Minimal hepatic encephalopathy (MHE) is highly prevalent, observed in up to 80% of patients with liver dysfunction. Minimal hepatic encephalopathy is defined as hepatic encephalopathy with cognitive deficits and no grossly evident neurologic abnormalities. Clinical management may be delayed due to the lack of in vivo quantitative methods needed to reveal changes in brain neurobiochemical biomarkers. To gain insight into the development of alcoholic liver disease–induced neurological dysfunction (NDF), a mouse model of late-stage alcoholic liver fibrosis (LALF) was used to investigate changes in neurochemical levels in the thalamus and hippocampus that relate to behavioral changes. Proton magnetic resonance spectroscopy of the brain and behavioral testing were performed to determine neurochemical alterations and their relationships to behavioral changes in LALF. Glutamine levels were higher in both the thalamus and hippocampus of alcohol-treated mice than in controls. Thalamic levels of taurine and creatine were significantly diminished and strongly correlated with alcohol-induced behavioral changes. Chronic long-term alcohol consumption gives rise to advanced liver fibrosis, neurochemical changes in the nuclei, and behavioral changes which may be linked to NDF. Magnetic resonance spectroscopy represents a sensitive and noninvasive measurement of pathological alterations in the brain, which may provide insight into the pathogenesis underlying the development of MHE.

345 Background: Minimal hepatic encephalopathy (MHE) is highly prevalent, observed in up to 80% of patients with liver fibrosis/cirrhosis. MHE is defined as HE with cognitive deficits and no grossly evident neurologic abnormalities, thus brain magnetic resonance imaging (MRI) usually plays no role in diagnosis of MHE. Clinical management is usually delayed due to the lack of in vivo non-invasive quantitative imaging technology needed to reveal changes in brain neurobiochemical biomarkers. Aim: To gain insight into the development of alcoholic liver fibrosis (ALF)-induced MHE, a mouse model of ALF was used to investigate changes in neurochemical levels in the thalamus and hippocampus that relate to behavioral changes. Proton magnetic resonance spectroscopy (MRS) of the brain and behavioral testing were performed to determine neurochemical alterations and their relationships to behavioral changes in ALF. Findings: MRS quantification data demonstrated glutamine levels were higher in both the thalamus and hippocampus of alcohol-treated mice than in controls. Thalamic levels of taurine and creatine were significantly diminished. Open field test identified significant depression in ALF mice compared to controls. Further correlation analysis found strong correlation of alcohol-induced behavioral changes with decreased levels of taurine and creatine in thalamus. In addition, brain MRI identified no anatomic structural damage, but significant neuron degeneration, astrocytosis, and neuroapoptosis in thalamus were found by histopathological, immunohistochemistry, and TUNEL analysis. Lastly, decreased taurine and creatine in livers of ALF mice by HPLC may at least in part contribute to the alteration of thalamic taurine and creatine. In conclusion, chronic long-term alcohol consumption gives rise to ALF, neurochemical changes in the nuclei, and behavioral changes which may be linked to MHE. MRS represents a sensitive and noninvasive measurement of pathological alterations in the brain, which may provide insight into the pathogenesis underlying the development of MHE.

The histidine triad nucleotide binding protein1(HINT1),which belongs to the histidine triad(HIT) enzyme superfamily,exerts its enzymic activities as hydrolase or transferase. Its physiological functions are still unclear. HINT1 protein is expressed in various tissues and plays an important role in transcription and signal transduction. Earlier studies have identified HINT1 as a haplo-insufficient tumor suppressor. Other evidences indicate that HINT1 is involved in a wide variety of physiological processes,some of which are irrelevant with its basic enzymic activities. Investigations recently suggest that HINT1 is closely related to many peripheral and central nervous system diseases,and plays a vital role in some of neuropsychiatric diseases such as inherited peripheral neuropathies,schizophrenia,mood disorder,drug addiction,and Down's syndrome. In this review,the role of HINT1 in above-mentioned neuropsychiatric disorders was summarised,and the research findings of HINT1 in each of the above diseases were summarized and analyzed,in order to provide some guidance for further research on this protein.

BACKGROUND:Histidine triad nucleotide-binding protein 1 (HINT1) is regarded as a haplo-insufficient tumor suppressor and is closely associated with diverse neuropsychiatric diseases. Moreover, HINT1 is related to gender-specific acute behavior changes in schizophrenia and in response to nicotine. Stress has a range of molecular effects in emotional disorders, which can cause a reduction in brain-derived neurotrophic factor (BDNF) expression in the hippocampus, resulting in hippocampal atrophy and neuronal cell loss.METHODS:This study examined the role of HINT1 deficiency in anxiety-related and depression-like behaviors and BDNF expression in the hippocampus under chronic immobilization stress, and investigated whether the sex-specific and haplo-insufficient effects exist in emotional-like behaviors under the same condition.RESULTS:In a battery of behavior tests, the results of the control group, not exposed to stress, showed that knockout (KO) and heterozygosity (HT) of Hint1 had anxiolytic-like and antidepression-like effects on the male and female mice. However, both male and female Hint1-KO mice showed elevated anxiety-related and antidepression-like behavior under chronic immobilization stress; moreover, both male and female Hint1-HT mice displayed elevated anxiety-related behavior and increased depression-like behavior under chronic immobilization stress. There were no significant differences in general locomotor activity between Hint1-KO and -HT mice and their wild-type (WT) littermates. Hint1-KO mice under basal and chronic immobilization stress conditions expressed more BDNF in the hippocampus than did Hint1-HT and WT mice; overall, there were no significant sex differences in emotional-like behaviors of Hint1-KO and -HT mice. Additionally, Hint1-HT mice showed haplo-insufficient effects on emotional-like behaviors under basic conditions, rather than under chronic immobilization stress.CONCLUSIONS:Both male and female HINT 1 KO and HT mice had a trend of anxiolytic-like behavior and antidepression-like behavior at control group. However, both male and female HINT1 KO mice showed elevated anxiety-related and antidepression-like behavior under chronic immobilization stress; moreover, both male and female HINT1 HT mice displayed elevated anxiety-related behavior and increased depression-like behavior under chronic immobilization stress.

IntroductionPrevious studies have indicated a possible role of histidine triad nucleotide-binding protein 1 (HINT1) on sustaining the regulatory crosstalk of N-methyl-D-aspartate acid glutamate receptors (NMDARs) and G-protein-coupled receptors (GPCRs) such as the -opioid receptor (MOR). Both receptors are present in the midbrain periaqueductal gray neurons, an area that plays a central role in the supraspinal antinociceptive process.MethodsIn the present study, a battery of pain-related behavioral experiments was applied to Hint1 knockout, heterozygous and wild-type mice. Both the male and female mice were investigated to assess the differences between genders.ResultsHint1-/- mice presented significant shorter latency at 50 degrees C in both male and female in hot plate test while no significant difference was found in tail filck test. In Von Frey hairs test Hint1-/- mice were more sensitive than Hint1+/+ mice, presenting a lower withdrawal threshold and enhanced relative frequency of paw withdrawal. The average flinches and licking time of Hint1-/- mice were more than that of Hint1+/+ mice in formalin test.ConclusionTheabsence of Hint1 gene-enhanced supraspinal nociceptive sensitivity in mice, including thermal, mechanical and inflammatory hyperalgesia. Meanwhile, there was no certain evidence indicating the haploinsufficiency and gender differences of Hint1 gene in pain-related behaviors.

Social isolation (SI) rearing has been demonstrated to induce behavioral abnormalities like anxiety, impulsivity, aggression, and learning and memory deficits which are relevant to core symptoms in patients with some certain neuropsychiatric disorders. But the underlying pathophysiological mechanisms remain unclear. Recent studies have revealed HINT1 has close relation with diverse neuropsychiatric diseases. In this present study, the SI rearing mice exhibited depression-like and aggressive behavior. Besides, HINT1 protein levels decreased in PFC but increased in HIP. Based on the data obtained, we concluded that HINT1 is involved in the behavioral abnormalities induced by social isolation and exerts distinct roles in different encephalic regions.

Histidine triad nucleotide-binding protein 1 (HINT1) is a member of a superfamily of histidine triad proteins named by the conserved nucleotide-binding motif histidine-x-histidine-x-histidine-xx, in which x represents hydrophobic amino acid. HINT1 is implicated in pathological progress of many human diseases including cancer and schizophrenia; however, little is known about the essential role and pathological consequences of HINT1 in cellular physiology and diseases. Therefore, we summarize the structure, distribution, and physiological function of HINT1 in cells and tissues as well as the correlation between HINT1 and human diseases.