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The following books are reviewed: Klaus-Peter Adam, Friedrich Avemarie och Nili Wazana (red.), Law and Narrative in the Bible and in Neighbouring Ancient Cultures (Josef Forsling) Stephen P. Ahearne-Kroll, Paul A. Holloway och James A. Kelhoffer (red.), Women and Gender in Ancient Religions: Interdisciplinary Approaches (Hanna Stenström) Dale C. Allison, Volker Leppin, Choon-Leong Seow, Hermann Spieckermann, Barry Dov Walfish och Eric Ziolkowski (red.), Encyclopedia of the Bible and Its Reception, v. 3 (Göran Eidevall) Dale C. Allison, Volker Leppin, Choon-Leong Seow, Hermann Spieckermann, Barry Dov Walfish och Eric Ziolkowski (red.), Encyclopedia of the Bible and Its Reception, v. 5 (Mikael Larsson) Joseph L. Angel, Otherworldly and Eschatological Priesthood in the Dead Sea Scrolls (Torleif Elgvin) Eve-Marie Becker och Anders Runesson (red.), Mark and Matthew I: Comparative Readings: Understanding the Earliest Gospels in their First-century Settings (Tobias Hägerland) Bob Becking, Ezra, Nehemiah, and the Construction of Early Jewish Identity (Lena-Sofia Tiemeyer) April D. DeConick, Holy Misogyny: Why the Sex and Gender Conflicts in the Early Church Still Matter (Hanna Stenström) Daniel R. Driver, Brevard Childs, Biblical Theologian: For the Church’ s One Bible (LarsOlov Eriksson) Göran Eidevall och Blaženka Scheuer (red.), Enigmas and Images: Studies in Honor of Tryggve N. D. Mettinger (Stig Norin) Weston W. Fields, The Dead Sea Scrolls: A Full History (Cecilia Wassén) Miriam Goldstein, Karaite Exegesis in Medieval Jerusalem: The Judeo-Arabic Pentateuch Commentary of Yūsuf ibn Nūḥ and Abū al-Faraj Hārūn (Lena- Sofia Tiemeyer) Leif Hongisto, Experiencing the Apocalypse at the Limits of Alterity (Hanna Stenström) Jan Joosten, The Verbal System of Biblical Hebrew: A New Synthesis Elaborated on the Basis of Classical Prose (Ulf Bergström) Christos Karakolis, Karl-Wilhelm Niebuhr och Sviatoslav Rogalsky (red.), Gospel Images of Jesus Christ in Church Tradition and in Biblical Scholarship (Mikael Sundkvist) Thomas Kazen, Issues of Impurity in Early Judaism (Cecilia Wassén) Chris Keith, Jesus’ Literacy: Scribal Culture and the Teacher from Galilee (Tobias Ålöw) Anthony Le Donne, The Historiographical Jesus: Memory, Typology, and the Son of David (Jennifer Nyström) Kenneth Liljeström (red.), The Early Reception of Paul (Martin Wessbrandt) Aren M. Maeir, Jodi Magness and Lawrence H. Schiffman (ed.), ‘Go Out and Study the Land’ (Judges 18:2): Archaeological, Historical and Textual Studies in Honor of Hanan Eshel (Torleif Elgvin) David L. Mathewson, Verbal Aspect in the Book of Revelation: The Function of Greek Verb Tenses in John’s Apocalypse (Jan H. Nylund) Robert K. McIver, Memory, Jesus, and the Synoptic Gospels (Jennifer Nyström) Sun Myung Lyu, Righteousness in the Book of Proverbs (Bo Johnson) Stefan Nordenson, Genom honom skapades allt: En exegetisk studie om Kristi preexistens och medlarfunktion i Nya testamentet (Hanna Stenström) Stefan Nordgaard Svendsen, Allegory Transformed: The Appropriation of Philonic Hermeneutics in the Letter to the Hebrews (Johannes Imberg) Donna Lee Petter, The Book of Ezekiel and Mesopotamian City Laments (Lena-Sofia Tiemeyer) Stanley E. Porter, Jeffrey T. Reed och Matthew Brook O’Donnell, Fundamentals of New Testament Greek (Jan H. Nylund) Stanley E. Porter och Jeffrey T. Reed, Fundamentals of New Testament Greek: Workbook (Jan H. Nylund) Karl Olav Sandnes, The Gospel ‘According to Homer and Virgil’: Cento and Canon (Maria Sturesson) Tanja Schultheiss, Das Petrusbild im Johannesevangelium (Finn Damgaard) William A. Tooman, Gog of Magog: Reuse of Scripture and Compositional Technique in Ezekiel 38–39 (Lena-Sofia Tiemeyer) Paul Trebilco, Self-designations and Group Identity in the New Testament (Rikard Roitto) Caroline Vander Stichele och Hugh Pyper (red.), Text, Image, and Otherness in Children’s Bibles: What Is in the Picture? (Mikael Larsson) Patricia Walters, The Assumed Authorial Unity of Luke and Acts: A Reassessment of the Evidence (Carl Johan Berglund) Amanda Witmer, Jesus, the Galilean Exorcist: His Exorcisms in Social and Political Context (Jennifer Nyström)

“Druggable genome” is a novel concept that emphasizes the importance of using the information of genome-wide genetic studies for drug discovery and development. Successful precedents of “druggable genome” have recently emerged for some disorders by combining genomic and gene expression profiles with medical and pharmacological knowledge. One of the key premises for the success is the good access to disease-relevant tissues from “living” patients in which we may observe molecular expression changes in association with symptomatic alteration. Thus, given brain biopsies are ethically and practically difficult, the application of the “druggable genome” approach is challenging for neuropsychiatric disorders. Here, to fill this gap, we propose the use of olfactory neuronal cells (ONCs) biopsied and established via nasal biopsy from living subjects. By using candidate genes that were proposed in a study in which genetic information, postmortem brain expression profiles, and pharmacological knowledge were considered for cognition in the general population, we addressed the utility of ONCs in the “druggable genome” approach by using the clinical and cell resources of an established psychosis cohort in our group. Through this pilot effort, we underscored the chloride voltage-gated channel 2 (CLCN2) gene as a possible druggable candidate for early-stage psychosis. The CLCN2 gene expression was associated with verbal memory, but not with other dimensions in cognition, nor psychiatric manifestations (positive and negative symptoms). The association between this candidate molecule and verbal memory was also confirmed at the protein level. By using ONCs from living subjects, we now provide more specific information regarding molecular expression and clinical phenotypes. The use of ONCs also provides the opportunity of validating the relationship not only at the RNA level but also protein level, leading to the potential of functional assays in the future. Taken together, we now provide evidence that supports the utility of ONCs as a tool for the “druggable genome” approach in translational psychiatry.

Data are vital for and creating knowledge-based solutions to development challenges facing Africa. As a result of gaps in government-funded data collection, and in the interest of promoting community engagement, there is a global movement towards consideration of nontraditional sources of data, including citizen science (CS) data. These data are particularly valuable when collected at a high resolution over large spatial extents and long time periods. CS projects and infrastructure are abundant and well documented in the Global North, while needs for participatory projects to fill environmental monitoring gaps may be greater in the Global South. The paper explores the contributions of citizen science projects originating in Africa for two Sustainable Development Goals (SDGs), namely SDG 6, and SDG 11 which are particularly important to the millions of low-income residents of cities across Africa. Using a mixed methods approach that involves online surveys, interviews, expert conference panels, and a desk review, we analyze a total of 53 CS projects focusing on water, sanitation, and urban planning. The paper addresses CS in Africa and CS for SDGs, and documents evidence for participatory and CS data collection in Africa. It also describes the survey methods, including approaches to training of volunteers, sources of funding, data collection methods, and objectives of the tools and projects. Finally, it provides reflections on the challenges of integrating CS into official statistics in Africa, and some lessons learnt from CS projects in Africa. This paper recommends the establishment of an open-source database, creation of a network of CS projects for communication and collaboration, the uptake of citizen-generated data, and continuous funding for such projects in Africa.

The energy market relies on forecasting capabilities of both demand and power generation that need to be kept in dynamic balance. Nowadays, contracts and auctions of renewable energy in a liberalized electricity market heavily rely on forecasting future power generation. The highly intermittent nature of renewable energy sources increases the uncertainty about future power generation. Since point forecast does not account for such uncertainties, it is necessary to rely on probabilistic forecasts.This work first introduces probabilistic forecasts with deep learning. Then, we show how deep learning models can be used to make probabilistic forecasts of day-ahead power generation from a wind power plant located in Northern Norway. The performance, in terms of the quality of the prediction intervals, is compared to different deep learning models and sets of covariates.The findings show that the accuracy of the predictions improves by 37% when historical data on measured weather and numerical weather predictions (NWPs) were included as exogenous variables. In particular, historical data allows the model to auto-correct systematic biases in the NWPs. Finally, we observe that when using only NWPs or only measured weather as exogenous variables, worse performances are obtained. The work shows the importance of understanding which variables must be included to improve the prediction performance, which is of fundamental value for the energy market that relies on accurate forecasting capabilities.

Citizen science is growing and increasingly realizing its potential in terms of benefiting science and society. However, there are significant barriers to engaging participants in non-Western, non-educated, non-industrialised, non-rich and non-democratic contexts. By reflecting on the experiences of 15 citizen science project coordinators, this paper contributes to the small but growing body of knowledge attempting to identify barriers and opportunities of doing citizen science with marginalised and Indigenous communities. Challenges affecting participation in the analysed projects include issues that range from lack of basic infrastructure and participant safety to unbalanced knowledge hierarchies and data rights. We found that, to overcome these challenges, projects have used several strategies, from promoting decentralized and low-tech solutions to engaging in bottom-up actions from a human-rights approach. Finally, our analysis of project impacts supports the idea that doing citizen science with marginalised and Indigenous communities might have a greater impact for participants than for science, as scientific achievements (although valuable) were not among the most important impacts highlighted in terms of project success. By providing stories from the field in a structured way, we aim to guide, to inform, and to inspire other citizen science projects, and to, ultimately, contribute to broader participation in citizen science in the future.

Abstract Recent attention to the role of Indigenous knowledge (IK) in environmental monitoring, research and decision‐making is likely to attract new people to this field of work. Advancing the bringing together of IK and science in a way that is desirable to IK holders can lead to successful and inclusive research and decision‐making. We used the Delphi technique with 18 expert participants who were IK holders or working closely with IK from across the Arctic to examine the drivers of progress and limitations to the use of IK along with science to inform decision‐making related to wildlife, reindeer herding and the environment. We also used this technique to identify participants' experiences of scientists' misconceptions concerning IK. Participants had a strong focus on transformative change relating to the structure of institutions, politics, rights, involvement, power and agency over technical issues advancing or limiting progress (e.g. new technologies and language barriers). Participants identified two modes of desirable research: coproducing knowledge with scientists and autonomous Indigenous‐led research. They highlighted the need for more collaborative and coproduction projects to allow further refinement of approaches and more funding to support autonomous, Indigenous‐led research. Most misconceptions held by scientists concerning IK that were identified by participants related to the spatial, temporal and conceptual scope of IK, and the perceived need to validate IK using Western science. Our research highlights some of the issues that need to be addressed by all participants in research and decision‐making involving IK and science. While exact approaches will need to be tailored to specific social‐ecological contexts, consideration of these broader concerns revealed by our analysis are likely to be central to effective partnerships. A free Plain Language Summary can be found within the Supporting Information of this article.

In this paper, we discuss the geography of a new digital governmentality. In recent years, and extending Foucauldian analyses of different modes of governing, several studies argue that the digital transformation is fundamentally changing the way people are governed and govern themselves: a new, digital governmentality is emerging and replacing (neo-)liberal forms of governing. Two core characteristics are described as the basic nexus of this shift: on the one hand, a change in knowledge production through the capture and analysis of behavioural data; and on the other hand, a change in the governing of subjects by influencing subconscious behavioural patterns. We show that the perspective of a digital governmentality can sensitise geography to this new mode of digital governing. Furthermore, the digital governmentality debate enables geography to explore interconnections within the power/knowledge nexus between different aspects of the digital transformation that have so far been analysed in rather isolated ways. At the same time, geographic inquiries in turn offer impulses for the digital governmentality debate: Firstly, scholarly debate on a digital governmentality has rarely addressed the geographies in and through which this new governmentality operates. Addressing this research desideratum, we conceive two interconnected geographies of a digital governmentality and combine them into an analytical perspective: a new micro-geography of hybrid, sensing, and adaptive environments and a new macro-geography of digital platforms. Secondly, this perspective contributes to unearth the complex, often contradictory and contested relationships of a digital governmentality to other modes of governing. We use this perspective on geographies of digital governmentality to understand the development of digital outdoor advertising by Europe's largest out-of-home advertising company.

Sammendrag Helseprofesjonene møter i økende grad pasienter, brukere og pårørende som trenger kunnskap om hvordan de kan leve best mulig med langvarige helseutfordringer. Det mangler imidlertid studier av hvordan læreplanene for helseprofesjonsutdanningene imøtekommer behovene i helsetjenesten for helsepedagogisk kompetanse. I denne artikkelen undersøker vi hvordan helsepedagogikk fremtrer i læreplaner til bachelorutdanningene i ergoterapi, sykepleie og fysioterapi. En summativ innholdsanalyse viser at det er en manglende sammenheng mellom læreplandokumenter på ulike nivå (ramme-, program-, og emneplaner) og mellom didaktiske kategorier som mål, innhold, arbeids- og undervisningsformer. Artikkelen avslutter med å vise til behov for videre forskning.

Citizen science is an important vehicle for democratizing science and promoting the goal of universal and equitable access to scientific data and information. Data generated by citizen science groups have become an increasingly important source for scientists, applied users and those pursuing the 2030 Agenda for Sustainable Development. Citizen science data are used extensively in studies of biodiversity and pollution; crowdsourced data are being used by UN operational agencies for humanitarian activities; and citizen scientists are providing data relevant to monitoring the sustainable development goals (SDGs). This article provides an International Science Council (ISC) perspective on citizen science data generating activities in support of the 2030 Agenda and on needed improvements to the citizen science community's data stewardship practices for the benefit of science and society by presenting results of research undertaken by an ISC-sponsored Task Group.

Teacher education is supposed to be able to offer student teachers professional learning that will enable them to deal with the academic and social needs they may be confronted with in school. This calls for teacher education based on a coherent and meaningful division of labour between the learning activities that take place on campus and in placement schools. This has proved difficult to achieve. Research shows a significant gap in the way teacher education is organised. The purpose of this article is to contribute to the development of a theoretically grounded account of the so-called “theory-practice” gap in teacher education, which can move us beyond the simple dichotomies that currently seem to annoy much research and practitioners’ interest in this field. We argue that achieving such an account will require the expansion of more equal and mutually negotiated professional learning in teacher education, that can contribute to enhancing student teachers’ professional learning, on and across the various learning arenas of teacher education. We seek to achieve this objective by following a theoretical line of inquiry, supported with empirical data. Our theoretical rationale is based on socio-cultural learning theory, where coherence, transboundary translation, and re-contextualisation are important subordinate theoretical-analytical terms.

Landslides, earthquakes and other natural disasters are expected to increase in the Arctic, yet our ability to make informed decisions about safety is tightly limited by lack of data. As part of the Integrated Arctic Observation System (INTAROS) project, geophones were installed by residents in Greenland and by University of Bergen in Svalbard in 2018. The purpose of the installations was to explore challenges and benefits of community-based data collection for seismological monitoring in the Arctic region. Raspberry Shake units with one/three-component velocity sensors were selected for the deployment, due to their user-friendly configuration, easy installation, and well established digital platform and web services. The purpose of engaging community members in the use of geophone sensors was to monitor earthquakes, cryoseisms (events generated by ice mass), and landslides. We report our findings with respect to challenges regarding the installation and operation of the Raspberry Shake sensors at both locations. Connecting community-based recordings with permanent seismological networks improved both the detection capability and the data support for understanding seismic events in Greenland. In contrast, finding suitable locations for deployments in Longyearbyen turned out to be challenging, because most buildings are constructed on poles due to the permafrost and indoor space is expensive. Promoting citizen seismology in the Arctic could improve monitoring of seismic events in the Arctic while simultaneously raising community awareness of natural hazards.

Abstract Indigenous people manage or have tenure rights on over a quarter of the world's land surface. While there is growing interest in “evidence‐based” natural resource management, there are few documented experiences with “evidence‐based” practice in community‐managed lands. We explore the evidence required for decisions about harvesting of a community‐managed muskox herd in Greenland, and the collaboration needed to acquire this evidence. We present the development, application, and outcome of a user‐friendly demographic model—a harvest calculator—and we show how Local Ecological Knowledge was used throughout the process and combined with scientific knowledge. The community members identified suitable harvest scenarios with the use of the calculator. The calculator's predictions corresponded with their own perceptions of declining numbers of muskox bulls and suggested that reversal was possible under an alternative harvest scenario. As a result, the community members used the findings to request a revised muskox harvest quota, which gained immediate approval by the government. We draw on our experience to propose where community‐led harvest calculators can be useful. Community‐led harvest calculators can help indigenous and local communities develop economically within environmentally sustainable limits, while at the same time providing community members a “voice” in natural resource governance. An effective local management regime will require the sustained application of this tool.

Monitoring vector–human interaction is pivotal for assessing potential transmission rates of vector borne diseases and their associated public health impact. People often seek information following an insect bite in order to identify hematophagous arthropods, which in recent years often is done using Internet resources. Through this activity, a record of net searches is generated, which include information that reflect local human–arthropod interaction, e.g., for the common tick (Ixodes ricinus) in European countries. Such records could in principle provide low cost real-time monitoring data, if indeed Internet search activities adequately reflect tick–human interaction. We here explore Google Trends records for within-year and between-year trends, for four different Danish search terms for “tick(s)”. We further assess the relationship between monthly search-frequencies and local weather conditions (temperatures and precipitation from 2007 to 2016) in nine European countries. Our findings point to significant limitations in the records due to changes in search-term preferences over the given years. However, the seasonal dynamics are comparable among search-terms. Moreover, the seasonal pattern in search terms vary across Europe in tune with changes in temperature and precipitation. We conclude that, the within-year variation for given search-terms provide credible information, which systematically vary with local weather patterns. We are not convinced that these records merely reflect general interest. It will, however, require a more in-depth analysis by researchers that have specific insight into local language practices to fully assess the strength and weaknesses of this approach

BACKGROUND: Allopregnanolone (ALLO) and structurally related endogenous neurosteroids are potent modulators of gamma-aminobutyric acid A (GABA(A)) receptor function at physiologically relevant concentrations. Accumulating evidence implicates a modulatory role for ALLO in behavioral processes underlying ethanol self-administration, discrimination, and reinstatement. The purpose of this study was to evaluate the impact of exogenous neurosteroid challenges with the agonist ALLO and the partial agonist/antagonist epipregnanolone (EPI) on the microarchitecture of ethanol drinking patterns. METHODS: Male C57BL/6J mice were initiated to consume an unsweetened 10% v/v ethanol solution (10 E) by a saccharin fading procedure during daily 2-hr limited-access sessions beginning 1-hr after dark-phase onset. Cumulative lick responses were recorded for 10 E and water by lickometer circuits. After establishing 10 E intake baselines, mice were habituated to vehicle injection (VEH; 20% w/v beta-cyclodextrin ip), and then were treated with either VEH or neurosteroid immediately before the drinking session. Each mouse received a series of ALLO doses (3.2, 10, 17, and 24 mg/kg) alone and EPI doses (0.15, 1, 3, and 10 mg/kg) alone in a counterbalanced within-group design. RESULTS: The GABA(A) receptor-positive modulator ALLO dose-dependently modulated overall ethanol intake throughout the 2-hr session with the 3.2 mg/kg dose eliciting a significant increase, whereas the 24 mg/kg dose produced a significant suppression of ethanol intake versus VEH pretreatment. ALLO-evoked alterations in intake corresponded to significant, dose-dependent alterations in bout frequency and interbout interval. ALLO also elicited robust, dose-dependent elevations in 10 E licks during the initial 5 min of access but subsequently produced in a dose-dependent suppression of 10 E licks during session minutes 20-80. In contrast, the partial agonist/antagonist neurosteroid EPI exhibited no influence on any consumption parameter evaluated. CONCLUSIONS: The present findings suggest that GABA(A) receptor-active neurosteroids may modulate the regulatory processes that govern the onset, maintenance, and termination of drinking episodes. The differential influence of ALLO and EPI on ethanol intake patterns may reflect an alteration in GABA-ergic inhibitory tone that is likely due to each neurosteroid's pharmacological profile at GABA(A) receptors. Manipulation of endogenous ALLO may prove a useful strategy for diminishing excessive intake and protecting against the loss of regulatory control over drinking. [ABSTRACT FROM AUTHOR]

BACKGROUND: The neurosteroid allopregnanolone (ALLO) is a potent positive modulator of gamma-aminobutyric acidA (GABAA) receptors that can modulate ethanol (EtOH) withdrawal. The 5alpha-reductase inhibitor finasteride blocks the formation of ALLO from progesterone and was recently found to reduce certain effects of EtOH. Using the Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) selected lines, in the present studies we examined the effect of finasteride on acute and chronic EtOH withdrawal severity. METHODS: In the first two studies, male WSP and WSR mice were exposed to 72-hr EtOH vapor or air and received four injections of finasteride (50 mg/kg intraperitoneal (IP) or vehicle 24 hr before and each day of the vapor exposure. After removal from the inhalation chamber, mice were scored for handling-induced convulsions (HICs) hourly for 12 hr and then again at 24 hr (study 1) or were tested on the elevated plus maze at 24 hr after removal from the inhalation chamber (study 2). In the third experiment, mice were pretreated with finasteride or vehicle 24 hr before an acute dose of EtOH (4 g/kg ip) or saline and then were tested for HICs as in the chronic study. RESULTS: In both chronic EtOH studies, finasteride pretreatment reduced EtOH withdrawal severity, measured by HICs, and anxiety-related behavior, but only in the WSP selected line. However, finasteride pretreatment also significantly decreased blood EtOH concentration on the initiation of withdrawal in both chronic EtOH studies in WSP and WSR mice. In contrast, pretreatment with finasteride slightly enhanced acute EtOH withdrawal severity in WSP mice, whereas there was no effect of finasteride or EtOH injection on HICs in WSR mice. CONCLUSIONS: Collectively, these findings indicate that the WSP line is more sensitive than the WSR line to the modulatory effects of finasteride in terms of both chronic and acute EtOH withdrawal severity. The differential effect of finasteride on acute versus chronic EtOH withdrawal severity may result from an indirect effect of finasteride on EtOH pharmacokinetics in the chronic paradigm. [ABSTRACT FROM AUTHOR]

Alcohol withdrawal syndrome is characterized by hyperactivity of the nervous system. This hyperactivity represents the brain's attempt to function normally despite the inhibitory effect of chronic alcohol consumption. The syndrome manifests when alcohol consumption ceases. Experimental, clinical, and genetic research have linked the development of withdrawal to alterations in the sensitivity of neuronal communication systems. Early treatment of the syndrome is advised, because the symptom severity may increase with each subsequent episode. [ABSTRACT FROM AUTHOR]

The use of smartphones for data collection has opened up new opportunities for communities wishing to engage in community-based monitoring. While information and communication technology (ICT) is able to systematize data collection, complex functions and observation types can present challenges for community members. ICT also may skew community participation towards young men, as they are sometimes more comfortable using smartphones. This study investigates the success and cost-effectiveness of having local forest monitors use ICT to collect data on forest crimes and forest resources in Prey Lang, Cambodia. A workshop was held with the Prey Lang Community Network to identify the resources and illegal activities to be monitored. Guided by the community members, a smartphone app was subsequently developed and a total of 36 community members were trained in its use. We examined the extent to which the capacity of community members to collect data was dependent upon the complexity of the ICT and on their age and gender. We also assessed the costs of the monitoring program over a two-year period. The community members were able to collect large amounts of data regardless of their gender or age. They made 10,842 entries of data on illegal logging and forest resources. Increased complexity of the app had no impact on the proportion of quality data collected. The cost of monitoring resembled other community-based monitoring programs but was notably less than for monitoring by professional foresters. Our findings suggest that local communities with little formal education are able to monitor forest crimes and forest resources cost-effectively using ICT; however, while the documentation collected was highly valuable, software and hardware maintenance, along with the digital data validation process, will continue to require external support.

Reducing emissions from deforestation and forest degradation in developing countries, and the role of conservation, sustainable management of forests, and enhancement of forest carbon stocks in developing countries (REDD+) is a potentially powerful international policy mechanism that many tropical countries are working towards implementing. Thus far, limited practical consideration has been paid to local rights to forests and forest resources in REDD+ readiness programs, beyond noting the importance of these issues. Previous studies have shown that community members can reliably and cost-effectively monitor forest biomass. At the same time, this can improve local ownership and forge important links between monitoring activities and local decision-making. Existing studies have, however, been static assessments of biomass at one point in time. REDD+ programs will require repeated surveys of biomass over extended time frames. Here, we examine trends in accuracy and costs of local forest monitoring over time. We analyse repeated measurements by community members and professional foresters of 289 plots over two years in four countries in Southeast Asia. This shows, for the first time, that with repeated measurements community members’ biomass measurements become increasingly accurate and costs decline. These findings provide additional support to available evidence that community members can play a strong role in monitoring forest biomass in the local implementation of REDD+.

Biodiversity conservation is a required co-benefit of REDD+. Biodiversity monitoring is therefore needed, yet in most areas it will be constrained by limitations in the available human professional and financial resources. REDD+ programs that use forest plots for biomass monitoring may be able to take advantage of the same data for detecting changes in the tree diversity, using the richness and abundance of canopy trees as a proxy for biodiversity. If local community members are already assessing the above-ground biomass in a representative network of forest vegetation plots, it may require minimal further effort to collect data on the diversity of trees. We compare community members and trained scientists' data on tree diversity in permanent vegetation plots in montane forest in Yunnan, China. We show that local community members here can collect tree diversity data of comparable quality to trained botanists, at one third the cost. Without access to herbaria, identification guides or the Internet, community members could provide the ethno-taxonomical names for 95% of 1071 trees in 60 vegetation plots. Moreover, we show that the community-led survey spent 89% of the expenses at village level as opposed to 23% of funds in the monitoring by botanists. In participatory REDD+ programs in areas where community members demonstrate great knowledge of forest trees, community-based collection of tree diversity data can be a cost-effective approach for obtaining tree diversity information.

Will community monitoring assist in delivering just and equitable REDD+? We assessed whether local communities can effectively estimate carbon stocks in some of the world's most carbon rich forests, using simple field protocols, and we reviewed whether community monitoring exists in current REDD+ pilots. We obtained similar results for forest carbon when measured by communities and professional foresters in 289 vegetation plots in Southeast Asia. Most REDD+ monitoring schemes, however, contain no community involvement. To close the gulf between United Nations Framework Convention on Climate Change texts on involving communities and field implementation realities, we propose greater embedding of community monitoring within national REDD+ pilot schemes, which we argue will lead to a more just REDD+.

Abstract Background Several factors contribute to the deterioration in synaptic plasticity which accompanies age and one of these is neuroinflammation. This is characterized by increased microglial activation associated with increased production of proinflammatory cytokines like interleukin-1β (IL-1β). In aged rats these neuroinflammatory changes are associated with a decreased ability of animals to sustain long-term potentiation (LTP) in the dentate gyrus. Importantly, treatment of aged rats with agents which possess anti-inflammatory properties to decrease microglial activation, improves LTP. It is known that endocannabinoids, such as anandamide (AEA), have anti-inflammatory properties and therefore have the potential to decrease the age-related microglial activation. However, endocannabinoids are extremely labile and are hydrolyzed quickly after production. Here we investigated the possibility that inhibiting the degradation of endocannabinoids with the fatty acid amide hydrolase (FAAH) inhibitor, URB597, could ameliorate age-related increases in microglial activation and the associated decrease in LTP. Methods Young and aged rats received subcutaneous injections of the FAAH inhibitor URB597 every second day and controls which received subcutaneous injections of 30% DMSO-saline every second day for 28 days. Long-term potentiation was recorded on day 28 and the animals were sacrificed. Brain tissue was analyzed for markers of microglial activation by PCR and for levels of endocannabinoids by liquid chromatography coupled to tandem mass spectrometry. Results The data indicate that expression of markers of microglial activation, MHCII, and CD68 mRNA, were increased in the hippocampus of aged, compared with young, rats and that these changes were associated with increased expression of the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor-α (TNFα) which were attenuated by treatment with URB597. Coupled with these changes, we observed an age-related decrease in LTP in the dentate gyrus which was partially restored in URB597-treated aged rats. The data suggest that enhancement of levels of endocannabinoids in the brain by URB597 has beneficial effects on synaptic function, perhaps by modulating microglial activation.

Anxiety is a prominent non-motor symptom of Parkinson's disease (PD). Changes in the B-spectrum recordings in PD patients of the prefrontal cortex correlate with increased anxiety. Using a rodent model of PD, we reported alterations in glutamate synapses in the striatum and substantia nigra following dopamine (DA) loss. We hypothesize that DA loss will result in increased anxiety-related behaviours and that this will be associated with alterations in glutamate synapses and transporters within the medial prefrontal cortex (mPFC). Following 4 weeks of progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, there was an increase in anxiety-related behaviours and a 78% decrease in plasma corticosterone levels versus the vehicle (VEH)-treated mice. This was associated with a 30% decrease in the density of dendritic spines in Layers Il/Ill, and a 53% decrease in the density of glutamate immuno-gold labelling within vesicular glutamate transporter 1 (Vglut1)-labelled nerve terminals and spines, with no change within vesicular glutamate transporter 2 (Vglut2) positive terminals/spines in the MPTP versus VEH groups. Our prior work determined that a decrease in striatal glutamate terminal density was associated with an increase in extracellular glutamate levels. There was an increase in protein expression of Vglut1 (40%), Vglut2 (37%) and glutamate aspartate transporter (GLAST) (225%), and a decrease in glutamate transporter 1 (GLT-1) (50%) and excitatory amino acid carrier 1 (EAAC1) (51%), in the MPTP versus VEH groups within the mPFC. These data suggest that the decrease in dendritic spines within the mPFC following nigrostriatal DA loss may be due to increased extracellular glutamate levels (decrease in glutamate transporters), leading to an increase in anxiety-related behaviours., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Research confirms that stress is associated with alcohol drinking and relapse in males and females and that there are sex differences in the alcohol-related adaptations of stress pathways. The predator stress (PS) model of traumatic stress produces an increase in alcohol drinking or self-administration in a subpopulation of rodents, so it is utilized as an animal model of comorbid alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD). Previous work determined that sensitivity to PS-enhanced drinking produced sex differences in proteins related to stress-regulating systems in the medial prefrontal cortex and hippocampus. The present studies examined whether male and female C57BL/6J mice differ in sensitivity to the ability of the corticotropin releasing factor receptor 1 antagonist CP-376395 to decrease PS-enhanced drinking. In control studies, CP-376395 doses of 5, 10, and 20 mg/kg dose-dependently decreased 4-h ethanol drinking. Next, CP-376395 doses of 5 and 10 mg/kg were tested for effects on ethanol drinking in mice with differential sensitivity to PS-enhanced drinking. Subgroups of "Sensitive" and "Resilient" male and female mice were identified based on changes in ethanol intake in an unrestricted-access ethanol-drinking procedure following four exposures to PS (dirty rat bedding). During the first 2 h post-injection of CP-376395, both doses significantly decreased ethanol licks versus vehicle in the females, with no significant interaction between subgroups, whereas the 10 mg/kg dose significantly decreased ethanol licks versus vehicle in the "Resilient" males. Thus, sensitivity to the suppressive effect of CP-376395 on stress-induced ethanol intake was greater in females versus males, whereas sensitivity and resilience to PS-enhanced drinking produced differential sensitivity to the ability of CP-376395 to decrease ethanol drinking only in male mice. Our results argue against greater efficacy of CRF-R1's ability to decrease ethanol intake in subjects with traumatic stress-enhanced ethanol drinking., Competing Interests: Declaration of competing interest None. The contents do not represent the views of the United States government or the National Institutes of Health., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose of Review: Stress is associated with alcohol drinking, and epidemiological studies document the comorbidity of alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD), with higher comorbid prevalence in females than in males. The aim of this paper is to highlight information related to sex differences in stress-enhanced alcohol drinking from clinical studies and from preclinical studies utilizing an animal model of traumatic stress., Recent Findings: Stress is associated with alcohol drinking and relapse in males and females, but there are sex differences in the alcohol-related adaptation of stress pathways and in the association of different prefrontal regions with stress-induced anxiety. The predator stress model of traumatic stress produced enhanced alcohol drinking in a subgroup of stress-sensitive male and female animals, which could be associated with sex and subgroup differences in stress axis responsivity, behavioral responses to predator odors, and epigenetic mechanisms engaged by traumatic experiences., Summary: While additional studies in females are necessary, existing clinical and preclinical evidence suggests that biological mechanisms underlying stress-enhanced drinking likely differ between males and females. Thus, effective treatment strategies may differ between the sexes., Competing Interests: Conflict of Interest: The authors declare that they have no conflict of interest and that there are no competing financial interests to disclose.

Comorbidity of post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) worsens the prognosis for each of these individual disorders. The current study aimed to identify neurocircuits potentially involved in regulation of PTSD-AUD comorbidity by mapping expression of c-Fos in male and female C57BL/6J mice following repeated predator stress (PS), modeled by exposure to dirty rat bedding. In experiment 1, the levels of c-Fos in the paraventricular nucleus of the hypothalamus (PVH) and the nucleus accumbens shell were higher after the second PS vs the first PS, indicating a sensitized response to this stressor. Additional brain regions showed varied sex-dependent and independent regulation by the two consecutive PS exposures. In experiment 2, mice that increased voluntary alcohol consumption following four exposures to PS (Sensitive subgroup) showed higher c-Fos induction in the PVH, piriform cortex and ventromedial hypothalamus than mice that decreased consumption following these exposures (Resilient subgroup). In contrast to these brain regions, c-Fos was higher in the anterior olfactory nucleus of Resilient vs Sensitive mice. Taken together, these data demonstrate that repeated PS exposure and voluntary alcohol consumption increase neuronal activity across neurocircuits in which specific components depend on the vulnerability of individual mice to these stressors. Increased PVH activity observed across both experiments suggests this brain area as a potential mediator of PS-induced increases in alcohol consumption. Future investigations of specific neuronal populations within the PVH activated by PS, and manipulation of these specific neuronal populations, could improve our understanding of the mechanisms leading to PTSD-AUD comorbidity., (Copyright © 2023 IBRO. All rights reserved.)

Sexually dimorphic effects of alcohol, following binge drinking, chronic intoxication, and withdrawal, are documented at the level of the transcriptome and in behavioral and physiological responses. The purpose of the current review is to update and to expand upon contributions of the endocrine system to alcohol drinking and withdrawal in females, with a focus on animal models. Steroids important in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes, the reciprocal interactions between these axes, the effects of chronic alcohol use on steroid levels, and the genomic and rapid membrane-associated effects of steroids and neurosteroids in models of alcohol drinking and withdrawal are described. Importantly, comparison between males and females highlight some divergent effects of sex- and stress-steroids on alcohol drinking- and withdrawal-related behaviors, and the distinct differences in response emphasize the importance of considering sex in the development of novel pharmacotherapies for the treatment of alcohol use disorder., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The High Drinking in the Dark (HDID-1) line of mice has been selectively bred for achieving high blood alcohol levels (BALs) in the Drinking in the Dark task, a model of binge-like drinking. Recently, we determined that glucocorticoid receptor (GR) antagonism with either mifepristone or CORT113176 (a selective GR antagonist) reduced binge-like ethanol intake in the HDID-1 mice, but not in their founder line, HS/NPT. Here, we examined whether the selection process may have altered glucocorticoid functioning by measuring (1) plasma corticosterone levels and (2) expression of the genes encoding GR ( Nr3c1 ) and two of its chaperone proteins FKBP51 and FKBP52 ( Fkbp5 and Fkbp4 ) in the brains (nucleus accumbens, NAc) of HDID-1 and HS/NPT mice. We observed no genotype differences in baseline circulating corticosterone levels. However, HDID-1 mice exhibited a greater stimulated peak corticosterone response to an IP injection (of either ethanol or saline) relative to their founder line. We further observed reduced basal expression of Fkbp4 and Nr3c1 in the NAc of HDID-1 mice relative to HS/NPT mice. Finally, HDID-1 mice exhibited reduced Fkbp5 expression in the NAc relative to HS/NPT mice following an injection of 2 g/kg ethanol. Together, these data suggest that selective breeding for high BALs may have altered stress signaling in the HDID-1 mice, which may contribute to the observed selective efficacy of GR antagonism in reducing binge-like ethanol intake in HDID-1, but not HS/NPT mice. These data have important implications for the role that stress signaling plays in the genetic risk for binge drinking., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Savarese, Grigsby, Jensen, Borrego, Finn, Crabbe and Ozburn.)

Stress can increase ethanol drinking, and evidence confirms an association between post-traumatic stress disorder (PTSD) and the development of alcohol use disorder (AUD). Exposure to predator odor is considered a traumatic stressor, and predator stress (PS) has been used extensively as an animal model of PTSD. Our prior work determined that repeated exposure to intermittent PS significantly increased anxiety-related behavior, corticosterone levels, and neuronal activation in the hippocampus and prefrontal cortex in naïve male and female C57BL/6J mice. Intermittent PS exposure also increased subsequent ethanol drinking in a subgroup of animals, with heterogeneity of responses as seen with comorbid PTSD and AUD. The present studies built upon this prior work and began to characterize "sensitivity" and "resilience" to PS-enhanced drinking. Ethanol drinking was measured during baseline, intermittent PS exposure, and post-stress; mice were euthanized after 24-h abstinence. Calculation of median and interquartile ranges identified "sensitive" (>20% increase in drinking over baseline) and "resilient" (no change or decrease in drinking from baseline) subgroups. Intermittent PS significantly increased subsequent ethanol intake in 24% of male (↑60%) and in 20% of female (↑71%) C57BL/6J mice in the "sensitive" subgroup. Plasma corticosterone levels were increased significantly after PS in both sexes, but levels were lower in the "sensitive" vs. "resilient" subgroups. In representative mice from "sensitive" and "resilient" subgroups, prefrontal cortex and hippocampus were analyzed by Western Blotting for levels of corticotropin releasing factor (CRF) receptor 1, CRF receptor 2, CRF binding protein, and glucocorticoid receptor, vs. separate naïve age-matched mice. In prefrontal cortex, CRF receptor 1, CRF receptor 2, CRF binding protein, and glucocorticoid receptor levels were significantly higher in "sensitive" vs. naïve and "resilient" mice only in females. In hippocampus, CRF receptor 1, CRF receptor 2 and glucocorticoid receptor levels were significantly lower in "resilient" vs. naïve and "sensitive" mice across both sexes. These results indicate that sex strongly influences the effects of ethanol drinking and stress on proteins regulating stress and anxiety responses. They further suggest that targeting the CRF system and glucocorticoid receptors in AUD needs to consider the comorbidity of PTSD with AUD and sex of treated individuals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alavi, Ryabinin, Helms, Nipper, Devaud and Finn.)

There is compelling evidence that sex and gender have crucial roles in excessive alcohol (ethanol) consumption. Here, we review some of the data from the perspective of brain transcriptional differences between males and females, focusing on rodent animal models. A key emerging transcriptional feature is the role of neuroimmune processes. Microglia are the resident neuroimmune cells in the brain and exhibit substantial functional differences between males and females. Selective breeding for binge ethanol consumption and the impacts of chronic ethanol consumption and withdrawal from chronic ethanol exposure all demonstrate sex-dependent neuroimmune signatures. A focus is on resolving sex-dependent differences in transcriptional responses to ethanol at the neurocircuitry level. Sex-dependent transcriptional differences are found in the extended amygdala and the nucleus accumbens. Telescoping of ethanol consumption is found in some, but not all, studies to be more prevalent in females. Recent transcriptional studies suggest that some sex differences may be due to female-dependent remodeling of the primary cilium. An interesting theme appears to be developing: at least from the animal model perspective, even when males and females are phenotypically similar, they differ significantly at the level of the transcriptome., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Sexually dimorphic effects of alcohol exposure throughout life have been documented in clinical and preclinical studies. In the past, rates of alcohol use disorder (AUD) were higher in men than in women, but over the past 10 years, the difference between sexes in prevalence of AUD and binge drinking has narrowed. Recent evidence adds to historical data regarding the influence of sex steroids on alcohol drinking and the interaction with stress-related steroids. This review considers the contribution of the endocrine system to alcohol drinking in females, with a focus on the hypothalamic pituitary gonadal axis and the hypothalamic pituitary adrenal axis and their reciprocal interactions. Emphasis is given to preclinical studies that examined genomic and rapid membrane effects of estrogen, progesterone, glucocorticoids, and GABAergic neurosteroids for their effects on alcohol drinking and models of relapse. Pertinent comparisons to data in males highlight divergent effects of sex and stress steroids on alcohol drinking and emphasize the importance of considering sex in the development of novel pharmacotherapeutic targets for the treatment of AUD. For instance, pharmacological strategies targeting the corticotropin releasing factor and glucocorticoid receptor systems may be differentially effective in males and females, whereas strategies to enhance GABAergic neurosteroids may represent a biomarker of treatment efficacy in both sexes., Competing Interests: Financial disclosure The author declares no competing financial interests.

Human studies reported that the number of past-year stressors was positively related to current drinking patterns, including binge drinking. In animal models, exposure to predator odor stress (PS), considered a model of traumatic stress, consistently increased ethanol intake. Recently, we reported that repeated PS significantly increased ethanol intake and had a synergistic interaction with prior binge drinking (binge group) in male but not in female C57BL/6J mice, when compared to mice without prior binge exposure (control group). The current studies utilized plasma and dissected prefrontal cortex (PFC) and hippocampal tissue from these animals and from age-matched naïve mice (naïve group). Western blots assessed relative protein levels of P450scc (an enzyme involved in the first step of steroidogenesis), of GABA A receptor α2 and α4 subunits, and of two proteins involved in synaptic plasticity - ARC (activity-regulated cytoskeletal protein) and synaptophysin. Gas chromatography-mass spectrometry simultaneously quantified 10 neurosteroid levels in plasma. A history of ethanol drinking and PS exposure produced brain regional and sex differences in the changes in proteins examined as well as in the pattern of neurosteroid levels versus (vs.) values in naïve mice. For instance, P450scc levels were significantly increased only in binge and control female PFC and hippocampus vs. naïve mice. Some neurosteroid levels were significantly altered by binge treatment in both males and females, whereas others were only significantly altered in males. These sexually divergent changes in neurosteroid and protein levels add to evidence for sex differences in the neurochemical systems influenced by traumatic stress and a history of ethanol drinking., Competing Interests: Declaration of competing interest None. The contents do not represent the views of the United States Department of Veterans Affairs, the United States government, or the National Institutes of Health., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sleep complaints are an early clinical symptom of neurodegenerative disorders. Patients with Parkinson's disease (PD) experience sleep disruption (SD). The objective of this study was to determine if preexisting, chronic SD leads to a greater loss of tyrosine hydroxylase (TH) within the striatum and the substantia nigra following chronic/progressive exposure with the neurotoxin, 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Male mice underwent chronic SD for 4 weeks, then injected with vehicle (VEH) or increasing doses of MPTP for 4 weeks. There was a significant decrease in the plasma corticosterone levels in the MPTP group, an increase in the SD group, and a return to the VEH levels in the SD+MPTP group. Protein expression levels for TH in the striatum (terminals) and substantia nigra pars compacta (dopamine [DA] cell counts) revealed up to a 78% and 38% decrease, respectively, in the MPTP and SD+MPTP groups compared to their relevant VEH and SD groups. DA transporter protein expression increased in the striatum in the MPTP versus VEH group and in the SN/midbrain between the SD+MPTP and the VEH group. There was a main effect of MPTP on various gait measures (e.g., braking) relative to the SD or VEH groups. In the SD+MPTP group, there were no differences compared to the VEH group. Thus, SD, prior to administration of MPTP, has effects on serum corticosterone and gait but more importantly does not potentiate greater loss of TH within the nigrostriatal pathway compared to the MPTP group, suggesting that in PD patients with SD, there is no exacerbation of the DA cell loss., (© 2019 Wiley Periodicals, Inc.)

Rationale: Sporadic reports of alcohol consumption being linked to menstrual cycle phase highlight the need to consider hormonally characterized menstrual cycle phase in understanding the sex-specific effects of risk for alcohol drinking in women., Objectives: We investigated the association between menstrual cycle phase, characterized by circulating progesterone and menses, with accurate daily alcohol intakes in rhesus monkeys, and the contribution of progesterone derived neuroactive steroids to cycle-related alcohol drinking., Methods: Menses (daily) and progesterone (2-3×/week) were obtained in female monkeys (n = 8, 5 ethanol, 3 control) for 12-18 months. Ethanol monkeys were then induced to drink ethanol (4% w/v; 3 months) and given 22 h/day access to ethanol and water for approximately 1 year. In selected cycles, a panel of neuroactive steroids were assayed during follicular and luteal phases from pre-ethanol and ethanol exposure., Results: There were minimal to no effects of ethanol on menstrual cycle length, progesterone levels, and follicular or luteal phase length. The monkeys drank more ethanol during the luteal phase, compared to the follicular phase, and ethanol intake was highest in the late luteal phase when progesterone declines rapidly. Two neuroactive steroids were higher during the luteal phase versus the follicular phase, and several neuroactive steroids were higher in the pre- vs. post-ethanol drinking menstrual cycles., Conclusions: This is the first study to show that normal menstrual cycle fluctuations in progesterone, particularly during the late luteal phase, can modulate ethanol intake. Two of 11 neuroactive steroids were selectively associated with the effect of cycle progesterone on ethanol drinking, suggesting possible links to CNS mechanisms of ethanol intake control.

Across mammals, juveniles sleep more than adults, with rapid eye movement (REM) sleep at a lifetime maximum early in life. One function of REM sleep may be to facilitate brain development of complex behaviors. Here, we applied 1 week of early-life sleep disruption (ELSD) in prairie voles ( Microtus ochrogaster ), a highly social rodent species that forms lifelong pair bonds. Electroencephalographic recordings from juvenile voles during ELSD revealed decreased REM sleep and reduced γ power compared to baseline. ELSD impaired pair bond formation and altered object preference in adulthood. Furthermore, ELSD increased GABAergic parvalbumin immunoreactivity in the primary somatosensory cortex in adulthood, a brain region relevant to both affected behaviors. We propose that, early in life, sleep is crucial for tuning inhibitory neural circuits and the development of species-typical affiliative social behavior.

Sensitivity to anticonvulsant effects of the γ-aminobutyric acid A receptor-active neurosteroid allopregnanolone (ALLO) during ethanol withdrawal varies across genotypes, with high sensitivity in genotypes with mild withdrawal and low sensitivity in genotypes with high withdrawal. The present studies determined whether the resistance to ALLO during withdrawal in mouse genotypes with high handling-induced convulsions (HICs) during withdrawal could be overcome with use of ganaxolone (GAN), the metabolically stable derivative of ALLO. In separate studies, male and female Withdrawal Seizure-Prone (WSP-1) and DBA/2J (D2) mice were exposed to air (controls) or 72-h ethanol vapor and then were scored for HICs during withdrawal (hourly for the first 12 h, then at hours 24 and 25). After the HIC scoring at hours 5 and 9, mice were injected with 10 mg/kg GAN or vehicle. Area under the HIC curve (AUC) for hours 5-12 was analyzed. In control WSP-1 mice, GAN significantly reduced AUC by 52% (males) and 63% (females), with effects that were absent or substantially reduced during withdrawal. In contrast, GAN significantly reduced AUC in both control and ethanol-withdrawing male and female D2 mice. AUC was decreased by 81% (males) and 70% (females) in controls and by 35% (males) and 21% (females) during withdrawal. The significant anticonvulsant effect of GAN during withdrawal in D2 but not WSP-1 mice suggests that different mechanisms may contribute to ALLO insensitivity during withdrawal in these two genotypes. Importantly, the results in D2 mice suggest that GAN may be a useful treatment for ethanol withdrawal-induced seizures., (Copyright © 2018 IBRO. All rights reserved.)

We previously determined that repeated binge ethanol drinking produced sex differences in the regulation of signaling downstream of Group 1 metabotropic glutamate receptors in the nucleus accumbens (NAc) of adult C57BL/6J mice. The purpose of the present study was to characterize RNA expression differences in the NAc of adult male and female C57BL/6J mice following 7 binge ethanol drinking sessions, when compared with controls consuming water. This binge drinking procedure produced high intakes (average >2.2 g/kg/30 min) and blood ethanol concentrations (average >1.3 mg/ml). Mice were euthanized at 24 h after the 7th binge session, and focused qPCR array analysis was employed on NAc tissue to quantify expression levels of 384 genes in a customized Mouse Mood Disorder array, with a focus on glutamatergic signaling (3 arrays/group). We identified significant regulation of 50 genes in male mice and 70 genes in female mice after 7 ethanol binges. Notably, 14 genes were regulated in both males and females, representing common targets to binge ethanol drinking. However, expression of 10 of these 14 genes was strongly dimorphic (e.g., opposite regulation for genes such as Crhr2 , Fos , Nos1 , and Star ), and only 4 of the 14 genes were regulated in the same direction ( Drd5 , Grm4 , Ranbp9 , and Reln ). Interestingly, the top 30 regulated genes by binge ethanol drinking for each sex differed markedly in the male and female mice, and this divergent neuroadaptive response in the NAc could result in dysregulation of distinct biological pathways between the sexes. Characterization of the expression differences with Ingenuity Pathway Analysis was used to identify Canonical Pathways, Upstream Regulators, and significant Biological Functions. Expression differences suggested that hormone signaling and immune function were altered by binge drinking in female mice, whereas neurotransmitter metabolism was a central target of binge ethanol drinking in male mice. Thus, these results indicate that the transcriptional response to repeated binge ethanol drinking was strongly influenced by sex, and they emphasize the importance of considering sex in the development of potential pharmacotherapeutic targets for the treatment of alcohol use disorder.

Alcohol-use disorders (AUDs) are characterized by repeated episodes of binge drinking. Based on reports that exposure to predator odor stress (PS) consistently increases ethanol intake, the present studies examined whether prior binge drinking differentially altered responsivity to PS and subsequent ethanol intake in male and female mice, when compared to mice without prior binge exposure. Initial studies in naïve male and female C57BL/6J mice confirmed that 30-min exposure to dirty rat bedding significantly increased plasma corticosterone (CORT) levels and anxiety-related behavior, justifying the use of dirty rat bedding as PS in the subsequent drinking studies. Next, separate groups of male and female C57BL/6J mice received seven binge ethanol sessions (binge) or drank water (controls), followed by a 1-month period of abstinence. Then, 2-bottle choice ethanol intake (10% or 10E vs. water, 23 h/day) was measured in lickometer chambers for 4 weeks. After baseline intake stabilized, exposure to intermittent PS (2×/week × 2 weeks) significantly enhanced ethanol intake after the 2nd PS in male, but not female, binge mice vs. baseline and vs. the increase in controls. However, in a subgroup of females (with low baselines), PS produced a similar increase in 10E intake in control and binge mice vs. baseline. Analysis of lick behavior determined that the enhanced 10E intake in binge male mice and in the female low baseline subgroup was associated with a significant increase in 10E bout frequency and 10E licks throughout the circadian dark phase. Thus, PS significantly increased 10E intake and had a synergistic interaction with prior binge drinking in males, whereas PS produced a similar significant increase in 10E intake in the low baseline subgroup of binge and control females. Plasma CORT levels were increased significantly in both binge and control animals after PS. CORT levels at 24-h withdrawal from daily 10E intake were highest in the groups with elevated 10E licks (i.e., binge males and control females). At 24-h withdrawal, protein levels of GABA A receptor α1 subunit, corticotropin releasing factor receptor 1, and glucocorticoid receptor in prefrontal cortex (PFC) and hippocampus (HC) were differentially altered in the male and female mice vs. levels in separate groups of age-matched naïve mice, with more changes in HC than in PFC and in females than in males. Importantly, the sexually divergent changes in protein levels in PFC and HC add to evidence for sex differences in the neurochemical systems influenced by stress and binge drinking, and argue for sex-specific pharmacological strategies to treat AUD., (Published by Elsevier Inc.)

Some of the neurobehavioral deficits identified in children with Fetal Alcohol Spectrum Disorders (FASDs) have been recapitulated in a binge model of gestational third trimester-equivalent ethanol (EtOH) exposure, in which Sprague-Dawley rats are intragastrically intubated between post-natal day (PD) 4 and PD9 with high doses of EtOH. In this model, the ameliorating effects of choline (Chol) administration on hippocampus-dependent behaviors altered by EtOH have also been extensively documented. In the present study, we investigated the effects of EtOH (5 g/kg/day) and/or Chol (100 mg/kg/day) on morphometric parameters of CA1 pyramidal neurons by Golgi-Cox staining followed by Neurolucida tracing and analysis. We found that EtOH increased apical dendrite complexity in male and female pups neonatally exposed to EtOH. EtOH did not significantly affect basal dendrite parameters in female and male rats. Interestingly, Chol treatments decreased basal dendrites' length, number, and maximal terminal distance in male pups. When pups were co-treated with EtOH and Chol, Chol did not rescue the effect of EtOH. In conclusion, EtOH increases while Chol decreases dendritic length and arborization of hippocampal CA1 neurons in PD9 rats. We hypothesize that developmental EtOH exposure induces a premature maturation of neurons, leading to early restriction of neuronal plasticity while Chol treatments delay the normal program of neuronal maturation and therefore prolong the window of maximal plasticity. Chol does not prevent the effects of developmental alcohol exposure on hippocampal pyramidal neurons' morphology characterized in the present study, although whether prolonged Chol administration after developmental EtOH exposure rectifies EtOH damage remains to be assessed., (Published by Elsevier Ltd.)

The term neurosteroid refers to rapid membrane actions of steroid hormones and their derivatives that can modulate physiological functions and behavior via their interactions with ligand-gated ion channels. This chapter will highlight recent advances pertaining to the modulatory effects of a select group of neurosteroids that are primarily potent positive allosteric modulators of γ-aminobutyric acid A receptors (GABA A Rs). Nanomolar concentrations of neurosteroids, which occur in vivo, potentiate phasic and tonic forms of GABA A R-mediated inhibition, indicating that both synaptic and extrasynaptic GABA A Rs possess sensitivity to neurosteroids and contribute to the overall ability of neurosteroids to modulate central nervous system excitability. Common effects of alcohol and neurosteroids at GABA A Rs have stimulated research on the ability of neurosteroids to modulate alcohol's acute and chronic effects. Background on neurosteroid pharmacology and biosynthetic enzymes will be provided as it relates to experimental findings. Data will be summarized on alcohol and neurosteroid interactions across neuroanatomical regions and models of intoxication, consumption, dependence, and withdrawal. Evidence supports independent regulation of neurosteroid synthesis between periphery and brain as well as across brain regions following acute alcohol administration and during withdrawal. Local mechanisms for fine-tuning neuronal excitability via manipulation of neurosteroid synthesis exert predicted behavioral and electrophysiological responses on GABA A R-mediated inhibition. Collectively, targeting neurosteroidogenesis may be a beneficial treatment strategy for alcohol use disorders.

Rationale: Endogenous γ-aminobutyric acid A receptor (GABA A R)-active neurosteroids (e.g., allopregnanolone) regulate central nervous system excitability and many physiological functions, so fluctuations are implicated in several neuropsychiatric disorders. Pertinently, evidence supports an inverse relationship between endogenous GABA A R-active neurosteroid levels and behavioral changes in excitability during ethanol withdrawal (WD)., Objectives: The present studies determined mouse genotype differences in ten neurosteroid levels in plasma, cortex, and hippocampus over the time course of ethanol WD in the WD Seizure-Prone (WSP) and WD Seizure-Resistant (WSR) selected lines and in the DBA/2J (DBA) inbred strain., Methods: Gas chromatography-mass spectrometry was utilized to simultaneously quantify neurosteroid levels from control-treated male WSP-1, WSR-1, and DBA mice and during 8 and 48 h of WD., Results: Combined with our prior work, there was a consistent decrease in plasma allopregnanolone levels at 8 h WD in all three genotypes, an effect that persisted at 48 h WD only in DBA mice. WSR-1 and WSP-1 mice exhibited unexpected divergent changes in cortical neurosteroids at 8 h WD, with the majority of neurosteroids (including allopregnanolone) being significantly decreased in WSR-1 mice, but unaffected or significantly increased in WSP-1 mice. In DBA mice, hippocampal allopregnanolone and tetrahydrodeoxycorticosterone were significantly decreased at 8 h WD. The pattern of significant correlations between allopregnanolone and other GABA A R-active neurosteroid levels differed between controls and withdrawing mice., Conclusions: Ethanol WD dysregulated neurosteroid synthesis. Results in WSP-1 mice suggest that diminished GABA A R function is more important for their high WD phenotype than fluctuations in neurosteroid levels.

Background: The chronic intermittent ethanol (CIE) paradigm is valuable for screening compounds for efficacy to reduce drinking traits related to alcohol use disorder (AUD), as it measures alcohol consumption and preference under physical dependence conditions. Air control-treated animals allow simultaneous testing of similarly treated, nondependent animals. As a consequence, we used CIE to test the hypothesis that tigecycline, a semisynthetic tetracycline similar to minocycline and doxycycline, would reduce alcohol consumption regardless of dependence status., Methods: Adult C57BL/6J female and male mice were tested for tigecycline efficacy to reduce ethanol (EtOH) consumption using a standard CIE paradigm. The ability of tigecycline to decrease 2-bottle choice of 15% EtOH (15E) versus water intake in dependent (CIE vapor) and nondependent (air-treated) male and female mice was tested after 4 cycles of CIE vapor or air exposure using a within-subjects design and a dose-response. Drug doses of 0, 40, 60, 80, and 100 mg/kg in saline were administered intraperitoneally (0.01 ml/g body weight) and in random order, with a 1-hour pretreatment time. Baseline 15E intake was re-established prior to administration of subsequent injections, with a maximum of 2 drug injections tested per week., Results: Tigecycline was found to effectively reduce high alcohol consumption in both dependent and nondependent female and male mice., Conclusions: Our data suggest that tigecycline may be a promising drug with novel pharmacotherapeutic characteristics for the treatment of mild-to-severe AUD in both sexes., (Copyright © 2016 by the Research Society on Alcoholism.)

Background: Alcohol use disorder (AUD) is a spectrum disorder characterized by mild to severe symptoms, including potential withdrawal signs upon cessation of consumption. Approximately five hundred thousand patients with AUD undergo clinically relevant episodes of withdrawal annually (New Engl J Med, 2003, 348, 1786). Recent evidence indicates potential for drugs that alter neuroimmune pathways as new AUD therapies. We have previously shown the immunomodulatory drugs, minocycline and tigecycline, were effective in reducing ethanol (EtOH) consumption in both the 2-bottle choice and drinking-in-the-dark paradigms. Here, we test the hypothesis that tigecycline, a tetracycline derivative, will reduce the severity of EtOH withdrawal symptoms in a common acute model of alcohol withdrawal (AWD) using a single anesthetic dose of EtOH in seizure sensitive DBA/2J (DBA) mice., Methods: Naïve adult female and male DBA mice were given separate injections of 4 g/kg i.p. EtOH with vehicle or tigecycline (0, 20, 40, or 80 mg/kg i.p.). The 80 mg/kg dose was tested at 3 time points (0, 4, and 7 hours) post EtOH treatment. Handling-induced convulsions (HICs) were measured before and then over 12 hours following EtOH injection. HIC scores and areas under the curve were tabulated. In separate mice, blood EtOH concentrations (BECs) were measured at 2, 4, and 7 hours postinjection of 4 g/kg i.p. EtOH in mice treated with 0 and 80 mg/kg i.p. tigecycline., Results: AWD symptom onset, peak magnitude, and overall HIC severity were reduced by tigecycline drug treatment compared to controls. Tigecycline treatment was effective regardless of timing throughout AWD, with earlier treatment showing greater efficacy. Tigecycline showed a dose-responsive reduction in acute AWD convulsions, with no sex differences in efficacy. Importantly, tigecycline did not affect BECs over a time course of elimination., Conclusions: Tigecycline effectively reduced AWD symptoms in DBA mice at all times and dosages tested, making it a promising lead compound for development of a novel pharmacotherapy for AWD. Further studies are needed to determine the mechanism of tigecycline action., (Copyright © 2016 by the Research Society on Alcoholism.)

Unlabelled: Cerebellar granule cell GABAA receptor responses to alcohol vary as a function of alcohol consumption phenotype, representing a potential neural mechanism for genetic predilection for alcohol abuse (Kaplan et al., 2013; Mohr et al., 2013). However, there are numerous molecular targets of alcohol in the cerebellum, and it is not known how they interact to affect cerebellar processing during consumption of socially relevant amounts of alcohol. Importantly, direct evidence for a causative role of the cerebellum in alcohol consumption phenotype is lacking. Here we determined that concentrations of alcohol that would be achieved in the blood after consumption of 1-2 standard units (9 mm) suppresses transmission through the cerebellar cortex in low, but not high, alcohol consuming rodent genotypes (DBA/2J and C57BL/6J mice, respectively). This genotype-selective suppression is mediated exclusively by enhancement of granule cell GABAA receptor currents, which only occurs in DBA/2J mice. Simulating the DBA/2J cellular phenotype in C57BL/6J mice by infusing the GABAA receptor agonist, 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol hydrochloride, into cerebellar lobules IV-VI, in vivo, significantly reduced their alcohol consumption and blood alcohol concentrations achieved. 4,5,6,7-Tetrahydroisoxazolo-[5,4-c]pyridine-3-ol hydrochloride infusions also significantly decreased sucrose consumption, but they did not affect consumption of water or general locomotion. Thus, genetic differences in cerebellar response to alcohol contributes to alcohol consumption phenotype, and targeting the cerebellar GABAA receptor system may be a clinically viable therapeutic strategy for reducing excessive alcohol consumption., Significance Statement: Alcohol abuse is a leading cause of preventable death and illness; and although alcohol use disorders are 50%-60% genetically determined, the cellular and molecular mechanisms of such genetic influences are largely unknown. Here we demonstrate that genetic differences in cerebellar granule cell GABAA receptor responses to recreational concentrations of alcohol are the primary determinant of alcohol's impact on cerebellar processing and that pharmacologically modifying such responses alters alcohol consumption. These data highlight the cerebellum as an important neuroanatomical region in alcohol consumption phenotype and as a target for pharmacological treatment of alcohol use disorders. The results also add to the growing list of cognitive/emotional roles of the cerebellum in psychiatric disease and drug abuse., (Copyright © 2016 the authors 0270-6474/16/369020-07$15.00/0.)

Background: Evidence indicates that the cerebellum plays a role in genetic predilection to excessive alcohol (ethanol [EtOH]) consumption in rodents and humans, but the molecular mechanisms mediating such predilection are not understood. We recently determined that EtOH has opposite actions (enhancement or suppression) on tonic GABAA receptor (GABAA R) currents in cerebellar granule cells (GCs) in low- and high-EtOH-consuming rodents, respectively, and proposed that variation in GC tonic GABAA R current responses to EtOH contributes to genetic variation in EtOH consumption phenotype., Methods: Voltage-clamp recordings of GCs in acutely prepared slices of cerebellum were used to evaluate the effect of EtOH on GC tonic GABAA R currents in another high-EtOH-consuming rodent, prairie voles (PVs)., Results: EtOH (52 mM) suppressed the magnitude of the tonic GABAA R current in 57% of cells, had no effect in 38% of cells, and enhanced the tonic GABAA R current in 5% of cells. This result is similar to GCs from high-EtOH-consuming C57BL/6J (B6) mice, but it differs from the enhancement of tonic GABAA R currents by EtOH in low-EtOH-consuming DBA/2J (D2) mice and Sprague Dawley (SD) rats. EtOH suppression of tonic GABAA R currents was not affected by the sodium channel blocker, tetrodotoxin (500 nM), and was independent of the frequency of phasic GABAA R-mediated currents, suggesting that suppression is mediated by postsynaptic actions on GABAA Rs, rather than a reduction of GABA release. Finally, immunohistochemical analysis of neuronal nitric oxide synthase (nNOS; which can mediate EtOH enhancement of GABA release) demonstrated that nNOS expression in the GC layer of PV cerebellum was similar to the levels seen in B6 mice, both being significantly reduced relative to D2 mice and SD rats., Conclusions: Combined, these data highlight the GC GABAA R response to EtOH in another species, the high-EtOH-consuming PV, which correlates with EtOH consumption phenotype and further implicates the GC GABAA R system as a contributing mechanism to high EtOH consumption., (Copyright © 2016 by the Research Society on Alcoholism.)

In May 2014, Dr. Francis Collins, the director of U.S. National Institutes of Health (NIH), and Dr. Janine Clayton, the director of the U.S. National Institutes of Health Office of Research on Women's Health, published a commentary in the journal Nature announcing new policies to ensure that preclinical research funded by the NIH considers both males and females. While these policies are still developing, they have already generated great interest by the scientific community and triggered both criticism and applause. This review provides a description and interpretation of the NIH guidelines, and it traces the history that led to their implementation. As expected, this NIH initiative generated some anxiety in the scientific community. The use of female animals in the investigation of basic mechanisms is perceived to increase variability in the results, and the use of both sexes has been claimed to slow the pace of scientific discoveries and to increase the cost at a time characterized by declining research support. This review discusses issues related to the study of sex as a biological variable (SABV) in alcohol studies and provides examples of how researchers have successfully addressed some of them. A practical strategy is provided to include both sexes in biomedical research while maintaining control of the research direction. The inclusion of sex as an important biological variable in experimental design, analysis, and reporting of preclinical alcohol research is likely to lead to a better understanding of alcohol pharmacology and the development of alcohol use disorder, may promote drug discovery for new pharmacotherapies by increasing scientific rigor, and may provide clinical benefit to women's health. This review aims to promote the understanding of the NIH's SABV guidelines and to provide alcohol researchers with a theoretical and practical framework for working with both sexes in preclinical research., (Copyright © 2016 by the Research Society on Alcoholism.)

It is well established that binge alcohol consumption produces alterations in Group 1 metabotropic glutamate receptors (mGlus) and related signaling cascades in the nucleus accumbens (NAC) of adult male mice, but female and adolescent mice have not been examined. Thus, the first set of studies determined whether repeated binge alcohol consumption produced similar alterations in protein and mRNA levels of Group 1 mGlu-associated signaling molecules in the NAC of male and female adult and adolescent mice. The adult (9 weeks) and adolescent (4 weeks) C57BL/6J mice were exposed to 7 binge alcohol sessions every 3rd day while controls drank water. Repeated binge alcohol consumption produced sexually divergent changes in protein levels and mRNA expression for Group 1 mGlus and downstream signaling molecules in the NAC, but there was no effect of age. Binge alcohol intake decreased mGlu5 levels in females, whereas it decreased indices of phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), 4E-binding protein 1, and p70 ribosomal protein S6 kinase in males. Expression of genes encoding mGlu1, mGlu5, the NR2A subunit of the NMDA receptor, and Homer2 were all decreased by binge alcohol consumption in males, while females were relatively resistant (only phosphoinositide-dependent protein kinase 1 was decreased). The functional implication of these differences was investigated in a separate study by inhibiting mTOR in the NAC (via infusions of rapamycin) before binge drinking sessions. Rapamycin (50 and 100 ng/side) significantly decreased binge alcohol consumption in males, while consumption in females was unaffected. Altogether these results highlight that mTOR signaling in the NAC was necessary to maintain binge alcohol consumption only in male mice and that binge drinking recruits sexually divergent signaling cascades downstream of PI3K and presumably, Group 1 mGlus. Importantly, these findings emphasize that sex should be considered in the development of potential pharmacotherapeutic targets., (Published by Elsevier Ltd.)

Background: Protein kinase C epsilon (PKCε) is emerging as a potential target for the development of pharmacotherapies to treat alcohol use disorders, yet little is known regarding how a history of a highly prevalent form of drinking, binge alcohol intake, influences enzyme priming or the functional relevance of kinase activity for excessive alcohol intake., Methods: Immunoblotting was employed on tissue from subregions of the nucleus accumbens (NAc) and the amygdala to examine both idiopathic and binge drinking-induced changes in constitutive PKCε priming. The functional relevance of PKCε translocation for binge drinking and determination of potential upstream signaling pathways involved were investigated using neuropharmacologic approaches within the context of two distinct binge drinking procedures, drinking in the dark and scheduled high alcohol consumption., Results: Binge alcohol drinking elevated p(Ser729)-PKCε levels in both the NAc and the central nucleus of the amygdala (CeA). Moreover, immunoblotting studies of selectively bred and transgenic mouse lines revealed a positive correlation between the propensity to binge drink alcohol and constitutive p(Ser729)-PKCε levels in the NAc and CeA. Finally, neuropharmacologic inhibition of PKCε translocation within both regions reduced binge alcohol consumption in a manner requiring intact group 1 metabotropic glutamate receptors, Homer2, phospholipase C, and/or phosphotidylinositide-3 kinase function., Conclusions: Taken together, these data indicate that PKCε signaling in both the NAc and CeA is a major contributor to binge alcohol drinking and to the genetic propensity to consume excessive amounts of alcohol., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)