Summary Injured peripheral neurons successfully activate a pro-regenerative transcriptional program to enable axon regeneration and functional recovery. How transcriptional regulators co-ordinate the expression of such program remains unclear. Here we show that hypoxia-inducible factor 1α (HIF-1α) controls multiple injury-induced genes in sensory neurons and contribute to the preconditioning lesion effect. Knockdown of HIF-1α in vitro or conditional knock out in vivo impairs sensory axon regeneration. The HIF-1α target gene Vascular Endothelial Growth Factor A (VEGFA) is expressed in injured neurons and contributes to stimulate axon regeneration. Induction of HIF-1α using hypoxia enhances axon regeneration in vitro and in vivo in sensory neurons. Hypoxia also stimulates motor neuron regeneration and accelerates neuromuscular junction re-innervation. This study demonstrates that HIF-1α represents a critical transcriptional regulator in regenerating neurons and suggests hypoxia as a tool to stimulate axon regeneration.

Sensory neurons with cell bodies in dorsal root ganglia (DRG) represent a useful model to study axon regeneration. Whereas regeneration and functional recovery occurs after peripheral nerve injury, spinal cord injury or dorsal root injury is not followed by regenerative outcomes. Regeneration of sensory axons in peripheral nerves is not entirely cell autonomous. Whether the DRG microenvironment influences the different regenerative capacities after injury to peripheral or central axons remains largely unknown. To answer this question, we performed a single-cell transcriptional profiling of mouse DRG in response to peripheral (sciatic nerve crush) and central axon injuries (dorsal root crush and spinal cord injury). Each cell type responded differently to the three types of injuries. All injuries increased the proportion of a cell type that shares features of both immune cells and glial cells. A distinct subset of satellite glial cells (SGC) appeared specifically in response to peripheral nerve injury. Activation of the PPARα signaling pathway in SGC, which promotes axon regeneration after peripheral nerve injury, failed to occur after central axon injuries. Treatment with the FDA-approved PPARα agonist fenofibrate increased axon regeneration after dorsal root injury. This study provides a map of the distinct DRG microenvironment responses to peripheral and central injuries at the single-cell level and highlights that manipulating non-neuronal cells could lead to avenues to promote functional recovery after CNS injuries or disease.

Injured peripheral sensory neurons switch to a regenerative state after axon injury, which requires transcriptional and epigenetic changes. However, the roles and mechanisms of gene inactivation after injury are poorly understood. Here, we show that DNA methylation, which generally leads to gene silencing, is required for robust axon regeneration after peripheral nerve lesion. Ubiquitin-like containing PHD ring finger 1 (UHRF1), a critical epigenetic regulator involved in DNA methylation, increases upon axon injury and is required for robust axon regeneration. The increased level of UHRF1 results from a decrease in miR-9. The level of another target of miR-9, the transcriptional regulator RE1 silencing transcription factor (REST), transiently increases after injury and is required for axon regeneration. Mechanistically, UHRF1 interacts with DNA methyltransferases (DNMTs) and H3K9me3 at the promoter region to repress the expression of the tumor suppressor gene phosphatase and tensin homolog (PTEN) and REST. Our study reveals an epigenetic mechanism that silences tumor suppressor genes and restricts REST expression in time after injury to promote axon regeneration.

Laboratory investigations of gambling are sometimes criticized as lacking ecological validity because the stakes wagered by human subjects are not real or no real monetary losses are experienced. These problems may be partially addressed by studying gambling in laboratory animals. Toward this end, data are summarized which demonstrate that laboratory animals will work substantially harder and prefer to work under gambling-like schedules of reinforcement in which the number of responses per win is unpredictable. These findings are consistent with a delay discounting model of gambling which holds that rewards obtained following unpredictable delays are more valuable than rewards obtained following predictable delays. According to the delay discounting model, individuals that discount delayed rewards at a high rate (like pathological gamblers) perceive unpredictably delayed rewards to be of substantially greater value than predictable rewards. The reviewed findings and empirical model support the utility of studying animal behavior as an ecologically valid first-approximation of human gambling.

Introduction: Opioids are powerful analgesics, but are also common drugs of abuse. Few studies have examined how neuropathic pain alters the pharmacology of opioids in modulating limbic pathways that underlie abuse liability. Methods: Rats with or without spinal nerve ligation (SNL) were implanted with electrodes into the left ventral tegmental area and trained to lever press for electrical stimulation. The effects of morphine, heroin, and cocaine on facilitating electrical stimulation of the ventral tegmental area and mechanical allodynia were assessed in SNL and control subjects. Results: Responding for electrical stimulation of the ventral tegmental area was similar in control and SNL rats. The frequency at which rats emitted 50% of maximal responding was 98.2 Ϯ 5.1 (mean Ϯ SEM) and 93.7 Ϯ 2.8 Hz in control and SNL rats, respectively. Morphine reduced the frequency at which rats emitted 50% of maximal responding in control (maximal shift of 14.8 Ϯ 3.1 Hz), but not SNL (2.3 Ϯ 2.2 Hz) rats. Heroin was less potent in SNL rats, whereas cocaine produced similar shifts in control (42.3 Ϯ 2.0 Hz) and SNL (37.5 Ϯ 4.2 Hz) rats. Conclusions: Nerve injury suppressed potentiation of electrical stimulation of the ventral tegmental area by opioids,