The medial preoptic area (mPOA) differs between males and females in nearly all species examined to date, including humans. Here, using fiber photometry recordings of Ca
transients in freely behaving ...mice, we show ramping activities in the mPOA that precede and correlate with sexually dimorphic display of male-typical mounting and female-typical pup retrieval. Strikingly, optogenetic stimulation of the mPOA elicits similar display of mounting and pup retrieval in both males and females. Furthermore, by means of recording, ablation, optogenetic activation, and inhibition, we show mPOA neurons expressing estrogen receptor alpha (Esr1) are essential for the sexually biased display of these behaviors. Together, these results underscore the shared layout of the brain that can mediate sex-specific behaviors in both male and female mice and provide an important functional frame to decode neural mechanisms governing sexually dimorphic behaviors in the future.
Uncontrollable itch-scratching cycles lead to serious skin damage in patients with chronic itch. However, the neural mechanism promoting the itch-scratching cycle remains elusive. Here, we report ...that tachykinin 1 (Tac1)-expressing glutamatergic neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) facilitate the itch-scratching cycle. We found that l/vlPAG neurons exhibited scratching-behavior-related neural activity and that itch-evoked scratching behavior was impaired after suppressing the activity of l/vlPAG neurons. Furthermore, we showed that the activity of Tac1-expressing glutamatergic neurons in the l/vlPAG was elevated during itch-induced scratching behavior and that ablating or suppressing the activity of these neurons decreased itch-induced scratching behavior. Importantly, activation of Tac1-expressing neurons induced robust spontaneous scratching and grooming behaviors. The scratching behavior evoked by Tac1-expressing neuron activation was suppressed by ablation of spinal neurons expressing gastrin-releasing peptide receptor (GRPR), the key relay neurons for itch. These results suggest that Tac1-expressing neurons in the l/vlPAG promote itch-scratching cycles.
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•Neurons in l/vlPAG exhibit scratching behavior related to neural activities•Ablation of Tac1+ but not SST+ neurons decreases itch-induced scratching behavior•Activation of Tac1+ neurons induces spontaneous scratching and grooming behaviors•l/vlPAG Tac1+ neurons modulate spinal itch processing via a RVM-dependent pathway
Gao et al. demonstrate that Tac1-expressing neurons in the l/vlPAG modulate spinal itch processing via a descending pathway. These neurons represent a critical component in the neural circuit that drives the itch-scratching cycle.
The parabrachial nucleus (PBN) is one of the major targets of spinal projection neurons and plays important roles in pain. However, the architecture of the spinoparabrachial pathway underlying its ...functional role in nociceptive information processing remains elusive. Here, we report that the PBN directly relays nociceptive signals from the spinal cord to the intralaminar thalamic nuclei (ILN). We demonstrate that the spinal cord connects with the PBN in a bilateral manner and that the ipsilateral spinoparabrachial pathway is critical for nocifensive behavior. We identify Tacr1-expressing neurons as the major neuronal subtype in the PBN that receives direct spinal input and show that these neurons are critical for processing nociceptive information. Furthermore, PBN neurons receiving spinal input form functional monosynaptic excitatory connections with neurons in the ILN, but not the amygdala. Together, our results delineate the neural circuit underlying nocifensive behavior, providing crucial insight into the circuit mechanism underlying nociceptive information processing.
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•The ipsi- and contralateral spinoparabrachial pathways are functionally distinct•The ipsilateral spinoparabrachial pathway mediates nocifensive behavior•Tacr1+ neurons in the PBN represent the major target of spinal projection•The PBN relays nociceptive information to the ILN via glutamatergic synapses
Deng et al. demonstrate that the ipsilateral spinoparabrachial pathway mediates nocifensive behavior and identify that the Tacr1+ neurons in the parabrachial nucleus represent the major target of the spinal projection. The authors also reveal the major downstream pathway for processing nociceptive information.
AGRP (agouti-related neuropeptide) expressing inhibitory neurons sense caloric needs of an animal to coordinate homeostatic feeding. Recent evidence suggests that AGRP neurons also suppress competing ...actions and motivations to mediate adaptive behavioral selection during starvation. Here, in adult mice of both sexes we show that AGRP neurons form inhibitory synapses onto ∼30% neurons in the medial preoptic area (mPOA), a region critical for maternal care. Remarkably, optogenetically stimulating AGRP neurons decreases maternal nest-building while minimally affecting pup retrieval, partly recapitulating suppression of maternal behaviors during food restriction. In parallel, optogenetically stimulating AGRP projections to the mPOA or to the paraventricular nucleus of hypothalamus but not to the LHA (lateral hypothalamus area) similarly decreases maternal nest-building. Chemogenetic inhibition of mPOA neurons that express Vgat (vesicular GABA transporter), the population targeted by AGRP terminals, also decreases maternal nest-building. In comparison, chemogenetic inhibition of neurons in the LHA that express vesicular glutamate transporter 2, another hypothalamic neuronal population critical for feeding and innate drives, is ineffective. Importantly, nest-building during low temperature thermal challenge is not affected by optogenetic stimulation of AGRP→mPOA projections. Finally, via optogenetic activation and inhibition we show that distinctive subsets of mPOA Vgat+ neurons likely underlie pup retrieval and maternal nest-building. Together, these results show that AGRP neurons can modulate maternal nest-building, in part through direct projections to the mPOA. This study corroborates other recent discoveries and underscores the broad functions that AGRP neurons play in antagonizing rivalry motivations to modulate behavioral outputs during hunger.
In order for animals to initiate ethologically appropriate behaviors, they must typically decide between behavioral repertoires driven by multiple and often conflicting internal states. How neural pathways underlying individual behaviors interact to coherently modulate behavioral outputs, in particular to achieve a proper balance between behaviors that serve immediate individual needs versus those that benefit the propagation of the species, remains poorly understood. Here, by investigating projections from a neuronal population known to drive hunger behaviors to a brain region critical for maternal care, we show that activation of AGRP→mPOA projections in females dramatically inhibits maternal nest-building while leaving mostly intact pup retrieval behavior. Our findings shed new light on neural organization of behaviors and neural mechanisms that coordinate behavioral selection.
Accumulated genetic evidences indicate that the contactin associated protein-like (CNTNAP) family is implicated in autism spectrum disorders (ASD). In this study, we identified genetic mutations in ...the CNTNAP3 gene from Chinese Han ASD cohorts and Simons Simplex Collections. We found that CNTNAP3 interacted with synaptic adhesion proteins Neuroligin1 and Neuroligin2, as well as scaffolding proteins PSD95 and Gephyrin. Significantly, we found that CNTNAP3 played an opposite role in controlling the development of excitatory and inhibitory synapses in vitro and in vivo, in which ASD mutants exhibited loss-of-function effects. In this study, we showed that the male Cntnap3-null mice exhibited deficits in social interaction， spatial learning and prominent repetitive behaviors. These evidences elucidate the pivotal role of CNTNAP3 in synapse development and social behaviors, providing mechanistic insights into ASD.
•Genetic mutations in the CNTNAP3 gene were identified from Chinese Han ASD cohorts and Simons Simplex Collections.•CNTNAP3 interacted with NLGN1 and NLGN2 via its LamG domain, as well as PSD95 and Gephyrin via its PDZ-binding domain.•Knocking down of Cntnap3 led to decrease of excitatory synapse and increase of the inhibitory synapse formation.•Cntnap3−/− mice exhibited deficits in social behavior, cognitive tasks and prominent repetitive behaviors.
BN is the currently required segregant for perpendicular FePt media. We found that BN can be diffused from the MgTiOBN intermediate layer during a high temperature process. The FePtCAg film sputtered ...on MgTiOBN layers illustrates higher perpendicular magnetocrystalline anisotropy (K
) (1.43 × 10
erg/cm
) and coercivity (normal to film surface) (17 kOe) at 350 K compared to BN/FePtCAg/MgTiON film. From the microstructure, the FePtCAg film shows the granular structure on the MgTiOBN intermediate layer, but parts of the irregular FePt grains are agglomerated and partially separated in the matrix, with grains size being, on average, 26.7 nm. Cross-sectional imaging showed that the FePt grains have a truncated pyramid shape with a lower wetting angle, which is influenced by the surface energy of MgTiOBN. BN segregation at FePt grains or boundaries is still not clear. Using the electron energy loss spectrum (EELS), we found that part of the BN atoms were clearly observed in the FePt lattice and iron-boride oxide was indexed in the x-ray photoelectron spectroscopy (XPS) spectra. To determine the effects of BN segregant (from capping layer or intermediate layer) on the magnetic switching behavior of FePtCAg film, the intrinsic-(ΔH
= 6.17 kOe, 6.54 kOe) and extrinsic- (ΔH
= 0.80 kOe, 0.39 kOe) switching field distribution (SFD) were measured by plotting saturated major- and unsaturated minor- hysteresis loops to evaluate the crystal orientation and microstructure (grains volume and distribution) for BN/FePtCAg/MgTiON and FePtCAg/MgTiOBN films, respectively. The main contribution of intrinsic SFD is the c-axis misalignment for the BN/FePt/MgTiON sample; however, the dispersed magnetic anisotropy has a higher input to intrinsic SFD for FePtCAg/MgTiOBN/CrRu film.
The homeostatic control of body temperature is essential for survival in mammals and is known to be regulated in part by temperature-sensitive neurons in the hypothalamus. However, the specific ...neural pathways and corresponding neural populations have not been fully elucidated. To identify these pathways, we used cFos staining to identify neurons that are activated by a thermal challenge and found induced expression in subsets of neurons within the ventral part of the lateral preoptic nucleus (vLPO) and the dorsal part of the dorsomedial hypothalamus (DMD). Activation of GABAergic neurons in the vLPO using optogenetics reduced body temperature, along with a decrease in physical activity. Optogenetic inhibition of these neurons resulted in fever-level hyperthermia. These GABAergic neurons project from the vLPO to the DMD and optogenetic stimulation of the nerve terminals in the DMD also reduced body temperature and activity. Electrophysiological recording revealed that the vLPO GABAergic neurons suppressed neural activity in DMD neurons, and fiber photometry of calcium transients revealed that DMD neurons were activated by cold. Accordingly, activation of DMD neurons using designer receptors exclusively activated by designer drugs (DREADDs) or optogenetics increased body temperature with a strong increase in energy expenditure and activity. Finally, optogenetic inhibition of DMD neurons triggered hypothermia, similar to stimulation of the GABAergic neurons in the vLPO. Thus, vLPO GABAergic neurons suppressed the thermogenic effect of DMD neurons. In aggregate, our data identify vLPO→DMD neural pathways that reduce core temperature in response to a thermal challenge, and we show that outputs from the DMD can induce activity-induced thermogenesis.
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•Stainless steel pipes are commonly used to replace lead pipes in Asia.•Three-metal galvanic system can form during partial replacement of lead pipes.•Lead release was the highest ...when materials were in order of reduction potential.•A more fluent electron transport resulted in more lead release.•The presence of a third metal can influence the magnitude of galvanic currents.
Lead pipe has been banned in the drinking water distribution system in most countries since 1980s. Although water authorities around the world have attempted to replace all remaining lead pipes in service, pipe replacement was often hindered by high cost and lack of access to private premises. Hence, partial replacement has become a common scenario where portions of lead pipes remain in the system. When the lead pipe is connected to two other different metallic materials at both ends, two different galvanic couples can form simultaneously in this three-metal system. The release of lead resulting from galvanic corrosion in such three-metal systems consisting of lead (Pb), copper (Cu) and stainless steel (SS) with three different configurations, namely Cu-SS-Pb, SS-Cu-Pb and Cu-Pb-SS was investigated in this study. The results showed that when the materials are arranged in order of reduction potential as in SS-Cu-Pb configuration, lead release was the highest. A more fluent electron transport across the system was proposed based on the direction and magnitude of galvanic currents measured at each galvanic couple.
Inhibition of tumor metastasis is one of the most important purposes in colorectal cancer (CRC) treatment. This study aimed to explore the effects of liquiritigenin, a flavonoid extracted from the ...roots of Glycyrrhiza uralensis Fisch, on HCT116 cell proliferation, invasion, and
epithelial-to-mesenchymal transition (EMT). We found that liquiritigenin significantly inhibited HCT116 cell proliferation, invasion, and the EMT process, but had no influence on cell apoptosis. Moreover, liquiritigenin remarkably reduced the expression of runt-related transcription factor
2 (Runx2) in HCT116 cells. Overexpression of Runx2 obviously reversed the liquiritigenin-induced invasion and EMT inhibition. Furthermore, liquiritigenin inactivated the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway in HCT116 cells. Upregulation of Runx2 reversed the liquiritigenin-induced
PI3K/AKT pathway inactivation. In conclusion, our research verified that liquiritigenin exerted significant inhibitory effects on CRC invasion and EMT process by downregulating the expression of Runx2 and inactivating the PI3K/AKT signaling pathway. Liquiritigenin could be an effective therapeutic
and preventative medicine for CRC treatment.
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