ABSTRACT
The lateral septum (LS) is composed of heterogeneous cell types that are important for various motivated behaviors. However, the transcriptional profiles, spatial arrangement, function, and connectivity of these cell types have not been systematically studied. Using single-nucleus RNA sequencing, we delineated diverse genetically defined cell types in the LS that play distinct roles in reward processing. Notably, we found that estrogen receptor 1 (Esr1)-expressing neurons in the ventral LS (LSEsr1) are key drivers of reward seeking via projections to the ventral tegmental area, and these neurons play an essential role in methamphetamine (METH) reward and METH-seeking behavior. Extended exposure to METH increases the excitability of LSEsr1 neurons by upregulating hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, thereby contributing to METH-induced locomotor sensitization. These insights not only elucidate the intricate molecular, circuit, and functional architecture of the septal region in reward processing but also reveal a neural pathway critical for METH reward and behavioral sensitization.
Subject(s)
Methamphetamine , Neurons , Reward , Septal Nuclei , Animals , Mice , Neurons/physiology , Neurons/metabolism , Methamphetamine/pharmacology , Septal Nuclei/physiology , Septal Nuclei/metabolism , Male , Ventral Tegmental Area/physiology , Ventral Tegmental Area/metabolism , Estrogen Receptor alpha/metabolism , Estrogen Receptor alpha/genetics , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics , Neural Pathways/physiology , Mice, Inbred C57BL , Drug-Seeking Behavior/physiologyABSTRACT
Although the brain can discriminate between various sweet substances, the underlying neural mechanisms of this complex behavior remain elusive. This study examines the role of the anterior paraventricular nucleus of the thalamus (aPVT) in governing sweet preference in mice. We fed the mice six different diets with equal sweetness for six weeks: control diet (CD), high sucrose diet (HSD), high stevioside diet (HSSD), high xylitol diet (HXD), high glycyrrhizin diet (HGD), and high mogroside diet (HMD). The mice exhibited a marked preference specifically for the HSD and HSSD. Following consumption of these diets, c-Fos expression levels in the aPVT were significantly higher in these two groups compared to the others. Utilizing fiber photometry calcium imaging, we observed rapid activation of aPVT neurons in response to sucrose and stevioside intake, but not to xylitol or water. Our findings suggest that aPVT activity aligns with sweet preference in mice, and notably, stevioside is the sole plant-based sweetener that elicits an aPVT response comparable to that of sucrose.
Subject(s)
Neurons , Sweetening Agents , Animals , Sweetening Agents/administration & dosage , Sweetening Agents/pharmacology , Male , Neurons/drug effects , Neurons/metabolism , Neurons/physiology , Mice , Mice, Inbred C57BL , Proto-Oncogene Proteins c-fos/metabolism , Food Preferences/physiology , Food Preferences/drug effectsABSTRACT
In this paper, the fatigue crack growth rates of typical pressure vessel material 4130X under different corrosion conditions are investigated, and the effects of corrosion modes and loading frequency on the fatigue crack growth rate of 4130X are discussed. The results show that under the same loading conditions, the pre-corroded crack propagation rate is increased by 1.26 times compared with the uncorroded specimens. The plastic deformation mechanism of the crack tip in air is dominated by phase transformation but the hydrogen introduced by pre-corrosion causes a small number of dislocations at the crack tip. The crack growth rate obtained by corrosion fatigue is four times that of the uncorroded specimen, and the fracture surface shows a strong corrosion effect. The molecular dynamics simulation shows that the hydrogen atoms accumulated at the crack tip make the plastic deformation mechanism dominated by dislocation in the crack propagation process, and the coupling interaction between low frequency and the corrosion environment aggravates the hydrogen embrittlement of the crack tip. In the air condition, the loading frequency has no obvious effect on the crack growth rate: when the frequency decreases from 100 Hz to 0.01 Hz and other conditions remain unchanged, the fatigue crack growth rate increases by 1.5 times. The parameter n in the Paris expression is mainly influenced by frequency. The molecular dynamics simulation shows that low frequency promotes crack tip propagation.
ABSTRACT
The paraventricular nucleus of the thalamus (PVT) is involved in drug addiction-related behaviors, and morphine is a widely used opioid for the relief of severe pain. Morphine acts via opioid receptors, but the function of opioid receptors in the PVT has not been fully elucidated. Here, we used in vitro electrophysiology to study neuronal activity and synaptic transmission in the PVT of male and female mice. Activation of opioid receptors suppresses the firing and inhibitory synaptic transmission of PVT neurons in brain slices. On the other hand, the involvement of opioid modulation is reduced after chronic morphine exposure, probably because of desensitization and internalization of opioid receptors in the PVT. Overall, the opioid system is essential for the modulation of PVT activities.SIGNIFICANCE STATEMENT Opioid receptors modulate the activities and synaptic transmission in the PVT by suppressing the firing rate and inhibitory synaptic inputs. These modulations were largely diminished after chronic morphine exposure.
Subject(s)
Analgesics, Opioid , Receptors, Opioid , Male , Female , Mice , Animals , Analgesics, Opioid/pharmacology , Paraventricular Hypothalamic Nucleus/physiology , Thalamus , Synaptic Transmission , Morphine/pharmacologyABSTRACT
The nucleus accumbens (NAc) is critical in mediating reward seeking and is also involved in negative emotion processing, but the cellular and circuitry mechanisms underlying such opposing behaviors remain elusive. Here, using the recently developed AAV1-mediated anterograde transsynaptic tagging technique in mice, we show that NAc neurons receiving basolateral amygdala inputs (NAcBLA) promote positive reinforcement via disinhibiting dopamine neurons in the ventral tegmental area (VTA). In contrast, NAc neurons receiving paraventricular thalamic inputs (NAcPVT) innervate GABAergic neurons in the lateral hypothalamus (LH) and mediate aversion. Silencing the synaptic output of NAcBLA neurons impairs reward seeking behavior, while silencing of NAcPVT or NAcPVTâLH pathway abolishes aversive symptoms of opiate withdrawal. Our results elucidate the afferent-specific circuit architecture of the NAc in controlling reward and aversion.
Subject(s)
Nucleus Accumbens , Opiate Alkaloids , Mice , Animals , Nucleus Accumbens/metabolism , Reward , Ventral Tegmental Area/physiology , Dopaminergic NeuronsABSTRACT
Feeding behavior is regulated by both the homeostatic needs of the body and hedonic values of the food. Easy access to palatable energy-dense foods and the consequent obesity epidemic stress the urgent need for a better understanding of neural circuits that regulate hedonic feeding. Here, we report that neurotensin-positive neurons in the lateral septum (LSNts) play a crucial role in regulating hedonic feeding. Silencing LSNts specifically promotes feeding of palatable food, whereas activation of LSNts suppresses overall feeding. LSNts neurons project to the tuberal nucleus (TU) via GABA signaling to regulate hedonic feeding, while the neurotensin signal from LSNtsâthe supramammillary nucleus (SUM) is sufficient to suppress overall feeding. In vivo calcium imaging and optogenetic manipulation reveal two populations of LSNts neurons that are activated and inhibited during feeding, which contribute to food seeking and consumption, respectively. Chronic activation of LSNts or LSNtsâTU is sufficient to reduce high-fat diet-induced obesity. Our findings suggest that LSNtsâTU is a key pathway in regulating hedonic feeding.