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Microglia and astrocytes show limited, acute alterations in morphology and protein expression following a single developmental alcohol exposure.

ABSTRACT: Fetal alcohol spectrum disorders (FASD) are the most common cause of nonheritable, preventable mental disability and are characterized by cognitive, behavioral, and physical impairments. FASD occurs in almost 5% of births in the United States, but despite this prevalence there is no known cure, largely because the biological mechanisms that translate alcohol exposure to neuropathology are not well understood. While the effects of early ethanol exposure on neuronal survival and circuitry have received more attention, glia, the cells most closely tied to initiating and propagating inflammatory events, could be an important target for alcohol in the developing brain. Inflammation is known to alter developmental trajectories, but it has recently been shown that even small changes in both astrocytes and microglia in the absence of full-blown inflammatory signaling can alter brain function long-term. Here, we studied the acute response of astrocytes and microglia to a single exposure to ethanol in development across sexes in a mouse model of human third trimester exposure, in order to understand how these cells may transition from their normal developmental path to a different program that leads to FASD neuropathology. We found that although a single ethanol exposure delivered subcutaneously on postnatal day 4 did not cause large changes in microglial morphology or the expression of AldH1L1 and GFAP in the cortex and hippocampus, subtle effects were observed. These findings suggest that even a single, early ethanol exposure can induce mild acute alterations in glia that could contribute to developmental deficits.

SUBMITTER: Lowery RL

PROVIDER: S-EPMC8349862 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Microglia and astrocytes show limited, acute alterations in morphology and protein expression following a single developmental alcohol exposure.

Lowery Rebecca L RL Cealie MaKenna Y MY Lamantia Cassandra E CE Mendes Monique S MS Drew Paul D PD Majewska Ania K AK

Journal of neuroscience research 20210219 8

Fetal alcohol spectrum disorders (FASD) are the most common cause of nonheritable, preventable mental disability and are characterized by cognitive, behavioral, and physical impairments. FASD occurs in almost 5% of births in the United States, but despite this prevalence there is no known cure, largely because the biological mechanisms that translate alcohol exposure to neuropathology are not well understood. While the effects of early ethanol exposure on neuronal survival and circuitry have rec ...[more]

PMID: 33606320

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Project description:Traumatic brain injury (TBI) is a common phenomenon, accounting for significant cost and adverse health effects. While there is information about focal pathologies following TBI, knowledge of more diffuse processes is lacking, particularly regarding how analgesics affect this pathology. As buprenorphine is the most commonly used analgesic in experimental TBI models, this study investigated the acute effects of the opioid analgesic buprenorphine (Bup-SR-Lab) on diffuse neuronal/glial pathology, neuroinflammation, cell damage, and systemic physiology. We utilized a model of central fluid percussion injury (CFPI) in adult male rats treated with a single subcutaneous bolus of Bup-SR-Lab or saline 15 min post-injury. Microscopic assessments were performed at 1 day post-injury. Cell impermeable dextran was infused intraventricularly prior to sacrifice to assess neuronal membrane disruption. Axonal injury was assessed by investigating labeling of the anterogradely transported amyloid precursor protein. Neuroinflammation was assessed by analyzing Iba-1 + microglial and GFAP + astrocyte histological/morphological features as well as cytokine levels in both regions of interest (ROIs). Myelin pathology was assessed by evaluating the expression of myelin basic protein (MBP) and the propensity of MBP + myelin debris. Acute physiologic data showed no difference between groups except for reduction in weight loss following cFPI in Bup treated animals compared to saline. There were no discernable differences in axonal injury or membrane disruption between treatment groups. Cytokine levels were consistent between Bup and saline treated animals, however, microglia and astrocytes revealed region specific histological changes at 1d following Bup treatment. Myelin integrity and overall MBP expression showed no differences between Bup and saline treated animals, but there were significant regional differences in MBP expression between the cortex and thalamus. These data suggest effects of Bup treatment on weight following CFPI and potential regional specificity of Bup-associated microglial and astrocyte alterations, but very little change in other acute pathology at 1-day post-injury. Overall, this preliminary study indicates that use of Bup-SR-Lab in preclinical work does have effects on acute glial pathology, however, longer term studies will be needed to assess potential effects of Bup treatment on more chronic pathological progressions.

Project description:BackgroundSpinal reactive astrocytes and microglia are known to participate to the initiation and maintenance of neuropathic pain. However, whether reactive astrocytes and microglia in thalamic nuclei that process sensory-discriminative aspects of pain play a role in pain behavior remains poorly investigated. Therefore, the present study evaluated whether the presence of reactive glia (hypertrophy, increased number and upregulation of glial markers) in the ventral posterolateral thalamic nucleus (VPL) correlates with pain symptoms, 14 and 28 days after unilateral L5/L6 spinal nerve ligation (SNL) in rats.MethodsMechanical allodynia and hyperalgesia (von Frey filament stimulation) as well as ambulatory pain (dynamic weight bearing apparatus) were assessed. Levels of nine glial transcripts were determined by quantitative real-time PCR on laser microdissected thalamic nuclei, and levels of proteins were assessed by Western blot. We also studied by immunohistofluorescence the expression of glial markers that label processes (GFAP for astrocytes and iba-1 for microglia) and cell body (S100β for astrocytes and iba-1 for microglia) and quantified the immunostained surface and the number of astrocytes and microglia (conventional counts and optical dissector method of stereological counting).ResultsDifferential, time-dependent responses were observed concerning microglia and astrocytes. Specifically, at day 14, iba-1 immunostained area and number of iba-1 immunopositive cells were decreased in the VPL of SNL as compared to naïve rats. By contrast, at day 28, GFAP-immunostained area was increased in the VPL of SNL as compared to naïve rats while number of GFAP/S100β immunopositive cells remained unchanged. Using quantitative real-time PCR of laser microdissected VPL, we found a sequential increase in mRNA expression of cathepsin S (day 14), fractalkine (day 28), and fractalkine receptor (day 14), three well-known markers of microglial reactivity. Using Western blot, we confirmed an increase in protein expression of fractalkine receptor at day 14.ConclusionsOur results demonstrate a sequential alteration of microglia and astrocytes in the thalamus of animals with lesioned peripheral nerves. Furthermore, our data report unprecedented concomitant molecular signs of microglial activation and morphological signs of microglial decline in the thalamus of these animals.

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Microglia and astrocytes show limited, acute alterations in morphology and protein expression following a single developmental alcohol exposure.

Publications

Microglia and astrocytes show limited, acute alterations in morphology and protein expression following a single developmental alcohol exposure.

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