Search

The use of the common marmoset ( Callithrix jacchus ) for neuroscientific inquiry has grown precipitously over the past two decades. Despite windfalls of grant support from funding initiatives in North America, Europe, and Asia to model human brain diseases in the marmoset, marmoset-specific apparatus are of sparse availability from commercial vendors and thus are often developed and reside within individual laboratories. Through our collective research efforts, we have designed and vetted myriad designs for awake or anesthetized magnetic resonance imaging (MRI), positron emission tomography (PET), computed tomography (CT), as well as focused ultrasound (FUS), electrophysiology, optical imaging, surgery, and behavior in marmosets across the age-span. This resource makes these designs openly available, reducing the burden of de novo development across the marmoset field. The computer-aided-design (CAD) files are publicly available through the Marmoset Brain Connectome (MBC) resource (https://www.marmosetbrainconnectome.org/apparatus/) and include dozens of downloadable CAD assemblies, software and online calculators for marmoset neuroscience. In addition, we make available a variety of vetted touchscreen and task-based fMRI code and stimuli. Here, we highlight the online interface and the development and validation of a few yet unpublished resources: Software to automatically extract the head morphology of a marmoset from a CT and produce a 3D printable helmet for awake neuroimaging, and the design and validation of 8-channel and 14-channel receive arrays for imaging deep structures during anatomical and functional MRI.

Introduction: Marmosets spontaneously develop pathological hallmarks of Alzheimer's disease (AD) including amyloid beta plaques. However, tau expression in the marmoset brain has been understudied., Methods: Isoforms of tau were examined by western blot, mass spectrometry, immunofluorescence, and immunohistochemical staining., Results: 3R and 4R tau isoforms are expressed in marmoset brains at both the transcript and protein levels across ages. Mass spectrometry analysis revealed that tau peptides in marmoset corresponded to the 3R and 4R peptides in human brain, with 3R predominating at birth and an ≈40%:60% 3R:4R ratios in adolescents and adults; tau was distributed widely in neurons, with localization in the soma and synaptic regions. Phosphorylation residues were observed on Threonine (Thr) Thr181, Thr217, Thr231, Serine (Ser) Ser202/Thr205, and Ser396/Ser404., Discussion: Our results confirm both 3R and 4R tau isoform expression and phosphorylation residues in the marmoset brain, and emphasize the significance of marmosets with natural expression of AD-related hallmarks as important translational models for AD. Highlights We report comprehensive characterization of tau isoform expression in marmoset brains across the lifespan. 3R and 4R tau isoforms are expressed in marmoset brains at both the transcript and protein levels across ages. These data emphasize the significance of marmosets with natural expression of primate-specific traits that are important for the study of Alzheimer's disease., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early-phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early-phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. HIGHLIGHTS: Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The fifth annual workshop on Principles and Techniques for Improving Preclinical Translation of Alzheimer's Disease Research was held in May 2023 at The Jackson Laboratory in Bar Harbor, Maine, USA. The workshop was established in 2018 to address training gaps in preclinical translational studies for Alzheimer's disease (AD). In addition to providing fundamental knowledge and hands-on skills essential for executing rigorous in vivo studies that are designed to facilitate translation, each year the workshop aims to provide insight on state-of-the-field technological advances and new resources including novel animal models, publicly available datasets, novel biomarkers, and new medical imaging tracers. This innovative and comprehensive workshop continues to deliver training for the greater AD research community in order to provide investigators and trainees with the knowledge and skillsets essential for enabling improved preclinical to clinical translation and accelerate the process of advancing safe and effective therapeutic interventions for AD. HIGHLIGHTS: Translational research is not typically available as a course of study at academic institutions, yet there are fundamental skillsets and knowledge required to enable successful translation from preclinical experiments to clinical efficacy. It is important that there are resources and opportunities available to researchers planning preclinical translational experiments. Here we present proceedings from the fifth annual NIA-sponsored workshop focused on enabling improved preclinical to clinical translation for Alzheimer's disease research that includes didactic lectures on state-of-the-field approaches and hands-on practicums for acquiring essential translational laboratory techniques., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: MODEL-AD (Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease) is creating and distributing novel mouse models with humanized, clinically relevant genetic risk factors to capture the trajectory and progression of late-onset Alzheimer's disease (LOAD) more accurately., Methods: We created the LOAD2 model by combining apolipoprotein E4 (APOE4), Trem2*R47H, and humanized amyloid-beta (Aβ). Mice were subjected to a control diet or a high-fat/high-sugar diet (LOAD2+HFD). We assessed disease-relevant outcome measures in plasma and brain including neuroinflammation, Aβ, neurodegeneration, neuroimaging, and multi-omics., Results: By 18 months, LOAD2+HFD mice exhibited sex-specific neuron loss, elevated insoluble brain Aβ42, increased plasma neurofilament light chain (NfL), and altered gene/protein expression related to lipid metabolism and synaptic function. Imaging showed reductions in brain volume and neurovascular uncoupling. Deficits in acquiring touchscreen-based cognitive tasks were observed., Discussion: The comprehensive characterization of LOAD2+HFD mice reveals that this model is important for preclinical studies seeking to understand disease trajectory and progression of LOAD prior to or independent of amyloid plaques and tau tangles., Highlights: By 18 months, unlike control mice (e.g., LOAD2 mice fed a control diet, CD), LOAD2+HFD mice presented subtle but significant loss of neurons in the cortex, elevated levels of insoluble Ab42 in the brain, and increased plasma neurofilament light chain (NfL). Transcriptomics and proteomics showed changes in gene/proteins relating to a variety of disease-relevant processes including lipid metabolism and synaptic function. In vivo imaging revealed an age-dependent reduction in brain region volume (MRI) and neurovascular uncoupling (PET/CT). LOAD2+HFD mice also demonstrated deficits in acquisition of touchscreen-based cognitive tasks., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Fundamental questions remain about the key mechanisms that initiate Alzheimer's disease (AD) and the factors that promote its progression. Here we report the successful generation of the first genetically engineered marmosets that carry knock-in (KI) point mutations in the presenilin 1 (PSEN1) gene that can be studied from birth throughout lifespan., Methods: CRISPR/Cas9 was used to generate marmosets with C410Y or A426P point mutations in PSEN1. Founders and their germline offspring are comprehensively studied longitudinally using non-invasive measures including behavior, biomarkers, neuroimaging, and multiomics signatures., Results: Prior to adulthood, increases in plasma amyloid beta were observed in PSEN1 mutation carriers relative to non-carriers. Analysis of brain revealed alterations in several enzyme-substrate interactions within the gamma secretase complex prior to adulthood., Discussion: Marmosets carrying KI point mutations in PSEN1 provide the opportunity to study the earliest primate-specific mechanisms that contribute to the molecular and cellular root causes of AD onset and progression., Highlights: We report the successful generation of genetically engineered marmosets harboring knock-in point mutations in the PSEN1 gene. PSEN1 marmosets and their germline offspring recapitulate the early emergence of AD-related biomarkers. Studies as early in life as possible in PSEN1 marmosets will enable the identification of primate-specific mechanisms that drive disease progression., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: A major goal of the Target Enablement to Accelerate Therapy Development for Alzheimer's disease (TREAT-AD) program is to develop and identify high-quality tools to test target or mechanistic hypotheses. As part of this initiative, it is important that commercial reagents including research antibodies being used to interrogate drug targets have confirmed validation data in knock-out cell lines. Ideally, these antibodies should also have utility for both in vitro and in vivo studies such that the levels of target proteins in target tissues can be quantified., Methods: We evaluated commercial antibodies against TREAT-AD protein targets Moesin (Uniprot ID: P26038), CD44 (Uniprot ID: P16070), Midkine (Uniprot ID: P21741) and Secreted frizzled-related protein 1, referred to as "sFRP-1" (sFRP-1; Uniprot ID: Q8N474). Moesin, Midkine and sFRP-1, that were confirmed as selective based on data in knock-out cell lines. Western blot analysis was used to compare protein levels in brain homogenates from a mouse model with AD-relevant pathology (5XFAD) versus age-matched C57BL/6J control mice., Results: Anti-Moesin ab52490 reacted in mouse brain homogenate with a predicted molecular weight of 68 kDa. Moesin protein expression was 2.8 times higher in 5xFAD compared to WT. Anti-CD44 ab189524 reacted with a band at the predicted size of 82 kDa. CD44 protein expression was 1.9 times higher in 5xFAD compared to WT. Anti-Midkine AF7769 reacted with a band ~16 kDa and a 17.8 times greater expression in 5xFAD compared to WT. Anti-sFRP-1 ab267466 reacted with a band at 35 kDa as predicted. sFRP-1 protein expression was 11.9 times greater in 5xFAD compared to WT., Conclusions: These data confirm the utility of these selective commercially available antibodies against Moesin, CD44, Midkine, and sFRP-1 for in vivo studies in mice and provide insight into the use of 5XFAD mice for in vivo target engagement studies for these target proteins., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Doolen S et al.)

Substance use disorders are heritable disorders characterized by compulsive drug use, the biological mechanisms for which remain largely unknown. Genetic correlations reveal that predisposing drug-naïve phenotypes, including anxiety, depression, novelty preference and sensation seeking, are predictive of drug-use phenotypes, thereby implicating shared genetic mechanisms. High-throughput behavioral screening in knockout (KO) mice allows efficient discovery of the function of genes. We used this strategy in two rounds of candidate prioritization in which we identified 33 drug-use candidate genes based upon predisposing drug-naïve phenotypes and ultimately validated the perturbation of 22 genes as causal drivers of substance intake. We selected 19/221 KO strains (8.5%) that had a difference from control on at least one drug-naïve predictive behavioral phenotype and determined that 15/19 (~80%) affected the consumption or preference for alcohol, methamphetamine or both. No mutant exhibited a difference in nicotine consumption or preference which was possibly confounded with saccharin. In the second round of prioritization, we employed a multivariate approach to identify outliers and performed validation using methamphetamine two-bottle choice and ethanol drinking-in-the-dark protocols. We identified 15/401 KO strains (3.7%, which included one gene from the first cohort) that differed most from controls for the predisposing phenotypes. 8 of 15 gene deletions (53%) affected intake or preference for alcohol, methamphetamine or both. Using multivariate and bioinformatic analyses, we observed multiple relations between predisposing behaviors and drug intake, revealing many distinct biobehavioral processes underlying these relationships. The set of mouse models identified in this study can be used to characterize these addiction-related processes further., (© 2023 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

Introduction: Our limited understanding of the mechanisms that trigger the emergence of Alzheimer's disease (AD) has contributed to the lack of interventions that stop, prevent, or fully treat this disease. We believe that the development of a non-human primate model of AD will be an essential step toward overcoming limitations of other model systems and is crucial for investigating primate-specific mechanisms underlying the cellular and molecular root causes of the pathogenesis and progression of AD., Methods: A new consortium has been established with funding support from the National Institute on Aging aimed at the generation, characterization, and validation of Marmosets As Research Models of AD (MARMO-AD). This consortium will study gene-edited marmoset models carrying genetic risk for AD and wild-type genetically diverse aging marmosets from birth throughout their lifespan, using non-invasive longitudinal assessments. These include characterizing the genetic, molecular, functional, behavioral, cognitive, and pathological features of aging and AD., Results: The consortium successfully generated viable founders carrying PSEN1 mutations in C410Y and A426P using CRISPR/Cas9 approaches, with germline transmission demonstrated in the C410Y line. Longitudinal characterization of these models, their germline offspring, and normal aging outbred marmosets is ongoing. All data and resources from this consortium will be shared with the greater AD research community., Discussion: By establishing marmoset models of AD, we will be able to investigate primate-specific cellular and molecular root causes that underlie the pathogenesis and progression of AD, overcome limitations of other model organisms, and support future translational studies to accelerate the pace of bringing therapies to patients., Competing Interests: S.J.S.R. has served as a consultant for Sage Therapeutics. G.W.C. has served as a consultant for Astex Pharmaceuticals. N.T.S. is a co‐founder and board member of Emtherapro Inc. G.E.H., D.J.S., L.S., J.E.P., J.U., T.Z., A.H., B.P., A.G., T.M., S.H.C., H.H., J.K., P.L.S., and A.C.S. report no competing interests to declare at the time of submission. Author disclosures are available in the Supporting Information., (© 2023 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Research on aging is at an important inflection point, where the insights accumulated over the last 2 decades in the basic biology of aging are poised to be translated into new interventions to promote health span and improve longevity. Progress in the basic science of aging is increasingly influencing medical practice, and the application and translation of geroscience require seamless integration of basic, translational, and clinical researchers. This includes the identification of new biomarkers, novel molecular targets as potential therapeutic agents, and translational in vivo studies to assess the potential efficacy of new interventions. To facilitate the required dialog between basic, translational, and clinical investigators, a multidisciplinary approach is essential and requires the collaborative expertise of investigators spanning molecular and cellular biology, neuroscience, physiology, animal models, physiologic and metabolic processes, pharmacology, genetics, and high-throughput drug screening approaches. In an effort to better enable the cross-talk of investigators across the broad spectrum of aging-related research disciplines, a goal of our University of Pittsburgh Claude D. Pepper Older Americans Independence Center has been to reduce the barriers to collaborative interactions by promoting a common language through team science. The culmination of these efforts will ultimately accelerate the ability to conduct first-in-human clinical trials of novel agents to extend health span and life span., Competing Interests: T.F. is a founder and stockholder in Generian Pharmaceuticals and Coloma Therapeutics. S.J.S.R, S.L.G., N.M.R., and J.S.B. have no conflicts to report., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Cocaine use and overdose deaths attributed to cocaine have increased significantly in the United States in the last 10 years. Despite the prevalence of cocaine use disorder (CUD) and the personal and societal problems it presents, there are currently no approved pharmaceutical treatments. The absence of treatment options is due, in part, to our lack of knowledge about the etiology of CUDs. There is ample evidence that genetics plays a role in increasing CUD risk but thus far, very few risk genes have been identified in human studies. Genetic studies in mice have been extremely useful for identifying genetic loci and genes, but have been limited to very few genetic backgrounds, leaving substantial phenotypic, and genetic diversity unexplored. Herein we report the measurement of cocaine-induced behavioral sensitization using a 19-day protocol that captures baseline locomotor activity, initial locomotor response to an acute exposure to cocaine and locomotor sensitization across 5 exposures to the drug. These behaviors were measured in 51 genetically diverse Collaborative Cross (CC) strains along with their inbred founder strains. The CC was generated by crossing eight genetically diverse inbred strains such that each inbred CC strain has genetic contributions from each of the founder strains. Inbred CC mice are infinitely reproducible and provide a stable, yet diverse genetic platform on which to study the genetic architecture and genetic correlations among phenotypes. We have identified significant differences in cocaine locomotor sensitivity and behavioral sensitization across the panel of CC strains and their founders. We have established relationships among cocaine sensitization behaviors and identified extreme responding strains that can be used in future studies aimed at understanding the genetic, biological, and pharmacological mechanisms that drive addiction-related behaviors. Finally, we have determined that these behaviors exhibit relatively robust heritability making them amenable to future genetic mapping studies to identify addiction risk genes and genetic pathways that can be studied as potential targets for the development of novel therapeutics., 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 Schoenrock, Gagnon, Olson, Leonardo, Philip, He, Reinholdt, Sukoff Rizzo, Jentsch, Chesler and Tarantino.)

Introduction: Alzheimer's disease (AD) is the most common form of dementia. Beta-secretase (BACE) inhibitors have been proposed as potential therapeutic interventions; however, initiating treatment once disease has significantly progressed has failed to effectively stop or treat disease. Whether BACE inhibition may have efficacy when administered prophylactically in the early stages of AD has been under-investigated. The present studies aimed to evaluate prophylactic treatment of the BACE inhibitor verubecestat in an AD mouse model using the National Institute on Aging (NIA) resources of the Model Organism Development for Late-Onset Alzheimer's Disease (MODEL-AD) Preclinical Testing Core (PTC) Drug Screening Pipeline., Methods: 5XFAD mice were administered verubecestat ad libitum in chow from 3 to 6 months of age, prior to the onset of significant disease pathology. Following treatment (6 months of age), in vivo imaging was conducted with 18F-florbetapir (AV-45/Amyvid) (18F-AV45) and 18-FDG (fluorodeoxyglucose)-PET (positron emission tomography)/MRI (magnetic resonance imaging), brain and plasma amyloid beta (Aβ) were measured, and the clinical and behavioral characteristics of the mice were assessed and correlated with the pharmacokinetic data., Results: Prophylactic verubecestat treatment resulted in dose- and region-dependent attenuations of 18F-AV45 uptake in male and female 5XFAD mice. Plasma Aβ40 and Aβ42 were also dose-dependently attenuated with treatment. Across the dose range evaluated, side effects including coat color changes and motor alterations were reported, in the absence of cognitive improvement or changes in 18F-FDG uptake., Discussion: Prophylactic treatment with verubecestat resulted in attenuated amyloid plaque deposition when treatment was initiated prior to significant pathology in 5XFAD mice. At the same dose range effective at attenuating Aβ levels, verubecestat produced side effects in the absence of improvements in cognitive function. Taken together these data demonstrate the rigorous translational approaches of the MODEL-AD PTC for interrogating potential therapeutics and provide insight into the limitations of verubecestat as a prophylactic intervention for early-stage AD., Competing Interests: The authors are supported by funding from the National Institutes of Health, National Institute on Aging U54 AG054345. Dr. Oblak is supported by funding from the National Institute on Aging K01AG054753. BTL has served as a consultant for AvroBio and Eli‐Lilly and is supported by additional funding: NIA R01 AG022304, RF1 AG051495, U54 AG065181, and U54 AG054345. Mass spectrometry and UV work was provided by the Clinical Pharmacology Analytical Core at Indiana University School of Medicine; a core facility supported by the IU Simon Cancer Center Support Grant P30 CA082709. A.L.O., Z.A.C., S.K.Q., R.P., C.B., A.R.M., K.D.O., L.H., K.J.K., J.A.M., J.P., S.C.P., A.A.B., K.E., R.S., G.L., S.P.W., B.N., A.O., M.S., G.R.H., G.W.C., H.W., B.T.L., P.R.T., and S.J.S.R. have no conflicts. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Clinical investigations have established that vascular-associated medical conditions are significant risk factors for various kinds of dementia. And yet, we are unable to associate certain types of vascular deficiencies with specific cognitive impairments. The reasons for this are many, not the least of which are that most vascular disorders are multi-factorial and the development of vascular dementia in humans is often a multi-year or multi-decade progression. To better study vascular disease and its underlying causes, the National Heart, Lung, and Blood Institute of the National Institutes of Health has invested considerable resources in the development of animal models that recapitulate various aspects of human vascular disease. Many of these models, mainly in the mouse, are based on genetic mutations, frequently using single-gene mutations to examine the role of specific proteins in vascular function. These models could serve as useful tools for understanding the association of specific vascular signaling pathways with specific neurological and cognitive impairments related to dementia. To advance the state of the vascular dementia field and improve the information sharing between the vascular biology and neurobehavioral research communities, National Heart, Lung, and Blood Institute convened a workshop to bring in scientists from these knowledge domains to discuss the potential utility of establishing a comprehensive phenotypic cognitive assessment of a selected set of existing mouse models, representative of the spectrum of vascular disorders, with particular attention focused on age, sex, and rigor and reproducibility. The workshop highlighted the potential of associating well-characterized vascular disease models, with validated cognitive outcomes, that can be used to link specific vascular signaling pathways with specific cognitive and neurobehavioral deficits.

Obesity is recognized as a significant risk factor for Alzheimer's disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies, to date, have focused on the use of early-onset AD models. Here, we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed with a high fat/high sugar diet (HFD). We focused on three mouse models created through the IU/JAX/PITT MODEL-AD Center. These included a combined risk model with APOE4 and a variant in triggering receptor expressed on myeloid cells 2 ( Trem2 R47H ). We have termed this model, LOAD1. Additional variants including the M28L variant in phospholipase C Gamma 2 ( Plcg2 M28L ) and the 677C > T variant in methylenetetrahydrofolate reductase ( Mthfr 677C > T ) were engineered by CRISPR onto LOAD1 to generate LOAD1. Plcg2 M28L and LOAD1. Mthfr 677C > T . At 2 months of age, animals were placed on an HFD that induces obesity or a control diet (CD), until 12 months of age. Throughout the study, blood was collected to assess the levels of cholesterol and glucose. Positron emission tomography/computed tomography (PET/CT) was completed prior to sacrifice to image for glucose utilization and brain perfusion. After the completion of the study, blood and brains were collected for analysis. As expected, animals fed a HFD, showed a significant increase in body weight compared to those fed a CD. Glucose increased as a function of HFD in females only with cholesterol increasing in both sexes. Interestingly, LOAD1. Plcg2 M28L demonstrated an increase in microglia density and alterations in regional brain glucose and perfusion on HFD. These changes were not observed in LOAD1 or LOAD1. Mthfr 677C > T animals fed with HFD. Furthermore, LOAD1. Plcg2 M28L but not LOAD1. Mthfr 677C > T or LOAD1 animals showed transcriptomics correlations with human AD modules. Our results show that HFD affects the brain in a genotype-specific manner. Further insight into this process may have significant implications for the development of lifestyle interventions for the treatment of AD., 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 Oblak, Kotredes, Pandey, Reagan, Ingraham, Perkins, Lloyd, Baker, Lin, Soni, Tsai, Persohn, Bedwell, Eldridge, Speedy, Meyer, Peters, Figueiredo, Sasner, Territo, Sukoff Rizzo, Carter, Lamb and Howell.)

Continually emerging data indicate that sub-clinical, non-convulsive epileptiform activity is not only prevalent in Alzheimer's disease (AD) but is detectable early in the course of the disease and predicts cognitive decline in both humans and animal models. Epileptiform activity and other electroencephalographic (EEG) measures may hold powerful, untapped potential to improve the translational validity of AD-related biomarkers in model animals ranging from mice, to rats, and non-human primates. In this review, we will focus on studies of epileptiform activity, EEG slowing, and theta-gamma coupling in preclinical models, with particular focus on its role in cognitive decline and relevance to AD. Here, each biomarker is described in the context of the contemporary literature and recent findings in AD relevant animal models are discussed., 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 Cope, Murai and Sukoff Rizzo.)

Drugs of abuse, including alcohol and stimulants like cocaine, produce effects that are subject to individual variability, and genetic variation accounts for at least a portion of those differences. Notably, research in both animal models and human subjects point toward reward sensitivity and impulsivity as being trait characteristics that predict relatively greater positive subjective responses to stimulant drugs. Here we describe use of the eight collaborative cross (CC) founder strains and 38 (reversal learning) or 10 (all other tests) CC strains to examine the heritability of reward sensitivity and impulsivity traits, as well as genetic correlations between these measures and existing addiction-related phenotypes. Strains were all tested for activity in an open field and reward sensitivity (intake of chocolate BOOST®). Mice were then divided into two counterbalanced groups and underwent reversal learning (impulsive action and waiting impulsivity) or delay discounting (impulsive choice). CC and founder mice show significant heritability for impulsive action, impulsive choice, waiting impulsivity, locomotor activity, and reward sensitivity, with each impulsive phenotype determined to be non-correlating, independent traits. This research was conducted within the broader, inter-laboratory effort of the Center for Systems Neurogenetics of Addiction (CSNA) to characterize CC and DO mice for multiple, cocaine abuse related traits. These data will facilitate the discovery of genetic correlations between predictive traits, which will then guide discovery of genes and genetic variants that contribute to addictive behaviors., (© 2021 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

Late-onset Alzheimer's disease (AD; LOAD) is the most common human neurodegenerative disease, however, the availability and efficacy of disease-modifying interventions is severely lacking. Despite exceptional efforts to understand disease progression via legacy amyloidogenic transgene mouse models, focus on disease translation with innovative mouse strains that better model the complexity of human AD is required to accelerate the development of future treatment modalities. LOAD within the human population is a polygenic and environmentally influenced disease with many risk factors acting in concert to produce disease processes parallel to those often muted by the early and aggressive aggregate formation in popular mouse strains. In addition to extracellular deposits of amyloid plaques and inclusions of the microtubule-associated protein tau, AD is also defined by synaptic/neuronal loss, vascular deficits, and neuroinflammation. These underlying processes need to be better defined, how the disease progresses with age, and compared to human-relevant outcomes. To create more translatable mouse models, MODEL-AD (Model Organism Development and Evaluation for Late-onset AD) groups are identifying and integrating disease-relevant, humanized gene sequences from public databases beginning with APOEε4 and Trem2*R4 7H, two of the most powerful risk factors present in human LOAD populations. Mice expressing endogenous, humanized APOEε4 and Trem2*R4 7H gene sequences were extensively aged and assayed using a multi-disciplined phenotyping approach associated with and relative to human AD pathology. Robust analytical pipelines measured behavioral, transcriptomic, metabolic, and neuropathological phenotypes in cross-sectional cohorts for progression of disease hallmarks at all life stages. In vivo PET/MRI neuroimaging revealed regional alterations in glycolytic metabolism and vascular perfusion. Transcriptional profiling by RNA-Seq of brain hemispheres identified sex and age as the main sources of variation between genotypes including age-specific enrichment of AD-related processes. Similarly, age was the strongest determinant of behavioral change. In the absence of mouse amyloid plaque formation, many of the hallmarks of AD were not observed in this strain. However, as a sensitized baseline model with many additional alleles and environmental modifications already appended, the dataset from this initial MODEL-AD strain serves an important role in establishing the individual effects and interaction between two strong genetic risk factors for LOAD in a mouse host., 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 © 2021 Kotredes, Oblak, Pandey, Lin, Garceau, Williams, Uyar, O’Rourke, O’Rourke, Ingraham, Bednarycek, Belanger, Cope, Foley, Logsdon, Mangravite, Sukoff Rizzo, Territo, Carter, Sasner, Lamb and Howell.)

The ability to investigate therapeutic interventions in animal models of neurodegenerative diseases depends on extensive characterization of the model(s) being used. There are numerous models that have been generated to study Alzheimer's disease (AD) and the underlying pathogenesis of the disease. While transgenic models have been instrumental in understanding AD mechanisms and risk factors, they are limited in the degree of characteristics displayed in comparison with AD in humans, and the full spectrum of AD effects has yet to be recapitulated in a single mouse model. The Model Organism Development and Evaluation for Late-Onset Alzheimer's Disease (MODEL-AD) consortium was assembled by the National Institute on Aging (NIA) to develop more robust animal models of AD with increased relevance to human disease, standardize the characterization of AD mouse models, improve preclinical testing in animals, and establish clinically relevant AD biomarkers, among other aims toward enhancing the translational value of AD models in clinical drug design and treatment development. Here we have conducted a detailed characterization of the 5XFAD mouse, including transcriptomics, electroencephalogram, in vivo imaging, biochemical characterization, and behavioral assessments. The data from this study is publicly available through the AD Knowledge Portal., Competing Interests: TR and AB are employees of TissueVision, Inc. TR is a shareholder of TissueVision, Inc. The remaining 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 © 2021 Oblak, Lin, Kotredes, Pandey, Garceau, Williams, Uyar, O’Rourke, O’Rourke, Ingraham, Bednarczyk, Belanger, Cope, Little, Williams, Ash, Bleckert, Ragan, Logsdon, Mangravite, Sukoff Rizzo, Territo, Carter, Howell, Sasner and Lamb.)

Interest in marmosets as research models has seen exponential growth over the last decade, especially given that the research community is eager to improve on gaps with historical animal models for behavioral and cognitive disorders. The spectrum of human disease traits that present naturally in marmosets, as well as the range of analogous human behaviors that can be assessed in marmosets, makes them ideally suited as translational models for behavioral and cognitive disorders. Regardless of the specific research aims of any project, without close collaboration between researchers, veterinarians, and animal care staff, it would be impossible to meet these goals. Behavior is inherently variable, as are marmosets that are genetically and phenotypically diverse. Thus, to ensure rigor, reliability, and reproducibility in results, it is important that in the research environment, the animal's daily husbandry and veterinary needs are being met and align with the research goals while keeping the welfare of the animal the most critical and highest priority. Much of the information described herein provides details on key components for successful behavioral testing, based on a compendium of methods from peer-reviewed publications and our own experiences. Specific areas highlighted include habituation procedures, selection of appropriate rewards, optimization of testing environments, and ways to integrate regular veterinary and husbandry procedures into the research program with minimal disruptions to the behavioral testing plan. This article aims to provide a broad foundation for researchers new to establishing behavioral and cognitive testing paradigms in marmosets and especially for the veterinary and husbandry colleagues who are indispensable collaborators of these research projects., (© The Author(s) 2021. Published by Oxford University Press on behalf of the National Academies of Sciences, Engineering, and Medicine. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Alzheimer's disease (AD) is a major cause of dementia, disability, and death in the elderly. Despite recent advances in our understanding of the basic biological mechanisms underlying AD, we do not know how to prevent it, nor do we have an approved disease-modifying intervention. Both are essential to slow or stop the growth in dementia prevalence. While our current animal models of AD have provided novel insights into AD disease mechanisms, thus far, they have not been successfully used to predict the effectiveness of therapies that have moved into AD clinical trials. The Model Organism Development and Evaluation for Late-onset Alzheimer's Disease (MODEL-AD; www.model-ad.org) Consortium was established to maximize human datasets to identify putative variants, genes, and biomarkers for AD; to generate, characterize, and validate the next generation of mouse models of AD; and to develop a preclinical testing pipeline. MODEL-AD is a collaboration among Indiana University (IU); The Jackson Laboratory (JAX); University of Pittsburgh School of Medicine (Pitt); Sage BioNetworks (Sage); and the University of California, Irvine (UCI) that will generate new AD modeling processes and pipelines, data resources, research results, standardized protocols, and models that will be shared through JAX's and Sage's proven dissemination pipelines with the National Institute on Aging-supported AD Centers, academic and medical research centers, research institutions, and the pharmaceutical industry worldwide., Competing Interests: The authors declare no conflicts of interest., (© 2020 The Authors. Alzheimer's & Dementia: Translational Research & Clinical Interventions published by Wiley Periodicals, Inc. on behalf of Alzheimer's Association.)

Selective activation of dopamine D1 receptors remains a promising pro-cognitive therapeutic strategy awaiting robust clinical investigation. PF-6142 is a key example from a recently disclosed novel series of non-catechol agonists and partial agonists of the dopamine D1/5 receptors (D1R) that exhibit pharmacokinetic (PK) properties suitable for oral delivery. Given their reported potential for functionally biased signaling compared to known catechol-based selective agonists, and the promising rodent PK profile of PF-6142, we utilized relevant in vivo assays in male rodents and male and female non-human primates (NHP) to evaluate the pharmacology of this new series. Studies in rodents showed that PF-6142 increased locomotor activity and prefrontal cortex acetylcholine release, increased time spent in wakefulness, and desynchronized the EEG, like known D1R agonists. D1R selectivity of PF-6142 was supported by lack of effect in D1R knock-out mice and blocked response in the presence of the D1R antagonist SCH-23390. Further, PF-6142 improved performance in rodent models of NMDA receptor antagonist-induced cognitive dysfunction, such as MK-801-disrupted paired-pulse facilitation, and ketamine-disrupted working memory performance in the radial arm maze. Similarly, PF-6142 reversed ketamine-induced deficits in NHP performing the spatial delayed recognition task. Of importance, PF-6142 did not alter the efficacy of risperidone in assays predictive of antipsychotic-like effect in rodents including pre-pulse inhibition and conditioned avoidance responding. These data support the continued development of non-catechol based D1R agonists for the treatment of cognitive impairment associated with brain disorders including schizophrenia., (Copyright © 2020 Kozak, Kiss, Dlugolenski, Johnson, Gorczyca, Kuszpit, Harvey, Stolyar, Sukoff Rizzo, Hoffmann, Volfson, Hajós, Davoren, Abbott, Williams, Castner and Gray.)

Introduction: Preclinical testing in animal models is a critical component of the drug discovery and development process. While hundreds of interventions have demonstrated preclinical efficacy for ameliorating cognitive impairments in animal models, none have confirmed efficacy in Alzheimer's disease (AD) clinical trials. Critically this lack of translation to the clinic points in part to issues with the animal models, the preclinical assays used, and lack of scientific rigor and reproducibility during execution. In an effort to improve this translation, the Preclinical Testing Core (PTC) of the Model Organism Development and Evaluation for Late-onset AD (MODEL-AD) consortium has established a rigorous screening strategy with go/no-go decision points that permits unbiased assessments of therapeutic agents., Methods: An initial screen evaluates drug stability, formulation, and pharmacokinetics (PK) to confirm appreciable brain exposure in the disease model at the pathologically relevant ages, followed by pharmacodynamics (PD) and predictive PK/PD modeling to inform the dose regimen for long-term studies. The secondary screen evaluates target engagement and disease modifying activity using non-invasive positron emission tomography/magnetic resonance imaging (PET/MRI). Provided the compound meets its "go" criteria for these endpoints, evaluation for efficacy on behavioral endpoints are conducted., Results: Validation of this pipeline using tool compounds revealed the importance of critical quality control (QC) steps that researchers need to be aware of when executing preclinical studies. These include confirmation of the active pharmaceutical ingredient and at the precise concentration expected; and an experimental design that is well powered and in line with the Animal Research Reporting of In vivo Experiments (ARRIVE) guidelines., Discussion: Taken together our experience executing a rigorous screening strategy with QC checkpoints provides insight to the challenges of conducting translational studies in animal models. The PTC pipeline is a National Institute on Aging (NIA)-supported resource accessible to the research community for investigators to nominate compounds for testing (https://stopadportal.synapse.org/), and these resources will ultimately enable better translational studies to be conducted., Competing Interests: The authors are supported by funding from the National Institutes of Health, National Institute on Aging U54 AG05434503, 1R13AG060708‐01. Bruce T. Lamb has served as a consultant for AvroBio and Eli‐Lilly, and is supported by additional funding: NIA R01 AG022304, RF1 AG051495, U54 AG065181, U54 AG054345. Mass spectrometry and UV work was provided by the Clinical Pharmacology Analytical Core at Indiana University School of Medicine; a core facility supported by the IU Simon Cancer Center Support Grant P30 CA082709., (© 2020 the Alzheimer's Association.)

Congenital muscular dystrophy with megaconial myopathy (MDCMC) is an autosomal recessive disorder characterized by progressive muscle weakness and wasting. The observation of megamitochondria in skeletal muscle biopsies is exclusive to this type of MD. The disease is caused by loss of function mutations in the choline kinase beta (CHKB) gene which results in dysfunction of the Kennedy pathway for the synthesis of phosphatidylcholine. We have previously reported a rostrocaudal MD (rmd) mouse with a deletion in the Chkb gene resulting in an MDCMC-like phenotype, and we used this mouse to test gene therapy strategies for the rescue and alleviation of the dystrophic phenotype. Introduction of a muscle-specific Chkb transgene completely rescues motor and behavioral function in the rmd mouse model, confirming the cell-autonomous nature of the disease. Intramuscular gene therapy post-disease onset using an adeno-associated viral 6 (AAV6) vector carrying a functional copy of Chkb is also capable of rescuing the dystrophy phenotype. In addition, we examined the ability of choline kinase alpha (Chka), a gene paralog of Chkb, to improve dystrophic phenotypes when upregulated in skeletal muscles of rmd mutant mice using a similar AAV6 vector. The sum of our results in a preclinical model of disease suggest that replacement of the Chkb gene or upregulation of endogenous Chka could serve as potential lines of therapy for MDCMC patients., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Classical laboratory strains show limited genetic diversity and do not harness natural genetic variation. Mouse models relevant to Alzheimer's disease (AD) have largely been developed using these classical laboratory strains, such as C57BL/6J (B6), and this has likely contributed to the failure of translation of findings from mice to the clinic. Therefore, here we test the potential for natural genetic variation to enhance the translatability of AD mouse models. Two widely used AD-relevant transgenes, APPswe and PS1de9 (APP/PS1), were backcrossed from B6 to three wild-derived strains CAST/EiJ, WSB/EiJ, PWK/PhJ, representative of three Mus musculus subspecies. These new AD strains were characterized using metabolic, functional, neuropathological and transcriptional assays. Strain-, sex- and genotype-specific differences were observed in cognitive ability, neurodegeneration, plaque load, cerebrovascular health and cerebral amyloid angiopathy. Analyses of brain transcriptional data showed strain was the greatest driver of variation. We identified significant variation in myeloid cell numbers in wild type mice of different strains as well as significant differences in plaque-associated myeloid responses in APP/PS1 mice between the strains. Collectively, these data support the use of wild-derived strains to better model the complexity of human AD., Competing Interests: NO authors have competing interests.

To follow-up on our previous report that acarbose (ACA), a drug that blocks postprandial glucose spikes, increases mouse lifespan, we studied ACA at three doses: 400, 1,000 (the original dose), and 2,500 ppm, using genetically heterogeneous mice at three sites. Each dose led to a significant change (by log-rank test) in both sexes, with larger effects in males, consistent with the original report. There were no significant differences among the three doses. The two higher doses produced 16% or 17% increases in median longevity of males, but only 4% or 5% increases in females. Age at the 90th percentile was increased significantly (8%-11%) in males at each dose, but was significantly increased (3%) in females only at 1,000 ppm. The sex effect on longevity is not explained simply by weight or fat mass, which were reduced by ACA more in females than in males. ACA at 1,000 ppm reduced lung tumors in males, diminished liver degeneration in both sexes and glomerulosclerosis in females, reduced blood glucose responses to refeeding in males, and improved rotarod performance in aging females, but not males. Three other interventions were also tested: ursolic acid, 2-(2-hydroxyphenyl) benzothiazole (HBX), and INT-767; none of these affected lifespan at the doses tested. The acarbose results confirm and extend our original report, prompt further attention to the effects of transient periods of high blood glucose on aging and the diseases of aging, including cancer, and should motivate studies of acarbose and other glucose-control drugs in humans., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe-S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans., (© The Author 2017. Published by Oxford University Press.)

Previous studies with continuous glucose monitoring in mice have been limited to several days or weeks, with the mouse's physical attachment to the equipment affecting behavior and measurements. In the current study, we measured blood glucose and body temperature at 10-second intervals for 12 weeks in a cohort of NOD/ShiLtJ female mice using wireless telemetry. This allowed us to obtain a high-resolution profile of the circadian rhythm of these two parameters and the onset of hyperglycemic development in real time. The most striking observations were the elevated nocturnal concentrations of glucose into the diabetic range days before elevations in diurnal glucose (when glucose concentrations are historically measured) and the strong, negative correlation between elevated blood glucose concentrations and body temperature with a steady decline of the body temperature with diabetes development. Taken together, this technological advancement provides improved resolution in the study of the disease trajectory of diabetes in mouse models, including relevant translatability to the current technologies of continuous glucose monitoring now regularly used in patients., (Copyright © 2017 Endocrine Society.)

Deficits in the basal ganglia pathways modulating cortical motor activity underlie both Parkinson disease (PD) and Huntington disease (HD). Phosphodiesterase 10A (PDE10A) is enriched in the striatum, and animal data suggest that it is a key regulator of this circuitry. Here, we report on germline PDE10A mutations in eight individuals from two families affected by a hyperkinetic movement disorder due to homozygous mutations c.320A>G (p.Tyr107Cys) and c.346G>C (p.Ala116Pro). Both mutations lead to a reduction in PDE10A levels in recombinant cellular systems, and critically, positron-emission-tomography (PET) studies with a specific PDE10A ligand confirmed that the p.Tyr107Cys variant also reduced striatal PDE10A levels in one of the affected individuals. A knock-in mouse model carrying the homologous p.Tyr97Cys variant had decreased striatal PDE10A and also displayed motor abnormalities. Striatal preparations from this animal had an impaired capacity to degrade cyclic adenosine monophosphate (cAMP) and a blunted pharmacological response to PDE10A inhibitors. These observations highlight the critical role of PDE10A in motor control across species., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The childhood epileptic encephalopathies (EE's) are seizure disorders that broadly impact development including cognitive, sensory and motor progress with severe consequences and comorbidities. Recently, mutations in DNM1 (dynamin 1) have been implicated in two EE syndromes, Lennox-Gastaut Syndrome and Infantile Spasms. Dnm1 encodes dynamin 1, a large multimeric GTPase necessary for activity-dependent membrane recycling in neurons, including synaptic vesicle endocytosis. Dnm1Ftfl or "fitful" mice carry a spontaneous mutation in the mouse ortholog of DNM1 and recapitulate many of the disease features associated with human DNM1 patients, providing a relevant disease model of human EE's. In order to examine the cellular etiology of seizures and behavioral and neurological comorbidities, we engineered a conditional Dnm1Ftfl mouse model of DNM1 EE. Observations of Dnm1Ftfl/flox mice in combination with various neuronal subpopulation specific cre strains demonstrate unique seizure phenotypes and clear separation of major neurobehavioral comorbidities from severe seizures associated with the germline model. This demonstration of pleiotropy suggests that treating seizures per se may not prevent severe comorbidity observed in EE associated with dynamin-1 mutations, and is likely to have implications for other genetic forms of EE.

Striatal-enriched protein tyrosine phosphatase (STEP) has been described as a regulator of multiple kinases and glutamate receptor subunits critical for synaptic plasticity. Published behavioral and biochemical characterization from the founder line of STEP knockout (KO) mice revealed superior cognitive performance, with enhanced phosphorylation of substrates such as ERK, Fyn and GluN2B; suggesting that inhibitors of STEP may have potential as therapeutic agents for the treatment of neuropsychiatric disorders. The objectives of this work aimed to replicate and extend the previously reported behavioral consequences of STEP knockout. Consistent with previous reported data, STEP KO mice demonstrated exploratory activity levels and similar motor coordination relative to WT littermate controls as well as intact memory in a Y-maze spatial novelty test. Interestingly, KO mice demonstrated deficits in pre-pulse inhibition as well as reduced seizure threshold relative to WT controls. Immunohistochemical staining of brains revealed the expected gene-dependent reduction in STEP protein confirming knockout in the mice. The present data confirm expression and localization of STEP and the absence in KO mice, and describe functional downstream implications of reducing STEP levels in vivo., (© 2014 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Parkinson's disease (PD) pathology is characterized by the formation of intra-neuronal inclusions called Lewy bodies, which are comprised of alpha-synuclein (α-syn). Duplication, triplication or genetic mutations in α-syn (A53T, A30P and E46K) are linked to autosomal dominant PD; thus implicating its role in the pathogenesis of PD. In both PD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of protein aggregates (i.e., α-syn) and neurodegeneration. Characterization of the timing and nature of symptomatic dysfunction is important for understanding the impact of α-syn on disease progression. Furthermore, this knowledge is essential for identifying pathways and molecular targets for therapeutic intervention. To this end, we examined various functional and morphological endpoints in the transgenic mouse model expressing the human A53T α-syn variant directed by the mouse prion promoter at specific ages relating to disease progression (2, 6 and 12 months of age). Our findings indicate A53T mice develop fine, sensorimotor, and synaptic deficits before the onset of age-related gross motor and cognitive dysfunction. Results from open field and rotarod tests show A53T mice develop age-dependent changes in locomotor activity and reduced anxiety-like behavior. Additionally, digigait analysis shows these mice develop an abnormal gait by 12 months of age. A53T mice also exhibit spatial memory deficits at 6 and 12 months, as demonstrated by Y-maze performance. In contrast to gross motor and cognitive changes, A53T mice display significant impairments in fine- and sensorimotor tasks such as grooming, nest building and acoustic startle as early as 1-2 months of age. These mice also show significant abnormalities in basal synaptic transmission, paired-pulse facilitation and long-term depression (LTD). Combined, these data indicate the A53T model exhibits early- and late-onset behavioral and synaptic impairments similar to PD patients and may provide useful endpoints for assessing novel therapeutic interventions for PD.

There is compelling clinical literature implicating a role for cytokines in the pathophysiology of major depressive disorder (MDD). Interleukin-6 (IL-6) and interleukin-1β (IL-1β) are pleiotropic inflammatory cytokines that have been reported to be elevated in patients with MDD. The present studies were undertaken to investigate the relationship between IL-6 and IL-1β in animal models of depressive-like behavior. Analysis of brain tissue homogenates in the cortex of rats subjected to chronic stress paradigms revealed elevated levels of IL-6 protein in the absence of elevations in IL-1β. Central administration of recombinant mouse IL-6 produced depressive-like phenotypes in mice, which were not accompanied by IL-1β-induced increases in the brain tissue or IL-1β-related sickness behavior typical of a general central nervous system inflammatory response. Systemic administration of fluoxetine in the presence of centrally administered IL-6 failed to produce the expected antidepressant-like response in mice relative to sham-infused controls. Further, administration of fluoxetine to mice with endogenous overexpression of brain IL-6 (MRL/MpJ-Fas(LPR/LPR) (LPR mice)) failed to produce the expected antidepressant-like effect relative to fluoxetine-treated control mice (MRL/MpJ(+/+)). Interestingly, blockade of IL-6 trans-signaling by coadministration of a gp130/Fc monomer or an anti-mouse IL-6 antibody with IL-6 prevented the IL-6-induced increases in immobility time as well as attenuated IL-6-induced increases of protein in the cortex. Taken together, these data indicate that elevations in IL-6 may have a pathophysiological role underlying depression and more specifically resistance to current classes of antidepressant medications and suggest that modulation of the IL-6 signaling pathway may have therapeutic potential for treatment-resistant depression.

Phosphodiesterase 11A (PDE11A) is the most recently identified family of phosphodiesterases (PDEs), the only known enzymes to break down cyclic nucleotides. The tissue expression profile of this dual specificity PDE is controversial, and little is understood of its biological function, particularly in the brain. We seek here to determine if PDE11A is expressed in the brain and to understand its function, using PDE11A(-/-) knockout (KO) mice. We show that PDE11A mRNA and protein are largely restricted to hippocampus CA1, subiculum, and the amygdalohippocampal area, with a two- to threefold enrichment in the ventral vs. dorsal hippocampus, equal distribution between cytosolic and membrane fractions, and increasing levels of protein expression from postnatal day 7 through adulthood. Interestingly, PDE11A KO mice show subtle psychiatric-disease-related deficits, including hyperactivity in an open field, increased sensitivity to the glutamate N-methyl-D-aspartate receptor antagonist MK-801, as well as deficits in social behaviors (social odor recognition memory and social avoidance). In addition, PDE11A KO mice show enlarged lateral ventricles and increased activity in CA1 (as per increased Arc mRNA), phenotypes associated with psychiatric disease. The increased sensitivity to MK-801 exhibited by PDE11A KO mice may be explained by the biochemical dysregulation observed around the glutamate alpha-amino-3-hydroxy-5-methyl-4-isozazolepropionic (AMPA) receptor, including decreased levels of phosphorylated-GluR1 at Ser845 and the prototypical transmembrane AMPA-receptor-associated proteins stargazin (gamma2) and gamma8. Together, our data provide convincing evidence that PDE11A expression is restricted in the brain but plays a significant role in regulating brain function.

Sexual dysfunction associated with antidepressant treatment continues to be a major compliance issue for antidepressant therapies. 5-HT(1A) antagonists have been suggested as beneficial adjunctive treatment in respect of antidepressant efficacy; however, the effects of 5-HT(1A) antagonism on antidepressant-induced side-effects has not been fully examined. The present study was conducted to evaluate the ability of acute or chronic treatment with 5-HT(1A) antagonists to alter chronic fluoxetine-induced impairments in sexual function. Chronic 14-d treatment with fluoxetine resulted in a marked reduction in the number of non-contact penile erections in sexually experienced male rats, relative to vehicle-treated controls. Acute administration of the 5-HT(1A) antagonist WAY-101405 resulted in a complete reversal of chronic fluoxetine-induced deficits on non-contact penile erections at doses that did not significantly alter baselines. Chronic co-administration of the 5-HT(1A) antagonists WAY-100635 or WAY-101405 with fluoxetine prevented fluoxetine-induced deficits in non-contact penile erections in sexually experienced male rats. Moreover, withdrawal of WAY-100635 from co-treatment with chonic fluoxetine, resulted in a time-dependent reinstatement of chronic fluoxetine-induced deficits in non-contact penile erections. Additionally, chronic administration of SSA-426, a molecule with dual activity as both a SSRI and 5-HT(1A) antagonist, did not produce deficits in non-contact penile erections at doses demonstrated to have antidepressant-like activity in the olfactory bulbectomy model. Taken together, these data suggest that 5-HT(1A) antagonist treatment may have utility for the management of SSRI-induced sexual dysfunction.