The Journal of neuroscience : the official journal of the Society for Neuroscience
-
The transient exposure of immature rodents to ethanol during postnatal day 7 (P7), which is comparable with the third trimester in human pregnancy, induces synaptic dysfunctions. However, the molecular mechanisms underlying these dysfunctions are still poorly understood. Although the endocannabinoid system has been shown to be an important modulator of ethanol sensitivity in adult mice, its potential role in synaptic dysfunctions in mice exposed to ethanol during early brain development is not examined. ⋯ CB1R knock-out mice exhibited no ethanol-induced neurodegeneration and inhibition of ERK1/2 phosphorylation. The protective effects of CB1R blockade through pharmacological or genetic deletion resulted in normal adult synaptic plasticity and novel object recognition memory in mice exposed to ethanol at P7. The AEA/CB1R/pERK1/2 signaling pathway may be directly responsible for the synaptic and memory deficits associated with fetal alcohol spectrum disorders.
-
Neural integration converts transient events into sustained neural activity. In the smooth pursuit eye movement system, neural integration is required to convert cerebellar output into the sustained discharge of extraocular motoneurons. We recorded the expression of integration in the time-varying firing rates of cerebellar and brainstem neurons in the monkey during pursuit of step-ramp target motion. ⋯ Neurons in the abducens nucleus discharge homogeneously in relation mainly to eye position, and reflect almost perfect integration of the cerebellar outputs. Average responses of neural populations and the diverse individual responses of large samples of individual neurons are reproduced by a hierarchical neural circuit based on a model suggested the anatomy and physiology of the larval zebrafish brainstem. The model uses a combination of feedforward and feedback connections to support a neural circuit basis for integration in monkeys and other species.
-
Positron emission tomography (PET) with [(18)F]2-fluoro-2-deoxy-D-glucose was used to measure changes in regional brain glucose metabolism (BGluM) in response to optogenetic stimulation (using the excitatory channelrhodopsin-2) of the nucleus accumbens (NAc) in awake rats. We demonstrated not only increases in BGluM that correlated with c-Fos expression in the region of stimulation, but also BGluM increases in the ipsilateral striatum, periaqueductal gray, and somatosensory cortex, and in contralateral amygdala, ventral pallidum, globus pallidus, and hippocampus, as well as decreases in BGluM in regions of the default mode network (retrosplenial cortex and cingulate gyrus) and secondary motor cortex. ⋯ These findings are consistent with optogenetic excitation of the area of stimulation (NAc), as well as with stimulatory and inhibitory effects on downstream regions. They also confirm the utility of PET imaging to monitor connectivity in the awake rodent brain.
-
There is compelling evidence that oligodendrocyte apoptosis, in response to CNS inflammation, contributes significantly to the development of the demyelinating disorder multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Therefore, approaches designed to protect oligodendrocytes would likely have therapeutic value. Activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in response to endoplasmic reticulum (ER) stress increases cell survival under various cytotoxic conditions. ⋯ Importantly, we found that enhanced activation of PERK signaling specifically in oligodendrocytes significantly attenuated EAE disease severity, which was associated with reduced oligodendrocyte apoptosis, demyelination, and axonal degeneration. This effect was not the result of an altered degree of the inflammatory response in EAE mice. Our results provide direct evidence that activation of PERK signaling in oligodendrocytes is cytoprotective, protecting mice against EAE.
-
Neuropathology after traumatic brain injury (TBI) is the result of both the immediate impact injury and secondary injury mechanisms. Unresolved post-traumatic glial activation is a secondary injury mechanism that contributes to a chronic state of neuroinflammation in both animal models of TBI and human head injury patients. We recently demonstrated, using in vitro models, that p38α MAPK signaling in microglia is a key event in promoting cytokine production in response to diverse disease-relevant stressors and subsequent inflammatory neuronal dysfunction. ⋯ The increased cytokine levels in the p38α KO mice could not be accounted for by more infiltration of macrophages or neutrophils, or increased astrogliosis. By 7 d after injury, the cytokine and chemokine levels remained elevated in injured WT mice but not in p38α KO mice. Together, these data suggest that p38α balances the inflammatory response by acutely attenuating the early proinflammatory cytokine surge while perpetuating the chronic microglia activation after TBI.