Epidemiological connectivity between humans and animals across an urban landscape.

Urbanization is predicted to be a key driver of disease emergence through human exposure to novel, animal-borne pathogens. However, while we suspect that urban landscapes are primed to expose people to novel animal-borne diseases, evidence for the mechanisms by which this occurs is lacking. To address this, we studied how bacterial genes are shared between wild animals, livestock, and humans (n = 1,428) across Nairobi, Kenya-one of the world's most rapidly developing cities. Applying a multilayer network framework, we show that low biodiversity (of both natural habitat and vertebrate wildlife communities), coupled with livestock management practices and more densely populated urban environments, promotes sharing of Escherichia coli-borne bacterial mobile genetic elements between animals and humans. These results provide empirical support for hypotheses linking resource provision, the biological simplification of urban landscapes, and human and livestock demography to urban dynamics of cross-species pathogen transmission at a landscape scale. Urban areas where high densities of people and livestock live in close association with synanthropes (species such as rodents that are more competent reservoirs for zoonotic pathogens) should be prioritized for disease surveillance and control.

Genomic epidemiology of Escherichia coli: antimicrobial resistance through a One Health lens in sympatric humans, livestock and peri-domestic wildlife in Nairobi, Kenya.

BACKGROUND: Livestock systems have been proposed as a reservoir for antimicrobial-resistant (AMR) bacteria and AMR genetic determinants that may infect or colonise humans, yet quantitative evidence regarding their epidemiological role remains lacking. Here, we used a combination of genomics, epidemiology and ecology to investigate patterns of AMR gene carriage in Escherichia coli, regarded as a sentinel organism. METHODS: We conducted a structured epidemiological survey of 99 households across Nairobi, Kenya, and whole genome sequenced E. coli isolates from 311 human, 606 livestock and 399 wildlife faecal samples. We used statistical models to investigate the prevalence of AMR carriage and characterise AMR gene diversity and structure of AMR genes in different host populations across the city. We also investigated household-level risk factors for the exchange of AMR genes between sympatric humans and livestock. RESULTS: We detected 56 unique acquired genes along with 13 point mutations present in variable proportions in human and animal isolates, known to confer resistance to nine antibiotic classes. We find that AMR gene community composition is not associated with host species, but AMR genes were frequently co-located, potentially enabling the acquisition and dispersal of multi-drug resistance in a single step. We find that whilst keeping livestock had no influence on human AMR gene carriage, the potential for AMR transmission across human-livestock interfaces is greatest when manure is poorly disposed of and in larger households. CONCLUSIONS: Findings of widespread carriage of AMR bacteria in human and animal populations, including in long-distance wildlife species, in community settings highlight the value of evidence-based surveillance to address antimicrobial resistance on a global scale. Our genomic analysis provided an in-depth understanding of AMR determinants at the interfaces of One Health sectors that will inform AMR prevention and control.

Vaccines That Reduce Viral Shedding Do Not Prevent Transmission of H1N1 Pandemic 2009 Swine Influenza A Virus Infection to Unvaccinated Pigs.

Swine influenza A virus (swIAV) infection causes substantial economic loss and disease burden in humans and animals. The 2009 pandemic H1N1 (pH1N1) influenza A virus is now endemic in both populations. In this study, we evaluated the efficacy of different vaccines in reducing nasal shedding in pigs following pH1N1 virus challenge. We also assessed transmission from immunized and challenged pigs to naive, directly in-contact pigs. Pigs were immunized with either adjuvanted, whole inactivated virus (WIV) vaccines or virus-vectored (ChAdOx1 and MVA) vaccines expressing either the homologous or heterologous influenza A virus hemagglutinin (HA) glycoprotein, as well as an influenza virus pseudotype (S-FLU) vaccine expressing heterologous HA. Only two vaccines containing homologous HA, which also induced high hemagglutination inhibitory antibody titers, significantly reduced virus shedding in challenged animals. Nevertheless, virus transmission from challenged to naive, in-contact animals occurred in all groups, although it was delayed in groups of vaccinated animals with reduced virus shedding.IMPORTANCE This study was designed to determine whether vaccination of pigs with conventional WIV or virus-vectored vaccines reduces pH1N1 swine influenza A virus shedding following challenge and can prevent transmission to naive in-contact animals. Even when viral shedding was significantly reduced following challenge, infection was transmissible to susceptible cohoused recipients. This knowledge is important to inform disease surveillance and control strategies and to determine the vaccine coverage required in a population, thereby defining disease moderation or herd protection. WIV or virus-vectored vaccines homologous to the challenge strain significantly reduced virus shedding from directly infected pigs, but vaccination did not completely prevent transmission to cohoused naive pigs.

Timelines of infection and transmission dynamics of H1N1pdm09 in swine.

Influenza is a major cause of mortality and morbidity worldwide. Despite numerous studies of the pathogenesis of influenza in humans and animal models the dynamics of infection and transmission in individual hosts remain poorly characterized. In this study, we experimentally modelled transmission using the H1N1pdm09 influenza A virus in pigs, which are considered a good model for influenza infection in humans. Using an experimental design that allowed us to observe individual transmission events occurring within an 18-hr period, we quantified the relationships between infectiousness, shed virus titre and antibody titre. Transmission event was observed on 60% of occasions when virus was detected in donor pig nasal swabs and transmission was more likely when donor pigs shed more virus. This led to the true infectious period (mean 3.9 days) being slightly shorter than that predicted by detection of virus (mean 4.5 days). The generation time of infection (which determines the rate of epidemic spread) was estimated for the first time in pigs at a mean of 4.6 days. We also found that the latent period of the contact pig was longer when they had been exposed to smaller amount of shed virus. Our study provides quantitative information on the time lines of infection and the dynamics of transmission that are key parts of the evidence base needed to understand the spread of influenza viruses though animal populations and, potentially, in humans.

Global discovery of human-infective RNA viruses: A modelling analysis.

RNA viruses are a leading cause of human infectious diseases and the prediction of where new RNA viruses are likely to be discovered is a significant public health concern. Here, we geocoded the first peer-reviewed reports of 223 human RNA viruses. Using a boosted regression tree model, we matched these virus data with 33 explanatory factors related to natural virus distribution and research effort to predict the probability of virus discovery across the globe in 2010-2019. Stratified analyses by virus transmissibility and transmission mode were also performed. The historical discovery of human RNA viruses has been concentrated in eastern North America, Europe, central Africa, eastern Australia, and north-eastern South America. The virus discovery can be predicted by a combination of socio-economic, land use, climate, and biodiversity variables. Remarkably, vector-borne viruses and strictly zoonotic viruses are more associated with climate and biodiversity whereas non-vector-borne viruses and human transmissible viruses are more associated with GDP and urbanization. The areas with the highest predicted probability for 2010-2019 include three new regions including East and Southeast Asia, India, and Central America, which likely reflect both increasing surveillance and diversity of their virome. Our findings can inform priority regions for investment in surveillance systems for new human RNA viruses.

Tissue tropism and transmission ecology predict virulence of human RNA viruses.

Novel infectious diseases continue to emerge within human populations. Predictive studies have begun to identify pathogen traits associated with emergence. However, emerging pathogens vary widely in virulence, a key determinant of their ultimate risk to public health. Here, we use structured literature searches to review the virulence of each of the 214 known human-infective RNA virus species. We then use a machine learning framework to determine whether viral virulence can be predicted by ecological traits, including human-to-human transmissibility, transmission routes, tissue tropisms, and host range. Using severity of clinical disease as a measurement of virulence, we identified potential risk factors using predictive classification tree and random forest ensemble models. The random forest approach predicted literature-assigned disease severity of test data with mean accuracy of 89.4% compared to a null accuracy of 74.2%. In addition to viral taxonomy, the ability to cause systemic infection was the strongest predictor of severe disease. Further notable predictors of severe disease included having neural and/or renal tropism, direct contact or respiratory transmission, and limited (0 < R0 ≤ 1) human-to-human transmissibility. We present a novel, to our knowledge, comparative perspective on the virulence of all currently known human RNA virus species. The risk factors identified may provide novel perspectives in understanding the evolution of virulence and elucidating molecular virulence mechanisms. These risk factors could also improve planning and preparedness in public health strategies as part of a predictive framework for novel human infections.

Calcium transient prevalence across the dendritic arbour predicts place field properties.

Establishing the hippocampal cellular ensemble that represents an animal's environment involves the emergence and disappearance of place fields in specific CA1 pyramidal neurons, and the acquisition of different spatial firing properties across the active population. While such firing flexibility and diversity have been linked to spatial memory, attention and task performance, the cellular and network origin of these place cell features is unknown. Basic integrate-and-fire models of place firing propose that such features result solely from varying inputs to place cells, but recent studies suggest instead that place cells themselves may play an active role through regenerative dendritic events. However, owing to the difficulty of performing functional recordings from place cell dendrites, no direct evidence of regenerative dendritic events exists, leaving any possible connection to place coding unknown. Using multi-plane two-photon calcium imaging of CA1 place cell somata, axons and dendrites in mice navigating a virtual environment, here we show that regenerative dendritic events do exist in place cells of behaving mice, and, surprisingly, their prevalence throughout the arbour is highly spatiotemporally variable. Furthermore, we show that the prevalence of such events predicts the spatial precision and persistence or disappearance of place fields. This suggests that the dynamics of spiking throughout the dendritic arbour may play a key role in forming the hippocampal representation of space.

Population level changes in schistosome-specific antibody levels following chemotherapy.

AIMS: Previous studies have reported that chemotherapy of schistosomiasis by praziquantel in humans boosts protective antibody responses against S mansoni and S haematobium. A number of studies have reported schistosome-specific antibody levels before and after chemotherapy. Using these reports, a meta-analysis was conducted to identify predictors of population level change in schistosome-specific antibody levels after chemotherapy. METHODS AND RESULTS: Following a systematic review, 92 observations from 26 articles published between 1988 and 2013 were included in this study. Observations were grouped by antigen type and antibody isotypes for the classification and regression tree (CART) analysis. The study showed that the change in antibody levels was variable: (a) between different human populations and (b) according to the parasite antigen and antibody isotypes. Thus, while anti-worm responses predominantly increased after chemotherapy, anti-egg responses decreased or did not show a significant trend. The change in antibody levels depended on a combination of age and infection intensity for anti-egg IgA, IgM, IgG1, IgG2 and anti-worm IgM and IgG. CONCLUSION: The study results are consistent with praziquantel treatment boosting anti-worm antibody responses. However, there is considerable heterogeneity in post-treatment changes in specific antibody levels that is related to host age and pre-treatment infection intensity.

Are Food Animals Responsible for Transfer of Antimicrobial-Resistant Escherichia coli or Their Resistance Determinants to Human Populations? A Systematic Review.

The role of farm animals in the emergence and dissemination of both AMR bacteria and their resistance determinants to humans is poorly understood and controversial. Here, we systematically reviewed the current evidence that food animals are responsible for transfer of AMR to humans. We searched PubMed, Web of Science, and EMBASE for literature published between 1940 and 2016. Our results show that eight studies (18%) suggested evidence of transmission of AMR from food animals to humans, 25 studies (56%) suggested transmission between animals and humans with no direction specified and 12 studies (26%) did not support transmission. Quality of evidence was variable among the included studies; one study (2%) used high resolution typing tools, 36 (80%) used intermediate resolution typing tools, six (13%) relied on low resolution typing tools, and two (5%) based conclusions on co-occurrence of resistance. While some studies suggested to provide evidence that transmission of AMR from food animals to humans may occur, robust conclusions on the directionality of transmission cannot be drawn due to limitations in study methodologies. Our findings highlight the need to combine high resolution genomic data analysis with systematically collected epidemiological evidence to reconstruct patterns of AMR transmission between food animals and humans.

Efficient surveillance for healthcare-associated infections spreading between hospitals.

Early detection of new or novel variants of nosocomial pathogens is a public health priority. We show that, for healthcare-associated infections that spread between hospitals as a result of patient movements, it is possible to design an effective surveillance system based on a relatively small number of sentinel hospitals. We apply recently developed mathematical models to patient admission data from the national healthcare systems of England and The Netherlands. Relatively short detection times are achieved once 10-20% hospitals are recruited as sentinels and only modest reductions are seen as more hospitals are recruited thereafter. Using a heuristic optimization approach to sentinel selection, the same expected time to detection can be achieved by recruiting approximately half as many hospitals. Our study provides a robust evidence base to underpin the design of an efficient sentinel hospital surveillance system for novel nosocomial pathogens, delivering early detection times for reduced expenditure and effort.

Assessing the Epidemic Potential of RNA and DNA Viruses.

Many new and emerging RNA and DNA viruses are zoonotic or have zoonotic origins in an animal reservoir that is usually mammalian and sometimes avian. Not all zoonotic viruses are transmissible (directly or by an arthropod vector) between human hosts. Virus genome sequence data provide the best evidence of transmission. Of human transmissible virus, 37 species have so far been restricted to self-limiting outbreaks. These viruses are priorities for surveillance because relatively minor changes in their epidemiologies can potentially lead to major changes in the threat they pose to public health. On the basis of comparisons across all recognized human viruses, we consider the characteristics of these priority viruses and assess the likelihood that they will further emerge in human populations. We also assess the likelihood that a virus that can infect humans but is not capable of transmission (directly or by a vector) between human hosts can acquire that capability.

Not just a matter of size: a hospital-level risk factor analysis of MRSA bacteraemia in Scotland.

BACKGROUND: Worldwide, there is a wealth of literature examining patient-level risk factors for methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia. At the hospital-level it is generally accepted that MRSA bacteraemia is more common in larger hospitals. In Scotland, size does not fully explain all the observed variation among hospitals. The aim of this study was to identify risk factors for the presence and rate of MRSA bacteraemia cases in Scottish mainland hospitals. Specific hypotheses regarding hospital size, type and connectivity were examined. METHODS: Data from 198 mainland Scottish hospitals (defined as having at least one inpatient per year) were analysed for financial year 2007-08 using logistic regression (Model 1: presence/absence of MRSA bacteraemia) and Poisson regression (Model 2: rate of MRSA bacteraemia). The significance of risk factors representing various measures of hospital size, type and connectivity were investigated. RESULTS: In Scotland, size was not the only significant risk factor identified for the presence and rate of MRSA bacteraemia. The probability of a hospital having at least one case of MRSA bacteraemia increased with hospital size only if the hospital exceeded a certain level of connectivity. Higher levels of MRSA bacteraemia were associated with the large, highly connected teaching hospitals with high ratios of patients to domestic staff. CONCLUSIONS: A hospital's level of connectedness within a network may be a better measure of a hospital's risk of MRSA bacteraemia than size. This result could be used to identify high risk hospitals which would benefit from intensified infection control measures.

Predicting the public health benefit of vaccinating cattle against Escherichia coli O157.

Identifying the major sources of risk in disease transmission is key to designing effective controls. However, understanding of transmission dynamics across species boundaries is typically poor, making the design and evaluation of controls particularly challenging for zoonotic pathogens. One such global pathogen is Escherichia coli O157, which causes a serious and sometimes fatal gastrointestinal illness. Cattle are the main reservoir for E. coli O157, and vaccines for cattle now exist. However, adoption of vaccines is being delayed by conflicting responsibilities of veterinary and public health agencies, economic drivers, and because clinical trials cannot easily test interventions across species boundaries, lack of information on the public health benefits. Here, we examine transmission risk across the cattle-human species boundary and show three key results. First, supershedding of the pathogen by cattle is associated with the genetic marker stx2. Second, by quantifying the link between shedding density in cattle and human risk, we show that only the relatively rare supershedding events contribute significantly to human risk. Third, we show that this finding has profound consequences for the public health benefits of the cattle vaccine. A naïve evaluation based on efficacy in cattle would suggest a 50% reduction in risk; however, because the vaccine targets the major source of human risk, we predict a reduction in human cases of nearly 85%. By accounting for nonlinearities in transmission across the human-animal interface, we show that adoption of these vaccines by the livestock industry could prevent substantial numbers of human E. coli O157 cases.

High rates of infection with novel enterovirus variants in wild populations of mandrills and other old world monkey species.

UNLABELLED: Enteroviruses (EVs) are a genetically and antigenically diverse group of viruses infecting humans. A mostly distinct set of EV variants have additionally been documented to infect wild apes and several, primarily captive, Old World monkey (OWM) species. To investigate the prevalence and genetic characteristics of EVs infecting OWMs in the wild, fecal samples from mandrills (Mandrillus sphinx) and other species collected in remote regions of southern Cameroon were screened for EV RNA. Remarkably high rates of EV positivity were detected in M. sphinx (100 of 102 screened), Cercocebus torquatus (7/7), and Cercopithecus cephus (2/4), with high viral loads indicative of active infection. Genetic characterization in VP4/VP2 and VP1 regions allowed EV variants to be assigned to simian species H (EV-H) and EV-J (including one or more new types), while seven matched simian EV-B variants, SA5 and EV110 (chimpanzee). Sequences from the remaining 70 formed a new genetic group distinct in VP4/2 and VP1 region from all currently recognized human or simian EV species. Complete genome sequences were obtained from three to determine their species assignment. In common with EV-J and the EV-A A13 isolate, new group sequences were chimeric, being most closely related to EV-A in capsid genes and to EV-B in the nonstructural gene region. Further recombination events created different groupings in 5' and 3' untranslated regions. While clearly a distinct EV group, the hybrid nature of new variants prevented their unambiguous classification as either members of a new species or as divergent members of EV-A using current International Committee on Taxonomy of Viruses (ICTV) assignment criteria. IMPORTANCE: This study is the first large-scale investigation of the frequency of infection and diversity of enteroviruses (EVs) infecting monkeys (primarily mandrills) in the wild. Our findings demonstrate extremely high frequencies of active infection (95%) among mandrills and other Old World monkey species inhabiting remote regions of Cameroon without human contact. EV variants detected were distinct from those infecting human populations, comprising members of enterovirus species B, J, and H and a large novel group of viruses most closely related to species A in the P1 region. The viral sequences obtained contribute substantially to our growing understanding of the genetic diversity of EVs and the existence of interspecies chimerism that characterizes the novel variants in the current study, as well as in previously characterized species A and J viruses infecting monkeys. The latter findings will contribute to future development of consensus criteria for species assignments in enteroviruses and other picornavirus genera.

Protective immunity to Schistosoma haematobium infection is primarily an anti-fecundity response stimulated by the death of adult worms.

Protective immunity against human schistosome infection develops slowly, for reasons that are not yet fully understood. For many decades, researchers have attempted to infer properties of the immune response from epidemiological studies, with mathematical models frequently being used to bridge the gap between immunological theory and population-level data on schistosome infection and immune responses. Here, building upon earlier model findings, stochastic individual-based models were used to identify model structures consistent with observed field patterns of Schistosoma haematobium infection and antibody responses, including their distributions in cross-sectional surveys, and the observed treatment-induced antibody switch. We found that the observed patterns of infection and antibody were most consistent with models in which a long-lived protective antibody response is stimulated by the death of adult S. haematobium worms and reduces worm fecundity. These findings are discussed with regard to current understanding of human immune responses to schistosome infection.

Novel porcine-like human G26P[19] rotavirus identified in hospitalized paediatric diarrhoea patients in Ho Chi Minh City, Vietnam.

During a hospital-based diarrhoeal disease study conducted in Ho Chi Minh City, Vietnam from 2009 to 2010, we identified four symptomatic children infected with G26P[19] rotavirus (RV)--an atypical variant that has not previously been reported in human gastroenteritis. To determine the genetic structure and investigate the origin of this G26P[19] strain, the whole genome of a representative example was characterized, revealing a novel genome constellation: G26-P[19]-I5-R1-C1-M1-A8-N1-T1-E1-H1. The genome segments were most closely related to porcine (VP7, VP4, VP6 and NSP1) and Wa-like porcine RVs (VP1-3 and NSP2-5). We proposed that this G26P[19] strain was the product of zoonotic transmission coupled with one or more reassortment events occurring in human and/or animal reservoirs. The identification of such strains has potential implications for vaccine efficacy in south-east Asia, and outlines the utility of whole-genome sequencing for studying RV diversity and zoonotic potential during disease surveillance.

Lysogeny with Shiga toxin 2-encoding bacteriophages represses type III secretion in enterohemorrhagic Escherichia coli.

Lytic or lysogenic infections by bacteriophages drive the evolution of enteric bacteria. Enterohemorrhagic Escherichia coli (EHEC) have recently emerged as a significant zoonotic infection of humans with the main serotypes carried by ruminants. Typical EHEC strains are defined by the expression of a type III secretion (T3S) system, the production of Shiga toxins (Stx) and association with specific clinical symptoms. The genes for Stx are present on lambdoid bacteriophages integrated into the E. coli genome. Phage type (PT) 21/28 is the most prevalent strain type linked with human EHEC infections in the United Kingdom and is more likely to be associated with cattle shedding high levels of the organism than PT32 strains. In this study we have demonstrated that the majority (90%) of PT 21/28 strains contain both Stx2 and Stx2c phages, irrespective of source. This is in contrast to PT 32 strains for which only a minority of strains contain both Stx2 and 2c phages (28%). PT21/28 strains had a lower median level of T3S compared to PT32 strains and so the relationship between Stx phage lysogeny and T3S was investigated. Deletion of Stx2 phages from EHEC strains increased the level of T3S whereas lysogeny decreased T3S. This regulation was confirmed in an E. coli K12 background transduced with a marked Stx2 phage followed by measurement of a T3S reporter controlled by induced levels of the LEE-encoded regulator (Ler). The presence of an integrated Stx2 phage was shown to repress Ler induction of LEE1 and this regulation involved the CII phage regulator. This repression could be relieved by ectopic expression of a cognate CI regulator. A model is proposed in which Stx2-encoding bacteriophages regulate T3S to co-ordinate epithelial cell colonisation that is promoted by Stx and secreted effector proteins.

Not all cows are epidemiologically equal: quantifying the risks of bovine viral diarrhoea virus (BVDV) transmission through cattle movements.

Many economically important cattle diseases spread between herds through livestock movements. Traditionally, most transmission models have assumed that all purchased cattle carry the same risk of generating outbreaks in the destination herd. Using data on bovine viral diarrhoea virus (BVDV) in Scotland as a case example, this study provides empirical and theoretical evidence that the risk of disease transmission varies substantially based on the animal and herd demographic characteristics at the time of purchase. Multivariable logistic regression analysis revealed that purchasing pregnant heifers and open cows sold with a calf at foot were associated with an increased risk of beef herds being seropositive for BVDV. Based on the results from a dynamic within-herd simulation model, these findings may be partly explained by the age-related probability of animals being persistently infected with BVDV as well as the herd demographic structure at the time of animal introductions. There was also evidence that an epidemiologically important network statistic, "betweenness centrality" (a measure frequently associated with the potential for herds to acquire and transmit disease), was significantly higher for herds that supplied these particular types of replacement beef cattle. The trends for dairy herds were not as clear, although there was some evidence that open heifers and open lactating cows were associated with an increased risk of BVDV. Overall, these findings have important implications for developing simulation models that more accurately reflect the industry-level transmission dynamics of infectious cattle diseases.

How commercial and non-commercial swine producers move pigs in Scotland: a detailed descriptive analysis.

BACKGROUND: The impact of non-commercial producers on disease spread via livestock movement is related to their level of interaction with other commercial actors within the industry. Although understanding these relationships is crucial in order to identify likely routes of disease incursion and transmission prior to disease detection, there has been little research in this area due to the difficulties of capturing movements of small producers with sufficient resolution. Here, we used the Scottish Livestock Electronic Identification and Traceability (ScotEID) database to describe the movement patterns of different pig production systems which may affect the risk of disease spread within the swine industry. In particular, we focused on the role of small pig producers. RESULTS: Between January 2012 and May 2013, 23,169 batches of pigs were recorded moving animals between 2382 known unique premises. Although the majority of movements (61%) were to a slaughterhouse, the non-commercial and the commercial sectors of the Scottish swine industry coexist, with on- and off-movement of animals occurring relatively frequently. For instance, 13% and 4% of non-slaughter movements from professional producers were sent to a non-assured commercial producer or to a small producer, respectively; whereas 43% and 22% of movements from non-assured commercial farms were sent to a professional or a small producer, respectively. We further identified differences between producer types in several animal movement characteristics which are known to increase the risk of disease spread. Particularly, the distance travelled and the use of haulage were found to be significantly different between producers. CONCLUSIONS: These results showed that commercial producers are not isolated from the non-commercial sector of the Scottish swine industry and may frequently interact, either directly or indirectly. The observed patterns in the frequency of movements, the type of producers involved, the distance travelled and the use of haulage companies provide insights into the structure of the Scottish swine industry, but also highlight different features that may increase the risk of infectious diseases spread in both Scotland and the UK. Such knowledge is critical for developing more robust biosecurity and surveillance plans and better preparing Scotland against incursions of emerging swine diseases.

Distinct catecholaminergic pathways projecting to hippocampal CA1 transmit contrasting signals during behavior and learning.

Neuromodulatory inputs to the hippocampus play pivotal roles in modulating synaptic plasticity, shaping neuronal activity, and influencing learning and memory. Recently it has been shown that the main sources of catecholamines to the hippocampus, ventral tegmental area (VTA) and locus coeruleus (LC), may have overlapping release of neurotransmitters and effects on the hippocampus. Therefore, to dissect the impacts of both VTA and LC circuits on hippocampal function, a thorough examination of how these pathways might differentially operate during behavior and learning is necessary. We therefore utilized 2-photon microscopy to functionally image the activity of VTA and LC axons within the CA1 region of the dorsal hippocampus in head-fixed male mice navigating linear paths within virtual reality (VR) environments. We found that within familiar environments some VTA axons and the vast majority of LC axons showed a correlation with the animals' running speed. However, as mice approached previously learned rewarded locations, a large majority of VTA axons exhibited a gradual ramping-up of activity, peaking at the reward location. In contrast, LC axons displayed a pre-movement signal predictive of the animal's transition from immobility to movement. Interestingly, a marked divergence emerged following a switch from the familiar to novel VR environments. Many LC axons showed large increases in activity that remained elevated for over a minute, while the previously observed VTA axon ramping-to-reward dynamics disappeared during the same period. In conclusion, these findings highlight distinct roles of VTA and LC catecholaminergic inputs in the dorsal CA1 hippocampal region. These inputs encode unique information, likely contributing to differential modulation of hippocampal activity during behavior and learning.