Cell-type–specific neuromodulation guides synaptic credit assignment in a spiking neural network

Brains learn tasks via experience-driven differential adjustment of their myriad individual synaptic connections, but the mechanisms that target appropriate adjustment to particular connections remain deeply enigmatic. While Hebbian synaptic plasticity, synaptic eligibility traces, and top-down feedback signals surely contribute to solving this synaptic credit-assignment problem, alone, they appear to be insufficient. Inspired by new genetic perspectives on neuronal signaling architectures, here, we present a normative theory for synaptic learning, where we predict that neurons communicate their contribution to the learning outcome to nearby neurons via cell-type–specific local neuromodulation. Computational tests suggest that neuron-type diversity and neuron-type–specific local neuromodulation may be critical pieces of the biological credit-assignment puzzle. They also suggest algorithms for improved artificial neural network learning efficiency.

The enteric nervous system of C. elegans is specified by the Sine Oculis-like homeobox gene ceh-34

Overarching themes in the terminal differentiation of the enteric nervous system, an autonomously acting unit of animal nervous systems, have so far eluded discovery. We describe here the overall regulatory logic of enteric nervous system differentiation of the nematode C. elegans that resides within the foregut (pharynx) of the worm. A Caenorhabditis elegans homolog of the Drosophila Sine Oculis homeobox gene, ceh-34, is expressed in all 14 classes of interconnected pharyngeal neurons from their birth throughout their life time, but in no other neuron type of the entire animal. Constitutive and temporally controlled ceh-34 removal shows that ceh-34 is required to initiate and maintain the neuron type-specific terminal differentiation program of all pharyngeal neuron classes, including their circuit assembly, without affecting panneuronal features. Through additional genetic loss of function analysis, we show that within each pharyngeal neuron class, ceh-34 cooperates with different homeodomain transcription factors to individuate distinct pharyngeal neuron classes. Our analysis underscores the critical role of homeobox genes in neuronal identity specification and links them to the control of neuronal circuit assembly of the enteric nervous system. Together with the pharyngeal nervous system simplicity as well as its specification by a Sine Oculis homolog, our findings invite speculations about the early evolution of nervous systems.

Context-dependent inversion of the response in a single sensory neuron type reverses olfactory preference behavior

The valence and salience of individual odorants are modulated by an animals innate preferences, learned associations, and internal state, as well as by the context of odorant presentation. The mechanisms underlying context-dependent flexibility in odor valence are not fully understood. Here we show that the behavioral response of C. elegans to bacterially-produced medium-chain alcohols switches from attraction to avoidance when presented in the background of a subset of additional attractive chemicals. This context-dependent reversal of odorant preference is driven by cell-autonomous inversion of the response to alcohols in the single AWC olfactory neuron pair. We find that while medium-chain alcohols inhibit the AWC olfactory neurons to drive attraction, these alcohols instead activate AWC to promote avoidance when presented in the background of a second AWC-sensed odorant. We show that these opposing responses are driven via engagement of different odorant-directed signal transduction pathways within AWC. Our results indicate that context-dependent recruitment of alternative intracellular signaling pathways within a single sensory neuron type conveys opposite hedonic valences, thereby providing a robust mechanism for odorant encoding and discrimination at the periphery.

Automatic Detection and Neurotransmitter Prediction of Synapses in Electron Microscopy

This paper presents a deep-learning based workflow to detect synapses and predict their neurotransmitter type in the primitive chordate Ciona intestinalis (Ciona) EM images. Identifying synapses from electron microscopy (EM) images to build a full map of connections between neurons is a labor-intensive process and requires significant domain expertise. Automation of synapse detection and classification would hasten the generation and analysis of connectomes. Furthermore, inferences concerning neuron type and function from synapse features are in many cases difficult to make. Finding the connection between synapse structure and function is an important step in fully understanding a connectome. Activation maps derived from the convolutional neural network provide insights on important features of synapses based on cell type and function. The main contribution of this work is in the differentiation of synapses by neurotransmitter type through the structural information in their EM images. This enables prediction of neurotransmitter types for neurons in Ciona which were previously unknown. The prediction model with code is available on Github.

Dietary vitamin B12 regulates chemosensory receptor gene expression via the MEF2 transcription factor in Caenorhabditis elegans

Dynamic changes in chemoreceptor gene expression levels in sensory neurons is one strategy that an animal can use to modify their responses to dietary changes. However, the mechanisms underlying diet-dependent modulation of chemosensory gene expression are unclear. Here, we show that the expression of the srh-234 chemoreceptor gene localized in a single ADL sensory neuron type of C. elegans is downregulated when animals are fed a Comamonas bacterial diet, but not on an E. coli diet. Remarkably, this diet-modulated effect on srh-234 gene expression levels is dependent on the micronutrient vitamin B12 endogenously produced by Comamonas bacteria. Excess propionate and genetic perturbations in the canonical and shunt propionate breakdown pathways are able to override the repressing effects of vitamin B12 on srh-234 expression. The vitamin B12-mediated regulation of srh-234 expression levels in ADL requires the MEF-2 transcription factor, providing a potential mechanism by which dietary vitamin B12 may transcriptionally tune individual chemoreceptor genes in a single sensory neuron type, which in turn may change animal responses to biologically relevant chemicals in their diet.

Evolution of Synapses and Neurotransmitter Systems: The Divide-and-Conquer Model for Early Neural Cell-Type Evolution

Nervous systems evolved around 560 million years ago to coordinate and empower animal bodies. Ctenophores – one of the earliest-branching lineages – are thought to share few neuronal genes with bilaterians and may have evolved neurons convergently. Here we review our current understanding of the evolution of neuronal molecules in non-bilaterians. We also reanalyse single-cell sequencing data in light of new cell-cluster identities from a ctenophore and uncover evidence supporting the homology of one ctenophore neuron-type with neurons in Bilateria. The specific coexpression of the presynaptic proteins Unc13 and RIM with voltage-gated channels, neuropeptides and homeobox genes pinpoint a spiking sensory-peptidergic cell in the ctenophore mouth. Similar Unc13-RIM neurons may have been present in the first eumetazoans to rise to dominance only in stem Bilateria. We hypothesize that the Unc13-RIM lineage ancestrally innervated the mouth and conquered other parts of the body with the rise of macrophagy and predation during the Cambrian explosion.

Eight-and-a-half syndrome: a rare presentation

Eight-and-a-half syndrome is a rare entity characterised by conjugate horizontal gaze palsy, ipsilateral internuclear ophthalmoplegia and ipsilateral lower motor neuron type facial palsy. It is due to a lesion affecting median longitudinal fasciculus, paramedian pontine reticular formation and facial nerve fascicle on the same side at the level of pons. The diagnosis is easily missed as it needs detailed ocular movement examination. It is mainly caused due to infarction or demyelinating conditions. We are reporting an interesting case of a 54-year-old man with right-side eight-and-a-half syndrome due to acute ischaemic stroke and ST-elevation myocardial infarction of the inferior wall.

In silico analysis of the transcriptional regulatory logic of neuronal identity specification throughout the C. elegans nervous system

The generation of the enormous diversity of neuronal cell types in a differentiating nervous system entails the activation of neuron type-specific gene batteries. To examine the regulatory logic that controls the expression of neuron type-specific gene batteries, we interrogate single cell expression profiles of all 118 neuron classes of the Caenorhabditis elegans nervous system for the presence of DNA binding motifs of 136 neuronally expressed C. elegans transcription factors. Using a phylogenetic footprinting pipeline, we identify cis-regulatory motif enrichments among neuron class-specific gene batteries and we identify cognate transcription factors for 117 of the 118 neuron classes. In addition to predicting novel regulators of neuronal identities, our nervous system-wide analysis at single cell resolution supports the hypothesis that many transcription factors directly co-regulate the cohort of effector genes that define a neuron type, thereby corroborating the concept of so-called terminal selectors of neuronal identity. Our analysis provides a blueprint for how individual components of an entire nervous system are genetically specified.

Physiologically distinct neurons within the ventrolateral periaqueductal gray are not defined by mu-opioid receptor expression but are differentially activated by persistent inflammation

The ventrolateral periaqueductal gray (vlPAG) is a key structure within the descending pain modulatory pathway and an important target for opioid-induced analgesia. This area contains heterogeneous neurons with respect to neurotransmitter and receptor expression so it is difficult to define vlPAG neurons that contribute to pain and analgesia. Characterization of intrinsic membrane properties of 371 vlPAG neurons from female and male Long-Evans rats identified 4 neuron types with distinct intrinsic firing patterns: Phasic, Tonic, Onset, and Random. Phasic and Tonic neurons comprise the majority of the neurons sampled. Mu-opioid receptor (MOR) expression was determined by the ability of the selective MOR agonist DAMGO to activate G protein-coupled inwardly-rectifying potassium channel (GIRK) currents. Opioid-sensitive and -insensitive neurons were observed within each neuron type in naive rats and in rats pretreated with Complete Freund's adjuvant in a hindpaw to produce persistent inflammation. The presence of low threshold spikes (LTS) did not correlate with MOR-mediated GIRK currents indicating that MOR expression alone does not define a physiologically distinct neuron type in the vlPAG. MOR activation inhibited firing in nearly all spontaneously active neurons, both in naive and persistent inflammation conditions. CFA-induced inflammation increased Fos expression at both acute (2 h) and persistent inflammation (5-7 d) time points. However, persistent, but not acute, inflammation selectively enhanced spontaneous firing and lowered firing thresholds of Phasic neurons which was maintained in the absence of synaptic inputs. Taken together, persistent inflammation selectively activates Phasic neurons, of which only a subset was opioid-sensitive.