Complementing its roles in cognitive and affective information processing, the medial prefrontal cortex (mPFC) is a nodal point of a limbic forebrain circuit that modulates stress-related homeostatic mechanisms, including the hypothalamic-pituitary-adrenal (HPA) axis. mPFC influences on HPA output are predominantly inhibitory and emanate from the prelimbic and/or dorsal anterior cingulate cortical fields (PL and ACd, respectively). mPFC projections do not target HPA effector neurons in the paraventricular hypothalamic nucleus (PVH) directly, distributing instead to nearby forebrain regions, including some that house GABAergic neurons implicated in inhibitory PVH control. To identify pathway(s) subserving HPA-inhibitory mPFC influences, an initial screen for sources of GABAergic input to PVH whose sensitivity to an acute emotional (restraint) stress was diminished by PL/ACd lesions identified a discrete region of the anterior bed nucleus of the stria terminalis (aBST) as a candidate for fulfilling this role. Anatomical tracing experiments confirmed projections from PL (but not ACd) to implicated aBST cell groups, and from these to PVH. Finally, selective immunotoxin-mediated ablation of GABAergic aBST neurons recapitulated the effects of PL/ACd lesions on acute stress-induced activation of HPA output. The identification of a proximate mediator of HPA-inhibitory limbic influences provides a framework for clarifying how inhibitory neural and hormonal controls of HPA output are integrated, adaptations of the axis to chronic stress are effected, and how endocrine abnormalities may contribute to stress-related psychiatric illnesses in which mPFC dysfunction is implicated.

There are forms of growth hormone (GH) in the plasma and pituitary of the rat and in the plasma of humans that are undetected by presently available immunoassays (iGH) but can be measured by bioassay (bGH). Although the regulation of iGH release is well documented, the mechanism(s) of bGH release is unclear. On the basis of changes in bGH and iGH secretion in rats that had been exposed to microgravity conditions, we hypothesized that neural afferents play a role in regulating the release of these hormones. To examine whether bGH secretion can be modulated by afferent input from skeletal muscle, the proximal or distal ends of severed hindlimb fast muscle nerves were stimulated ( approximately 2 times threshold) in anesthetized rats. Plasma bGH increased approximately 250%, and pituitary bGH decreased approximately 60% after proximal nerve trunk stimulation. The bGH response was independent of muscle mass or whether the muscles were flexors or extensors. Distal nerve stimulation had little or no effect on plasma or pituitary bGH. Plasma iGH concentrations were unchanged after proximal nerve stimulation. Although there may be multiple regulatory mechanisms of bGH, the present results demonstrate that the activation of low-threshold afferents from fast skeletal muscles can play a regulatory role in the release of bGH, but not iGH, from the pituitary in anesthetized rats.

Unweighting of rat hindlimb muscles results in skeletal muscle atrophy, decreased protein synthesis, and reduced growth hormone (GH) secretion. Resistance exercise (ladder climbing) and GH treatment partially attenuate skeletal muscle atrophy in hypophysectomized hindlimb-suspended rats. It was hypothesized that a combination of multiple bouts of daily resistance exercise and GH (1 mg.kg-1.day-1) would prevent skeletal muscle atrophy in growing nonhypophysectomized hindlimb-suspended rats. Hindlimb suspension decreased the absolute (mg/pair) and relative (mg/100 g body wt) weights of the soleus, a slow-twitch plantar flexor, by 30 and 21%, respectively, and the absolute and relative weights of the gastrocnemius, a predominantly fast-twitch plantar flexor, by 20 and 11%, respectively (P < 0.05). Exercise did not increase soleus mass but attenuated loss of relative wet weight in the gastrocnemius muscles of hindlimb-suspended rats (P < 0.05). Hindlimb suspension decreased gastrocnemius myofibrillar protein content and synthesis (mg/day) by 26 and 64%, respectively (P < 0.05). The combination of exercise and GH attenuated loss of gastrocnemius myofibrillar protein content and synthesis by 70 and 23%, respectively (P < 0.05). Results of the present investigation indicate that a combination of GH and resistance exercise attenuates atrophy of unweighted fast-twitch skeletal muscles.

Chronic stress is implicated in diseases which differentially affect men and women. This study investigated how the activation of neuronal subpopulations contributes to changes in neuroendocrine regulation that predispose members of each sex to stress-related health challenges. Adult male and female rats were restrained in single (acute) or 14 consecutive daily (repeated) 30 min sessions; brain sections were immunohistochemically stained for Fos, arginine vasopressin (AVP) or glucocorticoid receptor (GR) within the paraventricular hypothalamic nucleus (PVH). Acute restraint increased the number of PVH cells expressing Fos, with greater increases in males than females. Habituated responses were seen following repeated stress in both sexes, with no sex differences between groups. No sex differences were found in the number of neurons co-expressing Fos and AVP. Absolute counts of cellular Fos and GR co-localization mirrored Fos expression. In contrast, when doubly-labeled cells were normalized to staining for Fos alone, females showed greater numbers of Fos- and GR-positive cells than males after both acute and repeated stress. These data demonstrate that sex-specific stress responses are evident at the level of neuronal activation, and may contribute to different consequences of chronic stress in females versus males. Females may be more sensitive to glucocorticoid negative feedback, suggesting that sex-dependent differences in the efficiency of initiating and terminating stress responses may exist. Understanding the neural and endocrine pathways that mediate these functions in males and females will inform targeted therapeutic strategies to alleviate stress and the sex-specific afflictions with which it is associated.

The release of a bioassayable form of growth hormone (BGH), distinct from growth hormone as measured by immunoassay (IGH), from the rat pituitary into the blood is differentially regulated by afferent input from fast and slow skeletal muscles. Specifically, activation of low-threshold fast muscle afferents for 15 min increased plasma BGH by 217 and 295% and decreased pituitary BGH by 68 and 45% in male and female rats, respectively. In contrast, activation of slow muscle afferents inhibited BGH release, decreasing plasma BGH by approximately 60% and increasing pituitary BGH by 30-50% in male rats. Female rats from which food had been withheld for approximately 12 h had elevated basal plasma BGH levels, which then were decreased by 81% after slow muscle nerve stimulation. Plasma IGH concentrations were unchanged after any nerve stimulation condition. These results demonstrate that regulation of BGH release can be differentially mediated through low-threshold afferent inputs from fast or slow skeletal muscle. Furthermore, the results indicate that BGH responses are independent of gender or feeding status.

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Stress and obesity are highly prevalent conditions, and the mechanisms through which stress affects food intake are complex. In the present study, stress-induced activation in neuropeptide systems controlling ingestive behavior was determined. Adult male rats were exposed to acute (30 min/d × 1 d) or repeated (30 min/d × 14 d) restraint stress, followed by transcardial perfusion 2h after the termination of the stress exposure. Brain tissues were harvested, and 30 µm sections through the hypothalamus were immunohistochemically stained for Fos protein, which was then co-localized within neurons staining positively for the type 4 melanocortin receptor (MC4R), the glucagon-like peptide-1 receptor (GLP1R), or agouti-related peptide (AgRP). Cell counts were performed in the paraventricular (PVH), arcuate (ARC) and ventromedial (VMH) hypothalamic nuclei and in the lateral hypothalamic area (LHA). Fos was significantly increased in all regions except the VMH in acutely stressed rats, and habituated with repeated stress exposure, consistent with previous studies. In the ARC, repeated stress reduced MC4R cell activation while acute restraint decreased activation in GLP1R neurons. Both patterns of stress exposure reduced the number of AgRP-expressing cells that also expressed Fos in the ARC. Acute stress decreased Fos-GLP1R expression in the LHA, while repeated restraint increased the number of Fos-AgRP neurons in this region. The overall profile of orexigenic signaling in the brain is thus enhanced by acute and repeated restraint stress, with repeated stress leading to further increases in signaling, in a region-specific manner. Stress-induced modifications to feeding behavior appear to depend on both the duration of stress exposure and regional activation in the brain. These results suggest that food intake may be increased as a consequence of stress, and may play a role in obesity and other stress-associated metabolic disorders.

BackgroundProstate cancer is a major contributor to mortality worldwide, and significant efforts are being undertaken to decipher specific cellular and molecular pathways underlying the disease. Chronic stress is known to suppress reproductive function and promote tumor progression in several cancer models, but our understanding of the mechanisms through which stress contributes to cancer development and progression is incomplete. We therefore examined the relationship between stress, modulation of the gonadotropin-releasing hormone (GnRH) system, and changes in the expression of cancer-related genes in the rat prostate.MethodsAdult male rats were acutely or repeatedly exposed to restraint stress, and compared to unstressed controls and groups that were allowed 14 days of recovery from the stress. Prostate tissue was collected and frozen for gene expression analyses by PCR array before the rats were transcardially perfused; and brain tissues harvested and immunohistochemically stained for Fos to determine neuronal activation.ResultsAcute stress elevated Fos expression in the paraventricular nucleus of the hypothalamus (PVH), an effect that habituated with repeated stress exposure. Data from the PCR arrays showed that repeated stress significantly increases the transcript levels of several genes associated with cellular proliferation, including proto-oncogenes. Data from another array platform showed that both acute and repeated stress can induce significant changes in metastatic gene expression. The functional diversity of genes with altered expression, which includes transcription factors, growth factor receptors, apoptotic genes, and extracellular matrix components, suggests that stress is able to induce aberrant changes in pathways that are deregulated in prostate cancer.ConclusionsOur findings further support the notion that stress can affect cancer outcomes, perhaps by interfering with neuroendocrine mechanisms involved in the control of reproduction.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3635-4) contains supplementary material, which is available to authorized users.