Sleep and wakefulness are regulated to occur at appropriate times that are in accordance with our internal and external environments. Avoiding danger and finding food, which are life-essential ...activities that are regulated by emotion, reward and energy balance, require vigilance and therefore, by definition, wakefulness. The orexin (hypocretin) system regulates sleep and wakefulness through interactions with systems that regulate emotion, reward and energy homeostasis.
Social behavior involves many processes including cognitive functions. Altered social behaviors associated with many psychiatric disorders might have alterations in the processes. Poor social ...environment affects development and maturation of cognitive functions that are important for social cognition, possibly introducing social stress as well as vulnerability to the stress into the developing brain. Adolescence and early adulthood have higher sensitivity to social stress, which may be linked to the onset of psychiatric disorders during this time period. Understanding social behavioral processes in detail will be crucial for elucidating mechanisms of emerging the social behavior phenotypes in psychiatric disorders and for devising therapeutic and preventive interventions to introduce the resilience for the onset of psychiatric disorders through modulation of social circuitries.
NrCAM is a neuronal cell adhesion molecule of the L1 family of immunoglobulin super family. It plays a wide variety of roles in neural development, including cell proliferation and differentiation, ...axon growth and guidance, synapse formation, and the formation of the myelinated nerve structure. NrCAM functions in cell adhesion and modulates signaling pathways in neural development through multiple molecular interactions with guidance and other factors. Alterations in NrCAM structure/expression are associated with psychiatric disorders such as autism and drug addiction and with tumor progression. The mechanisms of NrCAM participation in development and how these might be perturbed in disorders are reviewed.
Cell adhesion molecules (CAMs) in the nervous system have long been a research focus, but many mice lacking CAMs show very subtle phenotypes, giving an impression that CAMs may not be major players ...in constructing the nervous system. However, recent human genetic studies suggest CAM involvement in many neuropsychiatric disorders, implicating that they must have significant functions in nervous system development, namely in circuitry formation. As CAMs can provide specificity through their molecular interactions, this review summarizes possible mechanisms on how alterations of CAMs can result in neuropsychiatric disorders through circuitry modification.
•Cell adhesion molecules (CAMs) important for brain wiring.•CAMs in the nervous system implicated in psychiatric disorders.•Potential mechanisms of involvement of CAMs in the disorders.
Recent studies have implicated the orexin system as a critical regulator of sleep/wake states as well as feeding behavior and reward processes. Orexin deficiency results in narcolepsy in humans, ...dogs, and rodents, suggesting that the orexin system is particularly important for maintenance of wakefulness. In addition, orexin deficiency also cause abnormalities in energy homeostasis and reward systems. Orexin activates waking active monoaminergic and cholinergic neurons in the hypothalamus and brainstem regions to maintain a long, consolidated waking period. Orexin neurons receive abundant input from the limbic system. Orexin neurons also have reciprocal links with the hypothalamic arcuate nucleus, which regulates feeding. Moreover, the responsiveness of orexin neurons to peripheral metabolic cues, such as leptin and glucose, suggest that these neurons have important role as a link between the energy homeostasis and vigilance states. Orexin neurons also have a link with the dopaminergic reward system in the ventral tegmental nucleus. These findings suggest that the orexin system interacts with systems that regulate emotion, reward, and energy homeostasis to maintain proper vigilance states. Therefore, this system may be a potentially important therapeutic target for treatment of sleep disorder, obesity, emotional stress, and addiction.
•The orexin system plays an essential role in consolidation and expression of fear memory.•The orexin → NALC → LA pathway is required for behavioral fear expression and fear generalization.•Orexin ...receptor 1 antagonists are promising candidate as a drug to ameliorate exaggerated and excessive fear.
Fear is an important physiological function for survival. It appears when animals or humans are confronted with an environmental threat. The amygdala has been shown to play a highly important role in emergence of fear. Hypothalamic orexin neurons are activated by fearful stimuli to evoke a ‘defense reaction’ with an increase in arousal level and sympathetic outflow to deal with the imminent danger. However, how this system contributes to the emergence of fear-related behavior is not well understood. Orexin neurons in the hypothalamus send excitatory innervations to noradrenergic neurons in the locus coeruleus (NALC) which express orexin receptor 1 (OX1R) and send projections to the lateral amygdala (LA). Inhibition of this di-synaptic orexin → NALC → LA pathway by pharmacological or opto/chemogenetic methods reduces cue-induced fear expression. Excitatory manipulation of this pathway induces freezing, a fear-related behavior that only occurs when the environment contains some elements suggestive of danger. Although, fear memory helps animals respond to a context or cue previously paired with an aversive stimulus, fear-related behavior is sometimes evoked even in a distinct context containing some similar elements, which is known as fear generalization. Our recent observation suggests that the orexin → NALC → LA pathway might contribute to this response. This review focuses on recent advances regarding the role of hypothalamic orexin neurons in behavioral fear expression. We also discuss the potential effectiveness of orexin receptor antagonists for treating excessive fear response or overgeneralization seen in anxiety disorder and post-traumatic stress disorder (PTSD).
The sleep cycle is characterized by alternating non-rapid eye movement (NREM) and rapid eye movement (REM) sleeps. The mechanisms by which this cycle is generated are incompletely understood. We ...found that a transient increase of dopamine (DA) in the basolateral amygdala (BLA) during NREM sleep terminates NREM sleep and initiates REM sleep. DA acts on dopamine receptor D2 (Drd2)-expressing neurons in the BLA to induce the NREM-to-REM transition. This mechanism also plays a role in cataplectic attacks-a pathological intrusion of REM sleep into wakefulness-in narcoleptics. These results show a critical role of DA signaling in the BLA in initiating REM sleep and provide a neuronal basis for sleep cycle generation.
Orexin deficiency results in narcolepsy in humans, dogs, and rodents, suggesting that the orexin system is particularly important for maintenance of wakefulness. However, orexin neurons are ..."multi-tasking" neurons that regulate sleep/wake states as well as feeding behavior, emotion, and reward processes. Orexin deficiency causes abnormalities in energy homeostasis, stress-related behavior, and reward systems. Orexin excites waking-active monoaminergic and cholinergic neurons in the hypothalamus and brain stem regions to maintain a long, consolidated waking period. Orexin neurons also have reciprocal links with the hypothalamic nuclei, which regulates feeding. Moreover, the responsiveness of orexin neurons to peripheral metabolic cues suggests that these neurons have an important role as a link between energy homeostasis and vigilance states. The link between orexin and the ventral tegmental nucleus serves to motivate an animal to engage in goal-directed behavior. This review focuses on the interaction of orexin neurons with emotion, reward, and energy homeostasis systems. These connectivities are likely to be highly important to maintain proper vigilance states.
The finding of orexin (hypocretin) deficiency in patients with narcolepsy suggests that this hypothalamic neuropeptide plays a crucial role in regulating and maintaining sleep/wakefulness states and ...energy homeostasis. Orexin might be especially important for stabilization of behavioral states, because the major symptom in narcolepsy is instability of each behavioral state, which results in sleep/wakefulness fragmentation. The efferent and afferent systems of orexin neurons suggest interactions between these cells and arousal/sleep–wakefulness centers in the brainstem as well as important feeding centers in the hypothalamus. Electrophysiological studies have shown that orexin neurons are regulated by monoamines and acetylcholine as well as metabolic cues, including leptin, glucose, and ghrelin. Thus, orexin neurons have the requisite functional interactions with hypothalamic feeding pathways and monoaminergic/cholinergic centers, and provide a critical link between peripheral energy balance and the central mechanisms that coordinate sleep/wakefulness and motivated behavior such as food seeking.
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