Phase I Trial Characterizing the Pharmacokinetic Profile of N-803, a Chimeric IL-15 Superagonist, in Healthy Volunteers.

The oncotherapeutic promise of IL-15, a potent immunostimulant, is limited by a short serum The fusion protein N-803 is a chimeric IL-15 superagonist that has a >20-fold longer in vivo versus IL-15. This phase 1 study characterized the pharmacokinetic (PK) profile and safety of N-803 after s.c.

The lateral hypothalamus to lateral habenula projection, but not the ventral pallidum to lateral habenula projection, regulates voluntary ethanol consumption.

The lateral habenula (LHb) is an epithalamic brain region implicated in aversive processing via negative modulation of midbrain dopamine (DA) and serotonin (5-HT) systems. Given the role of the LHb in inhibiting DA and 5-HT systems, it is thought to be involved in various psychiatric pathologies, including drug addiction. In support, it has been shown that LHb plays a critical role in cocaine- and ethanol-related behaviors, most likely by mediating drug-induced aversive conditioning.

Mu opioid receptor signaling in the nucleus accumbens shell increases responsiveness of satiety-modulated lateral hypothalamus neurons.

Opioid signaling in the nucleus accumbens shell (sNAcc) has been implicated in hedonic feeding and binge eating behavior. The sNAcc projects to the lateral hypothalamus (LH), and this pathway has been suggested to modulate palatability-driven feeding behavior. In this study, we investigated the effects of sNAcc mu opioid receptor (MOR) stimulation on firing rates of LH neurons in previously sated rats.

Excitation of lateral habenula neurons as a neural mechanism underlying ethanol-induced conditioned taste aversion.

Key Points: The lateral habenula (LHb) has been implicated in regulation of drug-seeking behaviours through aversion-mediated learning. In this study, we recorded neuronal activity in the LHb of rats during an operant task before and after ethanol-induced conditioned taste aversion (CTA) to saccharin. Ethanol-induced CTA caused significantly higher baseline firing rates in LHb neurons, as well as elevated firing rates in response to cue presentation, lever press and saccharin taste.

Lesion of the rostromedial tegmental nucleus increases voluntary ethanol consumption and accelerates extinction of ethanol-induced conditioned taste aversion.

Rationale: Ethanol has rewarding and aversive properties, and the balance of these properties influences voluntary ethanol consumption. Preclinical and clinical evidence show that the aversive properties of ethanol limit intake. The neural circuits underlying ethanol-induced aversion learning are not fully understood.

Acute ethanol effects on neural encoding of reward size and delay in the nucleus accumbens.

Acute ethanol administration can cause impulsivity, resulting in increased preference for immediately available rewards over delayed but more valuable alternatives. The manner in which reward size and delay are represented in neural firing is not fully understood, and very little is known about ethanol effects on this encoding. To address this issue, we used in vivo electrophysiology to characterize neural firing in the core of the nucleus accumbens (NAcc) in rats responding for rewards that varied in size or delay after vehicle or ethanol administration.

Lesions of the lateral habenula increase voluntary ethanol consumption and operant self-administration, block yohimbine-induced reinstatement of ethanol seeking, and attenuate ethanol-induced conditioned taste aversion.

The lateral habenula (LHb) plays an important role in learning driven by negative outcomes. Many drugs of abuse, including ethanol, have dose-dependent aversive effects that act to limit intake of the drug. However, the role of the LHb in regulating ethanol intake is unknown.

Impaired flexibility in decision making in rats after administration of the pharmacological stressor yohimbine.

Rationale: Stress-induced disruption of decision making has been hypothesized to contribute to drug-seeking behaviors and addiction. Noradrenergic signaling plays a central role in mediating stress responses. However, the effects of acute stress on decision making, and the role of noradrenergic signaling in regulating these effects, have not been well characterized.

Invigoration of reward seeking by cue and proximity encoding in the nucleus accumbens.

A key function of the nucleus accumbens is to promote vigorous reward seeking, but the corresponding neural mechanism has not been identified despite many years of research. Here, we study cued flexible approach behavior, a form of reward seeking that strongly depends on the accumbens, and we describe a robust, single-cell neural correlate of behavioral vigor in the excitatory response of accumbens neurons to reward-predictive cues. Well before locomotion begins, this cue-evoked excitation predicts both the movement initiation latency and the speed of subsequent flexible approach responses, but not those of stereotyped, inflexible responses.

mu-Opioid receptor stimulation in the nucleus accumbens elevates fatty tastant intake by increasing palatability and suppressing satiety signals.

Infusion of a μ-opioid receptor (MOR) agonist into the nucleus accumbens (NAcc) drives voracious food intake, an effect hypothesized to occur through increased tastant palatability. While intake of many palatable foods is elevated by MOR stimulation, this manipulation has a preferential effect on fatty food ingestion. Consumption of high-fat foods is increased by NAcc MOR stimulation even in rats that prefer a carbohydrate-rich alternative under baseline conditions.

A pause in nucleus accumbens neuron firing is required to initiate and maintain feeding.

Nucleus accumbens (NAc) inactivation increases food intake, indicating that NAc neurons exert ongoing inhibition of feeding. We previously described a subpopulation of NAc neurons that pause during sucrose licking and proposed that the pause permits consumption. We tested this hypothesis by first recording NAc neurons during sucrose consumption, and then electrically stimulating through the same electrodes.

Preference or fat? Revisiting opioid effects on food intake.

It is well established that opioid signaling in the central nervous system constitutes a powerful stimulus for food intake. The role of opioids in determining food preference, however, is less well defined. Opioids have been proposed to promote intake of preferred foods, or, alternatively, to preferentially increase consumption of fat.

Modulation of feeding and locomotion through mu and delta opioid receptor signaling in the nucleus accumbens.

Opioid signaling has been strongly implicated in driving palatable food consumption. The nucleus accumbens (NAcc) is one important site of this effect; hyperphagia elicited by administration of exogenous mu opioid receptor (MOR) ligands in this brain region has been well documented. However, the role that endogenous opioid ligands in the NAcc play in controlling food intake remains poorly understood.

Inhibition of orexin-1/hypocretin-1 receptors inhibits yohimbine-induced reinstatement of ethanol and sucrose seeking in Long-Evans rats.

Rationale: Previous studies have shown that orexin-1/hypocretin-1 receptors play a role in self-administration and cue-induced reinstatement of food, drug, and ethanol seeking. In the current study, we examined the role of orexin-1/hypocretin-1 receptors in operant self-administration of ethanol and sucrose and in yohimbine-induced reinstatement of ethanol and sucrose seeking.

Materials And Methods: Rats were trained to self-administer either 10% ethanol or 5% sucrose (30 min/day).

Cue-evoked encoding of movement planning and execution in the rat nucleus accumbens.

The nucleus accumbens is involved in the modulation of motivated behaviour by reward-associated sensory information. However, little is known about the specific nature of the nucleus accumbens' contribution to generating movement. We investigated motor encoding by nucleus accumbens neurons in rats performing a delayed response task that allowed us to dissociate the effects of sensory and motor events on firing.

Endogenous opioids encode relative taste preference.

Endogenous opioid signaling contributes to the neural control of food intake. Opioid signaling is thought to regulate palatability, the reward value of a food item as determined by orosensory cues such as taste and texture. The reward value of a food reflects not only these sensory properties but also the relative value of competing food choices.

Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine.

Dopamine neurons in the ventral tegmental area (VTA) represent a critical site of synaptic plasticity induced by addictive drugs. Orexin/hypocretin-containing neurons in the lateral hypothalamus project to the VTA, and behavioral studies have suggested that orexin neurons play an important role in motivation, feeding, and adaptive behaviors. However, the role of orexin signaling in neural plasticity is poorly understood.

Inhibitions of nucleus accumbens neurons encode a gating signal for reward-directed behavior.

The nucleus accumbens (NAcc) is critical in the control of goal-directed behavior. Pharmacological studies suggest that the NAcc may act in both instructive and permissive modes; however, previous electrophysiological studies in behaving rats have reported firing patterns consistent with an instructive, but not permissive, role for NAcc neurons. We now report that a subset of NAcc neurons shows a long-lasting inhibition in firing rate whose onset precedes initiation of goal-directed sequences of behavior and terminates at the conclusion of the sequence.

Ocular dominance plasticity is stably maintained in the absence of alpha calcium calmodulin kinase II (alphaCaMKII) autophosphorylation.

The molecule alpha calcium calmodulin kinase II (alphaCaMKII) is known to play a fundamental role in the induction of many forms of synaptic plasticity. A major theory of alphaCaMKII function proposes that autophosphorylation of the molecule mediates not only the induction but also the maintenance of synaptic plasticity. To test this hypothesis, we assessed ocular dominance plasticity in genetically engineered mice that carry a mutation preventing autophosphorylation of alphaCaMKII.

Encoding of palatability and appetitive behaviors by distinct neuronal populations in the nucleus accumbens.

Obesity is a major public health problem. Palatability (i.e.

Molecular substrates of plasticity in the developing visual cortex.

Ocular dominance plasticity may be the paradigmatic in vivo model of activity-dependent plasticity. More than four decades of intense research has delineated the network-level rules that govern synaptic change in this model. The recent characterization of a murine model for ocular dominance plasticity has facilitated rapid progress on a new front, extending our understanding of the molecular mechanisms underlying ocular dominance plasticity.