Adult alcohol drinking and emotional tone are mediated by neutral sphingomyelinase during development in males.

Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior.

Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects.

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone-brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental-physical co-morbidity trias of alcohol abuse-depression/anxiety-bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental-physical co-morbidity trias.

Facial muscle movements encoding pain-a systematic review.

Facial expressions of pain are not undefined grimaces, but they convey specific information about the internal state of the individual in pain. With this systematic review, we aim to answer the question of which facial movements are displayed most consistently during pain. We searched for studies that used the Facial Action Coding System to analyze facial activity during pain in adults, and that report on distinct facial responses (action units [AUs]). Twenty-seven studies using experimental pain and 10 clinical pain studies were included. We synthesized the data by taking into consideration (1) the criteria used to define whether an AU is pain-related; (2) types of pain; and (3) the cognitive status of the individuals. When AUs were selected as being pain-related based on a "pain > baseline" increase, a consistent subset of pain-related AUs emerged across studies: lowering the brows (AU4), cheek raise/lid tightening (AUs6_7), nose wrinkling/raising the upper lip (AUs9_10), and opening of the mouth (AUs25_26_27). This subset was found independently of the cognitive status of the individuals and was stable across clinical and experimental pain with only one variation, namely that eye closure (AU43) occurred more frequently during clinical pain. This subset of pain-related facial responses seems to encode the essential information about pain available in the face. However, given that these pain-related AUs are most often not displayed all at once, but are differently combined, health care professionals should use a more individualized approach, determining which pain-related facial responses an individual combines and aggregates to express pain, instead of erroneously searching for a uniform expression of pain.