Opioid reward has traditionally been thought to be mediated by GABA-induced disinhibition of dopamine (DA) neurons in the VTA. However, direct behavioral evidence supporting this hypothesis is still lacking. In this study, we found that the μ opioid receptor (MOR) gene, Oprm1 , is highly expressed in GABA neurons, with ∼50% of GABA neurons in the substantia nigra pars reticulata (SNr), ∼30% in the VTA, and ∼70% in the tail of the VTA (also called the rostromedial tegmental nucleus) in male rats. No Oprm1 mRNA was detected in midbrain DA neurons. We then found that optogenetic inhibition of VTA DA neurons reduced intravenous heroin self-administration, whereas activation of these neurons produced robust optical intracranial self-stimulation in DAT-Cre mice, supporting an important role of DA neurons in opioid reward. Unexpectedly, pharmacological blockade of MORs in the SNr was more effective than in the VTA in reducing heroin reward. Optogenetic activation of VTA GABA neurons caused place aversion and inhi...

The neurokinin-1 receptor (NK1R; encoded by Tacr1 ) is expressed in spinal dorsal horn neurons and has been suggested to mediate itch in rodents. However, previous studies relied heavily on neurotoxic ablation of NK1R spinal neurons, which limited further dissection of their function in spinal itch circuitry. To address this limitation, we leveraged a newly developed Tacr1CreER mouse line to characterize the role of NK1R spinal neurons in itch. We show that pharmacological activation of spinal NK1R and chemogenetic activation of Tacr1CreER spinal neurons increases itch behavior in male and female mice, whereas pharmacological inhibition of spinal NK1R suppresses itch behavior. We use fluorescence in situ hybridization (FISH) to characterize the endogenous expression of Tacr1 throughout the superficial and deeper dorsal horn (DDH), as well as the lateral spinal nucleus (LSN), of mouse and human spinal cord. Retrograde labeling studies in mice from the parabrachial nucleus (PBN) show that less than 20% of su...

Many mammals have evolved to be social creatures. In humans, the ability to learn from others' experiences is essential to survival; and from an early age, individuals are surrounded by a social environment that helps them develop a variety of skills, such as walking, talking, and avoiding danger. Similarly, in rodents, behaviors, such as food preference, exploration of novel contexts, and social approach, can be learned through social interaction. Social encounters facilitate new learning and help modify preexisting memories throughout the lifespan of an organism. Moreover, social encounters can help buffer stress or the effects of negative memories, as well as extinguish maladaptive behaviors. Given the importance of such interactions, there has been increasing work studying social learning and applying its concepts in a wide range of fields, including psychotherapy and medical sociology. The process of social learning, including its neural and behavioral mechanisms, has also been a rapidly growing field...

Studies in visual, auditory and somatosensory cortices have revealed that different cell types as well as neurons located in different laminae display distinct stimulus response profiles. The extent to which these layer and cell type specific distinctions generalize to gustatory cortex (GC) remains unknown. In this study, we performed extracellular recordings in adult female mice to monitor the activity of putative pyramidal and inhibitory neurons located in deep and superficial layers of GC. Awake, head-restrained mice were trained to lick different tastants (Sucrose, Salt, Citric Acid, Quinine, and Water) from a lick-spout. We found that deep layer neurons show higher baseline firing rates (FR) in GC with deep-layer inhibitory neurons displaying highest firing rates at baseline and following the stimulus. GC’s activity shows robust modulations prior to animals’ contact with tastants and this phenomenon is most prevalent in deep-layer inhibitory neurons. Furthermore, we show that licking activity strongly...

Dopamine is a wake-promoting neuromodulator in mammals and fruit flies. In Drosophila melanogaster , the network of clock neurons that drives sleep/activity cycles comprises both wake- and sleep-promoting cell types. The large and small ventrolateral neurons (l-LNvs and s-LNvs) have been identified as wake-promoting neurons within the clock neuron network. The l-LNvs are innervated by dopaminergic neurons, and earlier work proposed that dopamine signaling raises cAMP levels in the l-LNvs and thus induces excitatory electrical activity (action potential firing), which results in wakefulness and inhibits sleep. Here, we test this hypothesis by combining cAMP imaging and patch-clamp recordings in isolated brains. We find that dopamine application indeed increases cAMP levels and depolarizes the l-LNvs, but surprisingly, it does not result in increased firing rates. Down-regulation of the excitatory dopamine receptor, Dop1R1 in the l- and s-LNvs, but not of Dop1R2, abolished the depolarization of l-LNvs in res...

Itch can be induced by activation of small-diameter dorsal root ganglion (DRG) neurons which express abundant intracellular fibroblast growth factor 13 (FGF13). Although FGF13 is revealed to be essential for heat nociception, its role in mediating itch remains to be investigated. Here, we reported that loss of FGF13 in mouse DRG neurons impaired the histamine-induced scratching behavior. Calcium imaging showed that the percentage of histamine-responsive DRG neurons was largely decreased in FGF13-deficient mice, and consistently, electrophysiological recording exhibited that histamine failed to evoke action potential firing in most DRG neurons from these mice. Given that the reduced histamine-evoked neuronal response was caused by knockdown of FGF13 but not by FGF13A deficiency, FGF13B was supposed to mediate this process. Furthermore, overexpression of histamine type 1 receptor H1R, but not H2R, H3R nor H4R, increased the percentage of histamine-responsive DRG neurons, and the scratching behavior in FGF13-...

The ability to predict the timing of forthcoming events, known as temporal expectation, has a strong impact on human information processing. Although there is growing consensus that temporal expectations enhance the speed and accuracy of perceptual decisions, it remains unclear whether they affect the decision process itself, or non-decisional (sensory/motor) processes. Here, healthy human participants (N = 21; 18 female) used predictive auditory cues to anticipate the timing of low-contrast visual stimuli they were required to detect. Modelling of the behavioral data using a prominent sequential sampling model indicated that temporal expectations speeded up non-decisional processes but had no effect on decision formation. Electrophysiological recordings confirmed and extended this result: temporal expectations hastened the onset of a neural signature of decision formation, but had no effect on its build-up rate. Anticipatory alpha-band power was modulated by temporal expectation, and co-varied with intrin...

Oral squamous cell carcinoma (OSCC) is one of the most painful cancers, which interferes with orofacial function including talking and eating. We report that legumain (Lgmn) cleaves protease-activated receptor-2 (PAR2) in the acidic OSCC microenvironment to cause pain. Lgmn is a cysteine protease of late endosomes and lysosomes that can be secreted; it exhibits maximal activity in acidic environments. The role of Lgmn in PAR2-dependent cancer pain is unknown. We studied Lgmn activation in human oral cancers and oral cancer mouse models. Lgmn was activated in OSCC patient tumors, compared to matched normal oral tissue. After intraplantar, facial or lingual injection, Lgmn evoked nociception in wild-type (WT) female mice but not in female mice lacking PAR2 in NaV1.8-positive neurons ( Par2Nav1.8 ), nor in female mice treated with a Lgmn inhibitor, LI-1. Inoculation of an OSCC cell line caused mechanical and thermal hyperalgesia that was reversed by LI-1. Par2Nav1.8 and Lgmn deletion attenuated mechanical all...

Autism-associated genetic mutations may perturb the balance between stability and plasticity of synaptic connections in the brain. Here we report an increase in the formation and stabilization of dendritic spines in the cerebral cortex of the mouse model of MECP2 -duplication syndrome, a high-penetrance form of syndromic autism. Increased stabilization is mediated entirely by spines that form cooperatively in 10-micron clusters and is observable across multiple cortical areas both spontaneously and following motor training. Excessive stability of dendritic spine clusters could contribute to behavioral rigidity and other phenotypes in syndromic autism. Significance Statement The inflexible repetitive behaviors, "insistence on sameness," and at times exceptional learning abilities seen in autism imply a defect in the neural processes underlying learning and memory, potentially affecting the balance between stability and plasticity of synaptic connections in the brain. Here we report a pathological bias towa...