Selective overexpression of hippocampal CB1R alleviates chronic stress-induced neurogenesis impairment and behavior disorder in rats
- Journal of Army Medical University Vol. 48, Issue 4, Pages: 394-406(2026)
- 作者机构：
1.重庆医科大学，基础医学院放射医学教研室，重庆
2.重庆医科大学，基础医学院组织与胚胎学教研室，重庆
3.重庆医科大学，实验教学管理中心，重庆
- 作者简介：
- 基金信息：the General Program of National Natural Science Foundation of China(82171522);the National Natural Science Foundation for Young Scholars of China(82001435);the Postdoctoral Program of Chongqing Natural Science Foundation(cstc2020jcyj-bshX0098)
DOI：10.16016/j.2097-0927.202511032
CLC： R338.1;R338.26;R363.22Received：06 November 2025，
Revised：2026-01-11，
Accepted：16 January 2026，
Published：28 February 2026
- 稿件说明：
移动端阅览
游娅君，陈艳，黄杜娟，等.选择性过表达海马CB1R缓解慢性应激诱导的神经发生减弱及行为学损伤［J］.陆军军医大学学报，2026，48（04）：394-406.DOI：10.16016/j.2097-0927.202511032.
YOU Y J，CHEN Y，HUANG D J，et al.Selective overexpression of hippocampal CB1R alleviates chronic stress-induced neurogenesis impairment and behavior disorder in rats［J］.J Army Med Univ，2026，48（04）：394-406.DOI：10.16016/j.2097-0927.202511032.
游娅君，陈艳，黄杜娟，等.选择性过表达海马CB1R缓解慢性应激诱导的神经发生减弱及行为学损伤［J］.陆军军医大学学报，2026，48（04）：394-406.DOI：10.16016/j.2097-0927.202511032. DOI：
YOU Y J，CHEN Y，HUANG D J，et al.Selective overexpression of hippocampal CB1R alleviates chronic stress-induced neurogenesis impairment and behavior disorder in rats［J］.J Army Med Univ，2026，48（04）：394-406.DOI：10.16016/j.2097-0927.202511032. DOI：
摘要
目的
2
探究选择性过表达海马大麻素受体1（cannabinoid receptor 1，CB1R）对应激大鼠海马齿状回内新生细胞、新生成熟神经元的影响。
方法
2
将32只6~8周龄雄性SD大鼠（体质量180~220 g），按照随机抽样法分为对照（Control）组（
n
=10）和应激（Stress）组（
n
=22）。其中Stress组接受慢性束缚应激（chronic restraint stress，CRS）干预3周后，按随机抽样法抽取11只大鼠作为选择性过表达海马大麻素受体1（Stress+CB1R-OE）组，利用脑立体定位注射技术对Stress+CB1R-OE组大鼠海马体内注射CB1R过表达腺相关病毒，Control组和Stress组注射空载腺相关病毒，分别命名为Control+AAV-NC、Stress+AAV-NC组，病毒转染持续3周。实验进行的第1~7周的每周日上午检测各组大鼠体质量。采用新环境进食抑制实验评估各组大鼠的行为学水平。采用免疫荧光染色法检测各组大鼠海马齿状回（dentate gyrus，DG）内5-溴-2’-脱氧尿苷（5-bromo-2’-deoxyuridine，BrdU）、神经元核抗原（neuronal nuclei，NeuN）、CB1R的表达（
n
=5，每只取3片切片），采用激光共聚焦显微镜扫描，Imaris软件计算海马齿状回单位体积内BrdU
+
、BrdU
+
/NeuN
+
细胞密度，Image J软件测定海马齿状回CB1R及NeuN平均荧光强度。采用Western blot检测各组大鼠海马体内CB1R的蛋白表达水平。
结果
2
连续3周CRS干预后，Stress+AAV-NC组大鼠体质量显著低于Control+AAV-NC组（
P
=0.001），3周的选择性过表达海马CB1R对Stress+CB1R-OE组大鼠体质量增长具有一定作用，但Stress+CB1R-OE组大鼠体质量仍显著低于Control+AAV-NC组大鼠（
P
=0.004）。新环境进食抑制测试结果显示，与Control+AAV-NC组相比，Stress+AAV-NC组大鼠的进食潜伏期显著延长（
P
<
0.001），2组大鼠在5 min内的进食能力无显著差异。在选择性过表达海马CB1R后，Stress+CB1R-OE组进食潜伏期显著缩短（
P
=0.039），3组大鼠进食能力无显著差异。免疫荧光结果显示，与Control+AAV-NC组相比，Stress+AAV-NC组大鼠海马齿状回内CB1R
+
细胞荧光光度值显著减弱（
P
=0.008）。选择性过表达海马CB1R后，与Stress+AAV-NC组比较，Stress+CB1R-OE组大鼠海马齿状回内CB1R
+
平均荧光强度显著增强（
P
<
0.001）。Western blot结果显示，与Control+AAV-NC组相比，Stress+AAV-NC组大鼠海马内CB1R蛋白表达水平显著降低（
P
=0.001）。与Stress+AAV-NC组相比，Stress+CB1R-OE组大鼠海马CB1R表达水平显著增加（
P
<
0.001）。与Control+AAV-NC组相比，Stress+AAV-NC组大鼠海马齿状回中BrdU
+
新生细胞密度减少（
P
=0.003）、BrdU
+
/NeuN
+
的新生成熟神经元密度减少（
P
=0.001）。选择性过表达海马CB1R后，Stress+CB1R-OE组大鼠海马齿状回内BrdU
+
密度显著增加（
P
=0.035）、BrdU
+
/NeuN
+
的密度显著增多（
P
=0.028），3组大鼠海马齿状回内NeuN
+
的平均荧光
强度无显著差异。
结论
2
选择性过表达海马CB1R能够缓解应激介导的大鼠海马神经发生减弱，进而改善应激大鼠的行为学损伤。
Abstract
Objective
2
To investigate the effects of selective overexpression of hippocampal cannabinoid receptor 1 (CB1R) on newly generated cells and newly matured neurons in the hippocampus of stress-induced rats.
Methods
2
Thirty-two 6-8 week-old male SD rats (body weight 180 to 220 g) were randomly assigned to a Control group (
n
=10) and a Stress group (
n
=22). After the Stress group underwent 3 weeks of chronic restraint stress (CRS)
11 rats were randomly selected to form the Stress+CB1R-OE group
receiving hippocampal injections of an adeno-associated virus (AAV) for CB1R overexpression
via
stereotaxic surgery. The Control group and the remaining Stress group received a null AAV
designated as Control+AAV-NC and Stress+AAV-NC groups
respectively; viral transfection lasted 3 weeks. Body weight was measured every Sunday morning for weeks 1 to 7. Behavioral levels were assessed using the novel environment feeding suppression test. Immunofluorescence staining was used to detect the expression of 5-bromo-2'-deoxyuridine (BrdU)
Neuronal Nuclei (NeuN)
and CB1R in the hippocampal dentate gyrus (DG) (
n
=5 per group
3 slices per rat). A NOVEL confocal microscope was used for scanning. Imaris software calculated the density of BrdU⁺ and BrdU⁺/NeuN⁺ cells per unit volume in the DG
while Image J software measured the mean fluorescence intensity of CB1R and NeuN in the DG. Western blot assay was used to detect hippocampal CB1R protein expression levels.
Results
2
After 3 weeks of CRS
the body weight of the Stress+AAV-NC group was significantly lower than that of the Control+AAV-NC group (
P
=0.001). Selective hippocampal CB1R overexpression for 3 weeks partially ameliorated body weight gain in the Stre
ss+CB1R-OE group
but their weight remained significantly lower than the Control+AAV-NC group (
P
=0.004). The novel environment feeding suppression test showed that compared to the Control+AAV-NC group
the Stress+AAV-NC group had a significantly prolonged feeding latency (
P
<
0.001)
with no significant difference in feeding amount within 5 min. After selective CB1R overexpression
the Stress+CB1R-OE group showed a significantly shortened feeding latency (
P
=0.039)
with no significant differences in feeding amount among the three groups. Immunofluorescence results indicated that compared to the Control+AAV-NC group
the Stress+AAV-NC group had a significantly reduced mean fluorescence intensity of CB1R⁺ cells in the DG (
P
=0.008). After selective CB1R overexpression
the Stress+CB1R-OE group showed a significantly increased mean CB1R fluorescence intensity in the DG compared to the Stress+AAV-NC group (
P
<
0.001). Western blotting results showed that hippocampal CB1R protein expression was significantly lower in the Stress+AAV-NC group than in the Control+AAV-NC group (
P
=0.001). Compared to the Stress+AAV-NC group
the Stress+CB1R-OE group had a significantly increased hippocampal CB1R expression level (
P
<
0.001). Compared to the Control+AAV-NC group
the Stress+AAV-NC group had reduced densities of BrdU⁺ newborn cells (
P
=0.003) and BrdU⁺/NeuN⁺ newly matured neurons (
P
=0.001) in the DG. After selective CB1R overexpression
the Stress+CB1R-OE group showed significantly increased densities of BrdU⁺ cells (
P
=0.035) and BrdU⁺/NeuN⁺ neurons (
P
=0.028) in the DG. No significant difference was observed in the mean NeuN fluorescence intensity in the DG among the three groups.
Conclusion
2
Selective overexpression of hippocampal CB1R can alleviate stress-mediated reduction in hippocampal neurogenesis and subsequently improve behavioral deficits in stress-induced rats.
关键词
Keywords
references
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