Neuropathic pain resulting from nerve injury can become persistent and difficult to treat but the molecular signaling responsible for its development remains poorly described. Here, we identify the neuronal stress sensor dual leucine zipper kinase (DLK; Map3k12) as a key molecule controlling the maladaptive pathways that lead to pain following injury. Genetic or pharmacological inhibition of DLK reduces mechanical hypersensitivity in a mouse model of neuropathic pain. Furthermore, DLK inhibition also prevents the spinal cord microgliosis that results from nerve injury and arises distant from the injury site. These striking phenotypes result from the control by DLK of a transcriptional program in somatosensory neurons regulating the expression of numerous genes implicated in pain pathogenesis, including the immune gene Csf1. Thus, activation of DLK is an early event, or even the master regulator, controlling a wide variety of pathways downstream of nerve injury that ultimately lead to chronic pain.

In vertebrates, motor control relies on cholinergic neurons in the spinal cord that have been extensively studied over the past hundred years, yet the full heterogeneity of these neurons and their different functional roles in the adult remain to be defined. Here, we develop a targeted single nuclear RNA sequencing approach and use it to identify an array of cholinergic interneurons, visceral and skeletal motor neurons. Our data expose markers for distinguishing these classes of cholinergic neurons and their rich diversity. Specifically, visceral motor neurons, which provide autonomic control, can be divided into more than a dozen transcriptomic classes with anatomically restricted localization along the spinal cord. The complexity of the skeletal motor neurons is also reflected in our analysis with alpha, gamma, and a third subtype, possibly corresponding to the elusive beta motor neurons, clearly distinguished. In combination, our data provide a comprehensive transcriptomic description of this important population of neurons that control many aspects of physiology and movement and encompass the cellular substrates for debilitating degenerative disorders.

No abstract

In vertebrates, motor control relies on cholinergic neurons in the spinal cord that have been extensively studied over the past hundred years, yet the full heterogeneity of these neurons and their different functional roles in the adult remain to be defined. Here, we developed a targeted single nuclear RNA sequencing approach and used it to identify an array of cholinergic interneurons, visceral and skeletal motor neurons. Our data expose markers for distinguishing these classes of cholinergic neurons and their extremely rich diversity. Specifically, visceral motor neurons, which provide autonomic control, could be divided into more than a dozen transcriptomic classes with anatomically restricted localization along the spinal cord. The complexity of the skeletal motor neurons was also reflected in our analysis with alpha, beta, and gamma subtypes clearly distinguished. In combination, our data provide a comprehensive transcriptomic description of this important population of neurons that control many aspects of physiology and movement and encompass the cellular substrates for debilitating degenerative disorders.

A pause in firing of nucleus accumbens shell (NAcSh) neurons is critical for reward consumption; however, the substrate driving this pause is unknown. While ventral pallidal (VP) activity encodes reward value, the specific roles of VP subpopulations in computation and expression of this value are poorly understood. Here, we establish that inhibitory input from the VP is crucial for reward-related inhibition of NAc firing. A sparse, non-canonical subpopulation of VP neurons, the so-called "ventral arkypallidal (vArky)" neurons makes inhibitory synaptic contacts throughout the NAcSh, and drives inhibition of NAcSh neurons in vivo. Moreover, endogenous calcium activity of vArky neurons predicted subsequent reward consumption behavior, while optogenetically activating this pathway increased reward consumption by amplifying hedonic value of reward. Classically, the VP is considered downstream of the NAc; however, our results challenge this view and establish that vArky neurons in the VP promote reward consumption via potent modulation of NAcSh firing.

In perilous and stressful situations, the ability to suppress pain can be critical for survival. The rostral ventromedial medulla (RVM) contains neurons that robustly inhibit nociception at the level of the spinal cord through a top-down modulatory pathway. Although much is known about the role of the RVM in the inhibition of pain, the precise ability to directly manipulate pain-inhibitory neurons in the RVM has never been achieved. We now expose a cellular circuit that inhibits nociception and itch in mice. Through a combination of molecular, tracing, and behavioral approaches, we found that RVM neurons containing the kappa-opioid receptor (KOR) inhibit itch and nociception. With chemogenetic inhibition, we uncovered that these neurons are required for stress-induced analgesia. Using intersectional chemogenetic and pharmacological approaches, we determined that RVMKOR neurons inhibit nociception and itch through a descending circuit. Lastly, we identified a dynorphinergic pathway arising from the periaqueductal gray (PAG) that modulates nociception within the RVM. These discoveries highlight a distinct population of RVM neurons capable of broadly and robustly inhibiting itch and nociception.

No abstract

ABSTRACT:The effects of route and vehicle on blood and milk levels of decabromodiphenyl ether (DecaBDE; CASRN 1163-19-5) were investigated in the rat to assist in the design and conduct of a developmental neurotoxicity study. Blood plasma and/or milk concentrations were determined in dams, fetuses, and/or nursing pups after repeated DecaBDE administration by gavage throughout gestation or gestation and lactation using corn oil (CO) or soyaphospholipon/Lutrol F 127-water (SPL) as the vehicle. The impact of vehicle on plasma levels was also investigated in pups derived from naive dams after a single postnatal dose. This study reports for the first time fetal and neonatal plasma concentrations concurrent with those of maternal plasma and/or milk. Higher concentrations of DecaBDE were achieved in plasma and in milk with CO than with SPL. Furthermore, pups derived from dams treated with only SPL were lower in body weight, compared with those from dams treated with either CO, CO and DecaBDE, or SPL and DecaBDE. The study further shows that exposure to DecaBDE is relatively consistent across the dose range of 100 to 1000 mg/(kg ⅐ day) when administered in CO.