Prelimbic cortex-nucleus accumbens core projection positively regulates itch and itch-related aversion.

Itch is one of the most common clinical symptoms in patients with diseases of the skin, liver, or kidney, and it strongly triggers aversive emotion and scratching behavior. Previous studies have confirmed the role of the prelimbic cortex (Prl) and the nucleus accumbens core (NAcC), which are reward and motivation regulatory centers, in the regulation of itch. However, it is currently unclear whether the Prl-NAcC projection, an important pathway connecting these two brain regions, is involved in the regulation of itch and its associated negative emotions. In this study, rat models of acute neck and cheek itch were established by subcutaneous injection of 5-HT, compound 48/80, or chloroquine. Immunofluorescence experiments determined that the number of c-Fos-immunopositive neurons in the Prl increased during acute itch. Chemogenetic inhibition of Prl glutamatergic neurons or Prl-NAcC glutamatergic projections can inhibit both histaminergic and nonhistaminergic itch-scratching behaviors and rectify the itch-related conditioned place aversion (CPA) behavior associated with nonhistaminergic itch. The Prl-NAcC projection may play an important role in the positive regulation of itch-scratching behavior by mediating the negative emotions related to itch.

The Anterior Insula and its Projection to the Prelimbic Cortex are Involved in the Regulation of 5-HT-Induced Itch.

Itch is an unpleasant sensation that urges people and animals to scratch. Neuroimaging studies on itch have yielded extensive correlations with diverse cortical and subcortical regions, including the insular lobe. However, the role and functional specificity of the insular cortex (IC) and its subdivisions in itch mediation remains unclear. Here, we demonstrated by immunohistochemistry and fiber photometry tests, that neurons in both the anterior insular cortex (AIC) and the posterior insular cortex (PIC) are activated during acute itch processes. Pharmacogenetic experiments revealed that nonselective inhibition of global AIC neurons, or selective inhibition of the activity of glutaminergic neurons in the AIC, reduced the scratching behaviors induced by intradermal injection of 5-hydroxytryptamine (5-HT), but not those induced by compound 48/80. However, both nonselective inhibition of global PIC neurons and selective inhibition of glutaminergic neurons in the PIC failed to affect the itching-scratching behaviors induced by either 5-HT or compound 48/80. In addition, pharmacogenetic inhibition of AIC glutaminergic neurons effectively blocked itch-associated conditioned place aversion behavior, and inhibition of AIC glutaminergic neurons projecting to the prelimbic cortex significantly suppressed 5-HT-evoked scratching. These findings provide preliminary evidence that the AIC is involved, at least partially via aversive emotion mediation, in the regulation of 5-HT-, but not compound 48/80-induced itch.

Dysgranular retrosplenial cortex modulates histaminergic and nonhistaminergic itch processing.

Itch is an unpleasant sensation followed by an intense desire to scratch. Previous researches have advanced our understanding about the role of anterior cingulate cortex and prelimbic cortex in itch modulation, whereas little is known about the effects of retrosplenial cortex (RSC) during this process. Here we firstly confirmed that the neuronal activity of dysgranular RSC (RSCd) is significantly elevated during itch-scratching processing through c-Fos immunohistochemistry and fiber photometry recording. Then with designer receptors exclusively activated by designer drugs approaches, we found that pharmacogenetic inhibition of global RSCd neurons attenuated the number of scratching bouts as well as the cumulative duration of scratching bouts elicited by both 5-HT or compound 48/80 injection into rats' nape or cheek; selective inhibition of the pyramidal neurons in RSCd, or of the excitatory projections from caudal anterior cingulate cortex (cACC) to RSCd, demonstrated the similar effects of decreasing itch-related scratching induced by both 5-HT or compound 48/80. Pharmacogenetic intervention of the neuronal or circuitry activities did not affect rats' motor ability. This study presents direct evidence that pyramidal neurons in RSCd, and the excitatory projection from cACC to RSCd are critically involved in central regulation of both histaminergic and nonhistaminergic itch.

Differential roles of prelimbic and anterior cingulate cortical region in the modulation of histaminergic and non-histaminergic itch.

Itch is an unpleasant sensation that evokes a desire to scratch. Itch processing in the peripheral and spinal cord has been studied extensively, but the mechanism of itch in the central nervous system is still unclear. Anterior cingulate cortex (ACC) and prelimbic cortex (Prl), two subregions of the prefrontal cortex closely related to emotion and motivation, have been reported to be activated during itching in a series of functional imaging studies. However, the exact role of Prl and the differences between ACC and Prl in itch modulation remains unknown. To directly test the differential roles of ACC and Prl in itch processing, we chemogeneticlly inhibited the caudal ACC and Prl, respectively. We found that inhibition of caudal ACC reduced histaminergic but not non-histaminergic itch-induced scratching behaviors. In contrast, inhibition of Prl reduced both histaminergic and non-histaminergic itch-induced scratching behaviors. Our study provided direct evidence of Prl involvement in itch modulation and revealed the differential roles of caudal ACC and Prl in regulating histaminergic and non-histaminergic itch.

[Removal of Nitrogen and Phosphorus from Water by Biomass Carbon of Aquatic Plants].

In the bioremediation of eutrophic water, a large number of aquatic plants will be produced. How to continue the reasonable disposition is the question that needs to be solved. In this paper, biomass carbon was prepared from aquatic plants, and the adsorption capacity of the biomass carbon on nitrogen and phosphorus in water was improved by magnesium modification. The characterization results of material properties showed that magnesium modification not only formed nanometer MgO sheets on the surface of biomass carbon to increase the specific surface area, but also introduced hydroxyl functional groups to promote the adsorption of ammonium nitrogen. The adsorption processes of modified biomass carbon on nitrates and ammonium nitrogen belonged to multi-layer adsorption, and the adsorption isotherms conformed to the Freundlich model. The adsorption mechanism of modified biomass carbon changed from single layer adsorption to multi-layer diffusion. The maximum adsorption capacity of the modified biomass carbon on nitrate nitrogen, ammonium nitrogen, and phosphorus were 5.66, 62.53, and 90.92 mg·g-1, respectively. The adsorption capacity of the modified biomass carbon on ammonium nitrogen is 178 times that of unmodified biomass carbon. When phosphorus, nitrate nitrogen, and ammonium nitrogen coexist, the adsorption amounts of modified biomass carbon increase by 79.1%, 67.5%, and 47.1%, respectively. The results of this paper showed that the preparation of biomass carbon can realize the resource recovery of aquatic plants, and can be used for the removal of nitrogen and phosphorus pollution from water, which has good prospects for application.

Reevaluating the ability of cerebellum in associative motor learning.

It has been well established that the cerebellum and its associated circuitry constitute the essential neuronal system for both delay and trace classical eyeblink conditioning (DEC and TEC). However, whether the cerebellum is sufficient to independently modulate the DEC, and TEC with a shorter trace interval remained controversial. Here, we used direct optogenetic stimulation of mossy fibers in the middle cerebellar peduncle (MCP) as a conditioned stimulus (CS) replacement for the peripheral CS (eg, a tone CS or a light CS) paired with a periorbital shock unconditioned stimulus (US) to examine the ability of the cerebellum to learn the DEC and the TEC with various trace intervals. Moreover, neural inputs to the pontine nucleus (PN) were pharmacological blocked to limit the associative motor learning inside the cerebellum. We show that all rats quickly acquired the DEC, indicating that direct optogenetic stimulation of mossy fibers in the left MCP is a very effective and sufficient CS to establish DEC and to limit the motor learning process inside the cerebellum. However, only five out of seven rats acquired the TEC with a 150-ms trace interval, three out of nine rats acquired the TEC with a 350-ms trace interval, and none of the rats acquired the TEC with a 500-ms trace interval. Moreover, pharmacological blocking glutamatergic and GABAergic inputs to the PN from the extra-cerebellar and cerebellar regions has no significant effect on the DEC and TEC learning with the optogenetic CS. These results indicate that the cerebellum has the ability to independently support both the simple DEC, and the TEC with a trace interval of 150 or 350 ms, but not the TEC with a trace interval of 500 ms. The present results are of great importance in our understanding of the mechanisms and ability of the cerebellum in associative motor learning and memory.

Medial Prefrontal Cortex-Pontine Nuclei Projections Modulate Suboptimal Cue-Induced Associative Motor Learning.

Diverse and powerful mechanisms have evolved to enable organisms to modulate learning and memory under a variety of survival conditions. Cumulative evidence has shown that the prefrontal cortex (PFC) is closely involved in many higher-order cognitive functions. However, when and how the medial PFC (mPFC) modulates associative motor learning remains largely unknown. Here, we show that delay eyeblink conditioning (DEC) with the weak conditioned stimulus (wCS) but not the strong CS (sCS) elicited a significant increase in the levels of c-Fos expression in caudal mPFC. Both optogenetic inhibition and activation of the bilateral caudal mPFC, or its axon terminals at the pontine nucleus (PN) contralateral to the training eye, significantly impaired the acquisition, recent and remote retrieval of DEC with the wCS but not the sCS. However, direct optogenetic activation of the contralateral PN had no significant effect on the acquisition, recent and remote retrieval of DEC. These results are of great importance in understanding the elusive role of the mPFC and its projection to PN in subserving the associative motor learning under suboptimal learning cue.

Genome-wide association study identifies RBFOX1 locus influencing brain glucose metabolism.

BACKGROUND: Fluorodeoxyglucose f18 positron emission tomography (18F-FDG PET) is regarded as the only functional neuroimaging biomarker for degeneration which can be used to increase the certainty of Alzheimer's disease (AD) pathophysiological process in research settings or as an optional clinical tool where available. Although a decline in FDG metabolism was confirmed in some regions known to be associated with AD, there was little known about the genetic association of FDG metabolism in AD cohorts. In this study, we present the first genome-wide association study (GWAS) analysis of brain FDG metabolism. METHODS: A total of 222 individuals were included from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI-1) cohort. All subjects were restricted to non-Hispanic Caucasians and met all quality control (QC) criteria. Associations of 18F-FDG with the genetic variants were assessed using PLINK 1.07 under the additive genetic model. Genome-wide associations were visualized using a software program R 3.2.3. RESULTS: One significant SNP rs12444565 in RNA-binding Fox1 (RBFOX1) was found to have a strong association with 18F-FDG (P=6.06×10-8). Rs235141, rs79037, rs12526331 and rs12529764 were identified as four suggestive loci associated with 18F-FDG. CONCLUSIONS: Our study results suggest that a genome-wide significant SNP (rs12444565) in the RBFOX1, and four suggestive loci (rs235141, rs79037, rs12526331 and rs12529764) are associated with 18F-FDG.

Optogenetic Inhibition of Medial Prefrontal Cortex-Pontine Nuclei Projections During the Stimulus-free Trace Interval Impairs Temporal Associative Motor Learning.

The medial prefrontal cortex (mPFC) is closely involved in many higher-order cognitive functions, including learning to associate temporally discontiguous events (called temporal associative learning). However, direct evidence for the role of mPFC and the neural pathway underlying modulation of temporal associative motor learning is sparse. Here, we show that optogenetic inhibition of the mPFC or its axon terminals at the pontine nuclei (PN) during trace intervals or whole trial period significantly impaired the trace eyeblink conditioning (TEC), but had no significant effects on TEC during the conditioned stimulus or intertrial interval period. Our results suggest that activities associated with the mPFC-PN projection during trace intervals is crucial for trace associative motor learning. This finding is of great importance in understanding the mechanisms and the relevant neural pathways underlying mPFC modulation of temporal associative motor learning.

NME8 rs2718058 polymorphism with Alzheimer's disease risk: a replication and meta-analysis.

Recently, a large meta-analysis of five genome wide association studies (GWAS) has identified that a novel single nucleotide polymorphism (SNP) rs2718058, adjacent to gene NME8 on chromosome 7p14.1, was associated with late-onset Alzheimer's disease (LOAD) in Caucasians. However, the effect of rs2718058 on other populations remains unclear. In order to explore the relationship between rs2718058 and LOAD risk in a North Han Chinese population, we recruited 984 LOAD cases and 1354 healthy controls that matched for sex and age in this study. The results showed no significant differences in the genotypic or allelic distributions of rs2718058 polymorphism between LOAD cases and healthy controls, even though after stratification for APOE ε4 status and statistical adjustment for age, gender and APOE ε4 status (p > 0.05). However, a meta-analysis conducted in a sample of 82513 individuals confirmed a significant association between SNP rs2718058 and LOAD risk (OR = 1.08, 95%CI = 1.05-1.11) in the whole population. But there was still no positive results in Chinese subgroup (OR = 1.05, 95%CI = 0.93-1.17). In conclusion, the rs2718058 near gene NME8 on chromosome 7p14.1 might not play a major role in the genetic predisposition to LOAD in the North Han Chinese.

The Role of Cdk5 in Alzheimer's Disease.

Alzheimer's disease (AD) is known as the most fatal chronic neurodegenerative disease in adults along with progressive loss of memory and other cognitive function disorders. Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (Cdks), is reported to intimately associate with the process of the pathogenesis of AD. Cdk5 is of vital importance in the development of CNS and neuron movements such as neuronal migration and differentiation, synaptic functions, and memory consolidation. However, when neurons suffer from pathological stimuli, Cdk5 activity becomes hyperactive and causes aberrant hyperphosphorylation of various substrates of Cdk5 like amyloid precursor protein (APP), tau and neurofilament, resulting in neurodegenerative diseases like AD. Deregulation of Cdk5 contributes to an array of pathological events in AD, ranging from formation of senile plaques and neurofibrillary tangles, synaptic damage, mitochondrial dysfunction to cell cycle reactivation as well as neuronal cell apoptosis. More importantly, an inhibition of Cdk5 activity with inhibitors such as RNA inference (RNAi) could protect from memory decline and neuronal cell loss through suppressing ß-amyloid (Aß)-induced neurotoxicity and tauopathies. This review will briefly describe the above-mentioned possible roles of Cdk5 in the physiological and pathological mechanisms of AD, further discussing recent advances and challenges in Cdk5 as a therapeutic target.

Optogenetic stimulation of mPFC pyramidal neurons as a conditioned stimulus supports associative learning in rats.

It is generally accepted that the associative learning occurs when a behaviorally neutral conditioned stimulus (CS) is paired with an aversive unconditioned stimulus (US) in close temporal proximity. Eyeblink conditioning (EBC) is a simple form of associative learning for motor responses. Specific activation of a population of cells may be an effective and sufficient CS for establishing EBC. However, there has been no direct evidence to support this hypothesis. Here, we show in rats that optogenetic activation of the right caudal mPFC pyramidal neurons as a CS is sufficient to support the acquisition of delay eyeblink conditioning (DEC). Interestingly, the associative memory was not stably expressed during the initial period of daily conditioning session even after the CR acquisition reached the asymptotic level. Finally, the intensity and consistency of the CS were found to be crucial factors in regulating the retrieval of the associative memory. These results may be of importance in understanding the neural cellular mechanisms underlying associative learning and the mechanisms underlying retrieval process of memory.

Transfer of classical eyeblink conditioning with electrical stimulation of mPFC or tone as conditioned stimulus in guinea pigs.

Learning with a stimulus from one sensory modality can facilitate subsequent learning with a new stimulus from a different sensory modality. To date, the characteristics and mechanism of this phenomenon named transfer effect still remain ambiguous. Our previous work showed that electrical stimulation of medial prefrontal cortex (mPFC) as a conditioned stimulus (CS) could successfully establish classical eyeblink conditioning (EBC). The present study aimed to (1) observe whether transfer of EBC learning would occur when CSs shift between central (mPFC electrical stimulation as a CS, mPFC-CS) and peripheral (tone as a CS, tone CS); (2) compare the difference in transfer effect between the two paradigms, delay EBC (DEBC) and trace EBC (TEBC). A total of 8 groups of guinea pigs were tested in the study, including 4 experimental groups and 4 control groups. Firstly, the experimental groups accepted central (or peripheral) CS paired with corneal airpuff unconditioned stimulus (US); then, CS shifted to the peripheral (or central) and paired with US. The control groups accepted corresponding central (or peripheral) CS and pseudo-paired with US, and then shifted CS from central (or peripheral) to peripheral (or central) and paired with US. The results showed that the acquisition rates of EBC were higher in experimental groups than in control groups after CS switching from central to peripheral or vice versa, and the CR acquisition rate was remarkably higher in DEBC than in TEBC in both transfer ways. The results indicate that EBC transfer can occur between learning established with mPFC-CS and tone CS. Memory of CS-US association for delay paradigm was less disturbed by the sudden switch of CS than for trace paradigm. This study provides new insight into neural mechanisms underlying conditioned reflex as well as the role of mPFC.