@article{pmid39164106,

title = {Chronic Social Defeat Stress Induces Pathway-Specific Adaptations at Lateral Habenula Neuronal Outputs},

author = {Jose Cesar Hernandez Silva and Nikola Pausic and Arturo Marroquin Rivera and Benoît Labonté and Christophe D Proulx},

doi = {10.1523/JNEUROSCI.2082-23.2024},

issn = {1529-2401},

year  = {2024},

date = {2024-09-01},

journal = {J Neurosci},

volume = {44},

number = {39},

abstract = {The lateral habenula (LHb) has emerged as a pivotal brain region implicated in depression, displaying hyperactivity in human and animal models of depression. While the role of LHb efferents in depressive disorders has been acknowledged, the specific synaptic alterations remain elusive. Here, employing optogenetics, retrograde tracing, and ex vivo whole-cell patch-clamp techniques, we investigated synaptic transmission in male mice subjected to chronic social defeat stress (CSDS) at three major LHb neuronal outputs: the dorsal raphe nucleus (DRN), the ventral tegmental area (VTA), and the rostromedial tegmental nucleus (RMTg). Our findings uncovered distinct synaptic adaptations in LHb efferent circuits in response to CSDS. Specifically, CSDS induced in susceptible mice postsynaptic potentiation and postsynaptic depression at the DRN and VTA neurons, respectively, receiving excitatory inputs from the LHb, while CSDS altered presynaptic transmission at the LHb terminals in RMTg in both susceptible and resilient mice. Moreover, whole-cell recordings at projection-defined LHb neurons indicate decreased spontaneous activity in VTA-projecting LHb neurons, accompanied by an imbalance in excitatory-inhibitory inputs at the RMTg-projecting LHb neurons. Collectively, these novel findings underscore the circuit-specific alterations in LHb efferents following chronic social stress, shedding light on potential synaptic adaptations underlying stress-induced depressive-like states.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid39116256,

title = {Locking away depression},

author = {Jose Cesar Hernandez Silva and Christophe D Proulx},

doi = {10.1126/science.adq9566},

issn = {1095-9203},

year  = {2024},

date = {2024-08-01},

journal = {Science},

volume = {385},

number = {6709},

pages = {608--609},

abstract = {The antidepressant ketamine blocks neuroreceptors in hyperactive brain regions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid38026162,

title = {Hypothalamic neuronal outputs transmit sensorimotor signals at the onset of locomotor initiation},

author = {Ekaterina Martianova and Renata Sadretdinova and Alicia Pageau and Nikola Pausic and Tommy Doucet Gentiletti and Danahé Leblanc and Arturo Marroquin Rivera and Benoît Labonté and Christophe D Proulx},

doi = {10.1016/j.isci.2023.108328},

issn = {2589-0042},

year  = {2023},

date = {2023-11-01},

journal = {iScience},

volume = {26},

number = {11},

pages = {108328},

abstract = {The lateral hypothalamus (LH) plays a critical role in sensory integration to organize behavior responses. However, how projection-defined LH neuronal outputs dynamically transmit sensorimotor signals to major downstream targets to organize behavior is unknown. Here, using multi-fiber photometry, we show that three major LH neuronal outputs projecting to the dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and lateral habenula (LHb) exhibit significant coherent activity in mice engaging sensory-evoked or self-initiated motor responses. Increased activity at LH axon terminals precedes movement initiation during active coping responses and the activity of serotonin neurons and dopamine neurons. The optogenetic activation of LH axon terminals in either of the DRN, VTA, or LHb was sufficient to increase motor initiation but had different effects on passive avoidance and sucrose consumption. Our findings support the complementary role of three projection-defined LH neuronal outputs in the transmission of sensorimotor signals to major downstream regions at movement onset.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35217797,

title = {A novel role for the lateral habenula in fear learning},

author = {Tomas E Sachella and Marina R Ihidoype and Christophe D Proulx and Diego E Pafundo and Jorge H Medina and Pablo Mendez and Joaquin Piriz},

doi = {10.1038/s41386-022-01294-5},

issn = {1740-634X},

year  = {2022},

date = {2022-05-01},

journal = {Neuropsychopharmacology},

volume = {47},

number = {6},

pages = {1210--1219},

abstract = {Fear is an extreme form of aversion that underlies pathological conditions such as panic or phobias. Fear conditioning (FC) is the best-understood model of fear learning. In FC the context and a cue are independently associated with a threatening unconditioned stimulus (US). The lateral habenula (LHb) is a general encoder of aversion. However, its role in fear learning remains poorly understood. Here we studied in rats the role of the LHb in FC using optogenetics and pharmacological tools. We found that inhibition or activation of the LHb during entire FC training impaired both cued and contextual FC. In contrast, optogenetic inhibition of the LHb restricted to cue and US presentation impaired cued but not contextual FC. In either case, simultaneous activation of contextual and cued components of FC, by the presentation of the cue in the training context, recovered the conditioned fear response. Our results support the notion that the LHb is required for the formation of independent contextual and cued fear memories, a previously uncharacterized function for this structure, that could be critical in fear generalization.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid35165201,

title = {NPRL2 Inhibition of mTORC1 Controls Sodium Channel Expression and Brain Amino Acid Homeostasis},

author = {Jeremy B Hui and Jose Cesar Hernandez Silva and Mari Carmen Pelaez and Myriam Sévigny and Janani Priya Venkatasubramani and Quentin Plumereau and Mohamed Chahine and Christophe D Proulx and Chantelle F Sephton and Paul A Dutchak},

doi = {10.1523/ENEURO.0317-21.2022},

issn = {2373-2822},

year  = {2022},

date = {2022-01-01},

journal = {eNeuro},

volume = {9},

number = {2},

abstract = {Genetic mutations in nitrogen permease regulator-like 2 (NPRL2) are associated with a wide spectrum of familial focal epilepsies, autism, and sudden unexpected death of epileptics (SUDEP), but the mechanisms by which NPRL2 contributes to these effects are not well known. NPRL2 is a requisite subunit of the GAP activity toward Rags 1 (GATOR1) complex, which functions as a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) kinase when intracellular amino acids are low. Here, we show that loss of NPRL2 expression in mouse excitatory glutamatergic neurons causes seizures before death, consistent with SUDEP in humans with epilepsy. Additionally, the absence of NPRL2 expression increases mTORC1-dependent signal transduction and significantly alters amino acid homeostasis in the brain. Loss of NPRL2 reduces dendritic branching and increases the strength of electrically stimulated action potentials (APs) in neurons. The increased AP strength is consistent with elevated expression of epilepsy-linked, voltage-gated sodium channels in the NPRL2-deficient brain. Targeted deletion of NPRL2 in primary neurons increases the expression of sodium channel , whereas treatment with the pharmacological mTORC1 inhibitor called rapamycin prevents  upregulation. These studies demonstrate a novel role of NPRL2 and mTORC1 signaling in the regulation of sodium channels, which can contribute to seizures and early lethality.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid33867113,

title = {Chronic Stress Induces Sex-Specific Functional and Morphological Alterations in Corticoaccumbal and Corticotegmental Pathways},

author = {Thibault P Bittar and Mari Carmen Pelaez and Jose Cesar Hernandez Silva and Francis Quessy and Andrée-Anne Lavigne and Daphnée Morency and Léa-Jeanne Blanchette and Eric Arsenault and Yoan Cherasse and Josée Seigneur and Igor Timofeev and Chantelle F Sephton and Christophe D Proulx and Benoit Labonté},

doi = {10.1016/j.biopsych.2021.02.014},

issn = {1873-2402},

year  = {2021},

date = {2021-08-01},

journal = {Biol Psychiatry},

volume = {90},

number = {3},

pages = {194--205},

abstract = {BACKGROUND: The medial prefrontal cortex (mPFC) is part of a complex circuit controlling stress responses by sending projections to different limbic structures including the nucleus accumbens (NAc) and ventral tegmental area (VTA). However, the impact of chronic stress on NAc- and VTA-projecting mPFC neurons is still unknown, and the distinct contribution of these pathways to stress responses in males and females is unclear.nnMETHODS: Behavioral stress responses were induced by 21 days of chronic variable stress in male and female C57BL/6NCrl mice. An intersectional viral approach was used to label both pathways and assess the functional, morphological, and transcriptional adaptations in NAc- and VTA-projecting mPFC neurons in stressed males and females. Using chemogenetic approaches, we modified neuronal activity of NAc-projecting mPFC neurons to decipher their contribution to stress phenotypes.nnRESULTS: Chronic variable stress induced depressive-like behaviors in males and females. NAc- and VTA-projecting mPFC neurons exhibited sex-specific functional, morphological, and transcriptional alterations. The functional changes were more severe in females in NAc-projecting mPFC neurons, while males exhibited more drastic reductions in dendritic complexity in VTA-projecting mPFC neurons after chronic variable stress. Finally, chemogenetic overactivation of the corticoaccumbal pathway triggered anxiety and behavioral despair in both sexes, while its inhibition rescued the phenotype only in females.nnCONCLUSIONS: Our results suggest that stress responses in males and females result from pathway-specific changes in the activity of transcriptional programs controlling the morphological and synaptic properties of corticoaccumbal and corticotegmental pathways in a sex-specific fashion.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31680685,

title = {Multi-Fiber Photometry to Record Neural Activity in Freely-Moving Animals},

author = {Ekaterina Martianova and Sage Aronson and Christophe D Proulx},

doi = {10.3791/60278},

issn = {1940-087X},

year  = {2019},

date = {2019-10-01},

journal = {J Vis Exp},

number = {152},

abstract = {Recording the activity of a group of neurons in a freely-moving animal is a challenging undertaking. Moreover, as the brain is dissected into smaller and smaller functional subgroups, it becomes paramount to record from projections and/or genetically-defined subpopulations of neurons. Fiber photometry is an accessible and powerful approach that can overcome these challenges. By combining optical and genetic methodologies, neural activity can be measured in deep brain structures by expressing genetically-encoded calcium indicators, which translate neural activity into an optical signal that can be easily measured. The current protocol details the components of a multi-fiber photometry system, how to access deep brain structures to deliver and collect light, a method to account for motion artifacts, and how to process and analyze fluorescent signals. The protocol details experimental considerations when performing single and dual color imaging, from either single or multiple implanted optic fibers.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29877814,

title = {A Wireless Fiber Photometry System Based on a High-Precision CMOS Biosensor With Embedded Continuous-Time Modulation},

author = {Mehdi Noormohammadi Khiarak and Ekaterina Martianova and Cyril Bories and Sylvain Martel and Christophe D Proulx and Yves De Koninck and Benoit Gosselin},

doi = {10.1109/TBCAS.2018.2817200},

issn = {1940-9990},

year  = {2018},

date = {2018-06-01},

journal = {IEEE Trans Biomed Circuits Syst},

volume = {12},

number = {3},

pages = {495--509},

abstract = {Fluorescence biophotometry measurements require wide dynamic range (DR) and high-sensitivity laboratory apparatus. Indeed, it is often very challenging to accurately resolve the small fluorescence variations in presence of noise and high-background tissue autofluorescence. There is a great need for smaller detectors combining high linearity, high sensitivity, and high-energy efficiency. This paper presents a new biophotometry sensor merging two individual building blocks, namely a low-noise sensing front-end and a order continuous-time modulator (CTSDM), into a single module for enabling high-sensitivity and high energy-efficiency photo-sensing. In particular, a differential CMOS photodetector associated with a differential capacitive transimpedance amplifier-based sensing front-end is merged with an incremental order 1-bit CTSDM to achieve a large DR, low hardware complexity, and high-energy efficiency. The sensor leverages a hardware sharing strategy to simplify the implementation and reduce power consumption. The proposed CMOS biosensor is integrated within a miniature wireless head mountable prototype for enabling biophotometry with a single implantable fiber in the brain of live mice. The proposed biophotometry sensor is implemented in a 0.18- CMOS technology, consuming from a 1.8- supply voltage, while achieving a peak dynamic range of over a 50- input bandwidth, a sensitivity of 24 mV/nW, and a minimum detectable current of 2.46- at a 20- sampling rate.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25237099,

title = {Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment},

author = {Steven J Shabel and Christophe D Proulx and Joaquin Piriz and Roberto Malinow},

doi = {10.1126/science.1250469},

issn = {1095-9203},

year  = {2014},

date = {2014-09-01},

journal = {Science},

volume = {345},

number = {6203},

pages = {1494--1498},

abstract = {The lateral habenula (LHb), a key regulator of monoaminergic brain regions, is activated by negatively valenced events. Its hyperactivity is associated with depression. Although enhanced excitatory input to the LHb has been linked to depression, little is known about inhibitory transmission. We discovered that γ-aminobutyric acid (GABA) is co-released with its functional opponent, glutamate, from long-range basal ganglia inputs (which signal negative events) to limit LHb activity in rodents. At this synapse, the balance of GABA/glutamate signaling is shifted toward reduced GABA in a model of depression and increased GABA by antidepressant treatment. GABA and glutamate co-release therefore controls LHb activity, and regulation of this form of transmission may be important for determining the effect of negative life events on mood and behavior.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid25157511,

title = {Reward processing by the lateral habenula in normal and depressive behaviors},

author = {Christophe D Proulx and Okihide Hikosaka and Roberto Malinow},

doi = {10.1038/nn.3779},

issn = {1546-1726},

year  = {2014},

date = {2014-09-01},

journal = {Nat Neurosci},

volume = {17},

number = {9},

pages = {1146--1152},

abstract = {The brain reward circuit has a central role in reinforcing behaviors that are rewarding and preventing behaviors that lead to punishment. Recent work has shown that the lateral habenula is an important part of the reward circuit by providing 'negative value' signals to the dopaminergic and serotonergic systems. Studies have also suggested that dysfunction of the lateral habenula is associated with psychiatric disorders, including major depression. Here, we discuss insights gained from neuronal recordings in monkeys regarding how the lateral habenula processes reward-related information. We then highlight recent optogenetic experiments in rodents addressing normal and abnormal functions of the habenula. Finally, we discuss how deregulation of the lateral habenula may be involved in depressive behaviors.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}