Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal ...activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP-TRPV1). Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase-Cre mice, which express Cre in glucose-sensing neurons. Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types.
Few novel or emerging infectious diseases have posed such vital ethical challenges so quickly and dramatically as the novel coronavirus SARS‐CoV‐2. The World Health Organization declared a public ...health emergency of international concern and recently classified Covid‐19 as a worldwide pandemic. As of this writing, the epidemic has not yet peaked in the United States, but community transmission is widespread. President Trump declared a national emergency as fifty governors declared state emergencies. In the coming weeks, hospitals will become overrun, stretched to their capacities. When the health system becomes stretched beyond capacity, how can we ethically allocate scarce health goods and services? How can we ensure that marginalized populations can access the care they need? What ethical duties do we owe to vulnerable people separated from their families and communities? And how do we ethically and legally balance public health with civil liberties?
Means for temporally regulating gene expression and cellular activity are invaluable for elucidating underlying physiological processes and would have therapeutic implications. Here we report the ...development of a genetically encoded system for remote regulation of gene expression by low-frequency radio waves (RFs) or a magnetic field. Iron oxide nanoparticles are synthesized intracellularly as a GFP-tagged ferritin heavy and light chain fusion. The ferritin nanoparticles associate with a camelid anti-GFP-transient receptor potential vanilloid 1 fusion protein, αGFP-TRPV1, and can transduce noninvasive RF or magnetic fields into channel activation, also showing that TRPV1 can transduce a mechanical stimulus. This, in turn, initiates calcium-dependent transgene expression. In mice with stem cell or viral expression of these genetically encoded components, remote stimulation of insulin transgene expression with RF or a magnet lowers blood glucose. This robust, repeatable method for remote regulation in vivo may ultimately have applications in basic science, technology and therapeutics.
Individuals with ADHD are characterized as ubiquitously slower and more variable than their unaffected peers, and increased reaction time (RT) variability is considered by many to reflect an ...etiologically important characteristic of ADHD. The present review critically evaluates these claims through meta-analysis of 319 studies of RT variability in children, adolescents, and adults with ADHD relative to typically developing (TD) groups, clinical control groups, and themselves (subtype comparisons, treatment and motivation effects). Random effects models corrected for measurement unreliability and publication bias revealed that children/adolescents (Hedges' g=0.76) and adults (g=0.46) with ADHD demonstrated greater RT variability relative to TD groups. This increased variability was attenuated by psychostimulant treatment (g=−0.74), but unaffected by non-stimulant medical and psychosocial interventions. Individuals with ADHD did not evince slower processing speed (mean RT) after accounting for RT variability, whereas large magnitude RT variability deficits remained after accounting for mean RT. Adolescents and adults with ADHD were indistinguishable from clinical control groups, and children with ADHD were only minimally more variable than clinical control children (g=0.25). Collectively, results of the meta-analysis indicate that RT variability reflects a stable feature of ADHD and other clinical disorders that is robust to systematic differences across studies.
•Children & adults with ADHD exhibit increased RT variability (RTV) relative to nonclinical groups.•This RTV was attenuated by stimulants, but unaffected by psychosocial & other medical treatments.•Individuals with ADHD did not evince slower processing speed (mean RT) after accounting for RTV.•Comparison with clinical control groups reveals that RT variability is not specific to ADHD.•RTV is a stable feature of ADHD & other clinical disorders observed across diverse tasks and methods.
Medical applications of nanotechnology typically focus on drug delivery and biosensors. Here, we combine nanotechnology and bioengineering to demonstrate that nanoparticles can be used to remotely ...regulate protein production in vivo. We decorated a modified temperature-sensitive channel, TRPV1, with antibody-coated iron oxide nanoparticles that are heated in a low-frequency magnetic field. When local temperature rises, TRPV1 gates calcium to stimulate synthesis and release of bioengineered insulin driven by a Ca²⁺-sensitive promoter. Studying tumor xenografts expressing the bioengineered insulin gene, we show that exposure to radio waves stimulates insulin release from the tumors and lowers blood glucose in mice. We further show that cells can be engineered to synthesize genetically encoded ferritin nanoparticles and inducibly release insulin. These approaches provide a platform for using nanotechnology to activate cells.
Associative learning of food cues that link location in space to food availability guides feeding behavior in mammals. However, the function of specific neurons that are elements of the higher-order, ...cognitive circuitry controlling feeding behavior is largely unexplored. Here, we report that hippocampal dopamine 2 receptor (hD2R) neurons are specifically activated by food and that both acute and chronic modulation of their activity reduces food intake in mice. Upstream projections from the lateral entorhinal cortex (LEC) to the hippocampus activate hD2R cells and can also decrease food intake. Finally, activation of hD2R neurons interferes with the encoding of a spatial memory linking food to a specific location via projections from the hippocampus to the septal area. Altogether these data describe a previously unidentified LEC > hippocampus > septal higher-order circuit that regulates feeding behavior.
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•Hippocampal Dopamine 2 Receptor (hD2R) neurons are activated by food cues•hD2R neurons connect with the entorhinal cortex (LEC) and the septal area (SA)•The LEC-hD2R-SA circuit decreases food intake in mice•hD2R cells activation influences food-place, but not object-place, associations
Azevedo et al. identify a subpopulation of neurons expressing the dopamine receptor 2 (D2R) within the hippocampus that is activated by food. They show that these neurons regulate food intake and the encoding of a food-place memory.
Children with ADHD are characterized frequently as possessing underdeveloped executive functions and sustained attentional abilities, and recent commercial claims suggest that computer-based ...cognitive training can remediate these impairments and provide significant and lasting improvement in their attention, impulse control, social functioning, academic performance, and complex reasoning skills. The present review critically evaluates these claims through meta-analysis of 25 studies of facilitative intervention training (i.e., cognitive training) for children with ADHD. Random effects models corrected for publication bias and sampling error revealed that studies training short-term memory alone resulted in moderate magnitude improvements in short-term memory (d=0.63), whereas training attention did not significantly improve attention and training mixed executive functions did not significantly improve the targeted executive functions (both nonsignificant: 95% confidence intervals include 0.0). Far transfer effects of cognitive training on academic functioning, blinded ratings of behavior (both nonsignificant), and cognitive tests (d=0.14) were nonsignificant or negligible. Unblinded raters (d=0.48) reported significantly larger benefits relative to blinded raters and objective tests (both p<.05), indicating the likelihood of Hawthorne effects. Critical examination of training targets revealed incongruence with empirical evidence regarding the specific executive functions that are (a) most impaired in ADHD, and (b) functionally related to the behavioral and academic outcomes these training programs are intended to ameliorate. Collectively, meta-analytic results indicate that claims regarding the academic, behavioral, and cognitive benefits associated with extant cognitive training programs are unsupported in ADHD. The methodological limitations of the current evidence base, however, leave open the possibility that cognitive training techniques designed to improve empirically documented executive function deficits may benefit children with ADHD.
•Executive function and attention training for ADHD show limited efficacy.•Training short-term memory improves short-term memory moderately.•Training does not improve academic, behavioral, or cognitive functioning in ADHD.•Significant illusory rater effects are evident following cognitive training.
In the landscape of migraine treatment, many unanswered questions remain-particularly, which medications are most effective as acute agents and for which patients? Given the heterogeneity of ...patients, clinicians' practice, and the integration of new agents into migraine care, this is an ambitious question to address.
At the same time, this question is crucial both because proper acute treatment is an important metric of quality of care and such treatments are woefully underused in the general population.
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Associative learning allows animals to adapt their behavior in response to environmental cues. For example, sensory cues associated with food availability can trigger overconsumption even in sated ...animals. However, the neural mechanisms mediating cue-driven non-homeostatic feeding are poorly understood. To study this, we recently developed a behavioral task in which contextual cues increase feeding even in sated mice. Here, we show that an insular cortex to central amygdala circuit is necessary for conditioned overconsumption, but not for homeostatic feeding. This projection is marked by a population of glutamatergic nitric oxide synthase-1 (Nos1)-expressing neurons, which are specifically active during feeding bouts. Finally, we show that activation of insular cortex Nos1 neurons suppresses satiety signals in the central amygdala. The data, thus, indicate that the insular cortex provides top-down control of homeostatic circuits to promote overconsumption in response to learned cues.
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•An insula to central amygdala projection is required for conditioned overconsumption•The insula to central amygdala projection is marked by Nos1•Insular cortex Nos1 neurons are specifically active during food consumption bouts•Activation of insula Nos1 neurons suppresses activation of central amygdala Pkcδ neurons
Feeding is a complex motivated behavior and environmental cues can potentiate Pavlovian feeding responses. Here, Stern et al. explore the neural mechanisms underlying this effect and find a population of nitric oxide synthase-1 neurons in the insular cortex that project to the central amygdala and promote overconsumption.
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