Effect of early-life stress on chronic functional visceral pain and CRH R1 expression in the paraventricular nucleus in adult rats

We previously reported that maternal separation (MS), a model of early life stress, does not modify baseline blood pressure in adult rats, but increases sensitivity to hypertensive stimuli. Under baseline conditions, adult male rats exposed to MS have significantly reduced glomerular filtration rate (GFR). Acute phenylephrine-induced reductions in renal blood flow is significantly attenuated in rats exposed to MS compared to control rats. Furthermore, norephinephrine (NE) content was increased in renal cortex of MS rats compared to control rats (p<0.05). These data indicate that MS induces increased renal sympathetic outflow. Thus, we hypothesized that renal denervation will normalize GFR in rats exposed to MS. Male WKY rat pups were separated from their mothers for 3 hrs/day during the morning hours from day 2 to 14 of life. Male non-separated littermates served as control rats. Experiments were performed in 300-320 g adult rats. Denervation (DnX) was performed mechanically stripping all visible renal nerves followed by topical phenol (10%) on the renal artery. Control-sham, MS-sham, control-DnX, and MS-DnX rats were instrumented with catheters in the femoral vein and abdominal aorta. Rats were placed in metabolic cages, connected to swivels, and allowed to recover for 4-5 days. Sodium intake was clamped at 2.8 mEq/day in both groups by combining sodium deficient diet and 24 hr/day 0.9% iv saline infusion (20 ml/day). GFR was determined by plasma clearance of [125I]iothalamate in the conscious state. During baseline conditions, MAP was not different between control-sham and MS-sham rats (99±4 vs 97±2 mmHg, respectively). MAP was reduced in both control-DnX and MS-DnX rats (91±2 mmHg and 83±3 mmHg, p<0.05, respectively) compared with the respective sham group. The reduction in MAP tended to be greater in MS than in control rats (-9±1 and -14±2 mmHg, p=0.074). DnX did not modify GFR in control rats (sham: 3.1±0.1 ml/min vs DnX: 3.5±0.4 ml/min). However, DnX significantly increased GFR in rats exposed to MS (sham: 2.4±0.2 ml/min vs DnX: 3.8±0.4 ml/min, p<0.05). These data support our hypothesis that MS induces increased renal sympathetic tone to reduce GFR in MS male rats, and may contribute to the exacerbated response to hypertensive stimuli observed in MS rats.

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A Novel Mouse Model for Acute and Long-Lasting Consequences of Early Life Stress

Endocrinology ◽

10.1210/en.2008-0633 ◽

2008 ◽

Vol 149 (10) ◽

pp. 4892-4900 ◽

Cited By ~ 255

Author(s):

Courtney J. Rice ◽

Curt A. Sandman ◽

Mohammed R. Lenjavi ◽

Tallie Z. Baram

Keyword(s):

Mouse Model ◽

Paraventricular Nucleus ◽

Life Stress ◽

Early Life ◽

Molecular Mechanisms ◽

Early Life Stress ◽

Plasma Corticosterone ◽

Mrna Levels ◽

Dependent Manner ◽

Basal Plasma

Chronic early-life stress (ES) exerts profound acute and long-lasting effects on the hypothalamic-pituitary-adrenal system, with relevance to cognitive function and affective disorders. Our ability to determine the molecular mechanisms underlying these effects should benefit greatly from appropriate mouse models because these would enable use of powerful transgenic methods. Therefore, we have characterized a mouse model of chronic ES, which was provoked in mouse pups by abnormal, fragmented interactions with the dam. Dam-pup interaction was disrupted by limiting the nesting and bedding material in the cages, a manipulation that affected this parameter in a dose-dependent manner. At the end of their week-long rearing in the limited-nesting cages, mouse pups were stressed, as apparent from elevated basal plasma corticosterone levels. In addition, steady-state mRNA levels of CRH in the hypothalamic paraventricular nucleus of ES-experiencing pups were reduced, without significant change in mRNA levels of arginine vasopressin. Rearing mouse pups in this stress-provoking cage environment resulted in enduring effects: basal plasma corticosterone levels were still increased, and CRH mRNA levels in paraventricular nucleus remained reduced in adult ES mice, compared with those of controls. In addition, hippocampus-dependent learning and memory functions were impaired in 4- to 8-month-old ES mice. In summary, this novel, robust model of chronic early life stress in the mouse results in acute and enduring neuroendocrine and cognitive abnormalities. This model should facilitate the examination of the specific genes and molecules involved in the generation of this stress as well as in its consequences.

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Abstract 008: Early Life Stress Induces Renal Pro-inflammatory Immune Responses

Hypertension ◽

10.1161/hyp.66.suppl_1.008 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Carmen De Miguel ◽

Dao H Ho ◽

Analia S Loria ◽

Ijeoma Obi ◽

Jennifer S Pollock

Keyword(s):

Immune Response ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Immune Cell ◽

Early Life Stress ◽

Adult Rats ◽

Activation Markers ◽

Ifn Gamma ◽

Inflammatory Status

We previously reported that maternal separation (MatSep), an animal model of early life stress, sensitizes rats to pro-hypertensive stimuli in adulthood. We hypothesized that MatSep induces a renal pro-inflammatory immune response. Immune cell populations and expression of cytokines were assessed by magnetic bead isolation, FACS analysis, ELISA and RT-PCR in adult male MatSep and normally-reared littermate control rats. Circulating and renal mononuclear or T cell numbers were similar between control and MatSep rats (n=4-11/group, p>0.05). Both groups presented similar percentages of circulating macrophages and T H , T C , and T reg cells (n=4, p>0.05). However, the percentage of circulating B cells was significantly decreased in MatSep rats (23.7±1.2% vs. 20.1±0.7%; n=4, p<0.05). Pro-inflammatory cytokine IL-1Beta was significantly elevated in kidneys from MatSep rats (4.4±0.5 vs. 7.9±1.0 pg/mg prot; n=7-8/group; p<0.05). However, IFN-gamma, IL-6, and IL-4 were not different between control and MatSep rats. To further assess the immune system in MatSep and control rats, we acutely challenged adult rats with lipopolysaccharide (LPS; 2 mg/kg; i.v., 14 h). LPS significantly elevated renal expression of pro-inflammatory chemokine receptors (CCR3, CCR4, CXCR4), cytokines (IFN-gamma, CCL3, CCL4, IL-16), and activation markers (CD40, CD40lg) in MatSep rats (4 to 6 fold increase; n=5/group, p<0.05), suggesting that MatSep induces an exaggerated pro-inflammatory renal immune response to LPS. In conclusion, early life stress induces a renal pro-inflammatory status in adulthood that leads to sensitization to further immune challenges. Funded by P01 HL 69999 to JSP, NIH T32 DK007545 to CDM, F32 HL 116145 to DHH and K99/R00 HL 111354 to ASL.

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