c-Maf-positive spinal cord neurons are critical elements of a dorsal horn circuit for mechanical hypersensitivity in neuropathy

Corticospinal tract (CST) neurons innervate the deep spinal dorsal horn to sustain chronic neuropathic pain. The majority of neurons targeted by the CST are interneurons expressing the transcription factor c-Maf. Here, we used intersectional genetics to decipher the function of these neurons in dorsal horn sensory circuits. We find that excitatory c-Maf (c-Maf(EX)) neurons receive sensory input mainly from myelinated fibers and target deep dorsal horn parabrachial projection neurons and superficial dorsal horn neurons, thereby connecting non-nociceptive input to nociceptive output structures. Silencing c-Maf(EX) neurons has little effect in healthy mice but alleviates mechanical hypersensitivity in neuropathic mice. c-Maf(EX) neurons also receive input from inhibitory c-Maf and parvalbumin neurons, and compromising inhibition by these neurons caused mechanical hypersensitivity and spontaneous aversive behaviors reminiscent of c-Maf(EX) neuron activation. Our study identifies c-Maf(EX) neurons as normally silent second-order nociceptors that become engaged in pathological pain signaling upon loss of inhibitory control

In-Depth Characterization of Layer 5 Output Neurons of the Primary Somatosensory Cortex Innervating the Mouse Dorsal Spinal Cord

Neuronal circuits of the spinal dorsal horn integrate sensory information from the periphery with inhibitory and facilitating input from higher central nervous system areas. Most previous work focused on projections descending from the hindbrain. Less is known about inputs descending from the cerebral cortex. Here, we identified cholecystokinin (CCK) positive layer 5 pyramidal neurons of the primary somatosensory cortex (CCK + S1-corticospinal tract [CST] neurons) as a major source of input to the spinal dorsal horn. We combined intersectional genetics and virus-mediated gene transfer to characterize CCK+ S1-CST neurons and to define their presynaptic input and postsynaptic target neurons. We found that S1-CST neurons constitute a heterogeneous population that can be subdivided into distinct molecular subgroups. Rabies-based retrograde tracing revealed monosynaptic input from layer 2/3 pyramidal neurons, from parvalbumin positive cortical interneurons, and from thalamic relay neurons in the ventral posterolateral nucleus. Wheat germ agglutinin-based anterograde tracing identified postsynaptic target neurons in dorsal horn laminae III and IV. About 60% of these neurons were inhibitory and about 60% of all spinal target neurons expressed the transcription factor c-Maf. The heterogeneous nature of both S1-CST neurons and their spinal targets suggest complex roles in the fine-tuning of sensory processing

Inequalities in access to education and healthcare

The burden of disease is borne by those who suffer as patients but also by society at large, including health service providers. That burden is felt most severely in parts of the world where there is no infrastructure, or foreseeable prospects of any, to change the status quo without external support. Poverty, disease and inequality pervade all the activities of daily living in low-income regions and are inextricably linked. External interventions may not be the most appropriate way to impact on this positively in all circumstances, but targeted programmes to build social capital, within and by countries, are more likely to be sustainable. By these means, basic oral healthcare, underpinned by the primary healthcare approach, can be delivered to more equitably address needs and demands. Education is fundamental to building knowledge-based economies but is often lacking in such regions even at primary and secondary level. Provision of private education at tertiary level may also introduce its own inequities. Access to distance learning and community-based practice opens opportunities and is more likely to encourage graduates to work in similar areas. Recruitment of faculty from minority groups provides role models for students from similar backgrounds but all faculty staff must be involved in supporting and mentoring students from marginalized groups to ensure their retention. The developed world has to act responsibly in two crucial areas: first, not to exacerbate the shortage of skilled educators and healthcare workers in emerging economies by recruiting their staff; second, they must offer educational opportunities at an economic rate. Governments need to lead on developing initiatives to attract, support and retain a competent workforce. © 2008 Blackwell Munksgaard and The American Dental Education Association