Epigenetic upregulation of carotid body angiotensin signaling increases blood pressure.

Epigenetic changes can be shaped by a wide array of environmental cues as well as maternal health and behaviors. One of the most detrimental behaviors to the developing fetus is nicotine exposure. Perinatal nicotine exposure remains a significant risk factor for cardiovascular health and in particular, hypertension. Increased basal carotid body activity and excitation are significant contributors to hypertension. This study investigated the epigenetic changes to carotid body activity induced by perinatal nicotine exposure resulting in carotid body-mediated hypertension. Using a rodent model of perinatal nicotine exposure, we show that angiotensin II type 1 receptor signaling is upregulated in the carotid bodies of nicotine-exposed offspring. These changes were attributed to an upregulation of genetic promotion as DNA methylation of AT1r and PKC occurred within intron regions, exemplifying an upregulation of genetic transcription for these genes. Nicotine increased angiotensin signaling in vitro . Carotid body reactivity to angiotensin was increased in perinatal nicotine-exposed offspring compared to control offspring. Further, carotid body denervation reduced arterial pressure as a result of suppressed efferent sympathetic activity in perinatal nicotine-exposed offspring. Our data demonstrate that perinatal nicotine exposure adversely affects carotid body afferent sensing, which augments efferent sympathetic activity to increase vasoconstrictor signaling and induce hypertension. Targeting angiotensin signaling in the carotid bodies may provide a way to alleviate hypertension acquired by adverse maternal uterine environments in general and perinatal nicotine exposure in particular.

The neural correlates of value representation: From single items to bundles.

One of the core questions in Neuro-economics is to determine where value is represented. To date, most studies have focused on simple options and identified the ventromedial prefrontal cortex (VMPFC) as the common value region. We report the findings of an fMRI study in which we asked participants to make pairwise comparisons involving options of varying complexity: single items (Control condition), bundles made of the same two single items (Scaling condition) and bundles made of two different single items (Bundling condition). We construct a measure of choice consistency to capture how coherent the choices of a participant are with one another. We also record brain activity while participants make these choices. We find that a common core of regions involving the left VMPFC, the left dorsolateral prefrontal cortex (DLPFC), regions associated with complex visual processing and the left cerebellum track value across all conditions. Also, regions in the DLPFC, the ventrolateral prefrontal cortex (VLPFC) and the cerebellum are differentially recruited across conditions. Last, variations in activity in VMPFC and DLPFC value-tracking regions are associated with variations in choice consistency. This suggests that value based decision-making recruits a core set of regions as well as specific regions based on task demands. Further, correlations between consistency and the magnitude of signal change with lateral portions of the PFC suggest the possibility that activity in these regions may play a causal role in decision quality.

Neuroanatomical and neurophysiological evidence of pulmonary nociceptor and carotid chemoreceptor convergence in the nucleus tractus solitarius and nucleus ambiguus.

Pulmonary vagal nociceptors defend the airways. Cardiopulmonary vagal nociceptors synapse in the nucleus tractus solitarius (NTS). Evidence has demonstrated the convergence of cardiopulmonary nociceptors with afferents from carotid chemoreceptors. Whether sensory convergence occurs in motor nuclei and how sensory convergence affects reflexive efferent motor output directed toward the airways are critical knowledge gaps. Here, we show that distinct tracer injection into the pulmonary nociceptors and carotid chemoreceptors leads to co-labeled neurons in the nucleus tractus solitarius and nucleus ambiguus. Precise simultaneous stimulation delivered to pulmonary nociceptors and carotid chemoreceptors doubled efferent vagal output, enhanced phrenic pause, and subsequently augmented phrenic motor activity. These results suggest that multiple afferents are involved in protecting the airways and concurrent stimulation enhances airway defensive reflex output.NEW & NOTEWORTHY Sensory afferents have been shown to converge onto nucleus tractus solitarius primary neurons. Here, we show sensory convergence of two distinct sets of sensory afferents in motor nuclei of the nucleus ambiguus, which results in augmentation of airway defense motor output.

Heterogeneous incidence and propagation of spreading depolarizations.

Spreading depolarizations are implicated in a diverse set of neurologic diseases. They are unusual forms of nervous system activity in that they propagate very slowly and approximately concentrically, apparently not respecting the anatomic, synaptic, functional, or vascular architecture of the brain. However, there is evidence that spreading depolarizations are not truly concentric, isotropic, or homogeneous, either in space or in time. Here we present evidence from KCl-induced spreading depolarizations, in mouse and rat, in vivo and in vitro, showing the great variability that these depolarizations can exhibit. This variability can help inform the mechanistic understanding of spreading depolarizations, and it has implications for their phenomenology in neurologic disease.

The impact of precommitment on risk-taking while gambling: A preliminary study.

Background and aims Precommitment refers to the ability to prospectively restrict the access to temptations. This study examined whether risk-taking during gambling is decreased when an individual has the opportunity to precommit to his forthcoming bet. Methods Sixty individuals participated in a gambling task that consisted of direct choice (simply chose one monetary option among four available ones, ranging from low-risk to high-risk options) or precommitment trials (before choosing an amount, participants had the opportunity to make a binding choice that made high-risk options unavailable). Results We found that participants utilized the precommitment option, such that risk-taking was decreased on precommitment trials compared to direct choices. Within the precommitment trials, there was no significant difference in risk-taking following decisions to restrict versus non-restrict. Discussion These findings suggest that the opportunity to precommit may be sufficient to reduce the attractiveness of risk. Conclusions Present results might be exploited to create interventions aiming at enhancing one's ability to anticipate self-control failures while gambling.

δ-Opioid receptor agonists inhibit migraine-related hyperalgesia, aversive state and cortical spreading depression in mice.

BACKGROUND AND PURPOSE: Migraine is an extraordinarily common brain disorder for which treatment options continue to be limited. Agonists that activate the δ-opioid receptor may be promising for the treatment of migraine as they are highly effective for the treatment of chronic rather than acute pain, do not induce hyperalgesia, have low abuse potential and have anxiolytic and antidepressant properties. The aim of this study was to investigate the therapeutic potential of δ-opioid receptor agonists for migraine by characterizing their effects in mouse migraine models. EXPERIMENTAL APPROACH: Mechanical hypersensitivity was assessed in mice treated with acute and chronic doses of nitroglycerin (NTG), a known human migraine trigger. Conditioned place aversion to NTG was also measured as a model of migraine-associated negative affect. In addition, we assessed evoked cortical spreading depression (CSD), an established model of migraine aura, in a thinned skull preparation. KEY RESULTS: NTG evoked acute and chronic mechanical and thermal hyperalgesia in mice, as well as conditioned place aversion. Three different δ-opioid receptor agonists, SNC80, ARM390 and JNJ20788560, significantly reduced NTG-evoked hyperalgesia. SNC80 also abolished NTG-induced conditioned place aversion, suggesting that δ-opioid receptor activation may also alleviate the negative emotional state associated with migraine. We also found that SNC80 significantly attenuated CSD, a model that is considered predictive of migraine preventive therapies. CONCLUSIONS AND IMPLICATIONS: These data show that δ-opioid receptor agonists modulate multiple basic mechanisms associated with migraine, indicating that δ-opioid receptors are a promising therapeutic target for this disorder.

Casein kinase iδ mutations in familial migraine and advanced sleep phase.

Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Iδ (CKIδ), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIδ, where they caused reduced enzyme activity. Mice engineered to carry the CKIδ-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIδ-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIδ-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIδ activity can contribute to the pathogenesis of migraine.