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Neuromodulatory substances can be released from distal afferents for communication between brain structures or produced locally to modulate neighboring circuit elements. Corticotropin-releasing hormone (CRH) from long-range neurons in the hypothalamus projecting to the medial prefrontal cortex (mPFC) has been shown to induce anxiety-like behaviors. However, the role of CRH produced in the mPFC has not been investigated. Here we demonstrate that a specific class of mPFC interneurons that express CRH (CrhINs) releases CRH upon high-frequency stimulation to enhance excitability of layer 2/3 pyramidal cells (L2/3 PCs) expressing the CRH receptors. When stimulated at low frequency, CrhINs release GABA resulting in the inhibition of oxytocin receptor-expressing interneurons (OxtrINs) and L2/3 PCs. Conditional deletion of CRH in mPFC CrhINs and chemogenetic activation of CrhINs have opposite effects on novelty exploration in male but not in female mice, and do not affect anxiety-related behaviors in either males or females. Our data reveal that CRH produced by local interneurons in the mPFC is required for sex-specific novelty exploration and suggest that our understanding of complex behaviors may require knowledge of local and remote neuromodulatory action.

Oxytetracycline (OTC) is a widely used antibiotic in food-producing animals. Extralabel use of OTC is common and may lead to violative residues in edible tissues. It is important to have a quantitative tool to predict scientifically based withdrawal intervals (WDIs) after extralabel use in food animals to ensure human food safety. This study focuses on developing a physiologically based pharmacokinetic (PBPK) model for OTC in sheep and goats. The model included 7 compartments: plasma, lung, liver, kidneys, muscle, fat, and rest of the body. The model was calibrated with serum and tissue (liver, muscle, kidney, and fat) concentration data following a single intramuscular (IM, 20 mg/kg) and/or intravenous (IV, 10 mg/kg) administration of a long-acting formulation in sheep and goats. The model was evaluated with independent datasets from Food Animal Residue Avoidance Databank (FARAD). Results showed that the model adequately simulated the calibration datasets with an overall estimated coefficient of determination (R2) of 0.95 and 0.92, respectively, for sheep and goat models and had acceptable accuracy for the evaluation datasets. Monte Carlo sampling technique was applied to predict the time needed for drug concentrations in edible tissues to fall below tolerances for the 99th percentiles of the population. The model was converted to a web-based interactive PBPK (iPBPK) interface to facilitate model applications. This iPBPK model provides a useful tool to estimate WDIs for OTC after extralabel use in small ruminants to ensure food safety and serves as a basis for extrapolation to other tetracycline drugs and other food animals., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Vector-borne disease risk assessment is crucial to optimize surveillance, preventative measures (vector control), and resource allocation (medical supplies). High arthropod abundance and host interaction strongly correlate to vector-borne pathogen transmission. Increasing host density and movement increases the possibility of local and long-distance pathogen transmission. Therefore, we developed a risk-assessment framework using climate (average temperature and rainfall) and host demographic (host density and movement) data, particularly suitable for regions with unreported or underreported incidence data. This framework consisted of a spatiotemporal network-based approach coupled with a compartmental disease model and nonhomogeneous Gillespie algorithm. The correlation of climate data with vector abundance and host-vector interactions is expressed as vectorial capacity-a parameter that governs the spreading of infection from an infected host to a susceptible one via vectors. As an example, the framework is applied for dengue in Bangladesh. Vectorial capacity is inferred for each week throughout a year using average monthly temperature and rainfall data. Long-distance pathogen transmission is expressed with human movement data in the spatiotemporal network. We have identified the spatiotemporal suitability of dengue spreading in Bangladesh as well as the significant-incidence window and peak-incidence period. Analysis of yearly dengue data variation suggests the possibility of a significant outbreak with a new serotype introduction. The outcome of the framework comprised spatiotemporal suitability maps and probabilistic risk maps for spatial infection spreading. This framework is capable of vector-borne disease risk assessment without historical incidence data and can be a useful tool for preparedness with accurate human movement data.

The habenula, an ancient small brain area in the epithalamus, densely expresses nicotinic acetylcholine receptors and is critical for nicotine intake and aversion. As such, identification of strategies to manipulate habenular activity may yield approaches to treat nicotine addiction. Here we show that GPR151, an orphan G-protein-coupled receptor (GPCR) highly enriched in the habenula of humans and rodents, is expressed at presynaptic membranes and synaptic vesicles and associates with synaptic components controlling vesicle release and ion transport. Deletion of Gpr151 inhibits evoked neurotransmission but enhances spontaneous miniature synaptic currents and eliminates short-term plasticity induced by nicotine. We find that GPR151 couples to the G-alpha inhibitory protein Gα o1 to reduce cyclic adenosine monophosphate (cAMP) levels in mice and in GPR151-expressing cell lines that are amenable to ligand screens. Gpr151- knockout (KO) mice show diminished behavioral responses to nicotine and self-administer greater quantities of the drug, phenotypes rescued by viral reexpression of Gpr151 in the habenula. These data identify GPR151 as a critical modulator of habenular function that controls nicotine addiction vulnerability., Competing Interests: The authors declare no competing interest.

Network-based modelling of infectious diseases apply compartmental models on a contact network, which makes the epidemic process crucially dependent on the network structure. For highly contagious diseases such as Ebola virus disease (EVD), interpersonal contact plays the most vital role in human-to-human transmission. Therefore, for accurate representation of EVD spreading, the contact network needs to resemble the reality. Prior research has mainly focused on static networks (only permanent contacts) or activity-driven networks (only temporal contacts) for Ebola spreading. A comprehensive network for EVD spreading should include both these network structures, as there are always some permanent contacts together with temporal contacts. Therefore, we propose a two-layer temporal network for Uganda, which is at risk of an Ebola outbreak from the neighboring Democratic Republic of Congo (DRC) epidemic. The network has a permanent layer representing permanent contacts among individuals within the family level, and a data-driven temporal network for human movements motivated by cattle trade, fish trade, or general communications. We propose a Gillespie algorithm with the susceptible-infected-recovered (SIR) compartmental model to simulate the evolution of EVD spreading as well as to evaluate the risk throughout our network. As an example, we applied our method to a network consisting of 23 districts along different movement routes in Uganda starting from bordering districts of the DRC to Kampala. Simulation results show that some regions are at higher risk of infection, suggesting some focal points for Ebola preparedness and providing direction to inform interventions in the field. Simulation results also show that decreasing physical contact as well as increasing preventive measures result in a reduction of chances to develop an outbreak. Overall, the main contribution of this paper lies in the novel method for risk assessment, which can be more precise with an increasing volume of accurate data for creating the network model.

Rift Valley fever (RVF) is a zoonotic disease, that causes significant morbidity and mortality among ungulate livestock and humans in endemic regions. In East Africa, the causative agent of the disease is Rift Valley fever virus (RVFV) which is primarily transmitted by multiple mosquito species in Aedes and Mansonia genera during both epizootic and enzootic periods in a complex transmission cycle largely driven by environmental and climatic factors. However, recent RVFV activity in Uganda demonstrated the capability of the virus to spread into new regions through livestock movements, and underscored the need to develop effective mitigation strategies to reduce transmission and prevent spread among cattle populations. We simulated RVFV transmission among cows in 22 different locations of the Kabale District in Uganda using real world livestock data in a network-based model. This model considered livestock as a spatially explicit factor in different locations subjected to specific vector and environmental factors, and was configured to investigate and quantitatively evaluate the relative impacts of mosquito control, livestock movement, and diversity in cattle populations on the spread of the RVF epizootic. We concluded that cattle movement should be restricted for periods of high mosquito abundance to control epizootic spreading among locations during an RVF outbreak. Importantly, simulation results also showed that cattle populations with heterogeneous genetic diversity as crossbreeds were less susceptible to infection compared to homogenous cattle populations., Competing Interests: The authors have declared that no competing interests exist.

Repeated exposure to drugs of abuse can produce adaptive changes that lead to the establishment of dependence. It has been shown that allelic variation in the α5 nicotinic acetylcholine receptor (nAChR) gene CHRNA5 is associated with higher risk of tobacco dependence. In the brain, α5-containing nAChRs are expressed at very high levels in the interpeduncular nucleus (IPN). Here we identified two nonoverlapping α5 + cell populations (α5- Amigo1 and α5- Epyc ) in mouse IPN that respond differentially to nicotine. Chronic nicotine treatment altered the translational profile of more than 1,000 genes in α5- Amigo1 neurons, including neuronal nitric oxide synthase ( Nos1 ) and somatostatin ( Sst ). In contrast, expression of few genes was altered in the α5- Epyc population. We show that both nitric oxide and SST suppress optically evoked neurotransmitter release from the terminals of habenular (Hb) neurons in IPN. Moreover, in vivo silencing of neurotransmitter release from the α5- Amigo1 but not from the α5- Epyc population eliminates nicotine reward, measured using place preference. This loss of nicotine reward was mimicked by shRNA-mediated knockdown of Nos1 in the IPN. These findings reveal a proaddiction adaptive response to chronic nicotine in which nitric oxide and SST are released by a specific α5 + neuronal population to provide retrograde inhibition of the Hb-IPN circuit and thereby enhance the motivational properties of nicotine., Competing Interests: The authors declare no conflict of interest.

The dopamine systems of the brain powerfully influence movement and motivation. We demonstrate that striatonigral fibers originating in striosomes form highly unusual bouquet-like arborizations that target bundles of ventrally extending dopamine-containing dendrites and clusters of their parent nigral cell bodies. Retrograde tracing showed that these clustered cell bodies in turn project to the striatum as part of the classic nigrostriatal pathway. Thus, these striosome-dendron formations, here termed "striosome-dendron bouquets," likely represent subsystems with the nigro-striato-nigral loop that are affected in human disorders including Parkinson's disease. Within the bouquets, expansion microscopy resolved many individual striosomal fibers tightly intertwined with the dopamine-containing dendrites and also with afferents labeled by glutamatergic, GABAergic, and cholinergic markers and markers for astrocytic cells and fibers and connexin 43 puncta. We suggest that the striosome-dendron bouquets form specialized integrative units within the dopamine-containing nigral system. Given evidence that striosomes receive input from cortical regions related to the control of mood and motivation and that they link functionally to reinforcement and decision-making, the striosome-dendron bouquets could be critical to dopamine-related function in health and disease., Competing Interests: The authors declare no conflict of interest.

Rift Valley fever (RVF) is a zoonotic disease endemic in sub-Saharan Africa with periodic outbreaks in human and animal populations. Mosquitoes are the primary disease vectors; however, Rift Valley fever virus (RVFV) can also spread by direct contact with infected tissues. The transmission cycle is complex, involving humans, livestock, and multiple species of mosquitoes. The epidemiology of RVFV in endemic areas is strongly affected by climatic conditions and environmental variables. In this research, we adapt and use a network-based modeling framework to simulate the transmission of RVFV among hypothetical cattle operations in Kansas, US. Our model considers geo-located livestock populations at the individual level while incorporating the role of mosquito populations and the environment at a coarse resolution. Extensive simulations show the flexibility of our modeling framework when applied to specific scenarios to quantitatively evaluate the efficacy of mosquito control and livestock movement regulations in reducing the extent and intensity of RVF outbreaks in the United States., Competing Interests: The authors have declared that no competing interests exist.

A striking neurochemical form of compartmentalization has been found in the striatum of humans and other species, dividing it into striosomes and matrix. The function of this organization has been unclear, but the anatomical connections of striosomes indicate their relation to emotion-related brain regions, including the medial prefrontal cortex. We capitalized on this fact by combining pathway-specific optogenetics and electrophysiology in behaving rats to search for selective functions of striosomes. We demonstrate that a medial prefronto-striosomal circuit is selectively active in and causally necessary for cost-benefit decision-making under approach-avoidance conflict conditions known to evoke anxiety in humans. We show that this circuit has unique dynamic properties likely reflecting striatal interneuron function. These findings demonstrate that cognitive and emotion-related functions are, like sensory-motor processing, subject to encoding within compartmentally organized representations in the forebrain and suggest that striosome-targeting corticostriatal circuits can underlie neural processing of decisions fundamental for survival., (Copyright © 2015 Elsevier Inc. All rights reserved.)