Table of contents



Focus on pain

Pain can be defined simply as the subjective experience of harm in a part of one's body. However, there are multiple forms of pain, including nociceptive and inflammatory pain, that involve a complex set of biological processes. Although the pain system has an important physiological role in preserving the integrity of the body, it can sometimes become dysfunctional and generate prolonged pain states in the absence of noxious stimuli or injuries. Unfortunately, many pathological pain conditions remain poorly understood and resist currently available treatments. Developing new therapeutic approaches to managing pain will undoubtedly depend on a better understanding of the molecular, cellular and circuit mechanisms underlying acute and chronic pain states. In this special Nature Neuroscience issue on pain, we present a series of reviews by experts in the field that critically appraise recent research on the neurobiology of pain and itch.



Focus on Pain

Focus on pain p145


Nature Neuroscience presents a series of reviews highlighting recent progress in our understanding of the neurobiology of normal and pathological pain and itch.


News and Views

Ground zero in Alzheimer's disease pp146 - 147

Michael A Yassa


New findings in preclinical Alzheimer's disease patients and mouse models of the disease suggest that it is the lateral, rather than the medial, entorhinal cortex that is most susceptible to tau pathology early in Alzheimer's disease. Aberrations begin here and spread to other cortical sites.

See also: Article by Khan et al.

Stereotopy versus stochasticity in olfaction pp147 - 149

Rainer W Friedrich, Anastasios Moressis & Thomas Frank


Although projections from the insect antennal lobe to the mushroom body are probabilistic, those to the lateral horn are stereotyped, suggesting an interplay of preconfigured and plastic circuits in olfactory processing.

See also: Article by Fişek & Wilson

Motor variability is not noise, but grist for the learning mill pp149 - 150

David J Herzfeld & Reza Shadmehr


A study demonstrates that variability in how people perform a movement can predict the rate of motor learning on an individual basis. This suggests that motor 'noise' is a central component of motor learning.

See also: Article by Wu et al.

Stimulating memory consolidation pp151 - 152

Serra E Favila & Brice A Kuhl


A study in this issue of Nature Neuroscience reports that administering caffeine to humans immediately after memory encoding enhances consolidation, as reflected by improved performance in a memory test a day later.

See also: Brief Communication by Borota et al.

Deciphering CA2 connectivity p152

Hannah Bayer


See also: Article by Kohara et al.



Focus on Pain

Regulating excitability of peripheral afferents: emerging ion channel targets pp153 - 163

Stephen G Waxman & Gerald W Zamponi


Voltage-gated ion channels are key regulators of noxious signal transmission at the level of the periphery. In this Review, Zamponi and Waxman discuss recent advances in our understanding of the role of some of these channels in pain processing in primary afferent neurons, their dysfunction in congenital and acquired disease states and emerging possibilities for new analgesics.

Focus on Pain

Peripheral gating of pain signals by endogenous lipid mediators pp164 - 174

Daniele Piomelli & Oscar Sasso


In this Review, Piomelli and Sasso survey the functions of endogenous lipid mediators in the peripheral gating of nociceptive signals. They focus on the mechanisms and pathways associated with analgesic lipids, such as endocannabinoids, lipid amides, lipoxins and resolvins, and discuss their role in the interaction between nociceptive and immune systems in the context of pain.

Focus on Pain

Why we scratch an itch: the molecules, cells and circuits of itch pp175 - 182

Diana M Bautista, Sarah R Wilson & Mark A Hoon


Pain and itch are very distinct sensations that rely on both overlapping and orthogonal mechanisms in primary sensory afferents and in the spinal cord. In this article, Bautista, Wilson and Hoon review recent advances in our understanding of the molecular, cellular and circuit basis of acute and chronic itch in the peripheral and central nervous systems.

Focus on Pain

Normal and abnormal coding of somatosensory stimuli causing pain pp183 - 191

Steven A Prescott, Qiufu Ma & Yves De Koninck


There is growing evidence for the existence of cross-talk between somatosensory labeled lines during the processing of noxious information, lending support to the notion that the nociceptive system operates under combinatorial encoding rules. In this Review, Prescott, Ma and De Koninck present an update on a controversy that is probably as old as the field of somatosensation itself and propose that the next step forward in our understanding of pain will necessarily involve the meticulous dissection of spinal dorsal horn microcircuitry.

Focus on Pain

Pain vulnerability: a neurobiological perspective pp192 - 200

Franziska Denk, Stephen B McMahon & Irene Tracey


What makes certain individuals more susceptible to developing chronic pain? In this article, Denk, McMahon and Tracey review our current knowledge of the genetic, epigenetic and other environmental factors that contribute to pain vulnerability or resilience and delineate the brain networks that are involved in chronic pain states.


Brief Communications

Post-study caffeine administration enhances memory consolidation in humans pp201 - 203

Daniel Borota, Elizabeth Murray, Gizem Keceli, Allen Chang, Joseph M Watabe, Maria Ly, John P Toscano & Michael A Yassa


In this study, the authors examine the effects of caffeine on long-term memory. They find that a specific caffeine dose administered shortly after participants studied images improves image-recognition performance a day later. This suggests that caffeine may enhance memory consolidation separately from other cognition-enhancing effects.

See also: News and Views by Favila & Kuhl

An electroconvulsive therapy procedure impairs reconsolidation of episodic memories in humans pp204 - 206

Marijn C W Kroes, Indira Tendolkar, Guido A van Wingen, Jeroen A van Waarde, Bryan A Strange & Guillén Fernández


The reconsolidation hypothesis states that reactivated memory traces are vulnerable to disruption from treatments that also impair initial memory consolidation. In this study, the authors demonstrate that electroconvulsive therapy—an invasive procedure—disrupts reactivated episodic memories when tested 1 d later, but not when tested shortly after treatment.



Adult neural stem cells in distinct microdomains generate previously unknown interneuron types pp207 - 214

Florian T Merkle, Luis C Fuentealba, Timothy A Sanders, Lorenza Magno, Nicoletta Kessaris & Arturo Alvarez-Buylla


The authors report the generation of four previously unknown olfactory bulb interneuron subtypes by adult neural stem cells, organized into surprisingly small progenitor microdomains. These microdomains appear to be defined by unique combinations of transcription factors not previously known to be involved in adult neurogenesis, including Nkx6.2 and Zic.

Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain pp215 - 222

Junjie U Guo, Yijing Su, Joo Heon Shin, Jaehoon Shin, Hongda Li, Bin Xie, Chun Zhong, Shaohui Hu, Thuc Le, Guoping Fan, Heng Zhu, Qiang Chang, Yuan Gao, Guo-li Ming & Hongjun Song


This study maps the DNA methylome profile of adult mouse dentate gyrus neurons at the single-base resolution and finds prevalent methylation of both CpG dinucleotides and non-CpG cytosines (CpH). The study also shows that CpH methylation can repress transcription. Furthermore, CpH methylation is recognized by the Rett syndrome–associated protein MeCP2, which is established during neuronal maturation and maintained by DNA methyltransferase DNMT3A.

Epigenetic suppression of neuroligin 1 underlies amyloid-induced memory deficiency pp223 - 231

Bihua Bie, Jiang Wu, Hui Yang, Jijun J Xu, David L Brown & Mohamed Naguib


This study shows that the memory deficit caused by amyloid fibrils in rodents is mediated, in part, by neuroinflammation leading to histone modification via alteration of the interaction between HDAC2 and methyl-CpG-binding protein 2 (MeCP2) and resulting epigenetic modification of the neuroligin 1 promoter, causing a reduction in neuroligin 1 expression in neurons.

Presynaptic glycine receptors as a potential therapeutic target for hyperekplexia disease pp232 - 239

Wei Xiong, Shao-Rui Chen, Liming He, Kejun Cheng, Yi-Lin Zhao, Hong Chen, De-Pei Li, Gregg E Homanics, John Peever, Kenner C Rice, Ling-gang Wu, Hui-Lin Pan & Li Zhang


The authors show that a nonpsychoactive cannabinoid, DH-CBD, can rescue exaggerated acoustic startle phenotypes caused by startle disease–causing point mutations in the glycine receptor (GlyR) α1 subunit. Homomeric and presynaptic GlyRs showed significant impairment as a result of these mutations, which was selectively rescued by DH-CBD.

Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality pp240 - 247

Tzyy-Nan Huang, Hsiu-Chun Chuang, Wen-Hsi Chou, Chiung-Ya Chen, Hsiao-Fang Wang, Shen-Ju Chou & Yi-Ping Hsueh


The authors show that mice lacking one copy of gene encoding the transcription factor T-box brain 1 (TBR1) show deficient axonal projections from amygdala neurons, as well as social and cognitive behavioral deficits. Tbr1 haploinsufficiency alters expression of multiple Tbr1 target genes, and restoring their expression restores axon outgrowth defects in vivo.

Medial prefrontal D1 dopamine neurons control food intake pp248 - 253

Benjamin B Land, Nandakumar S Narayanan, Rong-Jian Liu, Carol A Gianessi, Catherine E Brayton, David M Grimaldi, Maysa Sarhan, Douglas J Guarnieri, Karl Deisseroth, George K Aghajanian & Ralph J DiLeone


The authors show that dopamine receptor 1 (D1)-expressing neurons in the medial prefrontal cortex (mPFC) of mice show increased activity in response to food intake. Using optogenetic stimulation and inhibition, they show that mPFC D1 neuron projections to the medial basolateral amygdala can increase or decrease food intake, respectively.

Targeted expression of μ-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward pp254 - 261

Yijun Cui, Sean B Ostlund, Alex S James, Chang Sin Park, Weihong Ge, Kristofer W Roberts, Nitish Mittal, Niall P Murphy, Carlos Cepeda, Brigitte L Kieffer, Michael S Levine, James David Jentsch, Wendy M Walwyn, Yi E Sun, Christopher J Evans, Nigel T Maidment & X William Yang


μ-opioid receptor (MOR) was previously shown to be necessary for opiate reward, analgesia and dependence. To better understand the specific anatomical and cell type loci of MOR action in opiate reward and reinforcement learning, the authors use cell-specific rescue expression of MOR in subtypes of neurons in the mouse brain that lack MOR globally and show that MOR in the striatal direct-pathway medium spiny neurons is sufficient to rescue the reward action of opioids without affecting opioid analgesia or withdrawal in MOR knockout mice.

Imaging an optogenetic pH sensor reveals that protons mediate lateral inhibition in the retina pp262 - 268

Tzu-Ming Wang, Lars C Holzhausen & Richard H Kramer


The mechanism behind lateral inhibition that establishes the receptive fields of retinal neurons has remained elusive. Here the authors show that synaptic proton concentration mediates horizontal cell negative feedback in the retina and that this transmission depends on activity of a proton pump and proton-permeant ion channel.

Cell type–specific genetic and optogenetic tools reveal hippocampal CA2 circuits pp269 - 279

Keigo Kohara, Michele Pignatelli, Alexander J Rivest, Hae-Yoon Jung, Takashi Kitamura, Junghyup Suh, Dominic Frank, Koichiro Kajikawa, Nathan Mise, Yuichi Obata, Ian R Wickersham & Susumu Tonegawa


The authors use cell type–specific transgenic mouse lines, optogenetics and patch-clamp recordings to provide new insights into hippocampal anatomy and function. They find that dentate granule cells of the hippocampus, which were believed to not project to CA2, do indeed send functional monosynaptic inputs to CA2 pyramidal cells. CA2 innervates CA1, but, unlike CA3, projects preferentially to the deep rather than superficial sublayer of CA1. Moreover, the authors find that layer 3 of the entorhinal cortex does not project to CA2.

See also: News and Views by Bayer

Stereotyped connectivity and computations in higher-order olfactory neurons pp280 - 288

Mehmet Fişek & Rachel I Wilson


The authors describe how glomerular signals are combined to generate odor representations in the Drosophila lateral horn region. They observe stereotypy and over-representation of certain glomerular combinations, a wiring pattern that contrasts with reports from the mushroom body but is consistent with roles of these regions in innate versus learned behaviors.

See also: News and Views by Friedrich et al.

Ultra-rapid axon-axon ephaptic inhibition of cerebellar Purkinje cells by the pinceau pp289 - 295

Antonin Blot & Boris Barbour


Inhibition sculpts neural activity through various cell types and circuits, but, unlike excitation, it is not self-propagating and must be locally recruited with a temporal delay. Here the authors show a fast, feedforward inhibitory mechanism that bypasses synaptic delay through ephaptic coupling of an interneuron to the axon initial segment of a projection cell.

Flies and humans share a motion estimation strategy that exploits natural scene statistics pp296 - 303

Damon A Clark, James E Fitzgerald, Justin M Ales, Daryl M Gohl, Marion A Silies, Anthony M Norcia & Thomas R Clandinin


Current models of how animals estimate motion involve correlations between pairs of points in space and time. Here the authors show that both fly and human visual systems can encode the direction and contrast polarity of moving edges using three-point correlations, and that this enhances motion estimation accuracy.

Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease pp304 - 311

Usman A Khan, Li Liu, Frank A Provenzano, Diego E Berman, Caterina P Profaci, Richard Sloan, Richard Mayeux, Karen E Duff & Scott A Small


In the brains of Alzheimer's disease patients, the entorhinal cortex is known to show signs of early pathology. In this study, Khan et al. performed cerebral blood volume imaging of patients with preclinical Alzheimer's disease and mouse models of disease. Their results pinpoint the subregion in the entorhinal cortex most sensitive to the disease, and show how amyloid and tau interact in driving dysfunction and how dysfunction spreads to distal cortical regions.

See also: News and Views by Yassa

Temporal structure of motor variability is dynamically regulated and predicts motor learning ability pp312 - 321

Howard G Wu, Yohsuke R Miyamoto, Luis Nicolas Gonzalez Castro, Bence P Ölveczky & Maurice A Smith


Here the authors report that higher levels of task-relevant motor variability predict faster learning both across individuals and across tasks in two different paradigms and that training can reshape the temporal structure of motor variability, aligning it with the trained task to improve learning. These results support the importance of action exploration, a key idea from reinforcement learning theory.

See also: News and Views by Herzfeld & Shadmehr


Technical Report

Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans pp322 - 329

Wynn Legon, Tomokazu F Sato, Alexander Opitz, Jerel Mueller, Aaron Barbour, Amanda Williams & William J Tyler


Existing noninvasive neuromodulation methods have poor spatial resolution and may affect neural activity in both the targeted cortical region and unintended surrounding networks. The authors demonstrate that transcranial focused ultrasound, a noninvasive technique with better spatial specificity, can alter neural activity within spatially confined regions of primary somatosensory cortex and enhance somatosensory discrimination.