It is a puzzle that troubles the field for many years that how pain and itch, two closely related sensations (once thought as one sensation), are differentiated by the nervous systems. Coding of pain and itch are heatedly debated for decades. The current specificity theory suggests that these two kinds of signals are carried by separate pathways, with some interactions, for example pain can inhibit itch and that explains why we all scratch to inhibit pain. It is true in the periphery (our previous study indicate a small population of neurons in the periphery only codes for itch sensation), but a study from our lab suggests that there could be more crosstalk between these two sensations in the central than we expected. People might not notice in real life, but in human psychophysical studies, well-isolated experimental environments, when human subjects are given itchy substances, they typically report intense itch sensations accompanied by minor noxious sensations, such as pricking, stinging and burning. Our new leaky gate model suggest in certain circumstances intense itch signals can trigger minor pain sensations, which can explain such phenomenon.   

Chronic pain is a major health and economic problem worldwide with an estimated prevalence reaching epidemic levels of >25% of the population. For example in the US, chronic pain affects over 116 million adults and costs up to $635 billion annually in treatment and lost productivity. Most drugs on the market for chronic pain have undesired side effects because their targets exist both inside and outside the pain pathways. MrgprX1, a human GPCR, is a promising target of novel pain inhibitors, mainly because of its restricted expression in pain-sensing neurons. Many pharmaceutical companies have conducted drug screens to target human MrgprX1. However, constrained by species differences across Mrgprs, many drug candidates activate MrgprX1 but not the rodent orthologues, leaving no animal model responsive to test the effect on pain in vivo. To overcome the species specificity problem, Xinzhong Dong's lab generated a transgenic mouse line in which they replaced mouse Mrgprs with human MrgprX1. This valuable humanized mouse allowed them to characterize a potent positive allosteric modulator of MrgprX1, ML382. Cellular studies in humanized MrgprX1 mice suggest that ML382 enhances the ability of MrgprX1 to inhibit N-type Ca²⁺ channels via the G_i pathway in nociceptive neurons and block presynaptic terminal transmission in spinal cord. Importantly, ML382 effectively attenuates evoked persistent and spontaneous pain without causing peripheral or central side effects such as itch, motor dysfunction, or reward in the naïve condition.  The group's findings suggest that humanized MrgprX1 mice provide an essential preclinical model and that activating MRGPRX1 is an effective way to treat persistent pain.

Kai Liu, a Neuroscience Gradaute student in Dr. Seth Blackshaw's lab, has been awarded the Mette Srand Research Award.  He will give a talk and receive his award as part of the Young Investigator's Day Program on May 9th, 2017 from 3-5pm in Mountcastle Auditorium.  This marks the 40th anniversary of the JHMI Young Investigator's Day which highlights talented graduate student and postdoctoral scientists.

The full Young Investigator's Day program will be released soon.  You can view the 2016 Young Investigator winners here. 

The hippocampus is a brain area involved in learning and memory.  The dentate gyrus, a subregion of the hippocampus, may prevent interference between similar memories, but it is unclear how the two main dentate gyrus cell types, granule cells and mossy cells, contribute to this process.  GoodSmith et al. recorded from granule cells and mossy cells as rats explored distinct environments.  Different groups of granule cells fired in different environments, but mossy cells fired in multiple locations in most environments, a feature previously attributed to granule cells. This study resolves a longstanding debate about the firing properties of granule cells, shows that mossy cells have spatial firing, and describes distinct ways in which granule cells and mossy cells can contribute to the ability to distinguish between environments.

Sleep is an essential process that plays a critical role in supporting cognitive functions such as learning and memory consolidation. Synapses in the brain are the structures responsible for forming and maintaining memories. Studying mice, we found that synapses become stronger while the mice were awake and weaker during sleep by removal of the neurotransmitter receptors called AMPA receptors. This is a process called homeostatic scaling-down. Scaling-down during sleep was driven by a protein called Homer1a which builds up in neurons while the mice were awake but is prevented from accessing the synapses until sleep, by the arousal promoting neuromodulator noradrenaline. In this way, the scaling of synapses is limited while awake and engaged as we transition to sleep. Homer1a targeting to synapses was also observed during sleep deprivation, activated by the sleep promoting neuromodulator adenosine. Sleep is well known to enhance memory consolidation whereas sleep deprivation greatly impairs memory formation. Our study suggests that weakening of synapses during sleep contributes to learning and memory, and that if this process is engaged during sleep deprivation memories become lost.

Eight recipients of the 2016 Martin Luther King Jr., Community Service Awards were honored at Johns Hopkins’ annual MLK commemoration.

Daniel Pham

Ph.D. candidate in neuroscience

Johns Hopkins University School of Medicine

Like many great ideas, Project Bridge emerged from confusion. Daniel Pham, a Ph.D. candidate in neuroscience, was unsuccessful in his attempt to describe to his partner the intricacies of his research. The communication breakdown led Pham and colleagues to found Project Bridge, “with the goal of getting scientists to communicate and connect with the public,” he says. The outreach program features talks and demonstrations by Johns Hopkins scientists in farmers markets, cafes and restaurants. In September, Project Bridge brought Baltimore Brain Fest, a daylong neuroscience expo, to a city elementary school. “It’s a very grass-roots approach, getting bystanders to come by and having scientists in the community, explaining rudimentary topics,” Pham says.

Publications from Primary Faculty Members - February 2017:

Agarwal A, Wu PH, Hughes EG, Fukaya M, Tischfield MA, Langseth AJ, Wirtz D, Bergles DE. Transient Opening of the Mitochondrial Permeability Transition Pore Induces Microdomain Calcium Transients in Astrocyte Processes. Neuron. 2017 Feb 8;93(3):587-605.e7. doi: 10.1016/j.neuron.2016.12.034. Epub 2017 Jan 26.

Diering GH, Nirujogi RS, Roth RH, Worley PF, Pandey A, Huganir RL. Homer1a drives homeostatic scaling-down of excitatory synapses during sleep. Science. 2017 Feb 3;355(6324):511-515. doi: 10.1126/science.aai8355. Epub 2017 Feb 2.

Fu C, Xu J, Cheng W, Rojas T, Chin AC, Snowman AM, Harraz MM, Snyder SH. Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via α-actinin and focal adhesion kinase. Proc Natl Acad Sci U S A. 2017 Feb 2. pii: 201700165. doi: 10.1073/pnas.1700165114. [Epub ahead of print]

GoodSmith D, Chen X, Wang C, Kim SH, Song H, Burgalossi A, Christian KM, Knierim JJ. Spatial Representations of Granule Cells and Mossy Cells of the Dentate Gyrus. Neuron. 2017 Feb 8;93(3):677-690.e5. doi: 10.1016/j.neuron.2016.12.026. Epub 2017 Jan 26.

Smith-Hicks CL, Cai P, Savonenko AV, Reeves RH, Worley PF. Increased Sparsity of Hippocampal CA1 Neuronal Ensembles in a Mouse Model of Down Syndrome.  Front Neural Circuits. 2017 Feb 3;11:6. doi: 10.3389/fncir.2017.00006. eCollection 2017.

Sun S, Xu Q, Guo C, Guan Y, Liu Q, Dong X. Leaky Gate Model: Intensity-Dependent Coding of Pain and Itch in the Spinal Cord. Neuron. 2017 Feb 22;93(4):840-853.e5. doi: 10.1016/j.neuron.2017.01.012.

Yue WW, Frederiksen R, Ren X, Luo DG, Yamashita T, Shichida Y, Cornwall MC, Yau KW. Spontaneous activation of visual pigments in relation to openness/closedness of chromophore-binding pocket. Elife. 2017 Feb 10;6. pii: e18492. doi: 10.7554/eLife.18492.