Hypothalamic neurons that co-express agouti-related protein (AgRP), neuropeptide Y (NPY), and γ-amino-butyric acid (GABA) are known to promote feeding and weight gain by integration of various nutritional, hormonal, and neuronal signals1,2. Ablation of these neurons leads to cessation of feeding that is accompanied by Fos activation in most regions where they project3–6. Previous experiments indicate that the ensuing starvation is due to aberrant activation of the parabrachial nucleus (PBN) and it could be prevented by facilitating GABAA receptor signaling in the PBN within a critical adaptation period5. We hypothesized that loss of GABAergic inhibition from AgRP neurons to the PBN leads to abnormal activation of the PBN, which in turn inhibits feeding. However, the source of the excitatory inputs to the PBN was unknown. Here we show that glutamatergic neurons in the nucleus tractus solitarius (NTS) and caudal serotonergic neurons control the excitability of PBN neurons and inhibit feeding. Blockade of 5-HT3 receptor signaling in the rostral NTS by either chronic administration of ondansetron or genetic inactivation of Tph2 in caudal serotonergic neurons that project to the NTS protects against starvation when AgRP neurons are ablated. Moreover, genetic inactivation of glutamatergic signaling by the NTS onto N-methyl D-aspartate (NMDA)-type glutamate receptors in the PBN prevents starvation. We also demonstrate that suppressing glutamatergic output of the PBN reinstates normal appetite after AgRP neuron ablation, whereas it promotes weight gain without AgRP neuron ablation. Hence, we identify the PBN as an important hub that integrates signals from several brain regions to bidirectionally modulate feeding and body weight.

Although chronic cocaine-induced changes in dendritic spines on nucleus accumbens (NAc) neurons have been correlated with behavioral sensitization, the molecular pathways governing these structural changes, and their resulting behavioral effects, are poorly understood. The transcription factor, nuclear factor B (NFB), is rapidly activated by diverse stimuli and regulates expression of many genes known to maintain cell structure. Therefore, we evaluated the role of NFB in regulating cocaine-induced dendritic spine changes on medium spiny neurons of the NAc and the rewarding effects of cocaine. We show that chronic cocaine induces NFB-dependent transcription in the NAc of NFB-Lac transgenic mice. This induction of NFB activity is accompanied by increased expression of several NFB genes, the promoters of which show chromatin modifications after chronic cocaine exposure consistent with their transcriptional activation. To study the functional significance of this induction, we used viral-mediated gene transfer to express either a constitutively active or dominant-negative mutant of Inhibitor of B kinase (IKKca or IKKdn), which normally activates NFB signaling, in the NAc. We found that activation of NFB by IKKca increases the number of dendritic spines on NAc neurons, whereas inhibition of NFB by IKKdn decreases basal dendritic spine number and blocks the increase in dendritic spines after chronic cocaine. Moreover, inhibition of NFB blocks the rewarding effects of cocaine and the ability of previous cocaine exposure to increase an animal's preference for cocaine. Together, these studies establish a direct role for NFB pathways in the NAc to regulate structural and behavioral plasticity to cocaine.

Summary Fear is a graded central motive state ranging from mild to intense. As threat intensity increases, fear transitions from discriminative to generalized. The circuit mechanisms that process threats of different intensity are not well resolved. Here, we isolate a unique population of locally projecting neurons in the central nucleus of the amygdala (CeA) that produce the neuropeptide corticotropin-releasing factor (CRF). CRF-producing neurons and CRF in the CeA are required for discriminative fear, but both are dispensable for generalized fear at high US intensities. Consistent with a role in discriminative fear, CRF neurons undergo plasticity following threat conditioning and selectively respond to threat-predictive cues. We further show that excitability of genetically isolated CRF-receptive (CRFR1) neurons in the CeA is potently enhanced by CRF and that CRFR1 signaling in the CeA is critical for discriminative fear. These findings demonstrate a novel CRF gain-control circuit and show separable pathways for graded fear processing.

Background and Purpose-We wished to examine the effectiveness of an early hospital discharge and home-based rehabilitation scheme for patients with acute stroke. Methods-This was a randomized, controlled trial comparing early hospital discharge and home-based rehabilitation with usual inpatient rehabilitation and follow-up care. The trial was carried out in 2 affiliated teaching hospitals in Adelaide, South Australia. Participants were 86 patients with acute stroke (mean age, 75 years) who were admitted to hospital and required rehabilitation. Forty-two patients received early hospital discharge and home-based rehabilitation (median duration, 5 weeks), and 44 patients continued with conventional rehabilitation care after randomization. The primary end point was self-reported general health status (SF-36) at 6 months after randomization. A variety of secondary outcome measures were also assessed. Results-Overall, clinical outcomes for patients did not differ significantly between the groups at 6 months after randomization, but the total duration of hospital stay in the experimental group was significantly reduced (15 versus 30 days; PϽ0.001). Caregivers among the home-based rehabilitation group had significantly lower mental health SF-36 scores (mean difference, 7 points). Conclusions-A policy of early hospital discharge and home-based rehabilitation for patients with stroke can reduce the use of hospital rehabilitation beds without compromising clinical patient outcomes. However, there is a potential risk of poorer mental health on the part of caregivers. The choice of this management strategy may therefore depend on convenience and costs but also on further evaluations of the impact of stroke on caregivers.