Somatic genomic changes in single Alzheimer's disease neurons.

Dementia in Alzheimer's disease progresses alongside neurodegeneration1-4, but the specific events that cause neuronal dysfunction and death remain poorly understood. During normal ageing, neurons progressively accumulate somatic mutations5 at rates similar to those of dividing cells6,7 which suggests that genetic factors, environmental exposures or disease states might influence this accumulation5. Here we analysed single-cell whole-genome sequencing data from 319 neurons from the prefrontal cortex and hippocampus of individuals with Alzheimer's disease and neurotypical control individuals. We found that somatic DNA alterations increase in individuals with Alzheimer's disease, with distinct molecular patterns. Normal neurons accumulate mutations primarily in an age-related pattern (signature A), which closely resembles 'clock-like' mutational signatures that have been previously described in healthy and cancerous cells6-10. In neurons affected by Alzheimer's disease, additional DNA alterations are driven by distinct processes (signature C) that highlight C>A and other specific nucleotide changes. These changes potentially implicate nucleotide oxidation4,11, which we show is increased in Alzheimer's-disease-affected neurons in situ. Expressed genes exhibit signature-specific damage, and mutations show a transcriptional strand bias, which suggests that transcription-coupled nucleotide excision repair has a role in the generation of mutations. The alterations in Alzheimer's disease affect coding exons and are predicted to create dysfunctional genetic knockout cells and proteostatic stress. Our results suggest that known pathogenic mechanisms in Alzheimer's disease may lead to genomic damage to neurons that can progressively impair function. The aberrant accumulation of DNA alterations in neurodegeneration provides insight into the cascade of molecular and cellular events that occurs in the development of Alzheimer's disease.

Brain Somatic Mutation in Aging and Alzheimer's Disease.

Somatic mutations arise postzygotically, producing genetic differences between cells in an organism. Well established as a driver of cancer, somatic mutations also exist in nonneoplastic cells, including in the brain. Technological advances in nucleic acid sequencing have enabled recent breakthroughs that illuminate the roles of somatic mutations in aging and degenerative diseases of the brain. Somatic mutations accumulate during aging in human neurons, a process termed genosenium. A number of recent studies have examined somatic mutations in Alzheimer's disease (AD), primarily from the perspective of genes causing familial AD. We have also gained new information on genome-wide mutations, providing insights into the cellular events driving somatic mutation and cellular dysfunction. This review highlights recent concepts, methods, and findings in the progress to understand the role of brain somatic mutation in aging and AD.

Influence of hybrid class and ensiling duration on deoxynivalenol accumulation and its derivative deoxynivalenol-3-glucoside while ensiling corn for silage.

In silage corn (Zea mays L.), Fusarium graminearum causes diseases and produces the mycotoxin deoxynivalenol (DON). The work presented here investigated DON accumulation and its fate during the ensiling of ground, whole-plant material obtained from dual-purpose (DP) and brown midrib (BMR) corn hybrids. Multi-year field trials arranged in a randomized complete block design were conducted in Wisconsin to evaluate BMR and DP corn hybrids in response to fungicide treatment. At harvest, the samples were chopped and vacuum sealed for a mini-silo time series assessment with silos opened following anaerobic fermentation for 0, 30, 60, 90 and 120 days. Repeated measures analysis of ensiled corn showed that hybrid (P < 0.01) and ensiling duration (P < 0.01) significantly impacted DON concentration through ensiling, while fungicide treatment had no significant effect (P > 0.05). Across hybrids and treatments, DON concentrations detected at harvest were the lowest with DON3G at harvest significantly (P < 0.01) and highly correlated (r = 0.74) with DON concentration 30-days post ensiling. These findings suggest that mycotoxin testing in corn should include not only DON but also for conjugates of DON that can be metabolized back to DON and increase the final DON concentration during ensiling.

The RAC1 activator Tiam1 regulates centriole duplication through controlling PLK4 levels.

Centriole duplication is tightly controlled to maintain correct centriole number through the cell cycle. Key to this is the regulated degradation of PLK4, the master regulator of centriole duplication. Here, we show that the Rac1 guanine nucleotide exchange factor (GEF) Tiam1 localises to centrosomes during S-phase, where it is required for the maintenance of normal centriole number. Depletion of Tiam1 leads to an increase in centrosomal PLK4 and centriole overduplication, whereas overexpression of Tiam1 can restrict centriole overduplication. Ultimately, Tiam1 depletion leads to lagging chromosomes at anaphase and aneuploidy, which are potential drivers of malignant progression. The effects of Tiam1 depletion on centrosomal PLK4 levels and centriole overduplication can be rescued by re-expression of both wild-type Tiam1 and catalytically inactive (GEF*) Tiam1, but not by Tiam1 mutants unable to bind to the F-box protein ßTRCP (also known as F-box/WD repeat-containing protein 1A) implying that Tiam1 regulates PLK4 levels through promoting ßTRCP-mediated degradation independently of Rac1 activation.

GABA Immunoreactivity and Pharmacological Effects vary Among Stylet-Bearing Nematodes.

Plant-parasitic nematodes conduct a series of sophisticated behaviors to complete their life cycles. Among these, locomotion behaviors, including finding the host and migrating to the feeding site, directly affect the success of parasitism. Thus, disrupting locomotion behaviors has the potential to control these parasites. γ-Aminobutyric acid (GABA) is the prominent inhibitory neurotransmitter in nematodes. GABA-immunoreactive neurons are mostly found in motor neurons, where they regulate behaviors in the model nematode C. elegans. However, the GABA system in most stylet-bearing nematodes has received little attention. Using immunohistochemistry, we found variation in the pattern of GABA-immunoreactivity among two major plant-parasites and a fungal feeder. Some of these GABA-immunoreactive neurons lack clear homologs to C. elegans. Pharmaceutical assays showed that applying GABA, its agonist, and its antagonist, can disrupt the locomotion behaviors of these nematodes, although sensitivity to a given compound varied between species. Our data suggest that the GABA system is a potential target for the control of plant-parasitic nematodes.

Presence and Correlation of Fusarium graminearum and Deoxynivalenol Accumulation in Silage Corn Plant Parts.

Corn silage, made from Zea mays, is a high-energy feed that is important for feeding dairy cows. Plant diseases, such as those caused by Fusarium graminearum, can decrease silage corn yields and quality. F. graminearum (teleomorph Gibberella zeae) is an ascomycete fungus that causes Gibberella ear and stalk rot in corn. F. graminearum produces deoxynivalenol (DON), a secondary metabolite toxic to humans and animals. An understanding of the distribution of DON and F. graminearum throughout the corn plant is important for determining the quality of corn silage. A partitioned sample experiment that included two brown midrib silage hybrids and three fungicide treatments was conducted in research plots located in Arlington, WI, U.S.A., in 2018 and 2019. At harvest, stalk and ear parts were physically separated, dried, and ground for analysis. DON concentration (in parts per million) was determined using an enzyme-linked immunosorbent assay, and F. graminearum DNA concentration (in picograms per nanogram) was determined using quantitative PCR. DON and F. graminearum DNA were detected in all samples, demonstrating accumulation of the fungus in stalks and ears of the plant. In 2018, DON contamination was as high as 30 ppm and varied drastically between stalks and ears. In 2019, DON concentrations were much lower (<5 ppm), but were consistently higher in stalk samples than ear samples. Across all samples, DON concentrations and F. graminearum accumulation were highly correlated within the separated stalk (r = 0.78) and ear portions (r = 0.87) but were not correlated between ears and stalks. Depending on the weather and planting conditions in a given year, stalk infections or ear infections may occur by F. graminearum, leading to subsequent DON increases in those respective parts that are independent of each other.

Identification of Soybean (Glycine max) Check Lines for Evaluating Genetic Resistance to Sclerotinia Stem Rot.

Soybean production in the upper midwestern United States is affected by Sclerotinia stem rot (SSR) caused by the fungal pathogen Sclerotinia sclerotiorum. Genetic resistance is an important management strategy for this disease; however, assessing genetic resistance to S. sclerotiorum is challenging because a standardized method of examining resistance across genotypes is lacking. Using a panel of nine diverse S. sclerotiorum isolates, four soybean lines were assessed for reproducible responses to S. sclerotiorum infection. Significant differences in SSR severity were found across isolates (P < 0.01) and soybean lines (P < 0.01), including one susceptible, two moderately resistant, and one highly resistant line. These four validated lines were used to screen 11 other soybean genotypes to evaluate their resistance levels, and significant differences were found across genotypes (P < 0.01). Among these 11 genotypes, five commercial and public cultivars displayed high resistance and were assessed during field studies across the upper midwestern United States growing region to determine their response to SSR and yield. These five cultivars resulted in low disease levels (P < 0.01) in the field that were consistent with greenhouse experiment results. The yields were significantly different in fields with disease present (P < 0.01) and disease absent (P < 0.01), and the order of cultivar performance was consistent between environments where disease was present or absent, suggesting that resistance prevented yield loss to disease. This study suggests that the use of a soybean check panel can accurately assess SSR resistance in soybean germplasm and aid in breeding and commercial soybean development.

Immobility in the sedentary plant-parasitic nematode H. glycines is associated with remodeling of neuromuscular tissue.

The sedentary plant-parasitic nematodes are considered among the most economically damaging pathogens of plants. Following infection and the establishment of a feeding site, sedentary nematodes become immobile. Loss of mobility is reversed in adult males while females never regain mobility. The structural basis for this change in mobility is unknown. We used a combination of light and transmission electron microscopy to demonstrate cell-specific muscle atrophy and sex-specific renewal of neuromuscular tissue in the sedentary nematode Heterodera glycines. We found that both females and males undergo body wall muscle atrophy and loss of attachment to the underlying cuticle during immobile developmental stages. Male H. glycines undergo somatic muscle renewal prior to molting into a mobile adult. In addition, we found developmental changes to the organization and number of motor neurons in the ventral nerve cord correlated with changes in mobility. To further examine neuronal changes associated with immobility, we used a combination of immunohistochemistry and molecular biology to characterize the GABAergic nervous system of H. glycines during mobile and immobile stages. We cloned and confirmed the function of the putative H. glycines GABA synthesis-encoding gene hg-unc-25 using heterologous rescue in C. elegans. We found a reduction in gene expression of hg-unc-25 as well as a reduction in the number of GABA-immunoreactive neurons during immobile developmental stages. Finally, we found evidence of similar muscle atrophy in the phylogenetically diverged plant-parasitic nematode Meloidogyne incognita. Together, our data demonstrate remodeling of neuromuscular structure and function during sedentary plant-parasitic nematode development.

Mechanisms and consequences of dysregulation of the Tiam family of Rac activators in disease.

The Tiam family proteins - Tiam1 and Tiam2/STEF - are Rac1-specific Guanine Nucleotide Exchange Factors (GEFs) with important functions in epithelial, neuronal, immune and other cell types. Tiam GEFs regulate cellular migration, proliferation and survival, mainly through activating and directing Rac1 signalling. Dysregulation of the Tiam GEFs is significantly associated with human diseases including cancer, immunological and neurological disorders. Uncovering the mechanisms and consequences of dysregulation is therefore imperative to improving the diagnosis and treatment of diseases. Here we compare and contrast the subcellular localisation and function of Tiam1 and Tiam2/STEF, and review the evidence for their dysregulation in disease.

Oxotremorine-M potentiates NMDA receptors by muscarinic receptor dependent and independent mechanisms.

Muscarinic acetylcholine M1 receptors play an important role in synaptic plasticity in the hippocampus and cortex. Potentiation of NMDA receptors as a consequence of muscarinic acetylcholine M1 receptor activation is a crucial event mediating the cholinergic modulation of synaptic plasticity, which is a cellular mechanism for learning and memory. In Alzheimer's disease, the cholinergic input to the hippocampus and cortex is severely degenerated, and agonists or positive allosteric modulators of M1 receptors are therefore thought to be of potential use to treat the deficits in cognitive functions in Alzheimer's disease. In this study we developed a simple system in which muscarinic modulation of NMDA receptors can be studied in vitro. Human M1 receptors and NR1/2B NMDA receptors were co-expressed in Xenopus oocytes and various muscarinic agonists were assessed for their modulatory effects on NMDA receptor-mediated responses. As expected, NMDA receptor-mediated responses were potentiated by oxotremorine-M, oxotremorine or xanomeline when the drugs were applied between subsequent NMDA responses, an effect which was fully blocked by the muscarinic receptor antagonist atropine. However, in oocytes expressing NR1/2B NMDA receptors but not muscarinic M1 receptors, oxotremorine-M co-applied with NMDA also resulted in a potentiation of NMDA currents and this effect was not blocked by atropine, demonstrating that oxotremorine-M is able to directly potentiate NMDA receptors. Oxotremorine, which is a close analogue of oxotremorine-M, and xanomeline, a chemically distinct muscarinic agonist, did not potentiate NMDA receptors by this direct mechanism. Comparing the chemical structures of the three different muscarinic agonists used in this study suggests that the tri-methyl ammonium moiety present in oxotremorine-M is important for the compound's interaction with NMDA receptors.

White Matter Abnormalities in Autism and Unaffected Siblings.

This study was conducted to identify a potential neuroendophenotype for autism using diffusion tensor imaging. Whole-brain, voxel-based analysis of fractional anisotropy was conducted in 50 children: 19 with autism, 20 unaffected siblings, and 11 controls. Relative to controls, participants with autism exhibited bilateral reductions in fractional anisotropy across association, commissure, and projection fibers. The most severely affected tracts included the uncinate fasciculus, forceps minor, and inferior fronto-occipital fasciculus. Unaffected siblings also exhibited reductions in fractional anisotropy, albeit less severe with fewer affected tracts, sparing the uncinate fasciculus and forceps minor. These results suggest the presence of a neuroendophenotype for autism.

How to Identify Success Among Networks That Promote Active Living.

OBJECTIVES: We evaluated organization- and network-level factors that influence organizations' perceived success. This is important for managing interorganizational networks, which can mobilize communities to address complex health issues such as physical activity, and for achieving change. METHODS: In 2011, we used structured interview and network survey data from 22 states in the United States to estimate multilevel random-intercept models to understand organization- and network-level factors that explain perceived network success. RESULTS: A total of 53 of 59 "whole networks" met the criteria for inclusion in the analysis (89.8%). Coordinators identified 559 organizations, with 3 to 12 organizations from each network taking the online survey (response rate = 69.7%; range = 33%-100%). Occupying a leadership position (P < .01), the amount of time with the network (P < .05), and support from community leaders (P < .05) emerged as correlates of perceived success. CONCLUSIONS: Organizations' perceptions of success can influence decisions about continuing involvement and investment in networks designed to promote environment and policy change for active living. Understanding these factors can help leaders manage complex networks that involve diverse memberships, varied interests, and competing community-level priorities.

In-depth interviews with state public health practitioners on the United States National Physical Activity Plan.

BACKGROUND: The United States National Physical Activity Plan (NPAP; 2010), the country's first national plan for physical activity, provides strategies to increase population-level physical activity to complement the 2008 physical activity guidelines. This study examined state public health practitioner awareness, dissemination, use, challenges, and recommendations for the NPAP. METHODS: In 2011-2012, we interviewed 27 state practitioners from 25 states. Interviews were recorded and transcribed verbatim. Transcripts were coded using a standard protocol, verified and reconciled by an independent coder, and input into qualitative software to facilitate development of common themes. RESULTS: NPAP awareness was high among state practitioners; dissemination to local constituents varied. Development of state-level strategies and goals was the most frequently reported use of the NPAP. Some respondents noted the usefulness of the NPAP for coalitions and local practitioners. Challenges to the plan included implementation cost, complexity, and consistency with other policies. The most frequent recommendation made was to directly link examples of implementation activities to the plan. CONCLUSIONS: These results provide early evidence of NPAP dissemination and use, along with challenges encountered and suggestions for future iterations. Public health is one of eight sectors in the NPAP. Further efforts are needed to understand uptake and use by other sectors, as well as to monitor long-term relevance, progress, and collaboration across sectors.

Local Wellness Policy 5 years later: is it making a difference for students in low-income, rural Colorado elementary schools?

INTRODUCTION: The federally mandated Local Wellness Policy (LWP) was intended to promote student health in schools. This study assesses the 5-year effects of the LWP on the health practices of rural elementary schools in Colorado. METHODS: One year before and 5 years after the LWP mandate, a survey was administered to a random sample of principals, physical education (PE) teachers, and food-service managers in 45 rural, low-income elementary schools in Colorado. Response rates were 71% in 2005 and 89% in 2011. RESULTS: Minutes for PE and recess did not increase, nor did offerings of fresh fruits and vegetables. More schools adopted policies prohibiting teachers from taking recess away as punishment (9.7% in 2005 vs 38.5% in 2011, P = .02) or for making up missed instructional time, class work, or tests in other subjects (3.2% in 2005 vs 28.2% in 2011, P = .03). More schools scheduled recess before lunch (22.6% in 2005 vs 46.2% in 2011, P = .04) and developed policies for vending machines (42.9% in 2005 vs 85.7% in 2011, P = .01) and parties (21.4% in 2005 vs 57.9% in 2011, P = .004). CONCLUSION: Changes in school practices are modest, and arguably the important school practices such as increased PE and recess time and increased offerings of fruits and vegetables in the lunch line have not changed in the 5 years since the mandate went into effect. Further investigation is needed to identify the knowledge, skills, and attitudes as well as financial and physical resources required for school administrators to make changes in school practices.

Active living collaboratives in the United States: understanding characteristics, activities, and achievement of environmental and policy change.

INTRODUCTION: Changing the built environment to promote active lifestyles requires collaboration among diverse sectors. Multisectoral collaborative groups in the United States promote active lifestyles through environmental and policy changes. The objective of this study was to examine the characteristics of these collaborative groups and the extent to which they have achieved change. METHODS: We identified, recruited, and interviewed the coordinators of active living collaborative groups in the United States. We used descriptive statistics to characterize groups by composition, stakeholder engagement, and the extent of environmental and policy change in 8 strategic areas. RESULTS: Fifty-nine groups from 22 states participated in the study. Most groups had a diverse set of partners and used a range of activities to advance their agendas. Most groups achieved some form of environmental or policy change. On average, groups reported working on 5 strategy areas; parks and recreation (86%) and Safe Routes to School (85%) were named most frequently. More than half of groups reported their environmental initiatives as either in progress or completed. Groups reported the most success in changing policy for public plazas, street improvements, streetscaping, and parks, open space, and recreation. Complete Streets policy and zoning ordinances were the most frequently cited policy types. Engaging in media activities and the policy-making process in addition to engaging stakeholders appear to influence success in achieving change. CONCLUSION: Although many groups successfully worked on parks and recreation improvements, opportunities remain in other areas, including transit and infill and redevelopment. Additional time and resources may be critical to realizing these types of changes.

Lessons in promoting active living: the collaborative perspective.

CONTEXT: Collaborative groups are integral in health promotion and disease prevention and use an ecological approach to address complex health conditions in community settings. Little is known about collaborative efforts to promote active living. OBJECTIVE: The objective of this analysis is to explore successes and challenges of collaborative groups in promoting active living in their communities. DESIGN/SETTING: One-time, structured telephone interviews were conducted to assess the composition tactics and activities and approaches used by collaboratives to promote active living. PARTICIPANTS: Collaborative groups were referred by Physical Activity Policy Research Network members or found through online searches. Interviews were conducted with coordinators of 59 collaborative groups. MAIN OUTCOME MEASURE(S): Analysis focused on successes and challenges of collaborative groups' policies, programs, and/or projects as described by collaborative group coordinators. We used the Grounded Theory method approach to code and abstract themes from 2 open-ended response sets. RESULTS: Collaboratives' most successful projects centered on strategies using environmental (41%) or policy (31%) approaches to promote active living. While 80% of groups reported that their most successful project was funded, funding was also identified as a primary challenge for 71% of the collaboratives. Personnel issues were a common challenge for 54%. Opposition to successful projects ranged from community issues to collaborative member issues, although more than half the groups experienced no opposition. CONCLUSIONS: Groups that aligned goals, strategies, and funding to advance changes to the built environment were likely to identify their projects as successful. Perceptions of opposition and attitudes toward success may be important precursors to project outcomes of active living collaboratives and warrant further investigation. Lessons from these active living collaborative groups can provide guidance for other groups planning for environmental and policy change.

Roles and strategies of state organizations related to school-based physical education and physical activity policies.

School-based physical education (PE) and physical activity (PA) policies can improve PA levels of students and promote health. Studies of policy implementation, communication, monitoring, enforcement, and evaluation are lacking. To describe how states implement, communicate, monitor, enforce, and evaluate key school-based PE and PA policies, researchers interviewed 24 key informants from state-level organizations in 9 states, including representatives from state departments of health and education, state boards of education, and advocacy/professional organizations. These states educate 27% of the US student population. Key informants described their organizations' roles in addressing 14 school-based PE and PA state laws and regulations identified by the Bridging the Gap research program and the National Cancer Institute's Classification of Laws Associated with School Students (C.L.A.S.S.) system. On average, states had 4 of 14 school-based PE and PA laws and regulations, and more than one-half of respondents reported different policies in practice besides the "on the books" laws. Respondents more often reported roles implementing and communicating policies compared with monitoring, enforcing, and evaluating them. Implementation and communication strategies used included training, technical assistance, and written communication of policy to local education agency administrators and teachers. State-level organizations have varying roles in addressing school-based PE and PA policies. Opportunities exist to focus state-level efforts on compliance with existing laws and regulations and evaluation of their impact.

Municipal officials' perceived barriers to consideration of physical activity in community design decision making.

CONTEXT: Built environment-focused interventions and policies are recommended as sustainable approaches for promoting physical activity. Physical activity has not traditionally been considered in land use and transportation decision making. Effective collaboration with non-public health partners requires knowledge of their perceived barriers to such consideration. OBJECTIVE: This analysis sought to (a) establish prevalence estimates of selected barriers to the consideration of physical activity in community design and layout decisions and (b) describe how barrier reporting by public health officials differs from other municipal officials among a wide range of job functions and departments in a geographically diverse sample. DESIGN: A Web-based survey was conducted among municipal officials in 94 cities and towns with populations of at least 50 000 residents in 8 states. PARTICIPANTS: A total of 453 municipal officials from public health, planning, transportation/public works, community and economic development, parks and recreation, city management, and municipal legislatures in 83 cities and towns responded to the survey. MAIN OUTCOME MEASURES: Five barriers to consideration of physical activity in community design and layout were assessed. RESULTS: The most common barriers included lack of political will (23.5%), limited staff (20.4%), and lack of collaboration across municipal departments (16.2%). Fewer participants reported opposition from the business community or residents as barriers. Public health department personnel were more likely to report the barriers of limited staff and lack of collaboration across municipal departments than other professionals. They were also more likely to report lack of political will than city managers or mayors and municipal legislators. CONCLUSIONS: Barriers to increasing consideration of physical activity in decision making about community design and layout are encouragingly low. Implications for public health practice include the need to strategically increase political will despite public health staffing constraints and perceived lack of collaboration with relevant departments such as planning and public works/transportation.

Advancing environmental and policy change through active living collaboratives: compositional and stakeholder engagement correlates of group effectiveness.

OBJECTIVE: This study aims to evaluate compositional factors, including collaborative age and size, and community, policy, and political engagement activities that may influence collaboratives' effectiveness in advancing environmental improvements and policies for active living. DESIGN/PARTICIPANTS/SETTING: Structured interviews were conducted with collaboratives' coordinators. Survey items included organizational composition, community, policy, and political engagement activities and reported environmental improvements and policy change. Descriptive statistics and multivariate models were used to investigate these relationships. MAIN OUTCOME MEASURE(S): Environmental improvement and policy change scores reflecting level of collaborative effectiveness across 8 strategy areas (eg, parks and recreation, transit, streetscaping, and land redevelopment). RESULTS: Fifty-nine collaborative groups participated in the interview, representing 22 states. Groups have made progress in identifying areas for environmental improvements and in many instances have received funding to support these changes. Results from multivariate models indicate that engagement in media communication and advocacy was statistically correlated with higher levels of environmental improvement, after adjusting for age of group and area poverty levels (P < .01). Groups that frequently solicited endorsements from community leaders and offered testimony in policy or legal hearings reported significantly more policy change, after adjusting for age of group and area poverty levels (P < .01 for both). CONCLUSIONS: Active living collaboratives are translating the evidence on environmental and policy approaches to promote active living from research to practice. Investing in community and policy engagement activities may represent important levers for achieving structural and policy changes to the built environment.

Maternal childhood maltreatment: associations to offspring brain volume and white matter connectivity.

The deleterious effects of adversity are likely intergenerational, such that one generation's adverse experiences can affect the next. Epidemiological studies link maternal adversity to offspring depression and anxiety, possibly via transmission mechanisms that influence offspring fronto-limbic connectivity. However, studies have not thoroughly disassociated postnatal exposure effects nor considered the role of offspring sex. We utilized infant neuroimaging to test the hypothesis that maternal childhood maltreatment (CM) would be associated with increased fronto-limbic connectivity in infancy and tested brain-behavior associations in childhood. Ninety-two dyads participated (32 mothers with CM, 60 without; 52 infant females, 40 infant males). Women reported on their experiences of CM and non-sedated sleeping infants underwent MRIs at 2.44 ± 2.74 weeks. Brain volumes were estimated via structural MRI and white matter structural connectivity (fiber counts) via diffusion MRI with probabilistic tractography. A subset of parents (n = 36) reported on children's behaviors at age 5.17 ± 1.73 years. Males in the maltreatment group demonstrated greater intra-hemispheric fronto-limbic connectivity (b = 0.96, p= 0.008, [95%CI 0.25, 1.66]), no differences emerged for females. Fronto-limbic connectivity was related to somatic complaints in childhood only for males (r = 0.673, p = 0.006). Our findings suggest that CM could have intergenerational associations to offspring brain development, yet mechanistic studies are needed.