and neuronal hyperactivity in the ipsilesional STN and in central pain-processing nuclei. Optogenetic inhibition of STN neurons reversed pain hypersensitivity phenotypes in parkinsonian mice, while hyperactivity in the STN was sufficient to induce pain hypersensitivity in control mice. We further demonstrated that the STN differentially regulates thermal and mechanical pain thresholds through its projections to the substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi)/ventral pallidum (VP), respectively. Interestingly, optogenetic inhibition of STN-GPi/STN-VP and STN-SNr projections differentially elevated mechanical and thermal pain thresholds in parkinsonian mice. In summary, our results support the hypothesis that the STN and its divergent projections play critical roles in modulating pain processing under both physiological and parkinsonian conditions, and suggest that inhibition of individual STN projections may be a therapeutic strategy to relieve distinct pain phenotypes in PD.

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“…These results suggest a global recruitment of numerous VP subregions during both context- and cue-induced reinstatement, including in the punished context where global VP inhibition failed to suppress cocaine seeking. One possible explanation for this puzzling pattern of effects is that functionally opposed VP cells are engaged in the safe- and punished-contexts, such as the intermingled VP GABA and glutamate neurons which drive appetitive and aversive behavior, respectively [30–32, 61, 62]. Our pan-neuronal chemogenetic approach primarily targeted reward-related VP GABA neurons (~85%), consistent with observed reinstatement suppression in the safe context, where aversion-related glutamate neurons would be less relevant.…”

Section: Discussionmentioning

confidence: 99%

Ventral Pallidum is Essential for Cocaine Reinstatement After Voluntary Abstinence

Castillo

et al. 2019

Preprint

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21Addiction is a chronic relapsing disorder, and during recovery many people experience several relapse events as 22 they attempt to voluntarily abstain from drug. New preclinical relapse models have emerged which capture this 23 common human experience of relapse after voluntary abstinence, and mounting evidence indicates that 24 reinstatement of drug seeking after voluntary abstinence recruits neural circuits distinct from reinstatement 25 following experimenter-imposed abstinence, or abstinence due to extinction training. Ventral pallidum (VP), a key 26 limbic node involved in drug seeking, has well-established roles in conventional reinstatement models tested 27 following extinction training, but it is unclear whether this region also participates in more translationally-relevant 28 models of relapse. Here we show that chemogenetic inhibition of VP neurons strongly attenuates cocaine-, 29 context-, and cue-induced reinstatement tested after voluntary, punishment-induced abstinence. This effect was 30 strongest in the most compulsive, punishment-resistant rats, and reinstatement was associated with neural 31 activity in anatomically-defined VP subregions. VP inhibition also attenuated the propensity of rats to display 32 'hesitations,' a risk assessment behavior seen during punished drug taking that is likely due to concurrent 33 approach and avoidance motivations. These results indicate that VP, unlike other connected limbic brain regions, 34 is essential for reinstatement of drug seeking after voluntary abstinence. Since VP inhibition effects were 35 strongest in the most compulsively cocaine-seeking individuals, this could indicate that VP plays a particularly 36 important role in the most pathological, addiction-like behavior, making it an attractive target for future 37 therapeutic interventions. 38 39 40 41 42

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Ventral pallidal modulation of aversion processing

Cited by 57 publications

References 78 publications

Characterization of basal forebrain glutamate neurons suggests a role in control of arousal and avoidance behavior

Characterization of basal forebrain glutamate neurons suggests a role in control of arousal and avoidance behavior

Reversal of hyperactive subthalamic circuits differentially mitigates pain hypersensitivity phenotypes in parkinsonian mice

Ventral Pallidum is Essential for Cocaine Reinstatement After Voluntary Abstinence

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