Neurobiology of disease
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Neurobiology of disease · Oct 2017
Conditional loss of progranulin in neurons is not sufficient to cause neuronal ceroid lipofuscinosis-like neuropathology in mice.
Progranulin deficiency due to heterozygous null mutations in the GRN gene is a common cause of familial frontotemporal lobar degeneration (FTLD), while homozygous loss-of-function GRN mutations cause neuronal ceroid lipofuscinosis (NCL). Aged progranulin-knockout mice display highly exaggerated lipofuscinosis, microgliosis, and astrogliosis, as well as mild cell loss in specific brain regions. Progranulin is a secreted glycoprotein expressed in both neurons and microglia, but not astrocytes, in the brain. ⋯ Nes-cKO mice aged to 12months did not display any increase in lipofuscin deposition, microgliosis, or astrogliosis in the four brain regions examined, though increases were observed for most of these measures in Grn-null animals. We conclude that neuron-specific loss of progranulin is not sufficient to cause similar neuropathological changes to those seen in constitutive Grn-null animals. Our results suggest that increased lipofuscinosis and gliosis in Grn-null animals are not caused by intrinsic progranulin deficiency in neurons, and that microglia-derived progranulin may be sufficient to maintain neuronal health and homeostasis in the brain.
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Neurobiology of disease · Oct 2017
Blast-related disinhibition and risk seeking in mice and combat Veterans: Potential role for dysfunctional phasic dopamine release.
Mild traumatic brain injury (mTBI) caused by exposure to high explosives has been called the "signature injury" of the wars in Iraq and Afghanistan. There is a wide array of chronic neurological and behavioral symptoms associated with blast-induced mTBI. However, the underlying mechanisms are not well understood. ⋯ In keeping with this, we found that veterans with blast-related mTBI reported greater disinhibition and risk taking on the Frontal Systems Behavior Scale (FrSBe). In addition, in mice we report that blast exposure causes potentiation of evoked phasic dopamine release in the nucleus accumbens. Taken together these findings suggest that blast-induced changes in the dopaminergic system may mediate aspects of the complex array of behavioral dysfunctions reported in blast-exposed veterans.