Potentiation of active locomotor state by spinal-projecting serotonergic neurons.

Animals produce diverse motor actions that enable expression of context-appropriate behaviors. Neuromodulators facilitate behavioral flexibility by altering the temporal dynamics and output of neural circuits. Discrete populations of serotonergic (5-HT) neurons target circuits in the brainstem and spinal cord, but their role in the control of motor behavior is unclear.

Adaptation to photoperiod via dynamic neurotransmitter segregation.

Changes in the amount of daylight (photoperiod) alter physiology and behaviour. Adaptive responses to seasonal photoperiods are vital to all organisms-dysregulation associates with disease, including affective disorders and metabolic syndromes. The circadian rhythm circuitry is implicated in such responses, yet little is known about the precise cellular substrates that underlie phase synchronization to photoperiod change.

Altered 5-HT2A/C receptor binding in the medulla oblongata in the sudden infant death syndrome (SIDS): Part II. Age-associated alterations in serotonin receptor binding profiles within medullary nuclei supporting cardiorespiratory homeostasis.

The failure of chemoreflexes, arousal, and/or autoresuscitation to asphyxia may underlie some sudden infant death syndrome (SIDS) cases. In Part I, we showed that some SIDS infants had altered 5-hydroxytryptamine (5-HT)2A/C receptor binding in medullary nuclei supporting chemoreflexes, arousal, and autoresuscitation. Here, using the same dataset, we tested the hypotheses that the prevalence of low 5-HT1A and/or 5-HT2A/C receptor binding (defined as levels below the 95% confidence interval of controls-a new approach), and the percentages of nuclei affected are greater in SIDS versus controls, and that the distribution of low binding varied with age of death.

A brain circuit and neuronal mechanism for decoding and adapting to change in daylength.

Changes in daylight amount (photoperiod) drive pronounced alterations in physiology and behaviour. Adaptive responses to seasonal photoperiods are vital to all organisms - dysregulation is associated with disease, from affective disorders to metabolic syndromes. Circadian rhythm circuitry has been implicated yet little is known about the precise neural and cellular substrates that underlie phase synchronization to photoperiod change.

Identification of an essential spinoparabrachial pathway for mechanical itch.

The sensation of itch is a protective response that is elicited by either mechanical or chemical stimuli. The neural pathways for itch transmission in the skin and spinal cord have been characterized previously, but the ascending pathways that transmit sensory information to the brain to evoke itch perception have not been identified. Here, we show that spinoparabrachial neurons co-expressing Calcrl and Lbx1 are essential for generating scratching responses to mechanical itch stimuli.

Social Interactions Increase Activation of Vasopressin-Responsive Neurons in the Dorsal Raphe.

Social interactions play an important role in our daily lives and can profoundly impact our health for better and worse. To better understand the neural circuitry underlying social behavior, we focused on neural circuits involving vasopressin neurons of the bed nucleus of the stria terminalis (BNST) and serotonin neurons of the dorsal raphe (DR). Previous research shows that BNST vasopressin neurons are activated in male mice by interaction with a female and that vasopressin indirectly excites serotonin neurons.

Neuronal pericellular baskets: neurotransmitter convergence and regulation of network excitability.

A pericellular basket is a presynaptic configuration of numerous axonal boutons outlining a target neuron soma and its proximal dendrites. Recent studies show neurochemical diversity of pericellular baskets and suggest that neurotransmitter usage together with the dense, soma-proximal boutons may permit strong input effects on different timescales. Here we review the development, distribution, neurochemical phenotypes, and possible functions of pericellular baskets.

Altered oligodendroglia and astroglia in chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a progressive tauopathy found in contact sport athletes, military veterans, and others exposed to repetitive head impacts. White matter rarefaction and axonal loss have been reported in CTE but have not been characterized on a molecular or cellular level. Here, we present RNA sequencing profiles of cell nuclei from postmortem dorsolateral frontal white matter from eight individuals with neuropathologically confirmed CTE and eight age- and sex-matched controls.

Reciprocal Lateral Hypothalamic and Raphe GABAergic Projections Promote Wakefulness.

The lateral hypothalamus (LH), together with multiple neuromodulatory systems of the brain, such as the dorsal raphe nucleus (DR), is implicated in arousal, yet interactions between these systems are just beginning to be explored. Using a combination of viral tracing, circuit mapping, electrophysiological recordings from identified neurons, and combinatorial optogenetics in mice, we show that GABAergic neurons in the LH selectively inhibit GABAergic neurons in the DR, resulting in increased firing of a substantial fraction of its neurons that ultimately promotes arousal. These DR neurons are wake active and project to multiple brain areas involved in the control of arousal, including the LH, where their specific activation potently influences local network activity leading to arousal from sleep.

Neurochemically and Hodologically Distinct Ascending VGLUT3 versus Serotonin Subsystems Comprise the r2- Median Raphe.

Brainstem median raphe (MR) neurons expressing the serotonergic regulator gene send collateralized projections to forebrain regions to modulate affective, memory-related, and circadian behaviors. Some neurons express a surprisingly incomplete battery of serotonin pathway genes, with somata lacking transcripts for tryptophan hydroxylase 2 () encoding the rate-limiting enzyme for serotonin [5-hydroxytryptamine (5-HT)] synthesis, but abundant for vesicular glutamate transporter type 3 () encoding a synaptic vesicle-associated glutamate transporter. Genetic fate maps show these nonclassical, putatively glutamatergic neurons in the MR arise embryonically from the same progenitor cell compartment-hindbrain rhombomere 2 (r2)-as serotonergic TPH2 MR neurons.

Sex-Specific Role for Dopamine Receptor D2 in Dorsal Raphe Serotonergic Neuron Modulation of Defensive Acoustic Startle and Dominance Behavior.

Brain networks underlying states of social and sensory alertness are normally adaptive, influenced by serotonin and dopamine (DA), and abnormal in neuropsychiatric disorders, often with sex-specific manifestations. Underlying circuits, cells, and molecules are just beginning to be delineated. Implicated is a subtype of serotonergic neuron denoted , distinguished by expression of the type-2 DA receptor () gene, inhibited cell-autonomously by DRD2 agonism in slice, and, when constitutively silenced in male mice, affects levels of defensive and exploratory behaviors (Niederkofler et al.

A single-cell transcriptomic and anatomic atlas of mouse dorsal raphe neurons.

Among the brainstem raphe nuclei, the dorsal raphe nucleus (DR) contains the greatest number of -lineage neurons, a predominantly serotonergic group distributed throughout DR subdomains. These neurons collectively regulate diverse physiology and behavior and are often therapeutically targeted to treat affective disorders. Characterizing neuron molecular heterogeneity and relating it to anatomy is vital for understanding DR functional organization, with potential to inform therapeutic separability.

Cocaine reward and memory after chemogenetic inhibition of distinct serotonin neuron subtypes in mice.

Rationale: We probed serotonin neurons, those denoted by their developmental gene expression as r2Hoxa2-Pet1 (experiment 1) and Drd1a-Pet1 (experiment 2), for differential modulation of cocaine reward and memory as revealed by the expression and development of conditioned place preference (CPP) in transgenic mice.

Objectives: To query roles in CPP, we inhibited neurons cell autonomously in vivo by activating the transgenically expressed, synthetic DREADD receptor hMDi (Di) with the exogenous ligand clozapine-N-oxide (CNO).

Methods: To examine CPP expression, mice were conditioned using behaviorally active doses of cocaine (10.

Serotonergic Modulation of Aggression in Drosophila Involves GABAergic and Cholinergic Opposing Pathways.

Pathological aggression is commonly associated with psychiatric and neurological disorders and can impose a substantial burden and cost on human society. Serotonin (5HT) has long been implicated in the regulation of aggression in a wide variety of animal species. In Drosophila, a small group of serotonergic neurons selectively modulates the escalation of aggression.

Embracing diversity in the 5-HT neuronal system.

Neurons that synthesize and release 5-hydroxytryptamine (5-HT; serotonin) express a core set of genes that establish and maintain this neurotransmitter phenotype and distinguish these neurons from other brain cells. Beyond a shared 5-HTergic phenotype, these neurons display divergent cellular properties in relation to anatomy, morphology, hodology, electrophysiology and gene expression, including differential expression of molecules supporting co-transmission of additional neurotransmitters. This diversity suggests that functionally heterogeneous subtypes of 5-HT neurons exist, but linking subsets of these neurons to particular functions has been technically challenging.

Molecular Profiling Defines Evolutionarily Conserved Transcription Factor Signatures of Major Vestibulospinal Neuron Groups.

Vestibulospinal neurons are organized into discrete groups projecting from brainstem to spinal cord, enabling vertebrates to maintain proper balance and posture. The two largest groups are the lateral vestibulospinal tract (LVST) group and the contralateral medial vestibulospinal tract (cMVST) group, with different projection lateralities and functional roles. In search of a molecular basis for these differences, we performed RNA sequencing on LVST and cMVST neurons from mouse and chicken embryos followed by immunohistofluorescence validation.

Chemogenetic silencing of hippocampal neurons suppresses epileptic neural circuits.

We investigated how pathological changes in newborn hippocampal dentate granule cells (DGCs) lead to epilepsy. Using a rabies virus-mediated retrograde tracing system and a designer receptors exclusively activated by designer drugs (DREADD) chemogenetic method, we demonstrated that newborn hippocampal DGCs are required for the formation of epileptic neural circuits and the induction of spontaneous recurrent seizures (SRS). A rabies virus-mediated mapping study revealed that aberrant circuit integration of hippocampal newborn DGCs formed excessive de novo excitatory connections as well as recurrent excitatory loops, allowing the hippocampus to produce, amplify, and propagate excessive recurrent excitatory signals.

Acute perturbation of neuron activity in neonatal mice impairs cardiorespiratory homeostatic recovery.

Cardiorespiratory recovery from apneas requires dynamic responses of brainstem circuitry. One implicated component is the raphe system of -expressing (largely serotonergic) neurons, however their precise requirement neonatally for homeostasis is unclear, yet central toward understanding newborn cardiorespiratory control and dysfunction. Here we show that acute in vivo perturbation of neuron activity, via triggering cell-autonomously the synthetic inhibitory receptor hM4D, resulted in altered baseline cardiorespiratory properties and diminished apnea survival.

Sexual dimorphism of microglia and synapses during mouse postnatal development.

Microglia participate in synapse remodeling in the cortex and hippocampus during mouse postnatal development. Although sex differences in microglia activity during embryonic development have been reported in these regions, it remains unexplored whether microglia show sexually dimorphic features during the early postnatal period, a critical window for synapse formation and maturation. Here, we investigated morphological and functional features of microglia across early postnatal development as well as morphological features of both pre- and postsynaptic neuronal compartments in the mouse hippocampus.

Activity of -Expressing Raphe Neurons Modulates the Respiratory Chemoreflex.

Homeostatic control of breathing, heart rate, and body temperature relies on circuits within the brainstem modulated by the neurotransmitter serotonin (5-HT). Mounting evidence points to specialized neuronal subtypes within the serotonergic neuronal system, borne out in functional studies, for the modulation of distinct facets of homeostasis. Such functional differences, read out at the organismal level, are likely subserved by differences among 5-HT neuron subtypes at the cellular and molecular levels, including differences in the capacity to coexpress other neurotransmitters such as glutamate, GABA, thyrotropin releasing hormone, and substance P encoded by the () gene.

The Cellular and Synaptic Architecture of the Mechanosensory Dorsal Horn.

The deep dorsal horn is a poorly characterized spinal cord region implicated in processing low-threshold mechanoreceptor (LTMR) information. We report an array of mouse genetic tools for defining neuronal components and functions of the dorsal horn LTMR-recipient zone (LTMR-RZ), a role for LTMR-RZ processing in tactile perception, and the basic logic of LTMR-RZ organization. We found an unexpectedly high degree of neuronal diversity in the LTMR-RZ: seven excitatory and four inhibitory subtypes of interneurons exhibiting unique morphological, physiological, and synaptic properties.

THSD1 (Thrombospondin Type 1 Domain Containing Protein 1) Mutation in the Pathogenesis of Intracranial Aneurysm and Subarachnoid Hemorrhage.

Background And Purpose: A ruptured intracranial aneurysm (IA) is the leading cause of a subarachnoid hemorrhage. This study seeks to define a specific gene whose mutation leads to disease.

Methods: More than 500 IA probands and 100 affected families were enrolled and clinically characterized.

Identification of Serotonergic Neuronal Modules that Affect Aggressive Behavior.

Escalated aggression can have devastating societal consequences, yet underlying neurobiological mechanisms are poorly understood. Here, we show significantly increased inter-male mouse aggression when neurotransmission is constitutively blocked from either of two subsets of serotonergic, Pet1 neurons: one identified by dopamine receptor D1(Drd1a)::cre-driven activity perinatally, and the other by Drd2::cre from pre-adolescence onward. Blocking neurotransmission from other Pet1 neuron subsets of similar size and/or overlapping anatomical domains had no effect on aggression compared with controls, suggesting subtype-specific serotonergic neuron influences on aggression.

Partial Raphe Dysfunction in Neurotransmission Is Sufficient to Increase Mortality after Anoxic Exposures in Mice at a Critical Period in Postnatal Development.

Unlabelled: Sudden infant death syndrome (SIDS) cases often have abnormalities of the brainstem raphe serotonergic (5-HT) system. We hypothesize that raphe dysfunction contributes to a failure to autoresuscitate from multiple hypoxic events, leading to SIDS. We studied autoresuscitation in two transgenic mouse models in which exocytic neurotransmitter release was impaired via conditional expression of the light chain from tetanus toxin (tox) in raphe neurons expressing serotonergic bacterial artificial chromosome drivers Pet1 or Slc6a4.