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Our results suggest that SMPD3 is associated with behavioural outcomes including alcohol consumption, as well as with anxiety and depressive symptoms Table S3. Based on the previously identified role of osteoblast SMPD3 expression in bone mineralisation [ 11 , 12 , 13 ], we determined the relationship between SMPD3 and bone density.
We conducted a univariate analysis between each haplotype phase and total bone mineral density BMD of the left and right femurs. Our findings in mice with reduced NSM function see below suggested a selectively altered development of the dorsal hippocampus DH and insular cortex IC. Thus, we investigated this relationship in human participants. These findings suggest a strong link between the natural variance in the SMPD3 gene with alcohol abuse, emotional behaviour and bone density.
Part of this association may be explained by the developmental effects of NSM on DH maturation in humans. A key behaviour of alcohol addiction is the consumption of easily available alcohol. We confirmed a role of NSM in voluntary alcohol consumption in a mouse model. In order to evaluate the effects of a reduced, but not absent NSM function, we tested heterozygous NSM-2 knock out mice fro [ 11 ] in a two-bottle free-choice alcohol consumption test [ 14 , 15 ].
Thereby, fro mice showed a reduced consumption and preference of alcohol compared to wild type WT controls Figs. There was no effect of NSM on total fluid intake Fig. Reduced NSM activity had no effect on preference of sweet tasting solution or avoidance of bitter tasting solution in the mice Fig. Neither did NSM affect alcohol bioavailability after drinking Fig.
We did not find a role of NSM in the sedating effects of alcohol as measured by the loss of the righting reflex latency Fig. In order to test whether the NSM role is an acute effect or depends on developmental function, as it would be the case in a natural mutation of the Smpd3 gene, we tested the effects of an acute pharmacological inhibition of NSM activity on alcohol drinking.
In a separate test, ES attenuated previously established voluntary alcohol consumption in an intermittent access 20 vol. These findings suggest that attenuated NSM activity reduces voluntary alcohol consumption.
A major driver of alcohol addiction is drug-seeking behaviour. This is based on the establishment and retrieval of the conditioned reinforcing effects of alcohol. We tested this in the establishment of an alcohol-induced conditioned place preference CPP in fro mice [ 17 ]. Neither did these treatments affect locomotor activity Figs. Altogether, these findings indicate that NSM is neither required for the establishment nor the retrieval of the conditioned reinforcing effects of alcohol, but is required for acute alcohol-induced locomotor stimulation.
Our human genetic study suggested an association of natural variability in SMPD3 and emotionality. We tested in mice how NSM would affect the depression- and anxiety-like phenotype of mice [ 18 , 19 ]. We found a significant reduction of depression-like behaviour in fro mice in the novelty supressed feeding NSF; Fig.
Anxiety-like behaviour was significantly reduced in the elevated plus maze EPM; Fig. A reduction of NSM activity had little effects on general locomotor activity of mice in all tests Figs. S10 — These data suggest that reduced NSM activity attenuates depression-like and anxiety-like behaviour in adults as a developmentally mediated effect.
Mice with a heterozygous NSM-2 knock out fro show reduced depression-like and anxiety-like behaviour, but preserved hedonic tone compared to wild type WT controls. Significant differences are displayed as 3D-networks within a transparent brain surface right at the respective 3D positions of the centre of gravity of each brain structure.
Colour-coded nodes represent one out of single brain regions orphan nodes are not shown. In order to identify a neuronal mechanism for the beneficial effects of a developmental NSM attenuation, a resting state fMRI analysis of the adult brain connectome was performed.
It showed largely enhanced functional connectivity of the somatosensory-, motor-, and association cortices and the amygdala in the NSM deficient compared to WT mice Fig. Based on the human association of SMPD3 with bone mineralisation, we tested how reduced NSM activity would affect bone density using bone-computed tomography CT in a mouse model.
Chronic free-choice alcohol consumption had no effect on bone density, and no interactions of NSM activity and alcohol effects were observed. These findings suggest that a heterozygous NSM depletion is not sufficient to induce obvious bone deficits in mice.
Since NSM was reported to be of crucial importance for bone mineralisation [ 11 ], we tested whether a developmental NSM deficit might trigger compensatory responses that maintain bone integrity [ 20 ]. We measured blood osteocalcin total levels. Carboxylated osteocalcin is an inductor of bone mineralisation by osteoblasts. Predominantly decarboxylated osteocalcin is released from osteoblasts.
Once released to the blood, osteocalcin reaches receptors in peripheral organs. It may also cross the blood—brain barrier and reach the brain [ 21 ], where it can improve cognitive performance [ 22 ]. Here, we found that fro mice show an up-regulation of blood total osteocalcin levels Fig. Besides rescuing bone development, this may suggest osteocalcin effects on behavioural control. OST limits alcohol consumption and has beneficial effects on emotional behaviour.
S15 — Next, we tested whether NSM mediates the interaction between the comorbid symptoms. We asked how NSM controls the effects of voluntary alcohol drinking on emotional state. We allowed fro and WT mice to voluntarily self-titrate their alcohol consumption for 6 weeks and tested the emotional state compared to mice that only drank water at all times.
While voluntary alcohol drinking had little effects on emotional behaviour in WT mice, it enhanced depression-like and anxiety-like behaviour in fro mice in the NSF Fig. S20 — These findings suggest that while reduced NSM activity causes a less depressed and less anxious emotional phenotype and elicits less alcohol drinking, it renders mice more susceptible to long-term negative emotional effects of alcohol.
Altogether, these findings suggest that NSM controls the way in which alcohol drinking affects the emotional phenotype. Voluntary alcohol drinking reduced DH size in fro mice to WT levels mice. After observing an NSM control of the self-regulation of emotional state with alcohol, we searched for the neuronal mechanisms that may be responsible for this effect.
We tested gross neuroanatomy of mice after chronic consumption of alcohol or water using magnet resonance imaging MRI [ 14 , 15 ].
We found that the less depressed fro mice showed a significantly enhanced DH volume Fig. No significant changes were seen in the other investigated brain areas Fig. This may explain the improved control of depression and anxiety levels in the fro mice. The chronic alcohol consumption in this schedule had no effect on brain area volume in WT mice Fig. This effect was reversed after alcohol consumption. No effect on catalase activity or lipid peroxidation were observed Fig. These findings identify the DH as a locus where NSM mediates the interaction of alcohol with the emotional phenotype with altered oxidative stress management as a potential mechanism.
To further characterise the effects of NSM on DH structure, we used electron microscopy after chronic alcohol consumption. Alcohol drinking reduced synaptic density Fig. Reduced NSM activity completely prevented the adverse effects of chronic alcohol consumption on synaptic morphology in the DH. These findings are in line with beneficial effect of reduced NSM function alone, but may counteract DH volume loss after chronic alcohol consumption. As the DH is a developmental focus of NSM activity, which is susceptible to self-administration of alcohol and subsequent regulation of emotional state, we tested how NSM controls hippocampal neurogenesis.
In female WT mice, chronic alcohol consumption in a free-choice paradigm had no effect on Nestin neural stem cells and early intermediate progenitor cells; Fig. There was no difference between fro and WT mice when drinking only water, which suggests that a reduction of NSM activity has no effect on hippocampal neurogenesis.
However, reduced NSM activity appeared to protect from negative alcohol effects on neurogenesis and may, thus counteract DH volume loss after chronic alcohol consumption. The pharmacological reinforcing action of alcohol and transition to addiction are under the control of the dopamine DA and serotonin 5-HT systems [ 30 , 31 ].
Previously, a strong interaction of acid sphingomyelinase ASM with brain monoamine tissue level control and dynamic responses was reported. This went along with potentiated DA responses to alcohol in both structures [ 32 ].
Voluntary alcohol drinking reduced ASM hyperactivity, normalised monoamine tissue levels and attenuated the depression [ 19 ]. Here we used in vivo microdialysis to test extracellular monoamine levels and responses to an acute alcohol challenge in mice in previously identified key areas of NSM action.
Acute alcohol administration increased extracellular DA levels. This effect was enhanced in the Nac Fig. The alcohol-induced peak increase in extracellular 5-HT levels in the Nac Fig. While alterations in neurotransmitter levels indicate an NSM control of monoaminergic signalling in reward and reinforcement related brain areas, synaptic throughput also requires receptor and transport mechanisms [ 33 ].
Monoamine receptor conformation and function as well as transporter efficacy crucially depend on sphingolipid membrane domains [ 34 , 35 ]. Therefore, we measured mRNA expression levels of major receptors and transporters involved in dopaminergic and serotonergic signalling in the ventral striatum vStr of mice. In contrast, enhancing sphingomyelinase activity resulted in a significant reduction of 5-HT uptake in synaptosomes of the ventral hippocampus VH and DH, but not in vStr of mice Fig.
Sphingolipids form lipid rafts and signalling platforms at the synapse [ 36 ], which harbour monoamine and other receptor proteins [ 34 , 35 , 37 ].
Thus, we investigated the vStr lipidome after voluntary alcohol or water consumption [ 38 ]. Neither reduced NSM activity nor voluntary alcohol drinking yielded a significant effect on lipid landscape in the vStr Figs.
S23 — Although Nac DA responses to alcohol are enhanced in fro mice, reduced D2 receptor expression may balance NSM control of the incentive properties of alcohol. This may explain why the conditioned reinforcing effects are not altered in mice with reduced NSM activity. Reduced NSM activity led to an increase in blood osteocalcin. In order to test whether the bone—brain signal interacts with alcohol consumption, we tested how increased osteocalcin would modulate alcohol consumption.
We further tested how increased osteocalcin would modulate affective behaviour. As osteocalcin effects emerged largely in the same direction for bone mineralisation protection , alcohol drinking protection , and antidepressive action enhanced , it may also suggest osteocalcin as a potential treatment specifically for this symptom trias in humans Figs.
S28 , Here we discovered a shared genetic basis for this symptom trias. This affects the behavioural phenotypes and endophenotypes of each single disorder as well as some of their interactions. We identified spontaneous genetic variations in the SMPD3 gene, which are related to alcohol abuse, affective behaviour, and bone mineralisation in humans. Furthermore, an SMPD3 haplotype polymorphism was related to hippocampal size in humans.
A functional analysis of NSM activity in genetic and pharmacological mouse models showed that chronic attenuation of NSM activity decreased alcohol consumption. Pharmacological challenge experiments confirmed this role of NSM in alcohol drinking.
Also the sedating properties of alcohol are not under NSM control. Mice with reduced NSM activity showed less depression- and anxiety-like behaviour. NSM is highly expressed in the brain [ 39 , 40 ]. Mice without NSM function in neurons showed a perturbed Golgi secretory pathway, dysproteostasis and impaired learning and memory [ 41 , 42 ]. In the present study, mice with partially reduced NSM function drank less alcohol, possibly because alcohol reduced their affective advantage, i.
This suggests an NSM control of the relationship between alcohol consumption and self-regulation of emotional states as shown in clinical and preclinical studies [ 43 , 44 , 45 ]. The reason why NSM deficient mice still consumed alcohol was most likely the enhanced dopaminergic and preserved serotonin activation, which counteracted the aversive emotional effects. The beneficial affective phenotype coincided with an enhanced DH volume and enhanced neocortex-amygdala resting state connectivity.
The increased DH volume may be supported by the observed enlargement of synaptic structures. NSM has its highest expression in the hippocampus where it is highly active during development. NSM enhances the excitability of hippocampal CA1 neurons [ 46 , 47 ]. Individual differences in NSM activity in this brain region predispose for efficient learning and adaptations in particularly appetitively motivated long-term memory tasks [ 42 , 48 , 49 ].
An enhanced capacity of the DH may serve better stress resistance and reduce depression-like behaviour, and provide resilience during initiation of alcohol use [ 50 ]. This supports the human association of SMPD3 with hippocampal volume. We observed that voluntary alcohol drinking did not only have depressogenic effects, but also reduced DH volume to control level.
A reduction in NSM activity had no major effects on hippocampal neurogenesis. In humans, we found a SMPD3 association with BMD, which expands a previously reported role in bone mineralisation from fragilitas ossium symptom patients to healthy subjects [ 11 ]. We found an up-regulation of osteocalcin, a potential compensatory signal, in the blood of NSM deficient mice. Osteocalcin regulates bone mineralisation [ 53 ].
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