Modulation of synaptic strength through trafficking of AMPA receptors (AMPARs) is a fundamental mechanism underlying synaptic plasticity, learning, and memory. However, the dynamics of AMPAR ...trafficking in vivo and its correlation with learning have not been resolved. Here, we used in vivo two-photon microscopy to visualize surface AMPARs in mouse cortex during the acquisition of a forelimb reaching task. Daily training leads to an increase in AMPAR levels at a subset of spatially clustered dendritic spines in the motor cortex. Surprisingly, we also observed increases in spine AMPAR levels in the visual cortex. There, synaptic potentiation depends on the availability of visual input during motor training, and optogenetic inhibition of visual cortex activity impairs task performance. These results indicate that motor learning induces widespread cortical synaptic potentiation by increasing the net trafficking of AMPARs into spines, including in non-motor brain regions.
•In vivo imaging of AMPA receptors reveals high dynamics at individual synapses•Motor learning induces potentiation of a clustered subset of dendritic spines•Motor learning increases AMPA receptor levels in motor and visual cortex•Plasticity of visual cortex during learning depends on visual input
Through in vivo imaging of synaptic AMPA receptors in mice, Roth et al. show that motor learning potentiates synapses in both motor and visual cortex. Recruitment and potentiation of the visual cortex require visual stimuli during motor training.
Schizophrenia is characterized by affective, cognitive, neuromorphological, and molecular abnormalities that may have a neurodevelopmental origin. MicroRNAs (miRNAs) are small noncoding RNA sequences ...critical to neurodevelopment and adult neuronal processes by coordinating the activity of multiple genes within biological networks. We examined the expression of 854 miRNAs in prefrontal cortical tissue from 100 control, schizophrenic, and bipolar subjects. The cyclic AMP-responsive element binding- and NMDA-regulated microRNA miR-132 was significantly down-regulated in both the schizophrenic discovery cohort and a second, independent set of schizophrenic subjects. Analysis of miR-132 target gene expression in schizophrenia gene-expression microarrays identified 26 genes upregulated in schizophrenia subjects. Consistent with NMDA-mediated hypofunction observed in schizophrenic subjects, administration of an NMDA antagonist to adult mice results in miR-132 down-regulation in the prefrontal cortex. Furthermore, miR-132 expression in the murine prefrontal cortex exhibits significant developmental regulation and overlaps with critical neurodevelopmental processes during adolescence. Adult prefrontal expression of miR-132 can be down-regulated by pharmacologie inhibition of NMDA receptor signaling during a brief postnatal period. Several key genes, including DNMT3A, GATA2, and DPYSL3, are regulated by miR-132 and exhibited altered expression either during normal neurodevelopment or in tissue from adult schizophrenic subjects. Our data suggest miR-132 dysregulation and subsequent abnormal expression of miR-132 target genes contribute to the neurodevelopmental and neuromorphological pathologies present in schizophrenia.
The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling ...energy metabolism as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding. Here we show that in mice and rats, ghrelin bound to neurons of the VTA, where it triggered increased dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens in a GHSR-dependent manner. Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting. In addition, ghrelin- and GHSR-deficient mice showed attenuated feeding responses to restricted feeding schedules. Taken together, these data suggest that the mesolimbic reward circuitry is targeted by peripheral ghrelin to influence physiological mechanisms related to feeding.
Perceptual learning improves our ability to interpret sensory stimuli present in our environment through experience. Despite its importance, the underlying mechanisms that enable perceptual learning ...in our sensory cortices are still not fully understood. In this study, we used in vivo two-photon imaging to investigate the functional and structural changes induced by visual stimulation in the mouse primary visual cortex (V1). Our results demonstrate that repeated stimulation leads to a refinement of V1 circuitry by decreasing the number of responsive neurons while potentiating their response. At the synaptic level, we observe a reduction in the number of dendritic spines and an overall increase in spine AMPA receptor levels in the same subset of neurons. In addition, visual stimulation induces synaptic potentiation in neighboring spines within individual dendrites. These findings provide insights into the mechanisms of synaptic plasticity underlying information processing in the neocortex.
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•The number of responsive neurons in mouse V1 decreases with repeated visual stimulation•Persistent neurons increase their response amplitude and synchrony•Repeated visual stimulation promotes spine pruning and increases spine AMPA receptor levels•Potentiated spines are found in well-defined clusters within dendrites
Lopez-Ortega et al. describe the changes in neuronal activity and synaptic plasticity induced by perceptual learning in mouse V1. Repeated visual stimulation refines V1 circuitry by reducing the number of responsive neurons and dendritic spines. Persistent neuronal responses increase in amplitude, while AMPAR levels increase in clustered persistent spines.
For >30 years, positron emission tomography (PET) has proven to be a powerful approach for measuring aspects of dopaminergic transmission in the living human brain; this technique has revealed ...important relationships between dopamine D2-like receptors and dimensions of normal behavior, such as human impulsivity, and psychopathology, particularly behavioral addictions. Nevertheless, PET is an indirect estimate that lacks cellular and functional resolution and, in some cases, is not entirely pharmacologically specific. To identify the relationships between PET estimates of D2-like receptor availability and direct in vitro measures of receptor number, affinity, and function, we conducted neuroimaging and behavioral and molecular pharmacological assessments in a group of adult male vervet monkeys. Data gathered from these studies indicate that variation in D2-like receptor PET measurements is related to reversal-learning performance and sensitivity to positive feedback and is associated with in vitro estimates of the density of functional dopamine D2-like receptors. Furthermore, we report that a simple behavioral measure, eyeblink rate, reveals novel and crucial links between neuroimaging assessments and in vitro measures of dopamine D2 receptors.
► The impact of environmental exposure to BPA on CNS development in primates is unknown. ► Pregnant monkeys were exposed each day during the last trimester to low levels of BPA. ► Fetal exposure to ...BPA led to detrimental changes in midbrain dopamine neurons. ► Fetal exposure to BPA led to a loss of spine synapses in hippocampus. ► Human fetal exposure to BPA may have adverse neurological or psychiatric consequences.
Prevalent use of bisphenol-A (BPA) in the manufacture of resins, plastics and paper products has led to frequent exposure of most people to this endocrine disruptor. Some rodent studies have suggested that BPA can exert detrimental effects on brain development. However as rodent models cannot be relied on to predict consequences of human exposure to BPA during development, it is important to investigate the effects of BPA on non-human primate brain development. Previous research suggests that BPA preferentially targets dopamine neurons in ventral mesencephalon and glutamatergic neurons in hippocampus, so the present work examined the susceptibility of these systems to low dose BPA exposure at the fetal and juvenile stages of development in non-human primates. Exposure of pregnant rhesus monkeys to relatively low levels of BPA during the final 2 months of gestation, induced abnormalities in fetal ventral mesencephalon and hippocampus. Specifically, light microscopy revealed a decrease in tyrosine hydroxylase-expressing (dopamine) neurons in the midbrain of BPA-exposed fetuses and electron microscopy identified a reduction in spine synapses in the CA1 region of hippocampus. In contrast, administration of BPA to juvenile vervet monkeys (14–18 months of age) was without effect on these indices, or on dopamine and serotonin concentrations in striatum and prefrontal cortex, or on performance of a cognitive task that tests working memory capacity. These data indicate that BPA exerts an age-dependent detrimental impact on primate brain development, at blood levels within the range measured in humans having only environmental contact with BPA.
Ghrelin targets the hypothalamus to regulate food intake and adiposity. Endogenous ghrelin receptors growth hormone secretagogue receptor (GHSR) are also present in extrahypothalamic sites where they ...promote circuit activity associated with learning and memory, and reward seeking behavior. Here, we show that the substantia nigra pars compacta (SNpc), a brain region where dopamine (DA) cell degeneration leads to Parkinson's disease (PD), expresses GHSR. Ghrelin binds to SNpc cells, electrically activates SNpc DA neurons, increases tyrosine hydroxylase mRNA and increases DA concentration in the dorsal striatum. Exogenous ghrelin administration decreased SNpc DA cell loss and restricted striatal dopamine loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) treatment. Genetic ablation of ghrelin or the ghrelin receptor (GHSR) increased SNpc DA cell loss and lowered striatal dopamine levels after MPTP treatment, an effect that was reversed by selective reactivation of GHSR in catecholaminergic neurons. Ghrelin-induced neuroprotection was dependent on the mitochondrial redox state via uncoupling protein 2 (UCP2)-dependent alterations in mitochondrial respiration, reactive oxygen species production, and biogenesis. Together, our data reveal that peripheral ghrelin plays an important role in the maintenance and protection of normal nigrostriatal dopamine function by activating UCP2-dependent mitochondrial mechanisms. These studies support ghrelin as a novel therapeutic strategy to combat neurodegeneration, loss of appetite and body weight associated with PD. Finally, we discuss the potential implications of these studies on the link between obesity and neurodegeneration.
Regulation of AMPA receptor (AMPAR) expression is central to synaptic plasticity and brain function, but how these changes occur in vivo remains elusive. Here, we developed a method to longitudinally ...monitor the expression of synaptic AMPARs across multiple cortical layers in awake mice using two-photon imaging. We observed that baseline AMPAR expression in individual spines is highly dynamic with more dynamics in primary visual cortex (V1) layer 2/3 (L2/3) neurons than V1 L5 neurons. Visual deprivation through binocular enucleation induces a synapse-specific and depth-dependent change of synaptic AMPARs in V1 L2/3 neurons, wherein deep synapses are potentiated more than superficial synapses. The increase is specific to L2/3 neurons and absent on apical dendrites of L5 neurons, and is dependent on expression of the AMPAR-binding protein GRIP1. Our study demonstrates that specific neuronal connections, across cortical layers and even within individual neurons, respond uniquely to changes in sensory experience.
Vitamin D supplementation may prevent falls in older persons, but evidence is inconsistent, possibly because of dosage differences.
To compare the effects of 4 doses of vitamin D
supplements on ...falls.
2-stage Bayesian, response-adaptive, randomized trial. (ClinicalTrials.gov: NCT02166333).
2 community-based research units.
688 participants, aged 70 years and older, with elevated fall risk and a serum 25-hydroxyvitamin D 25-(OH)D level of 25 to 72.5 nmol/L.
200 (control), 1000, 2000, or 4000 IU of vitamin D
per day. During the dose-finding stage, participants were randomly assigned to 1 of the 4 vitamin D
doses, and the best noncontrol dose for preventing falls was determined. After dose finding, participants previously assigned to receive noncontrol doses received the best dose, and new enrollees were randomly assigned to receive 200 IU/d or the best dose.
Time to first fall or death over 2 years (primary outcome).
During the dose-finding stage, the primary outcome rates were higher for the 2000- and 4000-IU/d doses than for the 1000-IU/d dose, which was selected as the best dose (posterior probability of being best, 0.90). In the confirmatory stage, event rates were not significantly different between participants with experience receiving the best dose (events and observation time limited to the period they were receiving 1000 IU/d;
= 308) and those randomly assigned to receive 200 IU/d (
= 339) (hazard ratio HR, 0.94 95% CI, 0.76 to 1.15;
= 0.54). Analysis of falls with adverse outcomes suggested greater risk in the experience-with-best-dose group versus the 200-IU/d group (serious fall: HR, 1.87 CI, 1.03 to 3.41; fall with hospitalization: HR, 2.48 CI, 1.13 to 5.46).
The control group received 200 IU of vitamin D
per day, not a placebo. Dose finding ended before the prespecified thresholds for dose suspension and dose selection were reached.
In older persons with elevated fall risk and low serum 25-(OH)D levels, vitamin D
supplementation at doses of 1000 IU/d or higher did not prevent falls compared with 200 IU/d. Several analyses raised safety concerns about vitamin D
doses of 1000 IU/d or higher.
National Institute on Aging.
Multidetector computed tomography (CT) is an excellent way to supplement the radiographic evaluation of problematic hip prostheses. Multidetector CT is well suited for assessing periprosthetic bone, ...determining precise acetabular cup position, and evaluating periprosthetic fluid collections or ossified masses. Metal implants pose a number of challenges in the performance and interpretation of CT examinations. However, metal artifacts can be minimized by decreasing the detector collimation and pitch, increasing the kilovolt peak and milliampere-seconds, and using appropriate reconstruction algorithms and section thickness. Image interpretation requires a basic understanding of hip reconstruction and hip implants, as well as use of a systematic method of analysis that incorporates prior radiographic findings and CT findings. Radiologists must be familiar with the normal and abnormal CT appearances of hip prostheses and be able to recognize common complications on CT scans.
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