{"title":"青少年间歇性接触乙醇期间和之后前额叶皮层和磁细胞基底核神经营养素表达的失调","authors":"Brian T. Kipp, Polliana T. Nunes, Lisa M. Savage","doi":"10.1016/j.alcohol.2024.06.001","DOIUrl":null,"url":null,"abstract":"<div><p>A preclinical model of human adolescent binge drinking, adolescent intermittent ethanol exposure (AIE) recreates the heavy binge withdrawal consummatory patterns of adolescents and has identified the loss of basal forebrain cholinergic neurons as a pathological hallmark of this model. Cholinergic neurons of the nucleus basalis magnocellularis (NbM) that innervate the prefrontal cortex (PFC) are particularly vulnerable to alcohol related neurodegeneration. Target derived neurotrophins (nerve growth factor [NGF] and brain-derived neurotrophic factor [BDNF]) regulate cholinergic phenotype expression and survival. Evidence from other disease models implicates the role of immature neurotrophin, or proneurotrophins, activity at neurotrophic receptors in promoting cholinergic degeneration; however, it has yet to be explored in adolescent binge drinking. We sought to characterize the pro- and mature neurotrophin expression, alongside their cognate receptors and cholinergic markers in an AIE model. Male and female Sprague Dawley rats underwent 5 g/kg 20% EtOH or water gavage on two-day-on, two-day-off cycles from post-natal day 25–57. Rats were sacrificed 2 h, 24 h, or 3 weeks following the last gavage, and tissue were collected for protein measurement. Western blot analyses revealed that ethanol intoxication reduced the expression of BDNF and vesicular acetylcholine transporter (vAChT) in the PFC, while NGF was lower in the NbM of AIE treated animals. During acute alcohol withdrawal, proNGF in the PFC was increased while proBDNF decreased, and in the NbM proBDNF increased while NGF decreased. During AIE abstinence, the expression of neurotrophins, their receptors, and vAChT did not differ from controls in the PFC. In contrast, in the NbM the expression of both NGF and choline acetyltransferase (ChAT) were reduced long-term following AIE. Taken together these findings suggest that AIE alters the expression of proneurotrophins and neurotrophins during intoxication and withdrawal that favor prodegenerative mechanisms by increasing the expression of proNGF and proBDNF, while also reducing NGF and BDNF.</p></div>","PeriodicalId":7712,"journal":{"name":"Alcohol","volume":null,"pages":null},"PeriodicalIF":2.5000,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Dysregulation of neurotrophin expression in prefrontal cortex and nucleus basalis magnocellularis during and after adolescent intermittent ethanol exposure\",\"authors\":\"Brian T. Kipp, Polliana T. Nunes, Lisa M. Savage\",\"doi\":\"10.1016/j.alcohol.2024.06.001\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>A preclinical model of human adolescent binge drinking, adolescent intermittent ethanol exposure (AIE) recreates the heavy binge withdrawal consummatory patterns of adolescents and has identified the loss of basal forebrain cholinergic neurons as a pathological hallmark of this model. Cholinergic neurons of the nucleus basalis magnocellularis (NbM) that innervate the prefrontal cortex (PFC) are particularly vulnerable to alcohol related neurodegeneration. Target derived neurotrophins (nerve growth factor [NGF] and brain-derived neurotrophic factor [BDNF]) regulate cholinergic phenotype expression and survival. Evidence from other disease models implicates the role of immature neurotrophin, or proneurotrophins, activity at neurotrophic receptors in promoting cholinergic degeneration; however, it has yet to be explored in adolescent binge drinking. We sought to characterize the pro- and mature neurotrophin expression, alongside their cognate receptors and cholinergic markers in an AIE model. Male and female Sprague Dawley rats underwent 5 g/kg 20% EtOH or water gavage on two-day-on, two-day-off cycles from post-natal day 25–57. Rats were sacrificed 2 h, 24 h, or 3 weeks following the last gavage, and tissue were collected for protein measurement. Western blot analyses revealed that ethanol intoxication reduced the expression of BDNF and vesicular acetylcholine transporter (vAChT) in the PFC, while NGF was lower in the NbM of AIE treated animals. During acute alcohol withdrawal, proNGF in the PFC was increased while proBDNF decreased, and in the NbM proBDNF increased while NGF decreased. During AIE abstinence, the expression of neurotrophins, their receptors, and vAChT did not differ from controls in the PFC. In contrast, in the NbM the expression of both NGF and choline acetyltransferase (ChAT) were reduced long-term following AIE. Taken together these findings suggest that AIE alters the expression of proneurotrophins and neurotrophins during intoxication and withdrawal that favor prodegenerative mechanisms by increasing the expression of proNGF and proBDNF, while also reducing NGF and BDNF.</p></div>\",\"PeriodicalId\":7712,\"journal\":{\"name\":\"Alcohol\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-06-17\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Alcohol\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0741832924000776\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alcohol","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0741832924000776","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Dysregulation of neurotrophin expression in prefrontal cortex and nucleus basalis magnocellularis during and after adolescent intermittent ethanol exposure
A preclinical model of human adolescent binge drinking, adolescent intermittent ethanol exposure (AIE) recreates the heavy binge withdrawal consummatory patterns of adolescents and has identified the loss of basal forebrain cholinergic neurons as a pathological hallmark of this model. Cholinergic neurons of the nucleus basalis magnocellularis (NbM) that innervate the prefrontal cortex (PFC) are particularly vulnerable to alcohol related neurodegeneration. Target derived neurotrophins (nerve growth factor [NGF] and brain-derived neurotrophic factor [BDNF]) regulate cholinergic phenotype expression and survival. Evidence from other disease models implicates the role of immature neurotrophin, or proneurotrophins, activity at neurotrophic receptors in promoting cholinergic degeneration; however, it has yet to be explored in adolescent binge drinking. We sought to characterize the pro- and mature neurotrophin expression, alongside their cognate receptors and cholinergic markers in an AIE model. Male and female Sprague Dawley rats underwent 5 g/kg 20% EtOH or water gavage on two-day-on, two-day-off cycles from post-natal day 25–57. Rats were sacrificed 2 h, 24 h, or 3 weeks following the last gavage, and tissue were collected for protein measurement. Western blot analyses revealed that ethanol intoxication reduced the expression of BDNF and vesicular acetylcholine transporter (vAChT) in the PFC, while NGF was lower in the NbM of AIE treated animals. During acute alcohol withdrawal, proNGF in the PFC was increased while proBDNF decreased, and in the NbM proBDNF increased while NGF decreased. During AIE abstinence, the expression of neurotrophins, their receptors, and vAChT did not differ from controls in the PFC. In contrast, in the NbM the expression of both NGF and choline acetyltransferase (ChAT) were reduced long-term following AIE. Taken together these findings suggest that AIE alters the expression of proneurotrophins and neurotrophins during intoxication and withdrawal that favor prodegenerative mechanisms by increasing the expression of proNGF and proBDNF, while also reducing NGF and BDNF.
期刊介绍:
Alcohol is an international, peer-reviewed journal that is devoted to publishing multi-disciplinary biomedical research on all aspects of the actions or effects of alcohol on the nervous system or on other organ systems. Emphasis is given to studies into the causes and consequences of alcohol abuse and alcoholism, and biomedical aspects of diagnosis, etiology, treatment or prevention of alcohol-related health effects.
Intended for both research scientists and practicing clinicians, the journal publishes original research on the neurobiological, neurobehavioral, and pathophysiological processes associated with alcohol drinking, alcohol abuse, alcohol-seeking behavior, tolerance, dependence, withdrawal, protracted abstinence, and relapse. In addition, the journal reports studies on the effects alcohol on brain mechanisms of neuroplasticity over the life span, biological factors associated with adolescent alcohol abuse, pharmacotherapeutic strategies in the treatment of alcoholism, biological and biochemical markers of alcohol abuse and alcoholism, pathological effects of uncontrolled drinking, biomedical and molecular factors in the effects on liver, immune system, and other organ systems, and biomedical aspects of fetal alcohol spectrum disorder including mechanisms of damage, diagnosis and early detection, treatment, and prevention. Articles are published from all levels of biomedical inquiry, including the following: molecular and cellular studies of alcohol''s actions in vitro and in vivo; animal model studies of genetic, pharmacological, behavioral, developmental or pathophysiological aspects of alcohol; human studies of genetic, behavioral, cognitive, neuroimaging, or pathological aspects of alcohol drinking; clinical studies of diagnosis (including dual diagnosis), treatment, prevention, and epidemiology. The journal will publish 9 issues per year; the accepted abbreviation for Alcohol for bibliographic citation is Alcohol.