The Serendipity of Viral Trans-Neuronal Specificity: More Than Meets the Eye

Trans-neuronal viruses are frequently used as neuroanatomical tools for mapping neuronal circuits. Specifically, recombinant one-step rabies viruses (RABV) have been instrumental in the widespread application of viral circuit mapping, as these viruses have enabled labs to map the direct inputs onto defined cell populations. Within the neuroscience community, it is widely believed that RABV spreads directly between neurons via synaptic connections, a hypothesis based principally on two observations. First, the virus labels neurons in a pattern consistent with known anatomical connectivity. Second, few glial cells appear to be infected following RABV injections, despite the fact that glial cells are abundant in the brain. However, there is no direct evidence that RABV can actually be transmitted through synaptic connections. Here we review the immunosubversive mechanisms that are critical to RABV’s success for infiltration of the central nervous system (CNS). These include interfering with and ultimately killing migratory T cells while maintaining levels of interferon (IFN) signaling in the brain parenchyma. Finally, we critically evaluate studies that support or are against synaptically-restricted RABV transmission and the implications of viral-host immune responses for RABV transmission in the brain.

How Do Neurons Signal Itch?

Mechanistic theories of itch are based on neuronal specificity, stimulus intensity, and temporal or spatial discharge patterns. Traditionally, these theories are conceptualized as mutually exclusive, assuming that finding evidence for one theory would exclude the others and could sufficiently explain itch. Current experimental data primarily support the specificity or pattern theory of itch. However, in contrast to an assumed inherent exclusivity, recent results have shown that even within itch-specific pathways in the spinal cord, temporal discharge patterns are important as sustained pruriceptor is required to allow successful transsynaptic signal progression. Also, optogenetic activation of pruriceptors suggest that the combination of neuronal specificity and temporal pattern determines the sensory effect: tonic activation of pruriceptors is required to induce scratching behavior whereas short-lasting stimulation rather causes withdrawal. In addition to the mere duration of discharge, also the temporal pattern or spatial aspects could critically contribute to elicit pruritus instead of pain. Basic neurophysiological studies trying to validate neuronal theories for pruritus in their pure form provide unitary concepts leading from neuronal discharge to the itch sensation. However, the crucial clinical questions have the opposite perspective: which mechanisms explain the chronic itch in a given patient or a given disease? In trying to solve these clinical problems we should not feel bound to the mutual exclusive nature of itch theories, but rather appreciate blending several theories and also accept combinations of itch and pain. Thus, blended versions of itch theories might better suffice for an explanation of chronic itch in patients and will improve the basis for mechanistic treatment options.

Neuronal Specificity of Acupuncture in Alzheimer’s Disease and Mild Cognitive Impairment Patients: A Functional MRI Study

Although acupuncture is considered to be effective and safe for Alzheimer’s disease (AD) and mild cognitive impairment (MCI), the mechanism underlying its therapeutic effect is still unknown. Most studies clarifying the neuronal pathway produced by acupuncture were still applied to healthy subjects with limited single acupuncture point stimulation, which was inconsistency with clinical practice. Thus, in our present study, we investigate the differences between brain activity changes in AD and MCI patients caused by multi-acupuncture point Siguan (four gates), in order to provide visualized evidence for neuronal specificity of clinical acupuncture. Forty-nine subjects were recruited, including 21 AD patients, 14 MCI patients, and 14 healthy controls (HC). AD and MCI patients were randomly divided into two groups, respectively: real acupuncture point group (14 AD and 8 MCI) and sham acupuncture point group (7 AD and 6 MCI). We adopted a 16-minute, single-block, experimental design for acquiring functional MRI images. We found, in AD and MCI patients, Siguan (four gates) elicited extensive activations and deactivations in cognitive-related areas, visual-related areas, the sensorimotor-related area, basal ganglia, and cerebellum. Compared with HC, AD and MCI patients showed similar activations in cognitive-related brain areas (inferior frontal gyrus, supramarginal gyrus, and rolandic operculum) as well as deactivations in cognitive-related areas, visual-related areas, basal ganglia, and cerebellum, which were not found in HC. Compared with sham acupuncture points, real acupuncture points produced more specific brain changes with both activated and deactivated brain activities in AD and MCI. The preliminary results in our study verified the objective evidence for neuronal specificity of acupuncture in AD and MCI patients.

Evolution of immune chemoreceptors into sensors of the outside world

Changes in gene expression patterns represent an essential source of evolutionary innovation. A striking case of neofunctionalization is the acquisition of neuronal specificity by immune formyl peptide receptors (Fprs). In mammals, Fprs are expressed by immune cells, where they detect pathogenic and inflammatory chemical cues. In rodents, these receptors are also expressed by sensory neurons of the vomeronasal organ, an olfactory structure mediating innate avoidance behaviors. Here we show that two gene shuffling events led to two independent acquisitions of neuronal specificity by Fprs. The first event targeted the promoter of a V1R receptor gene. This was followed some 30 million years later by a second genomic accident targeting the promoter of a V2R gene. Finally, we show that expression of a vomeronasal Fpr can reverse back to the immune system under inflammatory conditions via the production of an intergenic transcript linking neuronal and immune Fpr genes. Thus, three hijackings of regulatory elements are sufficient to explain all aspects of the complex expression patterns acquired by a receptor family that switched from sensing pathogens inside the organism to sensing the outside world through the nose.

An fMRI Study of Neuronal Specificity in Acupuncture: The Multiacupoint Siguan and Its Sham Point

Clarifying the intrinsic mechanisms of acupuncture’s clinical effects has recently been gaining popularity. Here, we choose the Siguan acupoint (a combination of bilateral LI4 and Liv3) and its sham point to evaluate multiacupoint specificity. Thirty-one healthy volunteers were randomly divided into real acupoint (21 subjects) and sham acupoint (10 subjects) groups. Our study used a single block experimental design to avoid the influence of posteffects. Functional magnetic resonance imaging data were acquired during acupuncture stimulation. Results showed extensive increase in neuronal activities with Siguan acupuncture and significant differences between stimulation at real and sham points. Brain regions that were activated more by real acupuncture stimulation than by sham point acupuncture included somatosensory cortex (the superior parietal lobule and postcentral gyrus), limbic-paralimbic system (the calcarine gyrus, precuneus, cingulate cortex, and parahippocampal gyrus), visual-related cortex (the fusiform and occipital gyri), basal ganglia, and the cerebellum. In this way, our study suggests Siguan may elicit specific activities in human brain.

The Effect of Imagination on Stimulation: The Functional Specificity of Efference Copies in Speech Processing

The computational role of efference copies is widely appreciated in action and perception research, but their properties for speech processing remain murky. We tested the functional specificity of auditory efference copies using magnetoencephalography recordings in an unconventional pairing: We used a classical cognitive manipulation (mental imagery—to elicit internal simulation and estimation) with a well-established experimental paradigm (one shot repetition—to assess neuronal specificity). Participants performed tasks that differentially implicated internal prediction of sensory consequences (overt speaking, imagined speaking, and imagined hearing) and their modulatory effects on the perception of an auditory (syllable) probe were assessed. Remarkably, the neural responses to overt syllable probes vary systematically, both in terms of directionality (suppression, enhancement) and temporal dynamics (early, late), as a function of the preceding covert mental imagery adaptor. We show, in the context of a dual-pathway model, that internal simulation shapes perception in a context-dependent manner.