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Unwanted proteins and metabolic waste in cerebral spinal fluid are cleared from the brain by meningeal and nasal lymphatics, and perineural sheath of cranial nerves; however, the distribution and clearance of CSF along the subarachnoid space of the entire spinal cord is not fully understood. It was hypothesized that the anatomical resolution of Cryo-Fluorescence Tomography (CFT) could provide the visual evidence of clearance across the spinal cord at each level of the vertebral column. To that end, isoflurane anesthetized mice were infused into the lateral cerebroventricle with 5.0 µl of quantum dots [QdotR 605 ITKTM amino (PEG)] over two mins. Mice were allowed to recover (ca 2-3 min) and remained awake and ambulatory for 5, 15, 30, 60 and 120 minutes after which they were euthanized, and the entire intact body frozen at -800. The entire mouse was sectioned and imaged to produce an isotropic voxel resolution of 35 µm. Both white light and fluorescent images were captured after each slice to produce high resolution three-dimensional volumes for each mouse. CFT highlighted the circulation of tracer throughout the ventricular system and central canal of the spinal cord and the entire subarachnoid space of the CNS. Signal could be visualized in the nasal cavity, deep cervical lymph nodes, thoracic lymph nodes and more superficial submandibular lymph nodes as early as 15 min post infusion. Fluorescent signal could be visualized along the dorsal root ganglia and down the proximal extension of the spinal nerves of the thoracic and lumbar segments at 30 min. There was significant accumulation of tracer in the lumbar and sacral lymph nodes between 15- 60 min. The dense fluorescent signal in the thoracic vertebrae noted at 5- and 15-mins post infusion was significantly reduced by 30 min. Indeed, all signal in the spinal cord was ostensibly absent by 120 min except for trace amounts in the coccyx. The brain still had some residual signal at 120 min. These data show that Qdots with a hydrodynamic diameter of 16-20 nm rapidly clear from the brain of awake mice. These data also clearly demonstrate the rapid distribution and efflux of trace along a major length of the vertebral column and the potential contribution of the spinal cord in the clearance of brain waste.

Background Maraviroc is an antiretroviral agent and C-C chemokine coreceptor 5 (CCR5) antagonist that is currently used to treat human immunodeficiency virus. CCR5/μ-opioid receptor heterodimerization suggests that maraviroc could be a treatment for oxycodone abuse. We treated rats with maraviroc to explore its effect on oxycodone-seeking and its interference with the analgesic effects of oxycodone. We used resting-state blood-oxygen-level-dependent functional connectivity to assess the effect of maraviroc on oxycodone-enhanced coupling in the reward circuitry and performed behavioural tests to evaluate the effect of maraviroc on oxycodone rewarding properties and on oxycodone-seeking after prolonged abstinence. Methods Two groups of rats were exposed to 8 consecutive days of oxycodone-conditioned place preference training and treatment with maraviroc or vehicle. Two additional groups were trained to self-administer oxycodone for 10 days and then tested for drug seeking after 14 days of abstinence with or without daily maraviroc treatment. We tested the effects of maraviroc on oxycodone analgesia using a tail-flick assay. We analyzed resting-state functional connectivity data using a rat 3-dimensional MRI atlas of 171 brain areas. Results Maraviroc significantly decreased conditioned place preference and attenuated oxycodone-seeking behaviour after prolonged abstinence. The analgesic effect of oxycodone was maintained after maraviroc treatment. Oxycodone increased functional coupling with the accumbens, ventral pallidum and olfactory tubercles, but this was reduced with maraviroc treatment. Limitations All experiments were performed in male rats only. Conclusion Maraviroc treatment attenuated oxycodone-seeking in abstinent rats and reduced functional coupling in the reward circuitry. The analgesic effects of oxycodone were not affected by maraviroc.

Background Does minor head impact without signs of structural brain damage cause short-term changes in vasogenic edema as measured by an increase apparent diffusion coefficient (ADC) using diffusion weighted imaging? If so, could the increase in vasogenic edema be treated with a vasopressin V1a receptor antagonist? We hypothesized that SRX251, a highly selective V1a antagonist, would reduce vasogenic edema in response to a single minor head impact. Methods Lightly anesthetized male rats were subjected to a sham procedure or a single hit to the forehead using a closed skull, momentum exchange model. Animals recovered in five min and were injected with saline vehicle (n = 8) or SRX251 (n = 8) at 15 min post head impact and again 7−8 hrs later. At 2 h, 6 h, and 24 h post injury, rats were anesthetized and scanned for increases in ADC, a neurological measure of vasogenic edema. Sham rats (n = 6) were exposed to anesthesia and scanned at all time points but were not hit or treated. Images were registered to and analyzed using a 3D MRI rat atlas providing site-specific data on 150 different brain areas. These brain areas were parsed into 11 major brain regions. Results Untreated rats with brain injury showed a significant increase in global brain vasogenic edema as compared to sham and SRX251 treated rats. Edema peaked at 6 h in injured, untreated rats in three brain regions where changes in ADC were observed, but returned to sham levels by 24 h. There were regional variations in the time course of vasogenic edema and drug efficacy. Edema was significantly reduced in cerebellum and thalamus with SRX251 treatment while the basal ganglia did not show a response to treatment. Conclusion A single minor impact to the forehead causes regional increases in vasogenic edema that peak at 6 h but return to baseline within a day in a subset of brain regions. Treatment with a selective V1a receptor antagonist can reduce much of the edema.

Background This is an exploratory study using multimodal magnetic resonance imaging (MRI) to interrogate the brain of rats with type 2 diabetes (T2DM) as compared to controls. It was hypothesized there would be changes in brain structure and function that reflected the human disorder, thus providing a model system by which to follow disease progression with noninvasive MRI. Methods The transgenic BBZDR/Wor rat, an animal model of T2MD, and age‐matched controls were studied for changes in brain structure using voxel‐based morphometry, alteration in white and gray matter microarchitecture using diffusion weighted imaging with indices of anisotropy, and functional coupling using resting‐state BOLD functional connectivity. Images from each modality were registered to, and analyzed, using a 3D MRI rat atlas providing site‐specific data on over 168 different brain areas. Results There was an overall reduction in brain volume focused primarily on the somatosensory cortex, cerebellum, and white matter tracts. The putative changes in white and gray matter microarchitecture were pervasive affecting much of the brain and not localized to any region. There was a general increase in connectivity in T2DM rats as compared to controls. The cerebellum presented with strong functional coupling to pons and brainstem in T2DM rats but negative connectivity to hippocampus. Conclusion The neuroradiological measures collected in BBBKZ/Wor rats using multimodal imaging methods did not reflect those reported for T2DB patients in the clinic. The data would suggest the BBBKZ/Wor rat is not an appropriate imaging model for T2DM.

Oxytocin is a pleiotropic, peptide hormone with broad implications for general health, adaptation, development, reproduction, and social behavior. Endogenous oxytocin and stimulation of the oxytocin receptor support patterns of growth, resilience, and healing. Oxytocin can function as a stress-coping molecule, an anti-inflammatory, and an antioxidant, with protective effects especially in the face of adversity or trauma. Oxytocin influences the autonomic nervous system and the immune system. These properties of oxytocin may help explain the benefits of positive social experiences and have drawn attention to this molecule as a possible therapeutic in a host of disorders. However, as detailed here, the unique chemical properties of oxytocin, including active disulfide bonds, and its capacity to shift chemical forms and bind to other molecules make this molecule difficult to work with and to measure. The effects of oxytocin also are context-dependent, sexually dimorphic, and altered by experience. In part, this is because many of the actions of oxytocin rely on its capacity to interact with the more ancient peptide molecule, vasopressin, and the vasopressin receptors. In addition, oxytocin receptor(s) are epigenetically tuned by experience, especially in early life. Stimulation of G-protein-coupled receptors triggers subcellular cascades allowing these neuropeptides to have multiple functions. The adaptive properties of oxytocin make this ancient molecule of special importance to human evolution as well as modern medicine and health; these same characteristics also present challenges to the use of oxytocin-like molecules as drugs that are only now being recognized. SIGNIFICANCE STATEMENT: Oxytocin is an ancient molecule with a major role in mammalian behavior and health. Although oxytocin has the capacity to act as a "natural medicine" protecting against stress and illness, the unique characteristics of the oxytocin molecule and its receptors and its relationship to a related hormone, vasopressin, have created challenges for its use as a therapeutic drug.

Head injury is a known risk factor for Parkinson’s disease. Disruption in the perivascular clearance of metabolic waste and unwanted proteins is thought to be a contributing factor to disease progression. We hypothesized that repetitive mild head impacts, without evidence of structural brain damage, would increase microgliosis and AQP4 expression and depolarization and alter perivascular flow in the midbrain dopaminergic system. Adult male rats were subjected to sham, or two mild head impacts separated by 48 h. Three weeks later, fully awake rats were imaged using dynamic, contrast-enhanced MRI to follow the distribution of intraventricular gadobenate dimeglumine contrast agent. Images were registered to and analysed using a 3D MRI rat atlas providing site-specific data on 171 different brain areas. Following imaging, rats were tested for cognitive function using the Barnes maze assay. Histological analyses of tyrosine hydroxylase, microglia activation and AQP4 expression and polarization were performed on a parallel cohort of head impacted rats at 20 days post insult to coordinate with the time of imaging. There was no change in the global flux of contrast agent between sham and head impacted rats. The midbrain dopaminergic system showed a significant decrease in the influx of contrast agent as compared to sham controls together with a significant increase in microgliosis, AQP4 expression and depolarization. There were no deficits in cognitive function. The histology showed a significant level of neuroinflammation in the midbrain dopaminergic system 3 weeks post mild repetitive head impact but no loss in tyrosine hydroxylase. MRI revealed no structural brain damage emphasizing the potential serious consequences of mild head impacts on sustained brain neuroinflammation in this area critical to the pathophysiology of Parkinson’s., Cai et al. report that mild head impact without evidence of brain damage can alter perivascular clearance and increase neuroinflammation around the dopaminergic neurons in the midbrain substantia nigra weeks after injury. These data support the notion that early head injury may be a risk factor for Parkinson’s disease., Graphical Abstract Graphical Abstract

BackgroundThe phytocannabinoid cannabidiol (CBD) exhibits anxiolytic activity and has been promoted as a potential treatment for post-traumatic stress disorders. How does CBD interact with the brain to alter behavior? We hypothesized that CBD would produce a dose-dependent reduction in brain activity and functional coupling in neural circuitry associated with fear and defense.MethodsDuring the scanning session awake mice were given vehicle or CBD (3, 10, or 30 mg/kg I.P.) and imaged for 10 min post treatment. Mice were also treated with the 10 mg/kg dose of CBD and imaged 1 h later for resting state BOLD functional connectivity (rsFC). Imaging data were registered to a 3D MRI mouse atlas providing site-specific information on 138 different brain areas. Blood samples were collected for CBD measurements.ResultsCBD produced a dose-dependent polarization of activation along the rostral-caudal axis of the brain. The olfactory bulb and prefrontal cortex showed an increase in positive BOLD whereas the brainstem and cerebellum showed a decrease in BOLD signal. This negative BOLD affected many areas connected to the ascending reticular activating system (ARAS). The ARAS was decoupled to much of the brain but was hyperconnected to the olfactory system and prefrontal cortex.ConclusionThe CBD-induced decrease in ARAS activity is consistent with an emerging literature suggesting that CBD reduces autonomic arousal under conditions of emotional and physical stress.

The main objective of this study was to develop and evaluate the CNS delivery efficiency, distribution, therapeutic efficacy, and safety of cyclosporine A (CSA) using a cationic oil-in-water nanoemulsion system upon intranasal administration. An omega-3 fatty acid–rich, flaxseed oil–based nanoemulsion was used for intranasal delivery to the brain, and further magnetic resonance imaging (MRI) was used to evaluate and confirm the transport of the positively charged CSA nanoemulsion (CSA-NE) in CNS. Furthermore, the anti-inflammatory potential of CSA peptide was evaluated using the lipopolysaccharide (LPS) model of neuroinflammation in rats. CSA-NE showed a good safety profile when tested in vitro in RPMI 2650 cells. Upon intranasal administration in rats, the nanoemulsion delivery system showed higher uptake in major regions of the brain based on changes in MRI T(1) (longitudinal relaxation time) values. Additionally, CSA nanoemulsion showed improved therapeutic efficacy by inhibiting proinflammatory cytokines in the LPS-stimulated rat model of neuroinflammation compared with solution formulation. Preliminary safety evaluations show that the nanoemulsion system was well tolerated and did not cause any acute negative effects in rats. Based on these results, intranasal delivery of CSA and other “neuroprotective peptides” may provide a clinically translatable strategy for treating neurologic diseases.

Presented is a diffusion weighted imaging protocol with measures of apparent diffusion coefficient which when registered to a 3D MRI rat brain atlas provides site-specific information on 173 different brain areas. This protocol coined “in vivo neuropathology” was used to follow the progressive neurotoxic effects of trimethyltin on global gray matter microarchitecture. Four rats were given an IP injection of 7 mg/kg of the neurotoxin trimethyltin and imaged for changes in water diffusivity at 3- and 7-days post injections. At 3 days, there was a significant decrease in apparent diffusion coefficient, a proxy for cytotoxic edema, in several cortical areas and cerebellum. At 7 days the level of injury expanded to include most of the cerebral cortex, hippocampus, olfactory system, and cerebellum/brainstem corroborating much of the work done with traditional histopathology. Analysis is achieved with a minimum number of rats adhering to the laws and regulations around the humane care and use of laboratory animals, providing an alternative to the traditional tests for assessing drug neurotoxicity. “In vivo neuropathology” can minimize the cost, expedite the process, and identify subtle changes in site-specific brain microarchitecture across the entire brain.

Critical studies that form the foundation of the glymphatic system and the clearance of metabolic by-products of unwanted proteins from the brain are reviewed. Concerns are raised about studying glymphatic flow in anesthetized animals and making assumptions about the whole brain based upon data collected from a cranial window on the cortex. A new model is proposed arguing that the flow of cerebral spinal fluid and parenchymal clearance in the perivascular system of unwanted proteins is regulated by circadian changes in brain temperature and blood flow at the level of the microvasculature.

Background Efficacy of inhaled cannabis for treating pain is controversial. Effective treatment for chemotherapy-induced neuropathy represents an unmet medical need. We hypothesized that cannabis reduces neuropathic pain by reducing functional coupling in the raphe nuclei. Methods We assessed the impact of inhalation of vaporized cannabis plant (containing 10.3% Δ9-tetrahydrocannabinol/0.05% cannabidiol) or placebo cannabis on brain resting-state blood oxygen level–dependent functional connectivity and pain behavior induced by paclitaxel in rats. Rats received paclitaxel to produce chemotherapy-induced peripheral neuropathy or its vehicle. Behavioral and imaging experiments were performed after neuropathy was established and stable. Images were registered to, and analyzed using, a 3D magnetic resonance imaging rat atlas providing site-specific data on more than 168 different brain areas. Results Prior to vaporization, paclitaxel produced cold allodynia. Inhaled vaporized cannabis increased cold withdrawal latencies relative to prevaporization or placebo cannabis, consistent with Δ9-tetrahydrocannabinol-induced antinociception. In paclitaxel-treated rats, the midbrain serotonergic system, comprising the dorsal and median raphe, showed hyperconnectivity to cortical, brainstem, and hippocampal areas, consistent with nociceptive processing. Inhalation of vaporized cannabis uncoupled paclitaxel-induced hyperconnectivity patterns. No such changes in connectivity or cold responsiveness were observed following placebo cannabis vaporization. Conclusions Inhaled vaporized cannabis plant uncoupled brain resting-state connectivity in the raphe nuclei, normalizing paclitaxel-induced hyperconnectivity to levels observed in vehicle-treated rats. Inhaled vaporized cannabis produced antinociception in both paclitaxel- and vehicle-treated rats. Our study elucidates neural circuitry implicated in the therapeutic effects of Δ9-tetrahydrocannabinol and supports a role for functional imaging studies in animals in guiding indications for future clinical trials.

Objectives This is an exploratory study using multimodal magnetic resonance imaging (MRI) to interrogate the brain of rats with type 2 diabetes (T2DM) as compared to controls. It was assumed there would be changes in brain structure and function that reflected the human disorder, thus providing a model system by which to follow disease progression with non-invasive MRI. Methods The transgenic BBZDR/Wor rat, an animal model of T2MD, and age-matched controls were studied for changes in brain structure using voxel-based morphometry, alteration in white and gray matter microarchitecture using diffusion weighted imaging with indices of anisotropy, and functional coupling using resting state BOLD functional connectivity. Images from each modality were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on over 168 different brain areas. Results There was an overall reduction in brain volume focused primarily on somatosensory cortex, cerebellum and white matter tracts. The putative changes in white and gray matter microarchitecture were pervasive affecting much of the brain and not localized to any region. There was a general increase in connectivity in T2DM rats as compared to controls. The cerebellum presented with strong functional coupling to pons and brainstem in T2DM rats but negative connectivity to hippocampus. Conclusion Are the neuroradiological measures collected in BBBKZ/Wor rats using multimodal imaging methods common to the clinic, similar to those reported in T2DM patents? In comparison to the clinical findings, the data would suggest the BBBKZ/Wor rat is not an appropriate imaging model for T2DM.

Exposure to early-life adversity (ELA) increases the risk for psychopathologies associated with amygdala-prefrontal cortex (PFC) circuits. While sex differences in vulnerability have been identified with a clear need for individualized intervention strategies, the neurobiological substrates of ELA-attributable differences remain unknown due to a paucity of translational investigations taking both development and sex into account. Male and female rats exposed to maternal separation ELA were analyzed with anterograde tracing from basolateral amygdala (BLA) to PFC to identify sex-specific innervation trajectories through juvenility (PD28) and adolescence (PD38;PD48). Resting-state functional connectivity (rsFC) was assessed longitudinally (PD28;PD48) in a separate cohort. All measures were related to anxiety-like behavior. ELA-exposed rats showed precocial maturation of BLA-PFC innervation, with females affected earlier than males. ELA also disrupted maturation of female rsFC, with enduring relationships between rsFC and anxiety-like behavior. This study is the first providing both anatomical and functional evidence for sex- and experience-dependent corticolimbic development., eLife digest Having a traumatic childhood increases the risk a person will develop anxiety disorders later in life. Early life adversity affects men and women differently, but scientists do not yet know why. Learning more could help scientists develop better ways to prevent or treat anxiety disorders in men and women who experienced childhood trauma. Anxiety occurs when threat-detecting brain circuits turn on. These circuits begin working in infancy, and during childhood and adolescence, experiences shape the brain to hone the body’s responses to perceived threats. Two areas of the brain that are important hubs for anxiety-related brain circuits include the basolateral amygdala (BLA) and the prefrontal cortex (PFC). Now, Honeycutt et al. show that rats that experience early life adversity develop stronger connections between the BLA and PFC, and these changes occur earlier in female rats. In the experiments, one group of rats was repeatedly separated from their mothers and littermates (an early life trauma), while a second group was not. Honeycutt et al. examined the connections between the BLA and PFC in the two groups at three different time periods during their development: the juvenile stage, early adolescence, and late adolescence. The experiments showed stronger connections between the BLA and PFC begin to appear earlier in juvenile traumatized female rats. But these changes did not appear in their male counterparts until adolescence. Lastly, the rats that developed these strengthened BLA-PFC connections also behaved more anxiously later in life. This may mean that the ideal timing for interventions may be different for males and females. More work is needed to see if these results translate to humans and then to find the best times and methods to help people who experienced childhood trauma.

Significance Homeostasis and the daily rhythms in brain function and temperature are coupled to the circadian light–dark cycle. MRI was used to study the redistribution of intraventricular contrast agent in awake rats during the night when they are active and during the day when at rest. Redistribution is lowest during the day and highest at night and parallels the gradients and regional variations in brain temperatures reported in the literature. The brain areas of low parenchymal redistribution are associated with high temperatures and have a high density of blood vessels that may be an essential part of the organization of the glymphatic system regulating brain temperature, blood gases, nutrients, metabolites, and waste products over the light–dark cycle., The glymphatic system functions in the removal of potentially harmful metabolites and proteins from the brain. Dynamic, contrast-enhanced MRI was used in fully awake rats to follow the redistribution of intraventricular contrast agent entrained to the light–dark cycle and its hypothetical relationship to the sleep–waking cycle, blood flow, and brain temperature in specific brain areas. Brain areas involved in circadian timing and sleep–wake rhythms showed the lowest redistribution of contrast agent during the light phase or time of inactivity and sleep in rats. Global brain redistribution of contrast agent was heterogeneous. The redistribution was highest along the dorsal cerebrum and lowest in the midbrain/pons and along the ventral surface of the brain. This heterogeneous redistribution of contrast agent paralleled the gradients and regional variations in brain temperatures reported in the literature for awake animals. Three-dimensional quantitative ultrashort time-to-echo contrast-enhanced imaging was used to reconstruct small, medium, and large arteries and veins in the rat brain and revealed areas of lowest redistribution overlapped with this macrovasculature. This study raises new questions and theoretical considerations of the impact of the light–dark cycle, brain temperature, and blood flow on the function of the glymphatic system.

A two-year old rat, R222, survived a life-time of extreme hydrocephaly affecting the size and organization of its brain. Much of the cortex was severely thinned and replaced by cerebrospinal fluid, yet R222 had normal motor function, could hear, see, smell, and respond to tactile stimulation. The hippocampus was malformed and compressed into the lower hindbrain together with the hypothalamus midbrain and pons, yet R222 showed normal spatial memory as compared to age-matched controls. BOLD MRI was used to study the reorganization of R222’s brain function showing global activation to visual, olfactory and tactile stimulation, particularly in the brainstem/cerebellum. The results are discussed in the context of neuroadaptation in the face of severe hydrocephaly and subsequent tissue loss, with an emphasis on what is the “bare minimum” for survival.

Cerebrovascular abnormality is linked to Alzheimer’s disease and related dementias (ADRDs). ApoE-Ɛ4 (APOE4) is known to play a critical role in neurovascular dysfunction, however current medical imaging technologies are limited in quantification. This cross-sectional study tested the feasibility of a recently established imaging modality, quantitative ultra-short time-to-echo contrast-enhanced magnetic resonance imaging (QUTE-CE MRI), to identify small vessel abnormality early in development of human APOE4 knock-in female rat (TGRA8960) animal model. At 8 months, 48.3% of the brain volume was found to have significant signal increase (75/173 anatomically segmented regions; q

Aging is a major risk factor for Alzheimer’s disease (AD), the most common cause of dementia worldwide. TDP-43 proteinopathy is reported to be associated with AD pathology is almost 50% of cases. Our exploratory study examined near end-stage (28 months old) mice selectively driving expression of human TDP-43 in the hippocampus and cortex in an APP/PSEN1 background. We hypothesized that hippocampal neuropathology caused by β-amyloidosis with TDP-43 proteinopathy induced in this model, resembling the pathology seen in AD cases, manifest with changes in resting state functional connectivity. In vivo magnetic resonance imaging and post-mortem histology were performed on four genotypes: wild type, APP/PSEN1, Camk2a/TDP-43, and Camk2a/TDP-43/APP/PSEN1. Our results revealed loss of functional coupling in hippocampus and amygdala that was associated with severe neuronal loss in dentate gyrus of Camk2a/TDP-43/APP/PSEN1 mice compared to APP/PSEN1 and wild type mice. The loss of cells was accompanied by high background of β-amyloid plaques with sparse phosphorylated TDP-43 pathology. The survival rate was also reduced in Camk2a/TDP-43/APP/PSEN1 mice compared to other groups. This end-of-life study provides exploratory data to reach a better understanding of the role of TDP-43 hippocampal neuropathology in diseases with co-pathologies of TDP-43 proteinopathy and β-amyloidosis such as AD and limbic predominant age-related TDP-43 encephalopathy (LATE).

The neuropeptide oxytocin (OT) regulates social behavior in sex-specific ways across species. OT has promising effects on alleviating social deficits in sex-biased neuropsychiatric disorders. However little is known about potential sexually dimorphic effects of OT on brain function. Using the rat as a model organism, we determined whether OT administered centrally or peripherally induces sex differences in brain activation. Functional magnetic resonance imaging was used to examine blood oxygen level-dependent (BOLD) signal intensity changes in the brains of awake rats during the 20 min following intracerebroventricular (ICV; 1μg/5μl) or intraperitoneal (IP; 0.1mg/kg) OT administration as compared to baseline. ICV OT induced sex differences in BOLD activation in 26 out of 172 brain regions analyzed, with 20 regions showing a greater volume of activation in males (most notably the nucleus accumbens and insular cortex), and 6 regions showing a greater volume of activation in females (including the lateral and central amygdala). IP OT also elicited sex differences in BOLD activation with a greater volume of activation in males, but this activation was found in different and fewer (10) brain regions compared to ICV OT. In conclusion, exogenous OT modulates neural activation differently in male versus female rats with the pattern and magnitude, but not the direction, of sex differences depending on the route of administration. These findings highlight the need to include both sexes in basic and clinical studies to fully understand the role of OT on brain function.

There is a need to understand pathologic processes of the brain following mild traumatic brain injury (mTBI). Previous studies report axonal injury and oedema in the first week after injury in a rodent model. This study aims to investigate the processes occurring 1 week after injury at the time of regeneration and degeneration using diffusion tensor imaging (DTI) in the impact acceleration rat mTBI model.Eighteen rats were subjected to impact acceleration injury, and three rats served as sham controls. Seven days post injury, DTI was acquired from fixed rat brains using a 7T scanner. Group comparison of Fractional Anisotropy (FA) values between traumatized and sham animals was performed using Tract-Based Spatial Statistics (TBSS), a method that we adapted for rats.TBSS revealed white matter regions of the brain with increased FA values in the traumatized versus sham rats, localized mainly to the contrecoup region. Regions of increased FA included the pyramidal tract, the cerebral peduncle, the superior cerebellar peduncle and to a lesser extent the fibre tracts of the corpus callosum, the anterior commissure, the fimbria of the hippocampus, the fornix, the medial forebrain bundle and the optic chiasm.Seven days post injury, during the period of tissue reparation in the impact acceleration rat model of mTBI, microstructural changes to white matter can be detected using DTI.

Adverse early experiences significantly alter behavioral and neural trajectories via aberrant brain maturation. Children with a history of early life stress (ELS) exhibit maladaptive behaviors and increased risk of mental illness later in life. Evidence in ELS-exposed humans identifies a role of atypical corticolimbic development; specifically, within amygdala-prefrontal cortex (PFC) circuits, and show precocially mature task-based corticolimbic functional connectivity (FC). However, the neurobiological substrates of such ELS-driven developmental changes remain unknown. Here, we identify putative neurobiological changes to determine the timeline of developmental perturbations following ELS in rats. Anterograde axonal tracing from basolateral amygdala (BLA) to pre- and infralimbic (PL, IL) PFC was quantified at postnatal days (PD)28, 38, and 48, along with anxiety-like behavior, in maternally separated (ELS) or control reared (CON) male and female rats. Resting state (rs)FC was assessed at PD28 and PD48 in a separate cohort. We report that ELS-exposed female rats show early maturation of BLA-PFC innervation at PD28, with ELS-related changes in males not appearing until PD38. ELS disrupted the maturation of rsFC from PD28 to PD48 in females, with enduring relationships between early rsFC and later anxiety-like behavior. Only transient ELS-related changes in rsFC were seen in male PL. Together, these data provide evidence that female rats may be more vulnerable to the effects of ELS via precocial BLA-PFC innervation, which may drive altered corticolimbic rsFC. These data also provide evidence that increased BLA-IL rsFC is associated with behavioral resiliency following ELS in female rats, providing mechanistic insight into the underlying etiology of adversity-induced vulnerability and resiliency.

The data in this article provide details about MRI lesion segmentation using K-means and Gaussian Mixture Model-Expectation Maximization (GMM-EM) algorithms. Both K-means and GMM-EM algorithms can segment lesion area from the rest of brain MRI automatically. The performance metrics (accuracy, sensitivity, specificity, false positive rate, misclassification rate) were estimated for the algorithms and there was no significant difference between K-means and GMM-EM. In addition, lesion size does not affect the accuracy and sensitivity for either method. Keywords: Ischemic stroke, Lesion, Magnetic resonance image (MRI), Segmentation

Maternally administered oxytocin leads to changes in offspring social behavior and neurobiology., Oxytocin is used in approximately half of all births in the United States during labor induction and/or augmentation. However, the effects of maternal oxytocin administration on offspring development have not been fully characterized. Here, we used the socially monogamous prairie vole to examine the hypothesis that oxytocin exposure at birth can have long-term developmental consequences. Maternally administered oxytocin increased methylation of the oxytocin receptor (Oxtr) in the fetal brain. As adults, oxytocin-exposed voles were more gregarious, with increased alloparental caregiving toward pups and increased close social contact with other adults. Cross-fostering indicated that these effects were the result of direct action on the offspring, rather than indirect effects via postnatal changes in maternal behavior. Male oxytocin-exposed offspring had increased oxytocin receptor density and expression in the brain as adults. These results show that long-term effects of perinatal oxytocin may be mediated by an epigenetic mechanism.

Highlights • Imaging the reorganization of pain neural circuitry within 8 days of chemotherapy. • Using rat model of neuropathy with multimodal MRI. • Showing loss of anticorrelation between prefrontal cortex and PAG. • Identifying the interaction between periaqueductal gray and brainstem raphe., Human and animal studies suggest that both traumatic nerve injury and toxic challenge with chemotherapeutic agents involves the reorganization of neural circuits in the brain. However, there have been no prospective studies, human or animal, using magnetic resonance imaging (MRI) to identify changes in brain neural circuitry that accompany the development of chemotherapy-induced neuropathic pain (i.e. within days following cessation of chemotherapy treatment and without the confound cancer). To this end, different MRI protocols were used to ascertain whether a reorganization of brain neural circuits is observed in otherwise normal rats exposed to the taxane chemotherapeutic agent paclitaxel. We conducted an imaging study to evaluate the impact of a well-established paclitaxel dosing regimen, validated to induce allodynia in control rats within eight days of treatment, on brain neural circuitry. Rats received either paclitaxel (2 mg/kg/day i.p; cumulative dose of 8 mg/kg) or its vehicle four times on alternate days (i.e. day 0, 2, 4, 6). Following the cessation of treatments (i.e. on day 8), all rats were tested for responsiveness to cold followed by diffusion weighted magnetic resonance imaging and assessment of resting state functional connectivity. Imaging data were analyzed using a 3D MRI rat with 173 segmented and annotated brain areas. Paclitaxel-treated rats were more sensitive to a cold stimulus compared to controls. Diffusion weighted imaging identified brain areas involved in the emotional and motivational response to chronic pain that were impacted by paclitaxel treatment. Affected brain regions included the prefrontal cortex, amygdala, hippocampus, hypothalamus and the striatum/nucleus accumbens. This putative reorganization of gray matter microarchitecture formed a continuum of brain areas stretching from the basal medial/lateral forebrain to the midbrain. Resting state functional connectivity showed reorganization between the periaqueductal gray, a key node in nociceptive neural circuitry, and connections to the brainstem. Our results, employing different imaging modalities to assess the central nervous system effects of chemotherapy, fit the theory that chronic pain is regulated by emotion and motivation and influences activity in the periaqueductal gray and brainstem to modulate pain perception.

Objectives To test the hypothesis that there are differences in neuroradiological measures between single and repeated mild traumatic brain injury using multimodal MRI. Methods A closed-head momentum exchange model was used to produce one or three mild head injuries in young adult male rats compared to non-injured, age and weight-matched controls. Six–seven weeks post-injury, rats were studied for deficits in cognitive and motor function. Seven–eight weeks post-injury changes in brain anatomy and function were evaluated through analysis of high resolution T2 weighted images, resting-state BOLD functional connectivity, and diffusion weighted imaging with quantitative anisotropy. Results Head injuries occurred without skull fracture or signs of intracranial bleeding or contusion. There were no significant differences in cognitive or motors behaviors between experimental groups. With a single mild hit, the affected areas were limited to the caudate/putamen and central amygdala. Rats hit three times showed altered diffusivity in white matter tracts, basal ganglia, central amygdala, brainstem, and cerebellum. Comparing three hits to one hit showed a similar pattern of change underscoring a dose effect of repeated head injury on the brainstem and cerebellum. Disruption of functional connectivity was pronounced with three mild hits. The midbrain dopamine system, hippocampus, and brainstem/cerebellum showed hypoconnectivity. Interestingly, rats exposed to one hit showed enhanced functional connectivity (or hyperconnectivity) across brain sites, particularly between the olfactory system and the cerebellum. Interpretation Neuroradiological evidence of altered brain structure and function, particularly in striatal and midbrain dopaminergic areas, persists long after mild repetitive head injury. These changes may serve as biomarkers of neurodegeneration and risk for dementia later in life.

Background and aims Endothelial surface glycocalyx shedding plays a role in endothelial dysfunction and increases vessel wall permeability, which can lead to inflammation and atherogenesis. We sought to elucidate whether a high fat diet (HFD) or disturbed blood flow conditions, both of which are atherogenic risk factors, would contribute more detrimentally to pre-atherosclerotic loss of endothelial glycocalyx integrity and vascular inflammation. Methods Six to seven week-old C57BL/6-background apolipoprotein-E-knockout (ApoE-KO) male mice were either fed a chow diet, fed a modified Western HFD, and/or subjected to a partial left carotid artery (LCA) ligation procedure to induce disturbed blood flow patterns in the LCA. Mice were sacrificed after 1 week of experimental conditions. Both LCA and right carotid artery (RCA) vessels were dissected and preserved to compare glycocalyx coverage and thickness as well as macrophage accumulation in carotid arterial walls amongst and between cohorts. Results Glycocalyx coverage of the endothelium was significantly reduced in the LCAs of HFD fed mice when compared to the control. More significant reduction in glycocalyx coverage occurred in the LCAs of mice exposed to disturbed flow by partial LCA ligation when compared to the control. No differences were found in glycocalyx coverage of RCAs from all cohorts. Regarding inflammation, no difference in macrophage accumulation in carotid arterial walls was observed when comparing the LCAs and RCAs of control and HFD fed mice. However, macrophage infiltration in vessel walls showed a 20-fold increase in the LCAs exposed to disturbed flow following ligation, when compared to control LCAs, while no such statistical difference was observed between the RCAs of the group. Conclusions In our mouse model, endothelial glycocalyx integrity was compromised more by disturbed blood flow patterns than by exposure of the carotid vessel to HFD conditions. The pathophysiological implications include endothelial dysfunction, which correlates to macrophage infiltration in vessel walls and promotes atherogenesis.

Background: The APOE Ɛ4 genotype is the most prevalent genetic risk for Alzheimer's disease (AD). Women carriers of Ɛ4 have higher risk for an early onset of AD than men. Human imaging studies suggest apolipoprotein E4 may affect brain structures associated with cognitive decline in AD many years before disease onset. It was hypothesized that female APOE Ɛ4 carriers would present with decreased cognitive function and neuroradiological evidence of early changes in brain structure and function as compared to male carriers. Methods: Six-month old wild-type (WT) and human APOE Ɛ4 knock-in (TGRA8960), male and female Sprague Dawley rats were studied for changes in brain structure using voxel-based morphometry, alteration in white and gray matter microarchitecture using diffusion weighted imaging with indices of anisotropy, and functional coupling using resting state BOLD functional connectivity. Images from each modality were registered to, and analyzed, using a 3D MRI rat atlas providing site-specific data on over 168 different brain areas. Results: Quantitative volumetric analysis revealed areas involved in memory and arousal were significantly different between Ɛ4 and wild-type (WT) females, with few differences between male genotypes. Diffusion weighted imaging showed few differences between WT and Ɛ4 females, while male genotypes showed significant different measures in fractional anisotropy and apparent diffusion coefficient. Resting state functional connectivity showed Ɛ4 females had greater connectivity between areas involved in cognition, emotion, and arousal compared to WT females, with male Ɛ4 showing few differences from controls. Interestingly, male Ɛ4 showed increased anxiety and decreased performance in spatial and episodic memory tasks compared to WT males, with female genotypes showing little difference across behavioral tests.Conclusion: The sex differences in behavior and diffusion weighted imaging suggest male carriers of the Ɛ4 allele may be more vulnerable to cognitive and emotional complications compared to female carriers early in life. Conversely, the data may also suggest that female carriers are more resilient to cognitive/emotional problems at this stage of life perhaps due to altered brain volumes and enhanced connectivity.