Dissecting the autism-associated 16p11.2 locus identifies multiple drivers in neuroanatomical phenotypes and unveils a male-specific role for the major vault protein.

Background: Using mouse genetic studies and systematic assessments of brain neuroanatomical phenotypes, we set out to identify which of the 30 genes causes brain defects at the autism-associated 16p11.2 locus.

Results: We show that multiple genes mapping to this region interact to regulate brain anatomy, with female mice exhibiting far fewer brain neuroanatomical phenotypes.

Neuropathic pain: From actual pharmacological treatments to new therapeutic horizons.

Neuropathic pain, caused by a lesion or disease affecting the somatosensory system, affects between 3 and 17% of the general population. The treatment of neuropathic pain is challenging due to its heterogeneous etiologies, lack of objective diagnostic tools and resistance to classical analgesic drugs. First-line treatments recommended by the Special Interest Group on Neuropathic Pain (NeuPSIG) and European Federation of Neurological Societies (EFNS) include gabapentinoids, tricyclic antidepressants (TCAs) and selective serotonin noradrenaline reuptake inhibitors (SNRIs).

Janus effect of the anterior cingulate cortex: Pain and emotion.

Over the past 20 years, clinical and preclinical studies point to the anterior cingulate cortex (ACC) as a site of interest for several neurological and psychiatric conditions. The ACC plays a critical role in emotion, autonomic regulation, pain processing, attention, memory and decision making. An increasing number of studies have demonstrated the involvement of the ACC in the emotional component of pain and its comorbidity with emotional disorders such as anxiety and depression.

Antiallodynic action of phosphodiesterase inhibitors in a mouse model of peripheral nerve injury.

Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory nervous system. It is accompanied by neuronal and non-neuronal alterations, including alterations in intracellular second messenger pathways. Cellular levels of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) are regulated by phosphodiesterase (PDE) enzymes.

Time Course of Homeostatic Structural Plasticity in Response to Optogenetic Stimulation in Mouse Anterior Cingulate Cortex.

Plasticity is the mechanistic basis of development, aging, learning, and memory, both in healthy and pathological brains. Structural plasticity is rarely accounted for in computational network models due to a lack of insight into the underlying neuronal mechanisms and processes. Little is known about how the rewiring of networks is dynamically regulated.

Platelet-rich plasma and cytokines in neuropathic pain: A narrative review and a clinical perspective.

Background And Objective: Neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system. A number of preclinical studies have provided evidence for the involvement of cytokines, predominantly secreted by a variety of immune cells and by glial cells from the nervous system, in neuropathic pain conditions. Clinical trials and the use of anti-cytokine drugs in different neuropathic aetiologies support the relevance of cytokines as treatment targets.

Enhanced analgesic cholinergic tone in the spinal cord in a mouse model of neuropathic pain.

Endogenous acetylcholine (ACh) is an important modulator of nociceptive sensory processing in the spinal cord. An increased level of spinal ACh induces analgesia both in humans and rodents while interfering with cholinergic signaling is allodynic, demonstrating that a basal tone of spinal ACh modulates nociceptive responses in naïve animals. The plasticity undergone by this cholinergic system in chronic pain situation is unknown, and the mere presence of this tone in neuropathic animals is controversial.

Action of mefloquine/amitriptyline THN101 combination on neuropathic mechanical hypersensitivity in mice.

Tricyclic antidepressants that inhibit serotonin and noradrenaline reuptake, such as amitriptyline, are among the first-line treatments for neuropathic pain, which is caused by a lesion or disease affecting the somatosensory nervous system. These treatments are, however, partially efficient to alleviate neuropathic pain symptoms, and better treatments are still highly required. Interactions between neurons and glial cells participate in neuropathic pain processes, and importantly, connexins-transmembrane proteins involved in cell-cell communication-contribute to these interactions.

Mapping the living mouse brain neural architecture: strain-specific patterns of brain structural and functional connectivity.

Mapping brain structural and functional connectivity (FC) became an essential approach in neuroscience as network properties can underlie behavioral phenotypes. In mouse models, revealing strain-related patterns of brain wiring is crucial, since these animals are used to answer questions related to neurological or neuropsychiatric disorders. C57BL/6 and BALB/cJ strains are two of the primary "genetic backgrounds" for modeling brain disease and testing therapeutic approaches.

Non-CG methylation and multiple histone profiles associate child abuse with immune and small GTPase dysregulation.

Early-life adversity (ELA) is a major predictor of psychopathology, and is thought to increase lifetime risk by epigenetically regulating the genome. Here, focusing on the lateral amygdala, a major brain site for emotional homeostasis, we describe molecular cross-talk among multiple mechanisms of genomic regulation, including 6 histone marks and DNA methylation, and the transcriptome, in subjects with a history of ELA and controls. In the healthy brain tissue, we first uncover interactions between different histone marks and non-CG methylation in the CAC context.

Long-lasting analgesic and neuroprotective action of the non-benzodiazepine anxiolytic etifoxine in a mouse model of neuropathic pain.

Neuropathic pain is frequently associated with anxiety and major depressive disorders, which considerably impact the overall patient experience. Favoring GABAergic inhibition through the pain matrix has emerged as a promising strategy to restore proper processing of nociceptive and affective information in neuropathic pain states. In this context, the non-benzodiazepine anxiolytic etifoxine (EFX), known to amplify GABAergic inhibition through positive modulation of GABA receptors and neurosteroidogenesis, presents several advantages.

Delta opioid receptors are essential to the antiallodynic action of Β-mimetics in a model of neuropathic pain.

The adrenergic system, because of its reported implication in pain mechanisms, may be a potential target for chronic pain treatment. We previously demonstrated that β-adrenoceptors (β-ARs) are essential for neuropathic pain treatment by antidepressant drugs, and we showed that agonists of β-ARs, that is, β-mimetics, had an antiallodynic effect per se following chronic administration. To further explore the downstream mechanism of this action, we studied here the role of the opioid system.

Peripheral Delta Opioid Receptors Mediate Formoterol Anti-allodynic Effect in a Mouse Model of Neuropathic Pain.

Neuropathic pain is a challenging condition for which current therapies often remain unsatisfactory. Chronic administration of β2 adrenergic agonists, including formoterol currently used to treat asthma and chronic obstructive pulmonary disease, alleviates mechanical allodynia in the sciatic nerve cuff model of neuropathic pain. The limited clinical data currently available also suggest that formoterol would be a suitable candidate for drug repurposing.

Ketamine induces rapid and sustained antidepressant-like effects in chronic pain induced depression: Role of MAPK signaling pathway.

Chronic pain produces psychologic distress, which often leads to mood disorders such as depression. Co-existing chronic pain and depression pose a serious socio-economic burden and result in disability affecting millions of individuals, which urges the development of treatment strategies targeting this comorbidity. Ketamine, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, is shown to be efficient in treating both pain and depression-related symptoms.

The molecular neurobiology of chronic pain-induced depression.

The increasing number of individuals with comorbidities poses an urgent need to improve the management of patients with multiple co-existing diseases. Among these comorbidities, chronic pain and mood disorders, two long-lasting disabling conditions that significantly reduce the quality of life, could be cited first. The recent development of animal models accelerated the studies focusing on the underlying mechanisms of the chronic pain and depression/anxiety comorbidity.

Cortical Excitability and Activation of TrkB Signaling During Rebound Slow Oscillations Are Critical for Rapid Antidepressant Responses.

Rapid antidepressant effects of ketamine become most evident when its psychotomimetic effects subside, but the neurobiological basis of this "lag" remains unclear. Laughing gas (NO), another NMDA-R (N-methyl-D-aspartate receptor) blocker, has been reported to bring antidepressant effects rapidly upon drug discontinuation. We took advantage of the exceptional pharmacokinetic properties of NO to investigate EEG (electroencephalogram) alterations and molecular determinants of antidepressant actions during and immediately after NMDA-R blockade.

A Dual Noradrenergic Mechanism for the Relief of Neuropathic Allodynia by the Antidepressant Drugs Duloxetine and Amitriptyline.

In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. Despite the widespread use of these drugs, the mechanism underlying their therapeutic action in this pain context remains partly elusive. The present study combined data collected in male and female mice from a model of neuropathic pain and data from the clinical setting to understand how antidepressant drugs act.

Peripheral delta opioid receptors mediate duloxetine antiallodynic effect in a mouse model of neuropathic pain.

Peripheral delta opioid (DOP) receptors are essential for the antiallodynic effect of the tricyclic antidepressant nortriptyline. However, the population of DOP-expressing cells affected in neuropathic conditions or underlying the antiallodynic activity of antidepressants remains unknown. Using a mouse line in which DOP receptors were selectively ablated in cells expressing Nav1.

Hyperactivity of Anterior Cingulate Cortex Areas 24a/24b Drives Chronic Pain-Induced Anxiodepressive-like Consequences.

Pain associates both sensory and emotional aversive components, and often leads to anxiety and depression when it becomes chronic. Here, we characterized, in a mouse model, the long-term development of these sensory and aversive components as well as anxiodepressive-like consequences of neuropathic pain and determined their electrophysiological impact on the anterior cingulate cortex (ACC, cortical areas 24a/24b). We show that these symptoms of neuropathic pain evolve and recover in different time courses following nerve injury in male mice.