The basolateral amygdala-anterior cingulate pathway contributes to depression and its comorbidity with chronic pain

Becker, Léa J.; Fillinger, Clémentine; Waegaert, Robin; Hener, Pierre; Ayazgök, Beyza; Humo, Muris; Journée, Sarah H.; Karatas, Meltem; Degiorgis, Laetitia; Santin, Marie des Neiges; Mondino, Mary; Barrot, Michel; Ibrahim, El Chérif; Turecki, Gustavo; Belzeaux, Raoul; Veinante, Pierre; Harsan, Laura; Hugel, Sylvain; Lutz, Pierre-Eric; Yalçın, İpek

doi:10.1101/2022.08.09.503276

Cited by 7 publications

(11 citation statements)

References 98 publications

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“…35 It is, therefore, possible that a different nesting protocol after SNI could reveal a phenotype as others have already shown across different pain-related models. 3,9,47,53 The same is true for our sucrose preference results (Fig. 3A).…”

Section: Discussionsupporting

confidence: 82%

“…Prior work has demonstrated that integrating performance across various behavioral assays can lead to more sensitive and reliable measures of the overall socalled "emotionality" of preclinical rodent models. 9,13,38,90 Whether this same approach would apply for injury-induced negative affect is unclear. To determine whether a normalized "emotionality" behavioral z-score could reflect chronic neuropathic injury, we next tested this concept by normalizing each individual output from a single behavioral assay (eg, % time in center and distance travelled in the open field; Table 1) into a single assay score.…”

Section: Integrated Behavioral Scores Provide Emergent Painrelated Ou...mentioning

confidence: 99%

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Spared nerve injury decreases motivation in long-access homecage-based operant tasks in mice

Norris,

Becker,

Bilbily

et al. 2023

Pain

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Neuropathic pain causes both sensory and emotional maladaptation. Preclinical animal studies of neuropathic pain-induced negative affect could result in novel insights into the mechanisms of chronic pain. Modeling pain–induced negative affect, however, is variable across research groups and conditions. The same injury may or may not produce robust negative affective behavioral responses across different species, strains, and laboratories. Here, we sought to identify negative affective consequences of the spared nerve injury model on C57BL/6J male and female mice. We found no significant effect of spared nerve injury across a variety of approach-avoidance conflict, hedonic choice, and coping strategy assays. We hypothesized these inconsistencies may stem in part from the short test duration of these assays. To test this hypothesis, we used the homecage-based Feeding Experimentation Device version 3 to conduct 12-hour, overnight progressive ratio testing to determine whether mice with chronic spared nerve injury had decreased motivation to earn palatable food rewards. Our data demonstrate that despite equivalent task learning, spared nerve injury mice are less motivated to work for a sugar pellet than sham controls. Furthermore, when we normalized behavioral responses across all the behavioral assays we tested, we found that a combined normalized behavioral score is predictive of injury state and significantly correlates with mechanical thresholds. Together, these results suggest that homecage-based operant behaviors provide a useful platform for modeling nerve injury-induced negative affect and that valuable pain-related information can arise from agglomerative data analyses across behavioral assays—even when individual inferential statistics do not demonstrate significant mean differences.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Integrated Behavioral Scores Provide Emergent Painrelated Ou...mentioning

confidence: 99%

Spared nerve injury decreases motivation in long-access homecage-based operant tasks in mice

Norris,

Becker,

Bilbily

et al. 2023

Pain

View full text Add to dashboard Cite

show abstract

“…Additionally, nestlet test duration and time of day is not consistent between protocols[32]. It is therefore possible, that using a different nesting protocol following SNI could reveal a clear phenotype as others have already shown across different pain-related models[3,9,43,47]. The same could be said for our sucrose preference results ( Figure 3A ).…”

Section: Discussionsupporting

confidence: 56%

“…The exception to that was in the more challenging operant tasks (i.e., FR3 and PR; Figures 6-9). Prior work has demonstrated that integrating performance across various behavioral assays can lead to more sensitive and reliable measures of the overall so-called 'emotionality' of preclinical rodent models [9,12,35,78]. Whether this same approach would apply for injury-induced negative affect is unclear.…”

Section: Integrated Behavioral Scores Provide Emergent Pain-related O...mentioning

confidence: 99%

Neuropathic injury drives a generalized negative affective state in mice

Norris

Bilbily

Becker

et al. 2022

Preprint

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Neuropathic pain causes both sensory and emotional maladaptation. Preclinical animal studies of neuropathic pain-induced negative affect could result in novel insights into the mechanisms of chronic pain. Modeling pain-induced negative affect, however, is variable across research groups and conditions. The same injury may or may not produce robust negative affective behavioral responses across different species, strains, and laboratories. Here we sought to identify negative affective consequences of the spared nerve injury model on C57BL/6J male and female mice. We found no significant effect of spared nerve injury across a variety of approach-avoidance, hedonic choice, and coping strategy assays. We hypothesized these inconsistencies may stem in part from the short test duration of these assays. To test this hypothesis, we used the homecage-based Feeding Experimentation Device version 3 to conduct 12-hour, overnight progressive ratio testing to determine whether mice with chronic spared nerve injury had decreased motivation to earn palatable food rewards. Our data demonstrate that despite equivalent task learning, spared nerve injury mice are less motivated to work for a sugar pellet than sham controls. Further, when we normalized behavioral responses across all the behavioral assays we tested, we found that a combined normalized behavioral score is predictive of injury-state and significantly correlates with mechanical thresholds. Together these results suggest that homecage-based operant behaviors provide a useful platform for modeling nerve injury-induced negative affect and that valuable pain-related information can arise from agglomerative data analyses across behavioral assays - even when individual inferential statistics do not demonstrate significant mean differences.

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“…The basal lateral amygdala (BLA) was chosen based on previous work that has identified neural populations linked to defensive coping behaviors like paw attending, paw guarding, and paw shaking (Corder 2019, Jones 2020). This has included both the identification of excitatory neural populations that when activated lead to increased (Becker 2023, Han 2010 or decreased (Cai 2018) pain behavior. Adjustments were made to the ARM's arduino component to sync the ARM's stimulus delivery with both the high-speed camera and Inscopix platform for cellular-resolved microendoscopy.…”

Section: Syncing Of Stimulus With Video and In Vivo Brain Imaging Datamentioning

confidence: 99%

Remote automated delivery of mechanical stimuli coupled to brain recordings in behaving mice

Burdge,

Jhumka,

Ogundare

et al. 2024

Preprint

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The canonical framework for testing pain and mechanical sensitivity in rodents is manual delivery of stimuli to the paw. However, this approach can produce variability in results, requires significant training, and is ergonomically unfavorable to the experimenter. To circumvent limitations in manual delivery of stimuli, we have created a device called the ARM (Automated Reproducible Mechano-stimulator). Built using a series of linear stages, cameras, and stimulus holders, the ARM is more accurate at hitting the desired target, delivers stimuli faster, and decreases variability in delivery of von Frey hair filaments. We demonstrate that the ARM can be combined with traditional measurements of pain behavior and automated machine-learning based pipelines. Importantly, the ARM enables remote testing of mice with experimenters outside the testing room. Using remote testing, we found that mice appeared to habituate more quickly when an experimenter was not present and experimenter presence leads to significant sex-dependent differences in withdrawal behavior. Lastly, to demonstrate the utility of the ARM for neural circuit dissection of pain mechanisms, we combined the ARM with cellular-resolved microendoscopy in the amygdala, linking stimulus, behavior, and brain activity of amygdalar neurons that encode negative pain states. Taken together, the ARM improves speed, accuracy, and robustness of mechanical pain assays and can be combined with automated pain detection systems and brain recordings to map pain sensation and affect.

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The basolateral amygdala-anterior cingulate pathway contributes to depression and its comorbidity with chronic pain

Cited by 7 publications

References 98 publications

Spared nerve injury decreases motivation in long-access homecage-based operant tasks in mice

Spared nerve injury decreases motivation in long-access homecage-based operant tasks in mice

Neuropathic injury drives a generalized negative affective state in mice

Remote automated delivery of mechanical stimuli coupled to brain recordings in behaving mice

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