Class 4 Semaphorins and Plexin-B receptors regulate GABAergic and glutamatergic synapse development in the mammalian hippocampus.

To understand how proper circuit formation and function is established in the mammalian brain, it is necessary to define the genes and signaling pathways that instruct excitatory and inhibitory synapse development. We previously demonstrated that the ligand-receptor pair, Sema4D and Plexin-B1, regulates inhibitory synapse development on an unprecedentedly fast time-scale while having no effect on excitatory synapse development. Here, we report previously undescribed synaptogenic roles for Sema4A and Plexin-B2 and provide new insight into Sema4D and Plexin-B1 regulation of synapse development in rodent hippocampus. First, we show that Sema4a, Sema4d, Plxnb1, and Plxnb2 have distinct and overlapping expression patterns in neurons and glia in the developing hippocampus. Second, we describe a requirement for Plexin-B1 in both the presynaptic axon of inhibitory interneurons as well as the postsynaptic dendrites of excitatory neurons for Sema4D-dependent inhibitory synapse development. Third, we define a new synaptogenic activity for Sema4A in mediating inhibitory and excitatory synapse development. Specifically, we demonstrate that Sema4A signals through the same pathway as Sema4D, via the postsynaptic Plexin-B1 receptor, to promote inhibitory synapse development. However, Sema4A also signals through the Plexin-B2 receptor to promote excitatory synapse development. Our results shed new light on the molecular cues that promote the development of either inhibitory or excitatory synapses in the mammalian hippocampus.

Development of the Motor Periphery is the Rate-Limiting Step in the Ontogeny of the Vestibulo-ocular Reflex.

Sensory deprivation reshapes developing neural circuits, and sensory feedback adjusts the strength of reflexive behaviors throughout life. Sensory development might therefore limit the rate with which behaviors mature, but the complexity of most sensorimotor circuits preclude identifying this fundamental constraint. Here we compared the functional development of components of the vertebrate vestibulo-ocular reflex circuit that stabilizes gaze. We found that vestibular interneuron responses to body tilt sensation developed well before behavioral performance peaked, even without motor neuron-derived feedback. Motor neuron responses developed similarly. Instead, the ontogeny of behavior matched the rate of neuromuscular junction development. When sensation was delayed until after the neuromuscular junction developed, behavioral performance was immediately strong. The matching timecourse and ability to determine behavior establish the development of the neuromuscular junction, and not sensory-derived information, as the rate-limiting process for an ancient and evolutionarilyconserved neural circuit.

Motor neurons are dispensable for the assembly of a sensorimotor circuit for gaze stabilization.

Sensorimotor reflex circuits engage distinct neuronal subtypes, defined by precise connectivity, to transform sensation into compensatory behavior. Whether and how motor neuron populations specify the subtype fate and/or sensory connectivity of their pre-motor partners remains controversial. Here, we discovered that motor neurons are dispensable for proper connectivity in the vestibular reflex circuit that stabilizes gaze. We first measured activity following vestibular sensation in pre-motor projection neurons after constitutive loss of their extraocular motor neuron partners. We observed normal responses and topography indicative of unchanged functional connectivity between sensory neurons and projection neurons. Next, we show that projection neurons remain anatomically and molecularly poised to connect appropriately with their downstream partners. Lastly, we show that the transcriptional signatures that typify projection neurons develop independently of motor partners. Our findings comprehensively overturn a long-standing model: that connectivity in the circuit for gaze stabilization is retrogradely determined by motor partner-derived signals. By defining the contribution of motor neurons to specification of an archetypal sensorimotor circuit, our work speaks to comparable processes in the spinal cord and advances our understanding of general principles of neural development.

Determinants of motor neuron functional subtypes important for locomotor speed.

Locomotion requires precise control of the strength and speed of muscle contraction and is achieved by recruiting functionally distinct subtypes of motor neurons (MNs). MNs are essential to movement and differentially susceptible in disease, but little is known about how MNs acquire functional subtype-specific features during development. Using single-cell RNA profiling in embryonic and larval zebrafish, we identify novel and conserved molecular signatures for MN functional subtypes and identify genes expressed in both early post-mitotic and mature MNs. Assessing MN development in genetic mutants, we define a molecular program essential for MN functional subtype specification. Two evolutionarily conserved transcription factors, Prdm16 and Mecom, are both functional subtype-specific determinants integral for fast MN development. Loss of prdm16 or mecom causes fast MNs to develop transcriptional profiles and innervation similar to slow MNs. These results reveal the molecular diversity of vertebrate axial MNs and demonstrate that functional subtypes are specified through intrinsic transcriptional codes.

Neuronal birthdate reveals topography in a vestibular brainstem circuit for gaze stabilization.

Across the nervous system, neurons with similar attributes are topographically organized. This topography reflects developmental pressures. Oddly, vestibular (balance) nuclei are thought to be disorganized. By measuring activity in birthdated neurons, we revealed a functional map within the central vestibular projection nucleus that stabilizes gaze in the larval zebrafish. We first discovered that both somatic position and stimulus selectivity follow projection neuron birthdate. Next, with electron microscopy and loss-of-function assays, we found that patterns of peripheral innervation to projection neurons were similarly organized by birthdate. Finally, birthdate revealed spatial patterns of axonal arborization and synapse formation to projection neuron outputs. Collectively, we find that development reveals previously hidden organization to the input, processing, and output layers of a highly conserved vertebrate sensorimotor circuit. The spatial and temporal attributes we uncover constrain the developmental mechanisms that may specify the fate, function, and organization of vestibulo-ocular reflex neurons. More broadly, our data suggest that, like invertebrates, temporal mechanisms may assemble vertebrate sensorimotor architecture.

Efference Copies: Hair Cells Are the Link.

Animals must distinguish external stimuli from self-generated sensory input to guide appropriate behaviors. A recent study elucidates a cellular mechanism by which zebrafish perform this distinction while maintaining sensitivity to external environmental signals.

Childhood Physical Neglect Is Associated With Exaggerated Systemic and Intracellular Inflammatory Responses to Repeated Psychosocial Stress in Adulthood.

Experiences of child maltreatment are associated with a host of adverse mental and physical health outcomes in adulthood. Altered reactivity to psychosocial stress exposure may partially explain known associations between early experiences of maltreatment and later life health. The present study focuses on examining whether experiences of child maltreatment are associated with physiological reactions to initial and repeated psychosocial stress in adulthood. To this end, 44 healthy adults (52% male, aged 18-65) completed the Childhood Trauma Questionnaire to provide information about exposure to child maltreatment and completed the Trier Social Stress Test (TSST) on 2 consecutive days. Peripheral blood was collected prior to as well as 30 and 120 min following the TSST on each day. Plasma Interleukin-6 (IL-6) and gene expression of IL-6, IL-1ß, nuclear factor-kB (NF-kB), and inhibitor of kB (IkB) were measured from each blood sample. Total CTQ scores were unrelated to plasma IL-6 and gene expression (ps > .10) but a history of childhood physical neglect was associated with increased interleukin-1ß (ß =.35; p =.02; R2 =.19) and nuclear factor-kB (ß =.30; p =.046; R2 =.13) expression following initial stress. Following repeated exposure to the TSST, childhood physical neglect was associated with increased plasma IL-6 reactivity (ß =.34; p =.02; R2 =.16) and increased expression of nuclear factor-kB (ß =.31; p =.04; R2 =.08). Finally, childhood physical neglect was associated with decreased habituation following repeated exposure to the TSST. Other CTQ subscales were not related to plasma IL-6 and gene expression when considered individually. Results from this study are suggestive of a unique effect of childhood physical neglect on the physiological stress response following initial and repeated exposure to a common psychosocial stressor. This provides important directions for future research because the effect of childhood physical neglect on long-term neglect are not well understood and in need of further investigation.