The orexin-producing neurons in the lateral hypothalamus play an essential role in promoting arousal and maintaining wakefulness. These neurons receive a broad variety of signals related to environmental, physiological and emotional stimuli; they project to almost every brain region involved in the regulation of wakefulness; and they fire most strongly during active wakefulness, high motor activation, and sustained attention. This review focuses on the specific neuronal pathways through which the orexin neurons promote wakefulness and maintain high level of arousal, and how recent studies using optogenetic and pharmacogenetic methods have demonstrated that the locus coeruleus, the tuberomammillary nucleus, and the basal forebrain are some of the key sites mediating the arousing actions of orexins.

All sexually reproducing animals exhibit gender differences in behavior. Such sexual dimorphisms in behavior are most obvious in stereotyped displays that enhance reproductive success such as mating, aggression, and parental care. Sexually dimorphic behaviors are a consequence of a sexually differentiated nervous system, and recent studies in fruit flies and mice reveal novel insights into the neural mechanisms that control these behaviors. In the main, these include a diverse array of novel sex differences in the nervous system, surprisingly modular control of various stereotyped dimorphic behavioral routines, and unanticipated sensory and central modulation of mating. We start with a brief overview to provide the appropriate conceptual framework so that the advances made by the newer studies discussed subsequently can be fully appreciated. We restrict our review to reporting progress in understanding the basis of mating and aggression in fruit flies and mice.

Addiction is a chronically relapsing brain disorder that insidiously affects the motivational and cognitive control systems of susceptible individuals. Clinical research over the last two decades has profited from the technique of positron emission tomography (PET), a non-invasive imaging technique that allows the longitudinal assessment of addiction-relevant biomarkers in current and former drug users. The vast majority of this research has unsurprisingly focused on the brain dopamine (DA) systems given their pivotal role in primary drug reinforcement and the rich abundance of dopaminergic PET tracers. However, the provocative failure of dopaminergic medications in addiction has fuelled the search for alternative treatments. This article considers current controversies in this field as well as prospects for elucidating neurotransmitter mechanisms in addiction beyond DA.

Orexin deficiency results in the sleep disorder narcolepsy in many mammalian species, including mice, dogs, and humans, suggesting that the orexin system is particularly important for normal regulation of sleep/wakefulness states, and especially for maintenance of wakefulness. This review discusses animal models of narcolepsy; the contribution of each orexin receptor subtype to the narcoleptic phenotypes; and the etiology of orexin neuronal death. It also raises the possibility of novel therapies targeting the orexin system for sleep disorders including insomia and narcolepsy-cataplexy.

Research on alcohol and drug dependence has shown that the development of addiction depends on a complex interplay of psychological factors, genetic or epigenetic predisposing factors, and neurobiological adaptations induced by drug consumption. A greater understanding of the mechanisms leading to alcohol abuse will allow researchers to identify genetic variation that corresponds to a specific biological vulnerability to addiction, thus defining robust endophenotypes that might help deconstruct these complex syndromes into more tractable components. To this end, it is critical to develop a translational framework that links alterations at the molecular level, to changes in neuronal function, and ultimately to changes at the behavioral and clinical levels. Translational phenotypes can be identified by the combination of animal and human studies designed to elucidate the neurofunctional, anatomical and pharmacological mechanisms underlying the etiology of alcohol addiction. The present article offers an overview of medication development in alcoholism with a focus on the critical aspect of translational research. Moreover, significant examples of promising targets from neuropeptidergic systems, namely nociceptin/orphanin FQ and neuropeptide S are given.

How does an organism's internal state direct its actions? At one moment an animal forages for food with acrobatic feats such as tree climbing and jumping between branches. At another time, it travels along the ground to find water or a mate, exposing itself to predators along the way. These behaviors are costly in terms of energy or physical risk, and the likelihood of performing one set of actions relative to another is strongly modulated by internal state. For example, an animal in energy deficit searches for food and a dehydrated animal looks for water. The crosstalk between physiological state and motivational processes influences behavioral intensity and intent, but the underlying neural circuits are poorly understood. Molecular genetics along with optogenetic and pharmacogenetic tools for perturbing neuron function have enabled cell type-selective dissection of circuits that mediate behavioral responses to physiological state changes. Here, we review recent progress into neural circuit analysis of hunger in the mouse by focusing on a starvation-sensitive neuron population in the hypothalamus that is sufficient to promote voracious eating. We also consider research into the motivational processes that are thought to underlie hunger in order to outline considerations for bridging the gap between homeostatic and motivational neural circuits.

Optogenetic tools have revolutionized the field of neuroscience, and brought the study of neural circuits to a higher level. Optogenetics has significantly improved our understanding not only of the neuronal connections and function of the healthy brain, but also of the neuronal changes that lead to psychiatric disorders. In this review, we summarize recent optogenetic studies that explored different brain circuits involved in natural behaviors, such as sleep and arousal, reward, fear, and social and aggressive behavior. In addition, we describe how alterations in these circuits may lead to psychiatric disorders such as addiction, anxiety, depression, or schizophrenia.

Drug seeking is associated with the activation of reward neural circuitry, but I argue that drug addiction also involves another major source of reinforcement, specifically negative reinforcement driven by the 'dark side' (i.e., a decrease in the function of normal reward-related neurocircuitry and persistent recruitment of the brain stress systems). This combination forms the antireward system or 'darkness within.' Understanding the neuroplasticity of the neurocircuitry that comprises the negative reinforcement associated with addiction is the key to understanding the vulnerability to the transition to addiction, misery of addiction, and persistence of addiction.

Several recent studies, using molecular, electrophysiological, or structural approaches, have investigated how synapses are affected by sleep, spontaneous wake, chronic sleep restriction, and acute sleep deprivation. Overall, the results have found that even a few hours of sleep or wake can modify the molecular composition of excitatory synapses, change their efficacy, and make synapses grow or shrink. Moreover, partial and total loss of sleep affect the ability of synapses to undergo long-term potentiation, an effect that may underlie some of the negative consequences of sleep deprivation on memory and other cognitive functions.