@article{pmid41962851,

title = {Excessive inhibition in the medial prefrontal cortex contributes to cognitive susceptibility in aging},

author = {Iason Keramidis and Patrick Desrosiers and Andrée-Anne Verreault and Romain Sansonetti and Reza Hazrati and Antoine G Godin and Yves De Koninck},

doi = {10.1016/j.nbd.2026.107385},

issn = {1095-953X},

year  = {2026},

date = {2026-04-01},

journal = {Neurobiol Dis},

volume = {224},

pages = {107385},

abstract = {Aging is the most impactful risk factor for cognitive decline. The prefrontal cortex (PFC), a brain region essential for higher-order cognition, undergoes age-related synaptic alterations which are postulated to yield an excitation/inhibition imbalance within the PFC. Here, we assessed cognitive performance in young and aged mice using a battery of behavioral tests linked to PFC function. Behavioral variability within the aged cohort suggested structured heterogeneity in cognitive performance. Using a data-driven analytical framework integrating behavioral dimensionality reduction, consensus clustering, and spectral embedding we achieved robust and stable behavioral subgroup separation within the aged population. This approach revealed a subset of "cognitively susceptible" aged mice with pronounced memory and novelty-directed exploration deficits, distinct from both "resilient" aged mice and young controls. Unlike resilient aged mice, susceptible mice showed intact social preference. Susceptible aged mice exhibited elevated levels of the inhibitory synaptic proteins Gephyrin and VGAT in the PFC, a pattern absent in resilient aged mice. Notably, the increase in Gephyrin was accounted for by a higher density of inhibitory synapses, indicating a structural shift toward inhibition. Consistent with this mechanism, optogenetically enhancing inhibition in the PFC of young mice was sufficient to recapitulate the memory and novelty-exploration deficits observed in susceptible aged mice. Altogether, these findings implicate excessive prefrontal inhibition as a mechanistic substrate contributing to cognitive susceptibility in unsuccessful aging.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41619726,

title = {Runx1 transcription factor modulates opioid analgesia and withdrawal in humans and rodents},

author = {Heather Leduc-Pessah and Brendan B McAllister and Sarthak Sinha and Sierra Stokes-Heck and Daisuke Nishizawa and Churmy Y Fan and Marie-Kim St-Pierre and Amyaouch Bradaia and Manon Defaye and Nicole E Burma and Jonathan Damblon and Einer Muñoz-Pino and Frank Visser and Marie-France Dorion and Luke M Healy and Ye Man Tang and Julia Canet-Pons and Nynke J van den Hoogen and Zizhen Zhang and Flavia T T Antunes and Valerio E C Piscopo and Margaret Medina and Ken-Ichi Fukuda and Tatsuya Ichinohe and Makoto Nagashima and Masakazu Hayashida and Emma Johnson and Arpana Agrawal and Louisa Degenhardt and Nicholas G Martin and Gerald W Zamponi and Elliot C Nelson and Christophe Altier and Marie-Eve Tremblay and Chad Bousman and Stefano Stifani and Yves De Koninck and Kazutaka Ikeda and Jeff Biernaskie and Tuan Trang},

doi = {10.1016/j.neuron.2025.11.018},

issn = {1097-4199},

year  = {2026},

date = {2026-03-01},

journal = {Neuron},

volume = {114},

number = {5},

pages = {903--921.e13},

abstract = {Opioid analgesia and adverse outcomes vary across individuals. We show that runt-related transcription factor 1 (Runx1) modulates the microglial transcriptome and is a genetic determinant of opioid antinociceptive responses and withdrawal. In mice, Runx1 deletion in microglia produces distinct ultrastructural and transcriptomic signatures, reducing morphine potency despite no prior opioid exposure. These mice also require greater post-operative morphine and display exacerbated morphine-induced hyperalgesia and withdrawal. Single-cell RNA sequencing (scRNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses reveal a unique microglial state, with Runx1 regulating inflammatory signaling and key microglial functions. In humans, association analyses link RUNX1 variants to inter-individual differences in perioperative opioid requirement and withdrawal severity. Identifying RUNX1 susceptibility genotypes may be important for understanding individual variability in opioid responses, with potential relevance for future personalized approaches.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40221111,

title = {Excitability properties of cardiac calbindin neurons: Identifying a unique neuronal population},

author = {Guénaëlle Lizot and Jocelyn Bescond and Yves De Koninck and Mohamed Chahine and Patrick Bois and Jean-François Faivre and Aurélien Chatelier},

doi = {10.1016/j.hrthm.2025.04.007},

issn = {1556-3871},

year  = {2026},

date = {2026-03-01},

journal = {Heart Rhythm},

volume = {23},

number = {3},

pages = {741--750},

abstract = {BACKGROUND: The intrinsic cardiac nervous system is a complex system that plays a critical role in the regulation of cardiac physiologic parameters and has been shown to contribute to cardiac arrhythmias. To date, several types of neurons with distinct neurochemical and electrophysiologic phenotypes have been identified. However, no study has correlated the neurochemical phenotype to a specific electrophysiologic behavior. Calbindin-D28k, a calcium-binding protein, is expressed in numerous cardiac neurons.nnOBJECTIVE: Given that changes in neuronal excitability have been associated with arrhythmia susceptibility and that calbindin expression has been associated with modulations of neuronal excitability, our objective was to assess whether the cardiac calbindin neuronal population has specific properties that could be involved in cardiac regulation and arrhythmias.nnMETHODS: By using a Cre-Lox mouse model to specifically target calbindin neurons with a fluorescent reporter, we characterized the neurochemical and electrophysiologic phenotype of this cardiac neuronal population.nnRESULTS: Calbindin neurons exhibit a specific neurochemical expression profile and a larger soma with shorter neurite length compared with other neurons. This was combined with a distinct electrophysiologic signature characterized by a lower excitability with a predominantly phasic profile associated to a lower N-type calcium current density.nnCONCLUSION: Calbindin cardiac neurons display distinct neurochemical, morphologic, and electrophysiologic properties, resembling the cardiac neuronal remodeling observed in pathologic processes such as heart failure. Therefore, we believe that this specific neuronal population deserves investigation in the context of cardiac diseases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41461929,

title = {Recommendations for the inclusion and study of sex and gender in research},

author = {David P Finn and Brian E McGuire and Simon Beggs and Katelynn E Boerner and Karen D Davis and Ruth Defrin and Yves De Koninck and Hemakumar Devan and Ryan Donovan and Eleonora Fetter and Herta Flor and Brona M Fullen and Catherine R Healy and Edmund Keogh and Rohini Kuner and Miriam Kunz and Rebecca M Lane and Stefan Lautenbacher and Emeran A Mayer and Jeffrey S Mogil and Siobhain M O'Mahony and Kieran O'Sullivan and Louise Riordan and Michael W Salter and Francesco Scarlatti and George Shorten and Kathleen A Sluka and Jennifer N Stinson and Kevin E Vowles and Suellen M Walker and Ipek Yalcin and Michelle Roche},

doi = {10.1038/s41593-025-02164-1},

issn = {1546-1726},

year  = {2026},

date = {2026-02-01},

journal = {Nat Neurosci},

volume = {29},

number = {2},

pages = {256--266},

abstract = {Sex and gender are important variables in research, but they are inconsistently explored. The international PAINDIFF Network makes 13 recommendations for studying sex and gender as variables in pain research, which are applicable across the spectrum of biopsychosocial research. Five universal recommendations apply to the majority of research studies: (1) include males and females as standard practice, (2) account for sex in randomization or counterbalancing and testing order, (3) power for sex differences when sex is a primary experimental variable, (4) include detailed reporting of experimental design, and (5) conduct sex-disaggregated analysis and reporting. Three additional recommendations specifically for preclinical studies and five additional recommendations for human and clinical studies are included. Recommendations for stakeholders, such as editors, reviewers, funding bodies and policymakers, have also been developed. Wide adoption and implementation of these recommendations will reduce variability, improve reproducibility and enhance the translatability of research findings within and beyond the field of pain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40667986,

title = {Decreased KCC2 expression in the human spinal dorsal horn associated with chronic pain and long-term opioid use},

author = {Olivia C Davis and Samuel Ferland and Louis-Etienne Lorenzo and Clare Murray-Lawson and Stephanie Shiers and Muhammad Saad Yousuf and Annemarie Dedek and Eve C Tsai and Erin Vines and Peter Horton and Anna Cervantes and Tariq Khan and Geoffrey Funk and Gregory Dussor and Antoine G Godin and Francesco Ferrini and Yves De Koninck and Michael E Hildebrand and Theodore J Price},

doi = {10.1097/j.pain.0000000000003700},

issn = {1872-6623},

year  = {2025},

date = {2025-11-01},

journal = {Pain},

volume = {166},

number = {11},

pages = {e665--e673},

abstract = {Loss of GABAergic and glycinergic inhibitory efficacy in the spinal dorsal horn is associated with neuropathic pain and opioid-induced hyperalgesia in rodent models. Downregulation of the KCC2 chloride extrusion transporter is a key mechanism underlying this decreased inhibitory efficacy, but to-date there is no evidence supporting or opposing this hypothesis in humans. Here, we demonstrate that KCC2 expression is decreased in superficial dorsal horn neurons of organ donors who died with a documented history of pain, or of long-term opioid use. We show profoundly decreased KCC2 dorsal horn membrane expression in a primary cohort associated with either chronic pain or opioid use, and in a replication cohort of mixed chronic pain and opioid use history. These results show that decreased dorsal horn inhibitory efficacy likely promotes chronic pain in humans and support the development of therapeutics augmenting KCC2 function as a treatment for chronic pain and opioid use disorders.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid41169497,

title = {Chronic optogenetic activation of hippocampal CA1 neurons triggers Alzheimer's disease-like proteomic remodeling},

author = {Iason Keramidis and Martina Samiotaki and Romain Sansonetti and Johanna Alonso and Patrick Desrosiers and Katerina Papanikolopoulou and Yves De Koninck},

doi = {10.1016/j.isci.2025.113454},

issn = {2589-0042},

year  = {2025},

date = {2025-10-01},

journal = {iScience},

volume = {28},

number = {10},

pages = {113454},

abstract = {Neuronal overexcitability triggers synaptic changes, leading to neural hyperactivity, network disruption, and is postulated to trigger neurodegeneration in Alzheimer's disease (AD). However, the sequence of synaptic changes from excessive activity remains unclear. We employed optogenetics to induce sustained neuronal hyperactivity in the hippocampi of wild-type and AD-like 5xFAD mice. After a month of daily optogenetic stimulation, the proteomic profiles of photoactivated wild-type and 5xFAD mice exhibited remarkable similarity. Proteins involved in translation, protein transport, autophagy, and notably in the AD pathology were upregulated in wild-type mice. Conversely, both glutamatergic and GABAergic synaptic proteins were downregulated. These hippocampal proteomic and signaling alterations in wild-type mice resulted in spatial memory loss and augmented Αβ42 secretion. Collectively, these findings indicate that sustained neuronal hyperactivity alone replicates proteome changes seen in AD-like mutant mice. Therefore, prolonged neuronal hyperactivity may contribute to synaptic transmission disruption, memory deficits and the neurodegenerative process associated with AD.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40280127,

title = {The gut microbiota promotes pain in fibromyalgia},

author = {Weihua Cai and May Haddad and Rana Haddad and Inbar Kesten and Tseela Hoffman and Reut Laan and Susan Westfall and Manon Defaye and Nasser S Abdullah and Calvin Wong and Nicole Brown and Shannon Tansley and Kevin C Lister and Mehdi Hooshmandi and Feng Wang and Louis-Etienne Lorenzo and Volodya Hovhannisyan and David Ho-Tieng and Vibhu Kumar and Behrang Sharif and Bavanitha Thurairajah and Jonathan Fan and Tali Sahar and Charlotte Clayton and Neil Wu and Ji Zhang and Haggai Bar-Yoseph and Milena Pitashny and Emerson Krock and Jeffrey S Mogil and Masha Prager-Khoutorsky and Philippe Séguéla and Christophe Altier and Irah L King and Yves De Koninck and Nicholas J B Brereton and Emmanuel Gonzalez and Yoram Shir and Amir Minerbi and Arkady Khoutorsky},

doi = {10.1016/j.neuron.2025.03.032},

issn = {1097-4199},

year  = {2025},

date = {2025-07-01},

journal = {Neuron},

volume = {113},

number = {13},

pages = {2161--2175.e13},

abstract = {Fibromyalgia is a prevalent syndrome characterized by widespread pain in the absence of evident tissue injury or pathology, making it one of the most mysterious chronic pain conditions. The composition of the gut microbiota in individuals with fibromyalgia differs from that of healthy controls, but its functional role in the syndrome is unknown. Here, we show that fecal microbiota transplantation from fibromyalgia patients, but not from healthy controls, into germ-free mice induces pain and numerous molecular phenotypes that parallel known changes in fibromyalgia patients, including immune activation and metabolomic profile alterations. Replacing the fibromyalgia microbiota with a healthy microbiota substantially alleviated pain in mice. An open-label trial in women with fibromyalgia (Registry MOH_2021-11-04_010374) showed that transplantation of a healthy microbiota is associated with reduced pain and improved quality of life. We conclude that altered gut microbiota has a role in fibromyalgia pain, highlighting it as a promising target for therapeutic interventions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid40382320,

title = {Targeting C1q prevents microglia-mediated synaptic removal in neuropathic pain},

author = {Noosha Yousefpour and Shannon N Tansley and Samantha Locke and Behrang Sharif and Marc Parisien and Farin B Bourojeni and Haley Deamond and Vidhu Mathur and Nia Rahman-Khan Arana and Jean Sebastien Austin and Valerie Bourassa and Chengyang Wang and Valérie C Cabana and Calvin Wong and Kevin C Lister and Rose Rodrigues and Manon St-Louis and Marie-Eve Paquet and Michael C Carroll and Yaisa Andrews-Zwilling and Philippe Seguela and Artur Kania and Ted Yednock and Jeffrey S Mogil and Yves De Koninck and Luda Diatchenko and Arkady Khoutorsky and Alfredo Ribeiro-da-Silva},

doi = {10.1038/s41467-025-59849-1},

issn = {2041-1723},

year  = {2025},

date = {2025-05-01},

journal = {Nat Commun},

volume = {16},

number = {1},

pages = {4590},

abstract = {Activation of spinal microglia following peripheral nerve injury is a central component of neuropathic pain pathology. While the contributions of microglia-mediated immune and neurotrophic signalling have been well-characterized, the phagocytic and synaptic pruning roles of microglia in neuropathic pain remain less understood. Here, we show that peripheral nerve injury induces microglial engulfment of dorsal horn synapses, leading to a preferential loss of inhibitory synapses and a shift in the balance between inhibitory and excitatory synapse density. This synapse removal is dependent on the microglial complement-mediated synapse pruning pathway, as mice deficient in complement C3 and C4 do not exhibit synapse elimination. Furthermore, pharmacological inhibition of the complement protein C1q prevents dorsal horn inhibitory synapse loss and attenuates neuropathic pain. Therefore, these results demonstrate that the complement pathway promotes persistent pain hypersensitivity via microglia-mediated engulfment of dorsal horn synapses in the spinal cord, revealing C1q as a therapeutic target in neuropathic pain.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38277178,

title = {An improved conflict avoidance assay reveals modality-specific differences in pain hypersensitivity across sexes},

author = {Samuel Ferland and Feng Wang and Yves De Koninck and Francesco Ferrini},

doi = {10.1097/j.pain.0000000000003132},

issn = {1872-6623},

year  = {2024},

date = {2024-06-01},

journal = {Pain},

volume = {165},

number = {6},

pages = {1304--1316},

abstract = {Abnormal encoding of somatosensory modalities (ie, mechanical, cold, and heat) are a critical part of pathological pain states. Detailed phenotyping of patients' responses to these modalities have raised hopes that analgesic treatments could one day be tailored to a patient's phenotype. Such precise treatment would require a profound understanding of the underlying mechanisms of specific pain phenotypes at molecular, cellular, and circuitry levels. Although preclinical pain models have helped in that regard, the lack of a unified assay quantifying detailed mechanical, cold, and heat pain responses on the same scale precludes comparing how analgesic compounds act on different sensory phenotypes. The conflict avoidance assay is promising in that regard, but testing conditions require validation for its use with multiple modalities. In this study, we improve upon the conflict avoidance assay to provide a validated and detailed assessment of all 3 modalities within the same animal, in mice. We first optimized testing conditions to minimize the necessary amount of training and to reduce sex differences in performances. We then tested what range of stimuli produce dynamic stimulus-response relationships for different outcome measures in naive mice. We finally used this assay to show that nerve injury produces modality-specific sex differences in pain behavior. Our improved assay opens new avenues to study the basis of modality-specific abnormalities in pain behavior.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38112748,

title = {Assessing spontaneous sensory neuron activity using in vivo calcium imaging},

author = {Sonia Ingram and Kim I Chisholm and Feng Wang and Yves De Koninck and Franziska Denk and George L Goodwin},

doi = {10.1097/j.pain.0000000000003116},

issn = {1872-6623},

year  = {2024},

date = {2024-05-01},

journal = {Pain},

volume = {165},

number = {5},

pages = {1131--1141},

abstract = {Heightened spontaneous activity in sensory neurons is often reported in individuals living with chronic pain. It is possible to study this activity in rodents using electrophysiology, but these experiments require great skill and can be prone to bias. Here, we have examined whether in vivo calcium imaging with GCaMP6s can be used as an alternative approach. We show that spontaneously active calcium transients can be visualised in the fourth lumbar dorsal root ganglion (L4 DRG) through in vivo imaging in a mouse model of inflammatory pain. Application of lidocaine to the nerve, between the inflamed site and the DRG, silenced spontaneous firing and revealed the true baseline level of calcium for spontaneously active neurons. We used these data to train a machine learning algorithm to predict when a neuron is spontaneously active. We show that our algorithm is accurate in 2 different models of pain: intraplantar complete Freund adjuvant and antigen-induced arthritis, with accuracies of 90.0% ±1.2 and 85.9% ±2.1, respectively, assessed against visual inspection by an experienced observer. The algorithm can also detect neuronal activity in imaging experiments generated in a different laboratory using a different microscope configuration (accuracy = 94.0% ±2.2). We conclude that in vivo calcium imaging can be used to assess spontaneous activity in sensory neurons and provide a Google Colaboratory Notebook to allow anyone easy access to our novel analysis tool, for the assessment of spontaneous neuronal activity in their own imaging setups.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}