The basolateral amygdala-anterior cingulate pathway contributes to depression-like behaviors and comorbidity with chronic pain behaviors in male mice

Becker, Léa J.; Fillinger, Clémentine; Waegaert, Robin; Journée, Sarah H.; Hener, Pierre; Ayazgök, Beyza; Humo, Muris; Karatas, Meltem; Thouaye, Maxime; Gaikwad, Mithil; 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:10.1038/s41467-023-37878-y

Cited by 24 publications

(21 citation statements)

References 103 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: 83%

“…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.

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Section: Discussionsupporting

confidence: 83%

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

Self Cite

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“…This study showed that Sema4A promotes dopaminergic synapse formation in the mouse brain after neonatal meningitis and in iPS cell-derived human neurons. Previous studies have reported that Sema4A regulates neural morphology or synapse formation in vitro 30,31 , and is essential for the developing depression-like behaviors by modulating the amygdala-cingulate pathway in vivo 41 . Taken together with the results of our study, these findings suggest that Sema4A likely plays a pivotal role in the development of neural connectivity in the brain.…”

Section: Discussionmentioning

confidence: 99%

Neonatal meningitis induces ADHD-like behaviors via modulation of dopaminergic inputs by macrophages

Tanabe,

Muramatsu

2024

Preprint

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Neonatal meningitis often causes neurodevelopmental disorders, including attention deficit hyperactivity disorder (ADHD), in adulthood. However, the molecular mechanism by which neonatal meningitis induces brain dysconnectivity, leading to neurodevelopmental disorders, remains unclear. To investigate the pathological mechanisms of neonatal meningitis-induced neurodevelopmental disorders, we established mouse model of neonatal meningitis by injecting carrageenan, and found that mice with neonatal meningitis exhibited ADHD-like behaviors later in life and neural hyperactivation in the nucleus accumbens due to the increase in dopaminergic inputs induced by macrophages. RNA-sequencing revealed macrophages in carrageenan-treated mice express increased level of Semaphorin 4A (Sema4A), and treatment with a Sema4A neutralizing antibody prevented ADHD-like behaviors after carrageenan treatment. In addition, Sema4A concentration was increased in the cerebrospinal fluid of patients with meningitis, and Sema4A promoted dopaminergic synapse formation in human neurons. Collectively, these findings suggest macrophages increase dopaminergic inputs by producing Sema4A, which is a critical factor in the development of neonatal meningitis-induced ADHD-like behaviors.

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“…To compare female and male data, we used Rank-Rank Hypergeometric Overlap (RRHO2 [37]), as described previously [38,39], using the R package available at: https://github.com/Caleb-Huo/RRHO2. For each omic, results from differential analysis in each sex were ranked based on the following metric: -log10(p-value) x sign(log2 Fold Change).…”

Section: Rank-rank Hypergeometric Overlap (Rrho) Analysismentioning

confidence: 99%

Sex-specific and multiomic integration enhance accuracy of peripheral blood biomarkers of major depressive disorder

Lutz,

Mokhtari,

Ibrahim

et al. 2024

Preprint

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Major depressive disorder (MDD) is a leading cause of disability and reduced life expectancy, with a two-fold increase in prevalence in women compared to men. Over the last few years, identifying reliable molecular biomarkers of MDD has proved challenging, likely reflecting the fact that, in addition to sex-differences, a variety of environmental and genetic risk factors are implicated. Recently, epigenetic processes have been proposed as mediators of the impact of life experiences on functional regulation of the genome, with the potential to contribute to MDD biomarker development. In this context, here we characterized and integrated gene expression data with two upstream mechanisms for epigenomic regulation, DNA methylation (DNAm) and microRNAs (miRNAs). The 3 molecular layers were analyzed in peripheral blood samples from a well-characterized cohort of individuals with MDD (n=80) and healthy controls (n=89), and explored using 3 complementary strategies. First, we conducted case-control comparisons for each single omic layer, and contrasted sex-specific adaptations. Second, we leveraged network theory to define gene co-expression modules, followed by step-by-step annotations across omic layers. Finally, we implemented a genome-wide and multiomic integration strategy that included cross-validation and bootstrapping. The approach was used to systematically compare the performance of MDD prediction across 6 methods for dimensionality reduction and, importantly, for every combination of 1, 2 or 3 types of molecular data. Results showed that performance was higher when female and male cohorts were analyzed separately, rather than combined, and also progressively increased with the number of molecular datasets considered. While multiomic informational gain has already been illustrated in other medical fields, our results pave the way towards similar advances in molecular psychiatry, and have practical implications towards developing clinically useful biomarkers of MDD.

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The basolateral amygdala-anterior cingulate pathway contributes to depression-like behaviors and comorbidity with chronic pain behaviors in male mice

Cited by 24 publications

References 103 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

Neonatal meningitis induces ADHD-like behaviors via modulation of dopaminergic inputs by macrophages

Sex-specific and multiomic integration enhance accuracy of peripheral blood biomarkers of major depressive disorder

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