Loss of hippocampal neuronal nitric oxide synthase contributes to the stress‐related deficit in learning and memory

Palumbo, María Laura; Fosser, Nicolás Sebastián; Rı́os, Hugo; Zubilete, Marı́a Aurelia Zorrilla; Guelman, Laura Ruth; Cremaschi, Graciela; Genaro, Ana Marı́a

doi:10.1111/j.1471-4159.2007.04528.x

Cited by 50 publications

(45 citation statements)

References 65 publications

(72 reference statements)

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“…We found that chronic mild stress (CMS) increased hippocampal NO production by nNOS in male mice (6)(7)(8)(9). In contrast, CMS diminished hippocampal NO production by nNOS in female mice (14). Here we show that hippocampal NO plays a role in the sex difference of depression-like behaviors in rodents.…”

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confidence: 57%

Hippocampal nitric oxide contributes to sex difference in affective behaviors

Luo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Mechanisms underlying the female preponderance in affective disorders are poorly understood. Here we show that hippocampal nitric oxide (NO) plays a role in the sex difference of depressionlike behaviors in rodents. Female mice had substantially lower NO production in the hippocampus and were significantly more likely to display negative affective behaviors than their male littermates. Eliminating the difference in the basal hippocampal NO level between male and female mice mended the sex gap of affective behaviors. Estradiol exerted a positive control on hippocampal NO production via estrogen receptor-β-mediated neuronal NO synthase expression. Thus, low estrogen in the female hippocampus accounts for lower local NO than in the male hippocampus. Although estrogen has important significance in modulating affective behaviors, it is not estrogen but NO in the hippocampus that mediates the sex difference of affective behaviors directly, because hippocampal NO was necessary for the behavioral effects of estradiol, and NO was an independent factor in modulating behaviors. Stress promoted hippocampal NO production in males because of glucocorticoid release, thus leading to local NO excess. In contrast, stress suppressed NO production in females because of decreased estrogen, thereby resulting in hippocampal NO shortage. Whereas activating cAMP response element binding protein (CREB) rescued the depression-like effects of the intrahippocampal NO donor diethylenetriamine/nitric oxide adduct (DETA/NONOate), inactivating CREB abolished the antidepressant-like effects of the intrahippocampal NO donor DETA/NONOate. Our findings suggest a molecular mechanism underlying the sex difference of affective behaviors.A ffective disorders such as depression and anxiety, lifethreatening and highly prevalent stress-related disorders, rank among the top causes of worldwide disease burden and disability (1, 2). It is commonly suggested that a female preponderance in depression and anxiety is universal and substantial. The prevalence of depression and anxiety for women is approximately twice that for men (2-6). Although there are advocates for the implications of hypothalamic-pituitary-adrenal axis hyperactivity in the sex differentiation in some expressions of both depression and anxiety (7), it is not clear what underlies the sex gap in these affective disorders.Neuronal nitric oxide synthase (nNOS) has been implicated in the psychiatric disorders characterized by depression (8, 9), schizophrenia (10), and aggressiveness (11). We recently demonstrated that hippocampal nNOS mediates the stress-related depressive behaviors of glucocorticoids (9) and the role of 5-hydroxytryptamine receptor 1A (5-HT1A) receptor in modulating anxiety-related behaviors (12). Evidence from clinical and biological studies indicates that the hippocampus plays an important role in major depression disorder (13). We found that chronic mild stress (CMS) increased hippocampal NO production by nNOS in male mice (6-9). In contrast, CMS diminished hippocampal NO prod...

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confidence: 57%

Hippocampal nitric oxide contributes to sex difference in affective behaviors

Luo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…In this study, to examine whether chronic stress modifies circadian rhythms of hepatic clock genes, we chose a CMS model that has been widely used for producing a state of chronic stress (34,38,39,53). This CMS procedure consists of stressors, including water deprivation, food deprivation, and 12-h overnight illumination, all of which can affect circadian expression rhythms of clock genes in peripheral tissues (11,32).…”

Section: Discussionmentioning

confidence: 99%

“…First, to examine the influence of chronic stress on circadian clock gene expressions in the liver, BALB/c mice were divided into two groups: one was housed under ordinary conditions (Control-BALB) and the other was subjected to CMS (CMS-BALB) (34,38,39,53). Serum parameters and hepatic gene expressions were analyzed 1 day after the last day of CMS (Fig.…”

Section: Cms Alters Circadian Mrna Expression Profiles Of Core Clock mentioning

confidence: 99%

“…Therefore, we hypothesized that chronic stress affects the circadian rhythm of core clock gene expressions in the liver via the HPA axis, followed by alterations in metabolism-related genes. The chronic mild stress (CMS) procedure is widely used for analyzing stress effects in experimental animal models (34,38,39,53). To test our hypothesis, we examined the influences of CMS on circadian clock gene expressions in the liver.…”

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confidence: 99%

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Chronic mild stress alters circadian expressions of molecular clock genes in the liver

Takahashi

Yamada

Tsukita

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

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Chronic stress is well known to affect metabolic regulation. However, molecular mechanisms interconnecting stress response systems and metabolic regulations have yet to be elucidated. Various physiological processes, including glucose/ lipid metabolism, are regulated by the circadian clock, and core clock gene dysregulation reportedly leads to metabolic disorders. Glucocorticoids, acting as end-effectors of the hypothalamus-pituitary-adrenal (HPA) axis, entrain the circadian rhythms of peripheral organs, including the liver, by phase-shifting core clock gene expressions. Therefore, we examined whether chronic stress affects circadian expressions of core clock genes and metabolism-related genes in the liver using the chronic mild stress (CMS) procedure. In BALB/c mice, CMS elevated and phase-shifted serum corticosterone levels, indicating overactivation of the HPA axis. The rhythmic expressions of core clock genes, e.g., Clock, Npas2, Bmal1, Per1, and Cry1, were altered in the liver while being completely preserved in the hypothalamic suprachiasmatic nuculeus (SCN), suggesting that the SCN is not involved in alterations in hepatic core clock gene expressions. In addition, circadian patterns of glucose and lipid metabolism-related genes, e.g., peroxisome proliferator activated receptor (Ppar) ␣, Ppar␥-1, Ppar␥-coactivator-1␣, and phosphoenolepyruvate carboxykinase, were also disturbed by CMS. In contrast, in C57BL/6 mice, the same CMS procedure altered neither serum corticosterone levels nor rhythmic expressions of hepatic core clock genes and metabolismrelated genes. Thus, chronic stress can interfere with the circadian expressions of both core clock genes and metabolism-related genes in the liver possibly involving HPA axis overactivation. This mechanism might contribute to metabolic disorders in stressful modern societies. stress; liver clock; metabolic disorders; hypothalamus-pituitary-adrenal axis VARIOUS BEHAVIORAL AND PHYSIOLOGICAL processes, including feeding behavior and energy metabolism, exhibit circadian (i.e., 24-h) rhythmicity, which may play a role in maintaining functional homeostasis. These rhythms are regulated by the circadian clock system, which is composed of transcriptional/ translational feedback loops. Although the mammalian master pacemaker is located in the hypothalamic suprachiasmatic nucleus (SCN), the core clock machinery has been identified in almost all peripheral tissues, including the liver (41). In brief, each cell contains a set of core clock genes, such as Clock, Bmal1, Cry 1-2, Per 1-3, and nuclear receptors (Rev-erb␣, ROR). The CLOCK/BMAL1 heterodimer regulates the production of proteins such as PERs and CRYs, which in turn regulate the production of BMAL1 (44). Through these feedback loops, the expressions of core clock genes generate endogenous rhythms of numerous protein expressions, leading to rhythmic functioning of cells and tissues over an ϳ24-h period (12). The molecular clock has been demonstrated to modulate energy metabolism by controlling the expressions and activi...

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“…Increasing evidence suggests that nitric oxide (NO) signaling might also be disrupted by PCBs and other endocrine disrupting chemicals (EDCs, Sharma and Kodavanti, 2002;Martini et al, 2010;Currá s-Collazo, 2011). NO which is produced by nitric oxide synthase (NOS), is a gaseous neurotransmitter that serves an important role in neuroendocrine function (Garthwaite and Boulton, 1995), in synaptic processes associated with learning and memory such as a retrograde messenger underlying long term potentiation (LTP), (Bohme et al, 1991;O'Dell et al, 1991;Schuman and Madison, 1991), and in neurodegeneration (Liberatore et al, 1999;Palumbo et al, 2007). Therefore, results from studies on the effect of EDCs on NO signaling can inform significantly about the broad range of adverse effects produced by these neuroactive chemicals.…”

Section: Introductionmentioning

confidence: 99%