Brain-to-gut trafficking of alpha-synuclein by CD11c cells in a mouse model of Parkinson's disease.

Inflammation in the brain and gut is a critical component of several neurological diseases, such as Parkinson's disease (PD). One trigger of the immune system in PD is aggregation of the pre-synaptic protein, α-synuclein (αSyn). Understanding the mechanism of propagation of αSyn aggregates is essential to developing disease-modifying therapeutics.

Light-induced silencing of neural activity in Rosa26 knock-in and BAC transgenic mice conditionally expressing the microbial halorhodopsin eNpHR3.

An engineered light-inducible chloride pump, Natronomonas pharaonis halorhodopsin 3 (eNpHR3) enables temporally and spatially precise inhibition of genetically defined cell populations in the intact nervous tissues. In this report, we show the generation of new mouse strains that express eNpHR3-EYFP fusion proteins after Cre- and/or Flp-mediated recombination to optically inhibit neuronal activity. In these mouse strains, Cre/Flp recombination induced high levels of opsin expression.

Pathway-Specific Drive of Cerebellar Golgi Cells Reveals Integrative Rules of Cortical Inhibition.

Cerebellar granule cells (GrCs) constitute over half of all neurons in the vertebrate brain and are proposed to decorrelate convergent mossy fiber (MF) inputs in service of learning. Interneurons within the GrC layer, Golgi cells (GoCs), are the primary inhibitors of this vast population and therefore play a major role in influencing the computations performed within the layer. Despite this central function for GoCs, few studies have directly examined how GoCs integrate inputs from specific afferents, which vary in density to regulate GrC population activity.

Progressive Loss of the Orexin Neurons Reveals Dual Effects on Wakefulness.

Study Objectives: Narcolepsy is caused by loss of the orexin (also known as hypocretin) neurons. In addition to the orexin peptides, these neurons release additional neurotransmitters, which may produce complex effects on sleep/wake behavior. Currently, it remains unknown whether the orexin neurons promote the initiation as well as the maintenance of wakefulness, and whether the orexin neurons influence initiation or maintenance of sleep.

Optogenetic activation of dorsal raphe serotonin neurons enhances patience for future rewards.

Serotonin is a neuromodulator that is involved extensively in behavioral, affective, and cognitive functions in the brain. Previous recording studies of the midbrain dorsal raphe nucleus (DRN) revealed that the activation of putative serotonin neurons correlates with the levels of behavioral arousal [1], rhythmic motor outputs [2], salient sensory stimuli [3-6], reward, and conditioned cues [5-8]. The classic theory on serotonin states that it opposes dopamine and inhibits behaviors when aversive events are predicted [9-14].

Concurrent and robust regulation of feeding behaviors and metabolism by orexin neurons.

Orexin neurons in the hypothalamus regulate energy homeostasis by coordinating various physiological responses. Past studies have shown the role of the orexin peptide itself; however, orexin neurons contain not only orexin but also other neurotransmitters such as glutamate and dynorphin. In this study, we examined the physiological role of orexin neurons in feeding behavior and metabolism by pharmacogenetic activation and chronic ablation.

Optogenetic manipulation of activity and temporally controlled cell-specific ablation reveal a role for MCH neurons in sleep/wake regulation.

Melanin-concentrating hormone (MCH) is a neuropeptide produced in neurons sparsely distributed in the lateral hypothalamic area. Recent studies have reported that MCH neurons are active during rapid eye movement (REM) sleep, but their physiological role in the regulation of sleep/wakefulness is not fully understood. To determine the physiological role of MCH neurons, newly developed transgenic mouse strains that enable manipulation of the activity and fate of MCH neurons in vivo were generated using the recently developed knockin-mediated enhanced gene expression by improved tetracycline-controlled gene induction system.

Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system function.

The sleep disorder narcolepsy results from loss of hypothalamic orexin/hypocretin neurons. Although narcolepsy onset is usually postpubertal, current mouse models involve loss of either orexin peptides or orexin neurons from birth. To create a model of orexin/hypocretin deficiency with closer fidelity to human narcolepsy, diphtheria toxin A (DTA) was expressed in orexin neurons under control of the Tet-off system.

Influence of inhibitory serotonergic inputs to orexin/hypocretin neurons on the diurnal rhythm of sleep and wakefulness.

Study Objective: Serotonergic (5HT) neurons of the dorsal raphe nuclei receive excitatory input from hypothalamic orexin (hypocretin) neurons and reciprocally inhibit orexin neurons through the 5HT1A receptor. However, the physiological significance of this negative feedback circuit for sleep/wakefulness regulation is little understood.

Design: 5HT1A receptor expression level was specifically and reversibly controlled in the orexin neurons using the Tet-off system.

Long-lasting silencing of orexin/hypocretin neurons using archaerhodopsin induces slow-wave sleep in mice.

Orexin/hypocretin neurons have a crucial role in the regulation of sleep and wakefulness. Recent optogenetic studies revealed that the activation or inhibition of orexin neuronal activity affects the probability of sleep/wakefulness transition in the acute phase. To expand our understanding of how orexin neurons maintain wakefulness, we generated new transgenic mice in which orexin neurons expressed archaerhodopsin from Halorubrum strain TP009 (ArchT), a green light-driven neuronal silencer, using the tet-off system (orexin-tTA; TetO ArchT mice).

Light-induced silencing of neural activity in Rosa26 knock-in mice conditionally expressing the microbial halorhodopsin eNpHR2.0.

Temporally precise inhibition of genetically defined cell populations in intact nervous systems has been enabled by the microbial halorhodopsin NpHR, a fast, light-activated chloride pump. Here, we report the generation of new mouse strains that express eNpHR2-EYFP fusion proteins after Cre- and/or Flp-mediated recombination to silence neural activity in vivo. In these mouse strains, Cre/Flp recombination induced a high-level of eNpHR2-EYFP expression.

Orexin directly excites orexin neurons through orexin 2 receptor.

Orexin neurons (hypocretin neurons) have a critical role in the regulation of sleep/wakefulness, especially in the maintenance of arousal. Here, we revealed that orexin neurons are directly and indirectly activated by orexin via the orexin 2 receptor (OX2R). Orexin B (1 μM) induced depolarization in orexin neurons, which was still observed in the presence of TTX (1 μM), AP-5 (50 μM), and CNQX (20 μM).