The glycosaminoglycan hyaluronan (HA) accumulates in central nervous system lesions where it limits astrogliosis but also inhibits oligodendrocyte progenitor cell (OPC) maturation. The role of hyaluronan in normative brain aging has not been previously investigated. Here, we tested the hypothesis that HA accumulates in the aging non-human primate brain. We found that HA levels significantly increase with age in the gray matter of rhesus macaques. HA accumulation was linked to age-related increases in the transcription of HA Synthase-1 (HAS1) expressed by reactive astrocytes but not changes in the expression of other HAS genes or hyaluronidases. HA accumulation was accompanied by increased expression of CD44, a transmembrane HA receptor. Areas of gray matter with elevated HA in older animals demonstrated increased numbers of olig2+ OPCs, consistent with the notion that HA may influence OPC expansion or maturation. Collectively, these data indicate that HAS1 and CD44 are transcriptionally upregulated in astrocytes during normative aging and are linked to HA accumulation in gray matter.

Objective To describe Japanese macaque encephalomyelitis (JME), a spontaneous inflammatory demyelinating disease occurring in the Oregon National Primate Research Center’s (ONPRC) colony of Japanese macaques (JM, Macaca fuscata). Methods JM with neurologic impairment were removed from the colony, evaluated and treated with supportive care. Animals were humanely euthanized and their central nervous system (CNS) examined. Results ONPRC’s JM colony was established in 1965 and no cases of JME occurred until 1986. Since 1986, 56 JM spontaneously developed a disease characterized clinically by paresis of one or more limbs, ataxia or ocular motor paresis. Most animals were humanely euthanized during their initial episode. Three recovered, later relapsed and were then euthanized. There was no gender predilection and the median age for disease was 4 years. Magnetic resonance imaging of eight cases of JME revealed multiple gadolinium enhancing T1-weighted hyperintensities in the white matter of the cerebral hemispheres, brainstem, cerebellum and cervical spinal cord. The CNS of monkeys with JME contained multifocal plaque-like demyelinated lesions of varying ages, including acute and chronic, active demyelinating lesions with macrophages and lymphocytic periventricular infiltrates, and chronic, inactive demyelinated lesions. A previously undescribed gamma-herpesvirus was cultured from acute JME white matter lesions. Cases of JME continue to affect 1–3% of the ONPRC colony per year. Interpretation JME is a unique spontaneous disease in a nonhuman primate that has similarities with multiple sclerosis (MS) and is associated with a novel simian herpesvirus. Elucidating the pathogenesis of JME may shed new light on MS and other human demyelinating diseases.

No abstract

Traumatic brain injury (TBI) affects millions of Americans annually, but effective treatments remain inadequate due to our poor understanding of how injury impacts neural function. Data are particularly limited for mild, closed-skull TBI, which forms the majority of human cases, and for acute injury phases, when trauma effects and compensatory responses appear highly dynamic. Here we use a mouse model of mild TBI to characterize injury-induced synaptic dysfunction, and examine its progression over the hours to days after trauma. Mild injury consistently caused both locomotor deficits and localized neuroinflammation in piriform and entorhinal cortices, along with reduced olfactory discrimination ability. Using whole-cell recordings to characterize synaptic input onto piriform pyramidal neurons, we found moderate effects on excitatory or inhibitory synaptic function at 48 h after TBI and robust increase in excitatory inputs in slices prepared 1 h after injury. Excitatory increases predominated over inhibitory effects, suggesting that loss of excitatory-inhibitory balance is a common feature of both mild and severe TBI. Our data indicate that mild injury drives rapidly evolving alterations in neural function in the hours following injury, highlighting the need to better characterize the interplay between the primary trauma responses and compensatory effects during this early time period.

Multiphoton microscopes are hampered by limited dynamic range, preventing weak sample features from being detected in the presence of strong features, or preventing the capture of unpredictable bursts in sample strength. We present a digital electronic add-on technique that vastly improves the dynamic range of a multiphoton microscope while limiting potential photodamage. The add-on provides real-time negative feedback to regulate the laser power delivered to the sample, and a log representation of the sample strength to accommodate ultrahigh dynamic range without loss of information. No microscope hardware modifications are required, making the technique readily compatible with commercial instruments. Benefits are shown in both structural and in-vivo functional mouse brain imaging applications.

Keywords: traumatic brain injury, mouse, weight drop injury, cerebral blood flow, capillary, in 21 vivo, laser speckle contrast imaging, optical coherence tomography, two-photon imaging 22 23 24 Acknowledgments: We thank Tim Otchy, Jennifer Morgan, and members of the Davison and 25 Boas laboratories for comments and discussion. This work was supported by Boston University 26 startup funds.Abstract 30 Traumatic brain injury (TBI) is a major source of cognitive deficits affecting millions annually. The 31 bulk of human injuries are mild, causing little or no macroscopic damage to neural tissue, yet can 32 still lead to long-term neuropathology manifesting months or years later. Although the cellular 33 stressors that ultimately lead to chronic pathology are poorly defined, one notable candidate is 34 metabolic stress due to reduced cerebral blood flow (CBF), which is common to many forms of 35 TBI. Here we used high-resolution in vivo intracranial imaging in a rodent injury model to 36 characterize deficits in the cortical microcirculation during both acute and chronic phases after 37 mild TBI. We found that CBF dropped precipitously during immediate post-injury periods, 38 decreasing to less than half of baseline levels within minutes and remaining suppressed for 1.5-39 2 hours. Repeated time-lapse imaging of the cortical microvasculature revealed further striking 40 flow deficits in the capillary network, where 18% of vessels were completely occluded for 41 extended periods after injury, and an additional >50% showed substantial stoppages. Decreased 42 CBF was paralleled by extensive vasoconstriction that is likely to contribute to loss of flow. Our 43 data indicate a major role for vascular dysfunction in even mild forms of TBI, and suggest that 44 acute post-injury periods may be key therapeutic windows for interventions that restore flow 45 and mitigate metabolic stress. 46 47 88 dysfunction across the cortical microvasculature, where a large fraction of individual capillaries 89were occluded for periods of minutes or longer, leading to localized regions with complete loss 90 5 of perfusion. CBF largely returned to normal by 3 hours after injury and showed no measurable 91 deficits when tracked until 3 weeks. Reduced CBF was paralleled by pronounced 92 vasoconstriction, identifying a potential mechanism contributing to disrupted flow. This rapid 93 and extensive vascular dysfunction highlights the importance of immediate post-injury periods 94 for delivering interventions, and suggests that relieving vasoconstriction will be a promising 95 avenue for countering the effects of mild injury. 96 97 Methods 98 99 Animals and surgical procedures 100 All experiments were performed in 2-5 month-old male and female C57BL6/J mice in accordance 101 with guidelines of the Boston University Institutional Animal Care and Use Committee. Animals 102 were group housed on a 12-hour light/dark cycle with ad libitum access to food and water. 103 Chronic cranial windows were implanted using standard procedures (30, 31). Brie...

Normal aging in the rhesus monkey is characterized by subtle sublethal changes that affect cell function and lead to cognitive impairments even though neurons are not lost. One sublethal change that correlates with cognitive decline is damaged myelin which can lead to action potential failure, decreased trophic factor support, loss of axons and synapses, and ultimately to cognitive decline but the cause of this damage is unknown. Hyaluronic acid (HA) has been shown to interfere with remyelination in various disease models by inhibiting differentiation of oligodendroglia precursor cells. HA has also been shown to increase in the prefrontal cortex of aged rhesus monkeys. We hypothesize that age‐related increases in HA contribute to myelin deterioration by interfering with myelin repair mechanisms. Tissue from behaviorally characterized young and old monkeys is being processed to quantitatively co‐localize HA (HA binding protein histochemistry) with damaged myelin (encephalitogenic peptide antibody) in white matter tracts critical to cognitive functions including learning and memory and executive function. This histological data will be compared with subjects’ cognitive impairment measures to identify the age of onset of significant changes for specific white matter tracts. (Supported by R01AG021133 and P01AG000001)