大鼠双侧腹侧被盖区头端毁损与抑郁行为的相关性
|
摘要
目的探索大鼠中脑双侧腹侧被盖区头端(anterior ventral tegmental area, aVTA)在抑郁行为发生机制中的作用。方法以6-OHDA损毁aVTA模型大鼠为研究对象,采用行为学方法(旷场实验、强迫游泳实验和蔗糖偏好实验)观察术后大鼠行格数、直立次数、不动时间、蔗糖消耗百分比的变化;以TH阳性神经元计数观察损毁组大鼠双侧aVTA和SNc的DA神经元损毁程度;通过高压液相在线递质测量技术测定大鼠相关脑区DA、5-HT和NA的含量变化,并与假手术组进行比较。结果①损毁组大鼠的穿行格数、直立次数显著降低,不动时间显著延长,蔗糖消耗百分比显著降低,差异均有统计学意义(P值均<0.001);②损毁组大鼠aVTA及SNc的DA能神经元数目显著减少(P值均<0.001);③损毁组大鼠的内侧前额叶皮质(medial prefrontal cortex, mPFC)、纹状体(striatum, STr)、腹侧海马(ventral hippocampus, VHPC)、外侧缰核(lateral habenula, LHb)中5-HT和NA的含量明显下降(P<0.001);STr中DA含量明显下降(P<0.001),而mPFC、LHb、VHPC中的DA含量变化没有统计学差异(P>0.05)。结论大鼠腹侧被盖区头端参与抑郁行为的发生,腹侧被盖区及其相关脑区单胺类神经递质的改变可能是其原因。
Objective To explore the correlation between bilateral anterior ventral tegmental area(aVTA) and depression-like behavior in rats. Methods The subjects in the study were aVTA-lesioned rats which were prepared by microinjecting 6-OHDA into their aVTA nucleus. Four weeks after the operation, all the rats were examined by behavior tests, including open-field test, sucrose preference test, and forced swimming test. We recorded and calculated the number of squares crossed, rearings, sucrose preference, immobility time. Immunohistochemistry method was used to observe the change of TH-positive neurons' number in bilateral aVTA and SNc of the 6-OHDA lesioned rats. Meanwhile, we analyzed and compared the changes of DA, 5-HT, NE levels in themPFC, LHb, STr and VHPC in the two groups of rats by high performance liquid chromatography with electrochemical detection(HPLC-ED). Results ① Bilateral aVTA lesions in the rats significantly decreased the number of squares crossed and rearings and sucrose preference, increased immobility time when compared with the sham-operated rats(P<0.001). ② In the lesioned rats, the aVTA of the bilateral injected side showed partial loss of TH-ir neurons when compared with the sham-operated rats, and the bilateral SNc in aVTA lesioned rats had a coherence of changing trend, showed a certain decrease(P<0.001). ③ Compared with sham-operated rats, bilateral aVTA 6-OHDA lesioned rats' 5-HT levels in the mPFC, STr, LHB and VHPC significantly decreased. Likewise, 6-OHDA lesioned rats' NA levels in the mPFC, striatum, and habenula vHPC significantly decreased, too (P<0.001).However,bilateral aVTA6-OHDA lesioned ratsDA levels only in the striatum showed significantly decreased when compared to the sham-operated rats(P<0.001).Conclusion Bilateral aVTA is involved in depression-like behavior.DA neurons of the VTA and the changes of monoamine neurotransmitters of the limbic and limbic-related areas may be involved in the development of depression.
Objective To explore the correlation between bilateral anterior ventral tegmental area(aVTA) and depression-like behavior in rats. Methods The subjects in the study were aVTA-lesioned rats which were prepared by microinjecting 6-OHDA into their aVTA nucleus. Four weeks after the operation, all the rats were examined by behavior tests, including open-field test, sucrose preference test, and forced swimming test. We recorded and calculated the number of squares crossed, rearings, sucrose preference, immobility time. Immunohistochemistry method was used to observe the change of TH-positive neurons' number in bilateral aVTA and SNc of the 6-OHDA lesioned rats. Meanwhile, we analyzed and compared the changes of DA, 5-HT, NE levels in themPFC, LHb, STr and VHPC in the two groups of rats by high performance liquid chromatography with electrochemical detection(HPLC-ED). Results ① Bilateral aVTA lesions in the rats significantly decreased the number of squares crossed and rearings and sucrose preference, increased immobility time when compared with the sham-operated rats(P<0.001). ② In the lesioned rats, the aVTA of the bilateral injected side showed partial loss of TH-ir neurons when compared with the sham-operated rats, and the bilateral SNc in aVTA lesioned rats had a coherence of changing trend, showed a certain decrease(P<0.001). ③ Compared with sham-operated rats, bilateral aVTA 6-OHDA lesioned rats' 5-HT levels in the mPFC, STr, LHB and VHPC significantly decreased. Likewise, 6-OHDA lesioned rats' NA levels in the mPFC, striatum, and habenula vHPC significantly decreased, too (P<0.001).However,bilateral aVTA6-OHDA lesioned ratsDA levels only in the striatum showed significantly decreased when compared to the sham-operated rats(P<0.001).Conclusion Bilateral aVTA is involved in depression-like behavior.DA neurons of the VTA and the changes of monoamine neurotransmitters of the limbic and limbic-related areas may be involved in the development of depression.
引文
[1] SAMII A,NUTT JG,RANSOM BR.Parkinson's disease[J].Lancet,2004,363(9423):1783-1793.
[2] DAVIDSON RJ,ABERCROMBIE H,NITSCHKE JB,et al.Regional brain function,emotion and disorders of emotion[J].Curr Opin Neurobiol,1999,9(2):228-234.
[3] RAJKOWSKA G,MIGUEL-HIDALGO JJ,WEI J,et al.Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression[J].Biol Psychiatry,1999,45(9):1085-1098.
[4] KOWSKI AB,GEISLER S,KRAUSS M,et al.Differential projections from subfields in the lateralpreoptic area to the lateral habenular complex of the rat[J].J Comp Neurol,2008,507(4):1465-1478.
[5] HERKENHAM M,NAUTA WJ.Efferent connections of thehabenular nuclei in the rat[J].J Comp Neurol,1979,187(1):19-47.
[6] SCHROEDER JA,HUMMEL M,SIMPSON AD,et al.A role for muopioid receptors in cocaine-induced activity,sensitization,and reward in the rat[J].Psychopharmacology (Berl),2007,195(2):265-272.
[7] OUACHIKH O,DIEB W,DURIF F,et al.Anterior ventraltegmental area dopaminergic neurons are not involved in the motivational effects of bromocriptine,pramipexole and cocaine in drug-free rats[J].Behav Brain Res,2014,262:1-7.
[8] SUN YN,WANG T,WANG Y,et al.Activation of 5-HT1A receptors in the medial subdivision of the central nucleus of the amygdala produces anxiolytic effects in a rat model of Parkinson's disease[J].Neuropharmacology,2015,8(95):181-191.
[9] 薛涛,邬丽莎,刘新民,王琼.抑郁症动物模型及评价方法研究进展[J].中国实验动物学报,2015,23(3):321-325.
[10] YETNIKOFF L,LAVEZZI HN,REICHARD RA,et al.An update on the connections of the ventral mesencephalic dopaminergic complex[J].Neuroscience,2014,12(282):23-48.
[11] MAHLER SV,ASTON-JONES GS.Fos activation of selective afferents to ventral tegmental area during cue-induced reinstatement of cocaine seeking in rats[J].J Neurosci,2012,32(38):13309-13326.
[12] LAMMEL S,LIM BK,RAN C,et al.Input-specific control of reward and aversion in the ventraltegmental area[J].Nature,2012,491(7423):212-217.
[13] SESACK SR,GRACE AA.Cortico-basal ganglia reward network:Microcircuitry[J].Neuropsychopharmacology,2010,35(1):27-47.
[14] HESSE S1 MP,STRECKER K,BARTHEL H,et al.Monoamine transporter availability in Parkinson's disease patients with or without depression[J].Eur J Nucl Med Mol Imaging,2009,36(3):428-435.
[15] BARTELS AL,LEENDERS KL.Parkinson's disease:The syndrome,the pathogenesis andpathophysiology[J].Cortex,2009,45(8):915-921.
[2] DAVIDSON RJ,ABERCROMBIE H,NITSCHKE JB,et al.Regional brain function,emotion and disorders of emotion[J].Curr Opin Neurobiol,1999,9(2):228-234.
[3] RAJKOWSKA G,MIGUEL-HIDALGO JJ,WEI J,et al.Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression[J].Biol Psychiatry,1999,45(9):1085-1098.
[4] KOWSKI AB,GEISLER S,KRAUSS M,et al.Differential projections from subfields in the lateralpreoptic area to the lateral habenular complex of the rat[J].J Comp Neurol,2008,507(4):1465-1478.
[5] HERKENHAM M,NAUTA WJ.Efferent connections of thehabenular nuclei in the rat[J].J Comp Neurol,1979,187(1):19-47.
[6] SCHROEDER JA,HUMMEL M,SIMPSON AD,et al.A role for muopioid receptors in cocaine-induced activity,sensitization,and reward in the rat[J].Psychopharmacology (Berl),2007,195(2):265-272.
[7] OUACHIKH O,DIEB W,DURIF F,et al.Anterior ventraltegmental area dopaminergic neurons are not involved in the motivational effects of bromocriptine,pramipexole and cocaine in drug-free rats[J].Behav Brain Res,2014,262:1-7.
[8] SUN YN,WANG T,WANG Y,et al.Activation of 5-HT1A receptors in the medial subdivision of the central nucleus of the amygdala produces anxiolytic effects in a rat model of Parkinson's disease[J].Neuropharmacology,2015,8(95):181-191.
[9] 薛涛,邬丽莎,刘新民,王琼.抑郁症动物模型及评价方法研究进展[J].中国实验动物学报,2015,23(3):321-325.
[10] YETNIKOFF L,LAVEZZI HN,REICHARD RA,et al.An update on the connections of the ventral mesencephalic dopaminergic complex[J].Neuroscience,2014,12(282):23-48.
[11] MAHLER SV,ASTON-JONES GS.Fos activation of selective afferents to ventral tegmental area during cue-induced reinstatement of cocaine seeking in rats[J].J Neurosci,2012,32(38):13309-13326.
[12] LAMMEL S,LIM BK,RAN C,et al.Input-specific control of reward and aversion in the ventraltegmental area[J].Nature,2012,491(7423):212-217.
[13] SESACK SR,GRACE AA.Cortico-basal ganglia reward network:Microcircuitry[J].Neuropsychopharmacology,2010,35(1):27-47.
[14] HESSE S1 MP,STRECKER K,BARTHEL H,et al.Monoamine transporter availability in Parkinson's disease patients with or without depression[J].Eur J Nucl Med Mol Imaging,2009,36(3):428-435.
[15] BARTELS AL,LEENDERS KL.Parkinson's disease:The syndrome,the pathogenesis andpathophysiology[J].Cortex,2009,45(8):915-921.