The tuberomammillary nucleus (TMN) is the major source of histaminergic innervation of the mammalian brain and is thought to play a major role in regulating wake-sleep states. We recently found that sleep-active neurons in the ventrolateral preoptic nucleus (VLPO) provide a major input to the TMN, but the specificity of this projection and the neurotransmitters involved remain unknown. In this study, we examined the relationship of VLPO efferents to the TMN using both retrograde and anterograde tracing, combined with immunocytochemistry. We found that the descending projection from the VLPO selectively targets the cell bodies and proximal dendrites of the histaminergic TMN. In addition, VLPO axons could be traced into the brainstem, where they provided terminals in the the serotoninergic dorsal and median raphe nuclei, and the core of the noradrenergic locus coeruleus. Approximately 80% of the VLPO neurons that were retrogradely labeled by tracer injections including the TMN were immunoreactive either for galanin or for glutamic acid decarboxylase (GAD), the synthetic enzyme for GABA. Virtually all of the galaninergic neurons in the VLPO were also GAD positive. Our results indicate that the VLPO may provide inhibitory GABAergic and galaninergic inputs to the cell bodies and proximal dendrites of the TMN and other components of the ascending monoaminergic arousal system. Because these cell groups are simultaneously inhibited during sleep, the VLPO sleep-active neurons may play a key role in silencing the ascending monoaminergic arousal system during sleep.

Addiction profoundly alters motivational circuits so that drugs become powerful reinforcers of behavior. The interoceptive system continuously updates homeostatic and emotional information that are important elements in motivational decisions. We tested the idea that interoceptive information is essential in drug craving and in the behavioral signs of malaise. We inactivated the primary interoceptive cortex in amphetamine-experienced rats, which prevented the urge to seek amphetamine in a place preference task. Interoceptive insula inactivation also blunted the signs of malaise induced by acute lithium administration. Drug-seeking and malaise both induced Fos expression, a marker of neuronal activation, in the insula. We conclude that the insular cortex is a key structure in the perception of bodily needs that provides direction to motivated behaviors.

The interesting observation was made 20 years ago that psychotic manifestations in patients with systemic lupus erythematosus are associated with the production of antiribosomal-P protein (anti-P) autoantibodies. Since then, the pathogenic role of anti-P antibodies has attracted considerable attention, giving rise to long-term controversies as evidence has either contradicted or confirmed their clinical association with lupus psychosis. Furthermore, a plausible mechanism supporting an anti-P–mediated neuronal dysfunction is still lacking. We show that anti-P antibodies recognize a new integral membrane protein of the neuronal cell surface. In the brain, this neuronal surface P antigen (NSPA) is preferentially distributed in areas involved in memory, cognition, and emotion. When added to brain cellular cultures, anti-P antibodies caused a rapid and sustained increase in calcium influx in neurons, resulting in apoptotic cell death. In contrast, astrocytes, which do not express NSPA, were not affected. Injection of anti-P antibodies into the brain of living rats also triggered neuronal death by apoptosis. These results demonstrate a neuropathogenic potential of anti-P antibodies and contribute a mechanistic basis for psychiatric lupus. They also provide a molecular target for future exploration of this and other psychiatric diseases.