Timing along the cardiac cycle modulates neural signals of reward-based learning.

Natural fluctuations in cardiac activity modulate brain activity associated with sensory stimuli, as well as perceptual decisions about low magnitude, near-threshold stimuli. However, little is known about the relationship between fluctuations in heart activity and other internal representations. Here we investigate whether the cardiac cycle relates to learning-related internal representations - absolute and signed prediction errors. We combined machine learning techniques with electroencephalography with both simple, direct indices of task performance and computational model-derived indices of learning. Our results demonstrate that just as people are more sensitive to low magnitude, near-threshold sensory stimuli in certain cardiac phases, so are they more sensitive to low magnitude absolute prediction errors in the same cycles. However, this occurs even when the low magnitude prediction errors are associated with clearly suprathreshold sensory events. In addition, participants exhibiting stronger differences in their prediction error representations between cardiac cycles exhibited higher learning rates and greater task accuracy.

Modulating the Zebrafish Camouflage Response Pathway to Illustrate Neuroendocrine Control Over a Robust and Quantifiable Behavior.

Zebrafish detect the light levels of their surroundings and adjust their coloration in response. By controlling the location of melanosome pigment granules within melanocytes in their dermis, fish can lighten or darken their appearance to blend in with their environment. This camouflage response pathway, which begins in the retina and ends in the melanocyte, involves both neuronal and endocrine signaling. Ultimately, two hormones, α-melanocyte stimulating hormone and melanin concentrating hormone, converge on the melanocyte and cause dispersion or aggregation of melanosomes, respectively; the camouflage behavior can therefore be modulated both environmentally and pharmacologically. Here, we describe a two-part protocol designed for use in an undergraduate laboratory. Students induce the camouflage response by exposing zebrafish larvae to darkness or bright light, in conjunction with pharmacological treatments that alter the ability of the larvae to properly respond to these environmental cues. Students then fix the larvae, take photographs of their samples using their smartphones and dissecting microscopes, and directly measure the camouflage response by quantifying the size of melanocytes using ImageJ software. Finally, students present their data in a single professional-quality figure with an accompanying detailed figure legend. This protocol enables students to gain unique laboratory experiences in which they modulate and quantify a hormone-driven behavior, observable on a cellular level. It can therefore complement course topics in neurobiology, endocrinology, animal physiology, animal behavior, and cell biology classes.

A Novel Peptide Restricts Ethanol Modulation of the BK Channel In Vitro and In Vivo.

Alcohol is a widely used and abused substance. A major unresolved issue in the alcohol research field is determining which of the many alcohol target proteins identified to date is responsible for shaping each specific alcohol-related behavior. The large-conductance, calcium- and voltage-activated potassium channel (BK channel) is a conserved target of ethanol. Genetic manipulation of the highly conserved BKα channel influences alcohol-related behaviors across phylogenetically diverse species that include worm, fly, mouse, and man. A pharmacological tool that prevents alcohol's action at a single target, like the BK channel, would complement genetic approaches in the quest to define the behavioral consequences of alcohol at each target. To identify agents that specifically modulate the action of ethanol at the BK channel, we executed a high-throughput phagemid-display screen in combination with a Caenorhabditis elegans behavioral genetics assay. This screen selected a novel nonapeptide, LS10, which moderated acute ethanol intoxication in a BK channel-humanized C. elegans strain without altering basal behavior. LS10's action in vivo was dependent upon BK channel functional activity. Single-channel electrophysiological recordings in vitro showed that preincubation with a submicromolar concentration of LS10 restricted ethanol-induced changes in human BKα channel gating. In contrast, no substantial changes in basal human BKα channel function were observed after LS10 application. The results obtained with the LS10 peptide provide proof-of-concept evidence that a combined phagemid-display/behavioral genetics screening approach can provide novel tools for understanding the action of alcohol at the BK channel and how this, in turn, exerts influence over central nervous system function.

Small molecule modulators of σ2R/Tmem97 reduce alcohol withdrawal-induced behaviors.

Repeated cycles of intoxication and withdrawal enhance the negative reinforcing properties of alcohol and lead to neuroadaptations that underlie withdrawal symptoms driving alcohol dependence. Pharmacotherapies that target these neuroadaptations may help break the cycle of dependence. The sigma-1 receptor (σ1R) subtype has attracted interest as a possible modulator of the rewarding and reinforcing effects of alcohol. However, whether the sigma-2 receptor, recently cloned and identified as transmembrane protein 97 (σ2R/TMEM97), plays a role in alcohol-related behaviors is currently unknown. Using a Caenorhabditis elegans model, we identified two novel, selective σ2R/Tmem97 modulators that reduce alcohol withdrawal behavior via an ortholog of σ2R/TMEM97. We then show that one of these compounds blunted withdrawal-induced excessive alcohol drinking in a well-established rodent model of alcohol dependence. These discoveries provide the first evidence that σ2R/TMEM97 is involved in alcohol withdrawal behaviors and that this receptor is a potential new target for treating alcohol use disorder.