Biology subjects

Obenaus, A.

Publications and source records attributed to Obenaus, A..

16 recordsLinked to original sources

bioRxiv2026

Neuro-Metabolic and Vascular Dysregulation are Functional Biomarkers of Acquired Brain Injury

Emerging clinical and neuropathological evidence suggests a direct link between traumatic brain injury (TBI) and neurodegenerative diseases (ND), but the mechanisms by which TBI contributes to ND onset and progression remain unclear. To bridge this gap, the NINDS TBI-ADRD consortium developed a diagnostic framework to guide the design and evaluation of TBI-ADRD experiments using translational neuroimaging (DCE-MRI, 18F-FDG-PET) and advanced image-processing pipelines. Neuro-metabolic and vascular dysregulation (MVD) and metabolic functional connectomics (MFC) were evaluated in 8-month C57BL/6J mice at 30- and 60-days post-injury (DPI). Both MVD and MFC revealed significant changes at 30- and 60-DPI that were sex- and injury side-dependent. Female mice showed greater regional MVD alterations, while MFC identified sex-dependent changes at 30-DPI that diminished by 60-DPI. These findings suggest that a single mid-life closed-head injury induces sexually dimorphic MVD and brain network remodeling, supporting the potential of MVD as a sensitive biomarker for improved clinical monitoring post-TBI.

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bioRxiv2026

Microtubule Stabilization and Biomaterial Guidance Synergize to Enhance CST Regeneration and Motor Recovery After Chronic SCI.

Spinal cord injury (SCI) results in loss of sensory and motor function below the level of damage, with chronic injuries presenting unique challenges for regenerative therapies. While multichannel biomaterial interventions have shown promise in promoting axonal regeneration, circuit restoration, and motor recovery in acute SCI, achieving similar outcomes in chronic injury models remains challenging due to a combination of intrinsic and extrinsic factors. These include the reduced capacity of the neuronal cell body to sustain a growth-activated state and the formation of a physical and chemical barrier at the injury site, preventing axonal growth. To address these challenges and promote motor recovery after chronic injury, we investigated the combinatorial effect of two regenerative approaches: 1) the implantation of poly (lactide-co-glycolide) (PLG) biomaterial bridge to guide axonal growth through the injury site, and 2) the delivery of Epothilone B (EpoB), a microtubule stabilizer that strengthens axons to promote regrowth. We used a transgenic mouse model that selectively expresses a red fluorescent protein variant (tdTomato) reporter throughout the corticospinal tract (CST) under control of the Crym promoter (Crym-tdTomato). We demonstrated that the combination of bridge implantation 60 days after surgical hemisection at C5 with EpoB improved locomotor function. At 12 weeks post-bridge implantation, immunohistology revealed axon regeneration in mice receiving implantation, but not EpoB or no-implant controls. The addition of EpoB significantly increased the volume of both total and CST axons regenerating through the biomaterial channels. Diffusion tensor magnetic resonance imaging (DTI) analysis identified enhanced fractional anisotropy (FA), axial diffusivity (AD), and mean diffusivity (MD) in the bridge region in the combination treatment group, consistent with new intact axons. Furthermore, EpoB enhanced the myelination of regenerated axons in the bridge. Finally, we investigated the proteomic profile of corticospinal neurons ipsilateral and contralateral to the SCI lesion and bridge, comparing the effect of EpoB treatment. Mass spectrometry-based analysis of laser-captured cells in this paradigm identified activation of a regeneration program by corticospinal neurons. These findings present a novel approach to enhance regenerative neural repair and locomotor recovery in chronic SCI.

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bioRxiv2025

Loss of white matter tracts and persistent microglial activation in the chronic phase of ischemic stroke in female rats and the effect of miR-20a-3p treatment

Our previous studies showed that intravenous injections of the small non-coding RNA mir-20a-3p is neuroprotective for stroke in the acute phase and attenuates long-term cognitive impairment in middle-aged female rats. In this study, we evaluated postmortem brain pathology at 100+d after stroke in a set of behaviorally characterized animals. This included Sham (no stroke) controls or stroke animals that received either mir20a-3p at 4h, 24h and 70d iv post stroke (MCAo+mir20a-3p) or a scrambled oligo (MCAo+Scr). Brain volumetric features were analyzed with T2 weighted and Diffusion Tensor magnetic resonance imaging (MRI) followed by histological analysis. Principal component analysis of Fractional Anisotropy (FA)-diffusion tensor MRI measures showed that MCAo+Scr and MCAo+mir20a-3p groups differed significantly in the volume of white matter but not gray matter. Weil myelin-stained sections confirmed decreased volume of the corpus callosum, internal capsule and the anterior commissure in the ischemic hemisphere of MCAo+Scr animals compared to the non-ischemic hemisphere, while sham and MCAo+Mir-20a-3p showed no hemispheric asymmetries. The MCAo+Scr group also exhibited asymmetry in hemisphere and lateral ventricle volumes, with ventricular enlargement in the ischemic hemisphere as compared to the non-ischemic hemisphere. The numbers of microglia were significantly elevated in white matter tracts in the MCAo+Scr group, with a trend towards increased myelin phagocytic microglia in these tracts. Regression analysis indicated that performance on an episodic memory test (novel object recognition test; NORT) was associated with decreased white matter volume and increased microglial numbers. These data support the hypothesis that stroke-induced cognitive impairment is accompanied by white matter attrition and persistent microglial activation and is consistent with reports that cognitive deterioration resulting from vascular diseases, such as stroke, is associated with secondary neurodegeneration in regions distal from the initial infarction.

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bioRxiv2024

Complimentary vertebrate Wac models exhibit phenotypes relevant to DeSanto-Shinawi Syndrome

Monogenic syndromes are associated with neurodevelopmental changes that result in cognitive impairments and neurobehavioral phenotypes including autism and seizures. Limited studies and resources are available to make meaningful headway into the underlying molecular mechanisms that result in these symptoms. One such example is DeSanto-Shinawi Syndrome (DESSH), a rare disorder caused by pathogenic variants in the WAC gene. Individuals with DESSH syndrome exhibit a recognizable craniofacial gestalt, developmental delay/intellectual disability, neurobehavioral symptoms that include autism, ADHD, behavioral difficulties and seizures. However, no thorough studies from a vertebrate model exist to understand how these changes occur. To overcome this, we developed both murine and zebrafish Wac/wac deletion mutants and studied whether their phenotypes recapitulate those described in individuals with DESSH syndrome. We first show that the two Wac models exhibit craniofacial and behavioral changes, reminiscent of abnormalities found in DESSH syndrome. In addition, each model revealed impacts to GABAergic neurons and further studies showed that the mouse mutants are susceptible to seizures, changes in brain volumes that are different between sexes and relevant behaviors. Finally, we uncovered transcriptional impacts of Wac loss of function in mice that will pave the way for future molecular studies into DESSH. These studies present two new animals that begin to uncover some biological underpinnings of DESSH syndrome and elucidate the biology of Wac.

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bioRxiv2024

Delayed cerebrovascular dysfunction and social deficits after traumatic brain injury

Traumatic brain injury (TBI) survivors face debilitating long-term psychosocial consequences, including social isolation and depression. Acute TBI modifies neurovascular physiology and behavior but a gap in our understanding are the chronic physiological implications of altered brain perfusion on behavioral activities, particularly social interactions. We investigated longitudinal functional vascular networks across the brain for 2-months post- TBI and its impact on social behavior. Adult C57/BL6 male mice received a moderate cortical TBI. Behavior (foot-fault, open-field, 3-chamber social preference) was assessed at baseline, 3-, 7-, 14-, 30-, and 60-days post injury (dpi) followed by magnetic resonance imaging (MRI, 9.4T). Anatomical MRI (T2-weighted), dynamic susceptibility contrast (DSC) perfusion weighted MRI (PWI) were acquired at each temporal epoch. After the final 60dpi MRI, animals underwent transcardial perfusion fixation to map angioarchitecture. MRI data were analyzed using standardized protocols followed by cross-correlations between social behavior, cerebral perfusion, and vascular metrics. Social behavior deficits at 60dpi emerged as reduced interaction with a familiar cage-mate (partner). We observed multiphasic decrements in cerebral blood flow (CBF) encompassing lesion and perilesional cortex where acute reductions at 3-14dpi partially recovered by 30dpi, followed by significant reductions in perfusion at 60dpi. The CBF perturbations extended antero-posteriorly from the ipsilateral TBI impact site but also adulterated contralateral brain regions. CBF reductions impacted regions known to regulate social behavior including hippocampus, hypothalamus, and rhinal cortex. Alongside perfusion deficits at 60dpi, social isolation in TBI-mice emerged with a significant decline in preference to spend time with a cage mate. Cortical vascular density was also reduced corroborating the decline in brain perfusion and social interaction. Thus, the novel temporal neurovascular loss, and subsequent recovery followed by chronic decrements are broadly reflected by social interaction perturbations. Our correlations strongly implicate a linkage between vascular density, cerebral perfusion, and social interactions, where early evaluation can potentially predict long-term outcomes. Thus, our study provides a clinically relevant timeline of alterations in functional vascular recovery that can guide research for future therapeutics.

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bioRxiv2024

Endocannabinoid-mediated rescue of somatosensory cortex activity, plasticity and related behaviors following an early in life concussion.

Due to the assumed plasticity of immature brain, early in life brain alterations are thought to lead to better recoveries in comparison to the mature brain. Despite clinical needs, how neuronal networks and associated behaviors are affected by early in life brain stresses, such as pediatric concussions, have been overlooked. Here we provide first evidence in mice that a single early in life concussion durably increases neuronal activity in the somatosensory cortex into adulthood, disrupting neuronal integration while the animal is performing sensory-related tasks. This represents a previously unappreciated clinically relevant mechanism for the impairment of sensory-related behavior performance. Furthermore, we demonstrate that pharmacological modulation of the endocannabinoid system a year post-concussion is well-suited to rescue neuronal activity and plasticity, and to normalize sensory-related behavioral performance, addressing the fundamental question of whether a treatment is still possible once post-concussive symptoms have developed, a time-window compatible with clinical treatment.

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bioRxiv2024

Maternal n-3 enriched diet reprograms neurovascular transcriptome and blunts inflammation in neonate

Infection during perinatal period can adversely affect brain development, predispose infants to ischemic stroke and have lifelong consequences. We previously demonstrated that diet enriched in n-3 polyunsaturated fatty acids (PUFA) transforms brain lipid composition and protects from neonatal stroke. Vasculature is a critical interface between blood and brain providing a barrier to systemic infection. Here we examined whether maternal PUFA-enriched diets exert reprograming of endothelial cell signalling in 9-day old mice after endotoxin (LPS)-induced infection. Transcriptome analysis was performed on brain microvessels from pups born to dams maintained on 3 diets: standard, n-3 or n-6 enriched. N-3 diet enabled higher immune reactivity in brain vasculature, while preventing imbalance of cell cycle regulation and extracellular matrix cascades that accompanied inflammatory response in standard diet. LPS response in blood and brain was blunted in n-3 offspring. Cerebral angioarchitecture analysis revealed modified vessel complexity after LPS. Thus, n-3-enriched maternal diet partially prevents imbalance in homeostatic processes and alters inflammation rather than affects brain vascularization during early life. Importantly, maternal diet may presage offspring neurovascular outcomes later in life.

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bioRxiv2023

Progressive lifespan modifications in the corpus callosum following a single juvenile concussion in male mice monitored by diffusion MRI

IntroductionThe sensitivity of white matter (WM) in acute and chronic moderate-severe traumatic brain injury (TBI) has been established. In concussion syndromes, particularly in preclinical rodent models, there is lacking a comprehensive longitudinal study spanning the lifespan of the mouse. We previously reported early modifications to WM using clinically relevant neuroimaging and histological measures in a model of juvenile concussion at one month post injury (mpi) who then exhibited cognitive deficits at 12mpi. For the first time, we assess corpus callosum (CC) integrity across the lifespan after a single juvenile concussion utilizing diffusion MRI (dMRI). MethodsC57Bl/6 mice were exposed to sham or two severities of closed-head concussion (Grade 1, G1, speed 2 m/sec, depth 1mm; Grade 2, G2, 3m/sec, 3mm) using an electromagnetic impactor at postnatal day 17. In vivo diffusion tensor imaging was conducted at 1, 3, 6, 12 and 18 mpi (21 directions, b=2000 mm2/sec) and processed for dMRI parametric maps: fractional anisotropy (FA), axial (AxD), radial (RD) and mean diffusivity (MD). Whole CC and regional CC data were extracted. To identify the biological basis of altered dMRI metrics, astrocyte and microglia in the CC were characterized at 1 and 12 mpi by immunohistochemistry. ResultsWhole CC analysis revealed altered FA and RD trajectories following juvenile concussion. Shams exhibited a temporally linear increase in FA with age while G1/G2 mice had plateaued FA values. G2 concussed mice exhibited high variance of dMRI metrics at 12mpi, which was attributed to the heterogeneity of TBI on the anterior CC. Regional analysis of dMRI metrics at the impact site unveiled significant differences between G2 and sham mice. The dMRI findings appear to be driven, in part, by loss of astrocyte process lengths and increased circularity and decreased cell span ratios in microglia. ConclusionFor the first time, we demonstrate progressive perturbations to WM of male mice after a single juvenile concussion across the mouse lifespan. The CC alterations were dependent on concussion severity with elevated sensitivity in the anterior CC that was related to astrocyte and microglial morphology. Our findings suggest that long-term monitoring of children with juvenile concussive episodes using dMRI is warranted, focusing on vulnerable WM tracts.

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bioRxiv2023

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer's disease

The 5xFAD mouse model is a popular model of familial Alzheimers Disease (AD) that is characterized by early beta-amyloid (A{beta}) deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic perturbations over its lifespan. Male and female 5xFAD and WT littermates underwent in vivo 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at 4, 6, and 12 months of age to assess regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent "vessel painting" which labels all cerebral vessels and were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals and vessel diameter. With increasing age, vessels on the cortical surface in both 5xFAD and WT mice showed increased vessel length, vessel and junction densities. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but collateral diameters were significantly increased only in 5xFAD mice. MCA total vessel length and junction density were decreased in 5xFAD mice compared to WT at 4 months. Analysis of 18F-FDG cortical uptake revealed significant differences between WT and 5xFAD mice spanning 4-12 months. Broadly, 5xFAD males had significantly increased 18F-FDG uptake at 12 months compared to WT mice. In most cortical regions, female 5xFAD mice had reduced 18F-FDG uptake compared to WT across their lifespan. While the 5xFAD mouse exhibits AD-like cognitive deficits as early as 4 months of age that are associated with increasing A{beta} deposition, we only found significant differences in cortical vascular features in males, not in females. Interestingly, 5xFAD male and female mice exhibited opposite effects in 18F-FDG uptake. The MCA supplies blood to large portions of the somatosensory cortex and portions of the motor and visual cortex and increased vessel lengths alongside decreased collaterals coincided with higher metabolic rates in 5xFAD mice. Thus, a potential mismatch between metabolic demand and vascular delivery of nutrients in the face of increasing A{beta} deposition could contribute to the progressive cognitive deficits seen in the 5xFAD mouse model.

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bioRxiv2023

Early-life obesogenic environment integrates immunometabolic and epigenetic signatures governing neuroinflammation

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=151 SRC="FIGDIR/small/537874v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1bb1277org.highwire.dtl.DTLVardef@b978dborg.highwire.dtl.DTLVardef@adafc8org.highwire.dtl.DTLVardef@efa0f3_HPS_FORMAT_FIGEXP M_FIG Early life trauma and obesogenic diet effects of feeding control.Consumption of a Western-like high-saturated fat diet (WD, 42% kcal from fat) during adolescence in combination with (2) Exposure to early-life psychosocial stress leads to (3) changes in brain neurocircuitry and metabolic dysregulation. These alterations lead to (4) stress susceptibility, (5) emotional and feeding dysregulation, and (6) obesity. Dysregulation of feeding control and obesity leads to increased hedonic feeding and engages individuals in a cycle of aberrant feeding behaviors. C_FIG BackgroundChildhood overweight/obesity is associated with the development of stress-related psychopathology. However, the pathways connecting childhood obesity to stress susceptibility remain poorly understood. Here, we used a systems biology approach to determine linkages underlying obesity-induced stress susceptibility. MethodsSixty-two (62) adolescent Lewis rats (PND21) were fed for four weeks with a Western-like high-saturated fat diet (WD, 41% kcal from fat) or a matched control diet (CD, 13% kcal from fat). Subsequently, a group of rats (n = 32) was exposed to a well-established 31-day model of predator exposures and social instability (PSS). The effects of the WD and PSS were assessed with a comprehensive battery of behavioral tests, DTI (diffusion tensor imaging), NODDI (neurite orientation dispersion and density imaging), high throughput 16S ribosomal RNA gene sequencing for gut microbiome profiling, hippocampal microglia morphological and gene analysis, and gene methylation status of the stress marker, FKBP5. Parallel experiments were performed on human microglial cells (HMC3) to examine molecular mechanisms by which palmitic acid primes these cells to aberrant responses to cortisol. ResultsRats exposed to the WD and PSS exhibited deficits in sociability indices and increased fear and anxiety-like behaviors, food consumption, and body weight. WD and PSS interacted to alter indices of microstructural integrity within the hippocampal formation (subiculum) and subfields (CA1). Microbiome diversity and taxa distribution revealed that WD/PSS exposure caused significant shifts in the diversity of gut dominant bacteria and decreased the abundance of various members of the Firmicutes phylum, including Lachnospiracae NK4A136. Interestingly, the WD and PSS synergized to promote hippocampal microglia morphological and gene signatures implicated in neuroinflammation. These alterations were associated with changes in the microbiome, and in the expression and methylation status of the corticosterone receptor chaperone rat gene Fkbp5. HMC3 responses to cortisol were markedly disrupted after incubating cells in palmitate, shown by morphological changes and pro-inflammatory cytokine expression and release. Notably, these effects were partly mediated by the human FKBP5 gene. ConclusionsThe combination of psychosocial stress and poor diet during adolescence has a deleterious synergistic impact on brain health. This study enhances our understanding of mechanisms and adaptations by which obesogenic environments shape the maturational trajectories of common neurobiological correlates of resilience. HighlightsO_LIObesogenic diet consumption during adolescence leads to stress-induced anxiety-like behaviors in rats. C_LIO_LIExposure to an obesogenic environment during adolescence alters indices of hippocampal microstructural integrity. C_LIO_LIObesogenic diet and chronic stress promote selective gut microbiota dysbiosis. C_LIO_LIObesogenic diet and chronic stress synergize to expand putative pro-inflammatory microglia populations in the CA1 subfield of the hippocampus. C_LIO_LIObesogenic diet and chronic stress influence hippocampal Fkbp5 gene methylation status at specific sites. C_LIO_LIFKBP5 integrates microglial pro-inflammatory signals under obesogenic conditions. C_LI

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bioRxiv2022

A single mild juvenile TBI in mice leads to regional brain tissue abnormalities at 12 months of age that correlate with cognitive impairment at the middle age in male mice

Traumatic brain injury (TBI) has the highest incidence amongst the pediatric population and its mild severity represents the most frequent cases. Moderate and severe injuries as well as repetitive mild TBI result in lasting morbidity. However, whether a single mild TBI sustained during childhood can produce long-lasting modifications within the brain is still debated. We aimed to assess the consequences of a single juvenile mild TBI (jmTBI) at 12 months post-injury in a mouse model. Non-invasive diffusion tensor imaging (DTI) revealed significant microstructural alterations in the hippocampus and the in the substantia innominata/nucleus basalis (SI/NB), structures known to be involved in spatial learning and memory. DTI changes paralled neuronal loss, increased astrocytic AQP4 and microglial activation in the hippocampus. In contrast, decreased astrocytic AQP4 expression and microglia activation were observed in SI/NB. Spatial learning and memory were impaired and correlated with alterations in DTI-derived derived fractional ansiotropy (FA) and axial diffusivity (AD). This study found that a single juvenile mild TBI leads to significant region-specific DTI microstructural alterations, distant from the site of impact, that correlated with cognitive discriminative novel object testing and spatial memory impairments at 12 months after a single concussive injury. Our findings suggest that exposure to jmTBI leads to a chronic abnormality, which confirms the need for continued monitoring of symptoms and the development of long-term treatment strategies to intervene in children with concussions.

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bioRxiv2022

Longitudinal dynamics of microvascular recovery after acquired cortical injury

Acquired brain injuries due to trauma damage cortical vasculature, which in turn impairs blood flow to injured tissues. There are reports of vascular morphological recovery following traumatic brain injury (TBI), but the remodeling process has not been examined longitudinally in detail after injury in vivo. Understanding the dynamic processes that influence recovery is thus critically important. We evaluated the longitudinal and dynamic microvascular recovery and remodeling up to 2 months post injury using live brain miniscope and 2-photon microscopic imaging. The new imaging approaches captured dynamic morphological and functional recovery processes at high spatial and temporal resolution in vivo. Vessel painting documented the initial loss and subsequent temporal morphological vascular recovery at the injury site. Miniscopes were used to longitudinally image the temporal dynamics of vascular repair in vivo after brain injury in individual mice across each cohort. We observe near-immediate nascent growth of new vessels in and adjacent to the injury site that peaks between 14-21 days post injury. 2-photon microscopy confirms new vascular growth and further demonstrates differences between cortical layers after cortical injury: large vessels persist in deeper cortical layers (>200 m), while superficial layers exhibit a dense plexus of fine (and often non-perfused) vessels displaying regrowth. Functionally, blood flow increases mirror increasing vascular density. Filopodia development and endothelial sprouting is measurable within 3 days post injury that rapidly transforms regions devoid of vessels to dense vascular plexus in which new vessels become increasingly perfused. Within 7 days post injury, blood flow is observed in these nascent vessels. Behavioral analysis reveals improved vascular modulation after 9 days post injury, consistent with vascular regrowth. We conclude that morphological recovery events are closely linked to functional recovery of blood flow to the compromised tissues, which subsequently leads to improved behavioral outcomes.

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bioRxiv2022

Vascular topology is acutely impacted by experimental febrile status epilepticus

Febrile status epilepticus (FSE) is an important risk factor for temporal lobe epilepsy and early identification is vital. In a rat model of FSE, we identified an acute novel MRI signal in the basolateral amygdala (BLA) at 2 hours post FSE that predicted epilepsy in adulthood. This signal remains incompletely understood and hypothesized that it might derive from changes to vascular topology. Experimental FSE was induced in rat pups and compared to normothermic littermate controls. We examined cerebral vascular topology at 2 hours, using a novel vessel painting and analysis protocol. Blood vessel density of the cortical vasculature was significantly reduced in FSE rats, and this effect was lateralized, as reported for the MRI signal. The middle cerebral artery (MCA) exhibited abnormal topology in FSE pups but not in controls. In the BLA, significant vessel junction reductions and decreased vessel diameter were observed, together with a strong trend for reduced vessel length. In summary, FSE results in acute vascular topological changes in the cortex and BLA that may underlie the acute MRI signal that predicts progression to future epilepsy. The altered vasculature may be amenable to intervention treatments to potentially reduce the probability of progression to epilepsy following FSE.

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bioRxiv2021

Early Life Adversity in Male Mice Sculpts Reward Circuits.

Early life adversity (ELA) comprises a wide variety of negative experiences during early life and has been linked to cognitive impairments, reduced experiences of pleasure (anhedonia), and other long-term consequences implying that ELA impacts the reward circuitry. In this study, we focused on the projections from the dorsal raphe (DR) to the ventral tegmental area (VTA) and on to the nucleus accumbens (NAcc), an important pathway within the reward circuit. We hypothesized that ELA alters connectivity within the DR-VTA- NAcc pathway, manifested behaviorally as anhedonia in adulthood. We used the limited bedding and nesting model to induce ELA in mice and measured reward-related behaviors in adulthood using the three-chamber social interaction and sucrose preference tests. High resolution ex vivo diffusion tensor imaging (DTI) was acquired and processed for regional DTI metrics, including tractography to assess circuit organization. We found brain-wide changes in radial diffusivity (RD) and altered connectivity of the reward circuit in the ELA group. DR-VTA-NAcc circuit tractography and axial diffusivity (AD) along this tract exhibited dispersed organization where AD was increased in the VTA segment. Behaviorally, ELA elicited an anhedonic phenotype in adulthood with decreased direct social approach and time spent with peer but no overt differences in sucrose preference test. Our findings suggest that reward circuits, assessed using DTI, are altered following ELA and that these changes may drive enduring reward deficits.

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bioRxiv2021

Early neuroadaptations to an obesogenic diet identify the schizophrenia-related ErbB4 receptor in obesity-induced hippocampal abnormalities

Childhood obesity leads to hippocampal atrophy and altered cognition. However, the molecular mechanisms underlying these impairments are poorly understood. The neurotrophic factor neuregulin-1 (NRG1) and its cognate ErbB4 receptor play critical roles in hippocampal maturation and function. This study aimed to determine whether altered NRG1-ErbB4 activities may partly explain hippocampal abnormalities in rats exposed to an obesogenic Western-like diet (WD). Lewis rats were randomly divided into four groups (12 rats/group): 1) control diet+vehicle (CDV); 2) CD+NRG1 (CDN) (daily intraperitoneal injections: 5 g/kg/day; between postnatal day, PND 21-PND 41); 3) WD+VEH (WDV); 4) WD+NRG1 (WDN). Neurobehavioral assessments were performed at PND 43-49. Brains were harvested for MRI and molecular analyses at PND 49. We found that NRG1 administration reduced hippocampal volume (7%) and attenuated hippocampal-dependent cued fear conditioning in CD rats (56%). NRG1 administration reduced PSD-95 protein expression (30%) and selectively reduced hippocampal cytokine levels (IL-33, GM-CSF, CCL-2, IFN-{gamma}) while significantly impacting microglia morphology (increased span ratio and reduced circularity). WD rats exhibited reduced right hippocampal volume (7%), altered microglia morphology (reduced density and increased lacunarity), and increased levels of cytokines implicated in neuroinflammation (IL-1, TNF-, IL-6). Notably, NRG1 synergized with the WD to increase hippocampal ErbB4 phosphorylation and the tumor necrosis alpha converting enzyme (TACE/ADAM17) protein levels. Together, these data suggest a novel interaction between obesogenic diet exposure and TACE/ADAM17-NRG1-ErbB4 signaling during hippocampal maturation. Our results indicate that supraoptimal ErbB4 activities may contribute to the abnormal hippocampal structure and cognitive vulnerabilities observed in obese individuals. HighlightsO_LIObesogenic diet consumption during adolescence induces anxiety-like behaviors before the onset of obesity-related changes in metabolism. C_LIO_LIObesogenic diet-driven abnormal behaviors co-occurred with alterations in hippocampal pro-inflammatory cytokine profiles. C_LIO_LIObesogenic diet consumption attenuates exogenous NRG1 effects on hippocampal-related behaviors and structure. C_LIO_LIExogenous NRG1 administration during adolescence resulted in reduced hippocampal volumes and domain-specific cognitive impairments. C_LIO_LIExogenous NRG1 administration has potent immunomodulatory actions and alters hippocampal microglia morphology. C_LI

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bioRxiv2018

Novel use of Diffusion Tensor Imaging to Delineate the Rat Basolateral Amygdala

The amygdaloid complex, including the basolateral nucleus (BLA) contributes crucially to emotional and cognitive brain functions, and is thus a major target of research in both humans and rodents. However, delineating structural amygdala plasticity in both normal and disease-related contexts using neuroimaging has been hampered by the difficulty of unequivocally identifying the boundaries of the BLA. This challenge is a result of poor contrast between BLA and the surrounding gray matter, including other amygdala nuclei. Here we describe a novel DTI approach to enhance contrast, enabling optimal identification of BLA in rodent brain from MR images. We employed this methodology together with a slice-shifting approach to measure BLA volume. We then validated the results by direct comparison to both histological and cellular-identity (parvalbumin)-based conventional techniques for defining BLA in the same brains used for MRI. We also confirmed the BLA region using DTI based tractography. The novel approach used here enables accurate and reliable delineation of BLA. Because this nucleus is involved in, and is changed by, developmental, degenerative and adaptive processes, the instruments provided here should be highly useful to a broad range of neuroimaging studies. Finally, the principles used here are readily applicable to numerous brain regions and across species.\n\nSummary StatementUse of MRI directionally encoded diffusion tensor imaging (DTI) can delineate the basolateral amygdala (BLA) and volumes derived from DTI were found to match those obtained using histological methods. Our approach can be used to identify the BLA.

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