Neuroscience
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The mature neocortex is a unique six-layered mammalian brain region. It is composed of morphologically and functionally distinct subpopulations of primary projection neurons that form complex circuits across the central nervous system. The precisely-timed generation of projection neurons from neural stem cells governs their differentiation, postmitotic specification, and signaling, and is critical for cognitive and sensorimotor ability. ⋯ Indeed, mRNA transcripts undergo many post-transcriptional regulatory steps before the production of functional proteins, which specify neocortical neural stem cells and subpopulations of neocortical neurons. Therefore, particular attention is paid to the differential post-transcriptional regulation of key transcripts by RNA-binding proteins, including splicing, localization, stability, and translation. We also present a transcriptome screen of candidate molecules associated with post-transcriptional mRNA processing that are differentially expressed at key developmental time points across neocortical prenatal neurogenesis.
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Children with autism spectrum disorder (ASD) and age-matched typically-developing (TD) peers were tested on two forms of eyeblink conditioning (EBC), a Pavlovian associative learning paradigm where subjects learn to execute an appropriately-timed eyeblink in response to a previously neutral conditioning stimulus (CS). One version of the task, trace EBC, interposes a stimulus-free interval between the presentation of the CS and the unconditioned stimulus (US), a puff of air to the eye which causes the subjects to blink. In delay EBC, the CS overlaps in time with the delivery of the US, usually with both stimuli terminating simultaneously. ⋯ However, when subsequently tested on delay EBC, subjects with ASD displayed abnormally-timed conditioned eye blinks that began earlier and peaked sooner than those of TD subjects, consistent with previous findings. The results suggest an impaired ability of children with ASD to properly time conditioned eye blinks which appears to be specific to delay EBC. We suggest that this deficit may reflect a dysfunction of the cerebellar cortex in which increases in the intensity or duration of sensory input can temporarily disrupt the accuracy of motor timing over short temporal intervals.
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The neuregulin 1 gene has repeatedly been identified as a susceptibility gene for schizophrenia, thus mice with genetic mutations in this gene offer a valuable tool for studying the role of neuregulin 1 in schizophrenia-related neurotransmission. In this study, slide-based receptor autoradiography was used to quantify glutamatergic N-methyl-d-aspartate (NMDA), dopaminergic D2, cannabinoid CB1 and acetylcholine M1/4 receptor levels in the brains of male heterozygous transmembrane domain neuregulin 1 mutant (Nrg1(+/-)) mice at two ages. Mutant mice expressed small but significant increases in NMDA receptor levels in the cingulate cortex (7%, p=0.044), sensory cortex (8%, p=0.024), and motor cortex (8%, p=0.047), effects that were independent of age. ⋯ While there was a borderline significant increase (6%, p=0.058) in cannabinoid CB1 receptor levels in the substantia nigra of Nrg1(+/-) mice compared to controls, CB1 as well as acetylcholine M1/4 receptors showed no change in Nrg1(+/-) mice in any other brain region examined. These data indicate that a Nrg1 transmembrane mutation produces selective imbalances in glutamatergic and dopaminergic neurotransmission, which are two key systems believed to contribute to schizophrenia pathogenesis. While the effects on these systems are subtle, they may underlie the susceptibility of these mutants to further impacts.
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The transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) are a family of auxiliary AMPA receptor subunits that differentially modulate trafficking and many functional properties of the receptor. To investigate which TARP isoforms may be involved in AMPA receptor-mediated spinal synaptic transmission, we have mapped the localization of five of the known TARP isoforms, namely γ-2 (also known as stargazin), γ-3, γ-4, γ-7 and γ-8, in the rat spinal cord. Immunoblotting showed expression of all isoforms in the spinal cord to varying degrees. ⋯ Synaptic immunogold labeling of γ-2 was sparse throughout the dorsal horn, with some primary afferent synapses weakly labeled, whereas relatively strong γ-7 immunogold labeling was found at deep dorsal horn synapses, including at synapses formed by low-threshold mechanosensitive primary afferent terminals. Prominent immunogold labeling of γ-8 was frequently detected at synapses established by primary afferent fibers. The spinal localization patterns of TARP isoforms reported here suggest that AMPA receptors at spinal synaptic populations and in glial cells may exhibit different functional characteristics owing to differences in auxiliary subunit composition.
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Pain encompasses both a sensory as well as an affective dimension and these are differentially processed in the cortex. Animal models typically use reflexive behaviors to test nociceptive responses; these are thought to reflect the sensory dimension of pain. While several behavioral tests are available for examining the affective dimension of pain it is unclear if these are appropriate in animal models of muscle pain. ⋯ When both muscles were inflamed, escape-avoidance behaviors did not develop suggesting that equivalent bilateral pain behaviors cannot be tested with an escape-avoidance test. In the non-inflammatory muscle pain model mice did not show significant changes in escape-avoidance behaviors or learned avoidance, but did avoid physical activity. In the exercise-enhanced pain model, there were no changes in escape-avoidance, learned avoidance of noxious or physical activity In conclusion, we developed several testing protocols that assess supraspinal processing of pain behaviors in models of muscle pain and that are most sensitive in animals with unilateral hyperalgesia.