Naltrexone treatment reverses astrocyte atrophy and immune dysfunction in self-harming macaques

Abstract

The role of glia in the development and treatment of behavioral abnormalities is understudied. Recent reports have observed glial activation in several disorders, including depression, autism spectrum disorders and self-injurious behaviors (SIB). In the current study, we examined SIB in the physiologically and anatomically relevant nonhuman primate (NHP) model. At the Tulane National Primate Research Center (TNPRC), approximately 5% of singly housed macaques develop symptoms of SIB. We have previously demonstrated that naltrexone hydrochloride can be effective in reducing SIB. We have also demonstrated that the astrocytes of animals with SIB are distinctly atrophic and display heightened innate immune activation compared with control animals. We have added a third group of animals (five macaques identified with SIB and treated with oral naltrexone at a dose of 3.2 mg/kg) to the previous cohort (six macaques with a history of SIB but not treated, and nine animals with no history of SIB) for this study. Gray and white matter astrocytes from frontal cortical tissue were examined following necropsy. Innate immune activation of astrocytes, which was increased in SIB animals, was markedly decreased in animals receiving naltrexone, as was atrophy of both grey and white matter astrocytes. This was concomitant with improved behavioral correlates. Preventing astrocyte activation in select areas of the brain to reduce injurious behavior is an innovative concept with implications for mental health studies. Differences in multiple areas of primate brain would help determine how self-injurious behavior develops. These studies suggest a stronger role for astrocytes in the cellular events associated with self-injurious behaviors.

Glial cell morphological and density changes through the lifespan of rhesus macaques

“…Astrocytic activation in adult macaques and subsequent loss of apparent complexity in geriatrics was in line with the typical onset of neurodegenerative diseases, or age-associated depression (Lalo et al, 2014). We have recently shown a connection between reversible astrocyte atrophy and mood disorders in rhesus macaques (Lee et al, 2015; Lee et al, 2013b). …”

The flavivirus dengue induces hypertrophy of white matter astrocytes

“…We have previously demonstrated morphometric changes in astrocyte processes in response to bacterial infection ( Brucella melitensis (Lee et al, 2013a)), Togavirus infection (Inglis et al, 2015) or lentiviral infection (Lee et al, 2014), and aberrant behavior (Lee et al, 2015; Lee et al, 2013b). The hypertrophy observed here in white matter was distinct from any of these, with significantly increased cell bodies and numbers of primary processes.…”

“…As has been described previously (Lee et al, 2015), animals were maintained in Animal Biosafety Level 2 housing with a 12:12-hour light:dark cycle, relative humidity 30% to 70%, and a temperature of 17.8 to 28.9°C, as is routine at Tulane National Primate Research Center. TNPRC is is fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care-International (Animal Welfare Assurance # A4499-01).…”

Neuropathogenesis of Chikungunya infection: astrogliosis and innate immune activation

“…We performed an established protocol for astrocyte morphometric analyses [16,32,17,25,20,19]. All samples were coded and analyzed randomly by a researcher blinded to animal number and condition.…”