Substantia Innominata Glutamatergic Neurons Modulate Sevoflurane Anesthesia in Male Mice.

Background: Accumulated evidence suggests that brain regions that promote wakefulness also facilitate emergence from general anesthesia (GA). Glutamatergic neurons in the substantia innominata (SI) regulate motivation-related aversive, depressive, and aggressive behaviors relying on heightened arousal. Here, we hypothesize that glutamatergic neurons in the SI are also involved in the regulation of the effects of sevoflurane anesthesia.

Optogenetic and pharmacological interventions link hypocretin neurons to impulsivity in mice.

Neurons in the lateral hypothalamus expressing the neuropeptide Hypocretin, also known as orexin, are known critical modulators of arousal stability. However, their role in the different components of the arousal construct such as attention and decision making is poorly understood. Here we study Hypocretin neuronal circuit dynamics during stop action impulsivity in a Go/NoGo task in mice.

Hyperexcitable arousal circuits drive sleep instability during aging.

Sleep quality declines with age; however, the underlying mechanisms remain elusive. We found that hyperexcitable hypocretin/orexin (Hcrt/OX) neurons drive sleep fragmentation during aging. In aged mice, Hcrt neurons exhibited more frequent neuronal activity epochs driving wake bouts, and optogenetic activation of Hcrt neurons elicited more prolonged wakefulness.

Lateral hypothalamic galanin neurons are activated by stress and blunt anxiety-like behavior in mice.

Despite the prevalence of anxiety disorders, the molecular identity of neural circuits underlying anxiety remains unclear. The lateral hypothalamus (LH) is one brain region implicated in the regulation of anxiety, and our recent data found that chemogenetic activation of LH galanin neurons attenuated the stress response to a novel environment as measured by the marble burying test. Thus, we hypothesize that LH galanin neurons may contribute to anxiety-related behavior.

Periodic B- and N-doped phenalenyl π-aggregates: unexpected nonlinear optical properties by tuning pancake π-π bonding.

Phenalenyl (PLY) and its derivatives could form one-dimensional π-aggregates through pancake π-π bonding, which would lead to exotic optoelectronic properties. We will highlight the key aspects of the PLY derivatives from the design strategies to exploration of the electronic properties. Here, we primarily construct alternating boron (B)- and nitrogen (N)-doped PLY π-aggregates: dimer[12], trimer[12-1], trimer[12-2], tetramer[12], pentamer[12]-1, pentamer[12]-2, and hexamer[12].

Voltage-independent GluN2A-type NMDA receptor Ca signaling promotes audiogenic seizures, attentional and cognitive deficits in mice.

The NMDA receptor-mediated Ca signaling during simultaneous pre- and postsynaptic activity is critically involved in synaptic plasticity and thus has a key role in the nervous system. In GRIN2-variant patients alterations of this coincidence detection provoked complex clinical phenotypes, ranging from reduced muscle strength to epileptic seizures and intellectual disability. By using our gene-targeted mouse line (Grin2a), we show that voltage-independent glutamate-gated signaling of GluN2A-containing NMDA receptors is associated with NMDAR-dependent audiogenic seizures due to hyperexcitable midbrain circuits.

Hypothalamic circuitry underlying stress-induced insomnia and peripheral immunosuppression.

The neural substrates of insomnia/hyperarousal induced by stress remain unknown. Here, we show that restraint stress leads to hyperarousal associated with strong activation of corticotropin-releasing hormone neurons in the paraventricular nucleus of hypothalamus (CRH) and hypocretin neurons in the lateral hypothalamus (Hcrt). CRH neurons directly innervate Hcrt neurons, and optogenetic stimulation of LH-projecting CRH neurons elicits hyperarousal.

Brain Circuit of Claustrophobia-like Behavior in Mice Identified by Upstream Tracing of Sighing.

Emotions are distinct patterns of behavioral and physiological responses triggered by stimuli that induce different brain states. Elucidating the circuits is difficult because of challenges in interrogating emotional brain states and their complex outputs. Here, we leverage the recent discovery in mice of a neural circuit for sighing, a simple, quantifiable output of various emotions.

The hypocretin (orexin) system: from a neural circuitry perspective.

Hypocretin/orexin neurons are distributed restrictively in the hypothalamus, a brain region known to orchestrate diverse functions including sleep, reward processing, food intake, thermogenesis, and mood. Since the hypocretins/orexins were discovered more than two decades ago, extensive studies have accumulated concrete evidence showing the pivotal role of hypocretin/orexin in diverse neural modulation. New method of viral-mediated tracing system offers the possibility to map the monosynaptic inputs and detailed anatomical connectivity of Hcrt neurons.

In vivo cell type-specific CRISPR knockdown of dopamine beta hydroxylase reduces locus coeruleus evoked wakefulness.

Locus coeruleus (LC) neurons in the brainstem have long been associated with attention and arousal. Optogenetic stimulation of LC-NE neurons induces immediate sleep-to-wake transitions. However, LC neurons also secrete other neurotransmitters in addition to NE.

Optical probing of orexin/hypocretin receptor antagonists.

Study Objectives: The present study investigated the function of Hypocretin (Hcrt or Orexin/OX) receptor antagonists in sleep modulation and memory function with optical methods in transgenic mice.

Methods: We used Hcrt-IRES-Cre knock-in mice and AAV vectors expressing channelrhodopsin-2 (ChR2) to render Hcrt neurons sensitive to blue light stimulation. We optogenetically stimulated Hcrt neurons and measured latencies to wakefulness in the presence or absence of OX1/2R antagonists and Zolpidem.

Parallel circuits from the bed nuclei of stria terminalis to the lateral hypothalamus drive opposing emotional states.

Lateral hypothalamus (LH) neurons containing the neuropeptide hypocretin (HCRT; orexin) modulate affective components of arousal, but their relevant synaptic inputs remain poorly defined. Here we identified inputs onto LH neurons that originate from neuronal populations in the bed nuclei of stria terminalis (BNST; a heterogeneous region of extended amygdala). We characterized two non-overlapping LH-projecting GABAergic BNST subpopulations that express distinct neuropeptides (corticotropin-releasing factor, CRF, and cholecystokinin, CCK).

Hypocretins and Arousal.

How the brain controls vigilance state transitions remains to be fully understood. The discovery of hypocretins, also known as orexins, and their link to narcolepsy has undoubtedly allowed us to advance our knowledge on key mechanisms controlling the boundaries and transitions between sleep and wakefulness. Lack of function of hypocretin neurons (a relatively simple and non-redundant neuronal system) results in inappropriate control of sleep states without affecting the total amount of sleep or homeostatic mechanisms.

In vivo assessment of behavioral recovery and circulatory exchange in the peritoneal parabiosis model.

The sharing of circulation between two animals using a surgical procedure known as parabiosis has created a wealth of information towards our understanding of physiology, most recently in the neuroscience arena. The systemic milieu is a complex reservoir of tissues, immune cells, and circulating molecules that is surprisingly not well understood in terms of its communication across organ systems. While the model has been used to probe complex physiological questions for many years, critical parameters of recovery and exchange kinetics remain incompletely characterized, limiting the ability to design experiments and interpret results for complex questions.

Hypocretins, Neural Systems, Physiology, and Psychiatric Disorders.

The hypocretins (Hcrts), also known as orexins, have been among the most intensely studied neuropeptide systems since their discovery about two decades ago. Anatomical evidence shows that the hypothalamic neurons that produce hypocretins/orexins project widely throughout the entire brain, innervating the noradrenergic locus coeruleus, the cholinergic basal forebrain, the dopaminergic ventral tegmental area, the serotonergic raphe nuclei, the histaminergic tuberomammillary nucleus, and many other brain regions. By interacting with other neural systems, the Hcrt system profoundly modulates versatile physiological processes including arousal, food intake, emotion, attention, and reward.

D4 Receptor Activation Differentially Modulates Hippocampal Basal and Apical Dendritic Synapses in Freely Moving Mice.

Activation of D4 receptors (D4Rs) has been shown to improve cognitive performance, potentially affecting synaptic strength. We investigated the D4R agonist PD 168077 (PD) in hippocampal CA1 of freely moving mice. We electrically stimulated in stratum oriens (OR) or radiatum (RAD) and evoked local field potentials (LFPs).

Controlled variations in stimulus similarity during learning determine visual discrimination capacity in freely moving mice.

The mouse is receiving growing interest as a model organism for studying visual perception. However, little is known about how discrimination and learning interact to produce visual conditioned responses. Here, we adapted a two-alternative forced-choice visual discrimination task for mice and examined how training with equiprobable stimuli of varying similarity influenced conditioned response and discrimination performance as a function of learning.

Discrimination learning with variable stimulus 'salience'.

Background: In nature, sensory stimuli are organized in heterogeneous combinations. Salient items from these combinations 'stand-out' from their surroundings and determine what and how we learn. Yet, the relationship between varying stimulus salience and discrimination learning remains unclear.