Touch neurons underlying dopaminergic pleasurable touch and sexual receptivity.

Pleasurable touch is paramount during social behavior, including sexual encounters. However, the identity and precise role of sensory neurons that transduce sexual touch remain unknown. A population of sensory neurons labeled by developmental expression of the G protein-coupled receptor Mrgprb4 detects mechanical stimulation in mice. Here, we study the social relevance of Mrgprb4-lineage neurons and reveal that these neurons are required for sexual receptivity and sufficient to induce dopamine release in the brain. Even in social isolation, optogenetic stimulation of Mrgprb4-lineage neurons through the back skin is sufficient to induce a conditioned place preference and a striking dorsiflexion resembling the lordotic copulatory posture. In the absence of Mrgprb4-lineage neurons, female mice no longer find male mounts rewarding: sexual receptivity is supplanted by aggression and a coincident decline in dopamine release in the nucleus accumbens. Together, these findings establish that Mrgprb4-lineage neurons initiate a skin-to-brain circuit encoding the rewarding quality of social touch.

Proposing a neural framework for the evolution of elaborate courtship displays.

In many vertebrates, courtship occurs through the performance of elaborate behavioral displays that are as spectacular as they are complex. The question of how sexual selection acts upon these animals' neuromuscular systems to transform a repertoire of pre-existing movements into such remarkable (if not unusual) display routines has received relatively little research attention. This is a surprising gap in knowledge, given that unraveling this extraordinary process is central to understanding the evolution of behavioral diversity and its neural control. In many vertebrates, courtship displays often push the limits of neuromuscular performance, and often in a ritualized manner. These displays can range from songs that require rapid switching between two independently controlled 'voice boxes' to precisely choreographed acrobatics. Here, we propose a framework for thinking about how the brain might not only control these displays, but also shape their evolution. Our framework focuses specifically on a major midbrain area, which we view as a likely important node in the orchestration of the complex neural control of behavior used in the courtship process. This area is the periaqueductal grey (PAG), as studies suggest that it is both necessary and sufficient for the production of many instinctive survival behaviors, including courtship vocalizations. Thus, we speculate about why the PAG, as well as its key inputs, might serve as targets of sexual selection for display behavior. In doing so, we attempt to combine core ideas about the neural control of behavior with principles of display evolution. Our intent is to spur research in this area and bring together neurobiologists and behavioral ecologists to more fully understand the role that the brain might play in behavioral innovation and diversification.

Synapsin II Directly Suppresses Epileptic Seizures In Vivo.

The synapsin family offers a strong linkage between synaptic mechanisms and the epileptic phenotype. Synapsins are phosphoproteins reversibly associated with synaptic vesicles. Synapsin deficiency can cause epilepsy in humans, and synapsin II (SynII) in knockout (KO) mice causes generalized epileptic seizures. To differentiate between the direct effect of SynII versus its secondary adaptations, we used neonatal intracerebroventricular injections of the adeno-associated virus (AAV) expressing SynII. We found that SynII reintroduction diminished the enhanced synaptic activity in Syn2 KO hippocampal slices. Next, we employed the epileptogenic agent 4-aminopyridine (4-AP) and found that SynII reintroduction completely rescued the epileptiform activity observed in Syn2 KO slices upon 4-AP application. Finally, we developed a protocol to provoke behavioral seizures in young Syn2 KO animals and found that SynII reintroduction balances the behavioral seizures. To elucidate the mechanisms through which SynII suppresses hyperexcitability, we injected the phospho-incompetent version of Syn2 that had the mutated protein kinase A (PKA) phosphorylation site. The introduction of the phospho-incompetent SynII mutant suppressed the epileptiform and seizure activity in Syn2 KO mice, but not to the extent observed upon the reintroduction of native SynII. These findings show that SynII can directly suppress seizure activity and that PKA phosphorylation contributes to this function.

Chronic paternal morphine exposure increases sensitivity to morphine-derived pain relief in male progeny.

Parental history of opioid exposure is seldom considered when prescribing opioids for pain relief. To explore whether parental opioid exposure may affect sensitivity to morphine in offspring, we developed a "rat pain scale" with high-speed imaging, machine learning, and mathematical modeling in a multigenerational model of paternal morphine self-administration. We find that the most commonly used tool to measure mechanical sensitivity in rodents, the von Frey hair, is not painful in rats during baseline conditions. We also find that male progeny of morphine-treated sires had no baseline changes in mechanical pain sensitivity but were more sensitive to the pain-relieving effects of morphine. Using RNA sequencing across pain-relevant brain regions, we identify gene expression changes within the regulator of G protein signaling family of proteins that may underlie this multigenerational phenotype. Together, this rat pain scale revealed that paternal opioid exposure increases sensitivity to morphine's pain-relieving effects in male offspring.

Serotonin Differentially Regulates L5 Pyramidal Cell Classes of the Medial Prefrontal Cortex in Rats and Mice.

The prefrontal cortex receives a dense serotonergic innervation that plays an important role in its regulation. However, how serotonin regulates different pyramidal and interneuron cell classes in this area is incompletely understood. Previous work in rats has shown that serotonin differentially regulates two classes of pyramidal cells in layer 5. It excites one class by activating 5-HT2A receptors, whereas it more subtly modulates the integrative properties of the other by co-activating 5-HT1A and 5-HT2A receptors. Here we have used electrophysiological recordings, combined with retrograde labeling and morphological reconstruction, to show that the first cell class corresponds to long range corticofugal neurons and the second corresponds to intratelencephalic neurons. These results suggest that, in rats, serotonin facilitates subcortical output while more subtly modulating cortico-cortical and cortico-striatal output. Interestingly, these results obtained in rats differ from those previously reported for mouse prefrontal cortex. Therefore we reinvestigated the effects of serotonin in mice and confirmed that serotonin predominantly activates inhibitory 5-HT1A receptors on long-range corticofugal cells. Thus serotonin exerts opposite effects on these cells in rats and mice. Finally, we determined whether cortical serotonin responsiveness in mice is regulated during development. Serotonin elicited predominantly depolarizing inward current responses during the early postnatal period, whereas inhibitory 5-HT1A receptor-mediated responses did not become evident until the end of the second postnatal week. These results reveal commonalities as well as unexpected differences in the serotonergic regulation of long-range corticofugal and intratelencephalic neurons of layer 5 in rat and mouse.