Ethanol's interaction with BK channel α subunit residue K361 does not mediate behavioral responses to alcohol in mice.

Large conductance potassium (BK) channels are among the most sensitive molecular targets of ethanol and genetic variations in the channel-forming α subunit have been nominally associated with alcohol use disorders. However, whether the action of ethanol at BK α influences the motivation to drink alcohol remains to be determined. To address this question, we first tested the effect of systemically administered BK channel modulators on voluntary alcohol consumption in C57BL/6J males. Penitrem A (blocker) exerted dose-dependent effects on moderate alcohol intake, while paxilline (blocker) and BMS-204352 (opener) were ineffective. Because pharmacological manipulations are inherently limited by non-specific effects, we then sought to investigate the behavioral relevance of ethanol's direct interaction with BK α by introducing in the mouse genome a point mutation known to render BK channels insensitive to ethanol while preserving their physiological function. The BK α K361N substitution prevented ethanol from reducing spike threshold in medial habenula neurons. However, it did not alter acute responses to ethanol in vivo, including ataxia, sedation, hypothermia, analgesia, and conditioned place preference. Furthermore, the mutation did not have reproducible effects on alcohol consumption in limited, continuous, or intermittent access home cage two-bottle choice paradigms conducted in both males and females. Notably, in contrast to previous observations made in mice missing BK channel auxiliary ß subunits, the BK α K361N substitution had no significant impact on ethanol intake escalation induced by chronic intermittent alcohol vapor inhalation. It also did not affect the metabolic and locomotor consequences of chronic alcohol exposure. Altogether, these data suggest that the direct interaction of ethanol with BK α does not mediate the alcohol-related phenotypes examined here in mice.

Grapheme-Color Synesthesia in an Abugida: a Bengali Case Study.

Grapheme-color synesthetes experience graphemes (e.g., letters of the alphabet) as having a specific, consistent color. Most studies of grapheme-color synesthesia have only examined synesthetes in English, leaving underexplored the question of how synesthetic phenomenology might differ in languages that do not use alphabets. In particular, grapheme-color synesthesia in an abugida (a segmental writing system in which vowels are added to consonant graphemes using 'accent'-like diacritical marks) has never been studied. Here, we present a case study of a Bengali synesthete, MJ, the first report of a grapheme-color synesthete in an abugida. First, we show that for MJ, diacritics influence the overall color of the consonant grapheme they modify, 'pulling' it toward the color she experiences for the vowel. Second, we describe and analyze the complex synesthetic experiences reported by MJ for conjunct graphemes, a unique orthographic feature of Brahmi-derived scripts (such as Bengali) in which multiple graphemes are visually combined into a single 'merged' grapheme. Finally, we show that in addition to these language-specific features, MJ's synesthetic associations are influenced by some of the same linguistic properties (such as orthography and phonology) that influence synesthetic associations in other languages. We conclude that the idiosyncratic features of MJ's synesthesia reflect unique properties of the Bengali writing system, that more studies of synesthesia in non-alphabetic scripts are needed, and that synesthetic phenomenology can offer insights into how linguistic properties shape grapheme representation in the brain.