Repeated stress impairs endocannabinoid signaling in the paraventricular nucleus of the hypothalamus.

Endocannabinoids (eCBs) are ubiquitous retrograde signaling molecules in the nervous system that are recruited in response to robust neuronal activity or the activation of postsynaptic G-protein-coupled receptors. Physiologically, eCBs have been implicated as important mediators of the stress axis and they may contribute to the rapid feedback inhibition of the hypothalamic-pituitary-adrenal axis (HPA) by circulating corticosteroids (CORTs). Understanding the relationship between stress and eCBs, however, is complicated by observations that eCB signaling is itself sensitive to stress. The mechanisms that link stress to changes in synaptic eCB signaling and the impact of these changes on CORT-mediated negative feedback have not been resolved. Here, we show that repetitive immobilization stress, in juvenile male rats, causes a functional downregulation of CB(1) receptors in the paraventricular nucleus of the hypothalamus (PVN). This loss of CB(1) receptor signaling, which requires the activation of genomic glucocorticoid receptors, impairs both activity and receptor-dependent eCB signaling at GABA and glutamate synapses on parvocellular neuroendocrine cells in PVN. Our results provide a plausible mechanism for how stress can lead to alterations in CORT-mediated negative feedback and may contribute to the development of plasticity of HPA responses.

A synaptocentric view of the neuroendocrine response to stress.

The essential role of parvocellular neuroendocrine cells (PNCs) in the paraventricular nucleus of the hypothalamus (PVN) is to translate real or perceived challenges into a comprehensive glucocorticoid (GC) hormone response. Synaptic inputs encoding physical and psychological stress engage the hypothalamic-pituitary-adrenal axis (HPA) by increasing PNC activity, and corticotropin-releasing hormone production and release. Following robust recruitment in response to stress, GCs feedback to dampen PNC responses. Here we review the contributions of glutamate and GABA synapses in PVN to the initiation and termination of the stress response. The reliability of HPA responses to a given stress can vary as a function of prior experience. Within this context, we examine possible synaptic correlates that allow this neuroendocrine system to learn and adapt following stress challenges.

Transient hypertension concurrent with forepaw stimulation enhances functional MRI responsiveness in infarct and peri-infarct regions.

Although functional magnetic resonance imaging (fMRI) is gaining use as a tool to assess cerebral recovery following various insults, the effects of potential confounders such as hypertension are poorly defined. We hypothesized that after stroke, transient hypertension during an fMRI study could produce a detected activation unrelated to neuronal activity within the infarct. Thus, the effect of norepinephrine induced increases in blood pressure (BP) on the fMRI response to forepaw stimulation were investigated in controls or 1 week after transient middle cerebral artery occlusion in rats. Images were smoothed spatially and voxels correlating to either forepaw stimulation or the change in BP time courses were analyzed. Transient hypertension increased the signal intensity and numbers of voxels correlating to the BP time courses within and adjacent to the ischemic infarct and these exceeded the response in the contralateral hemisphere or in controls. With left paw stimulation at normotension, there was a loss of activation in right sensory-motor cortex -- a region with necrosis and disruption of cerebral vessels. As BP increased left paw stimulation also resulted in the detection of activation in the infarcted sensory-motor cortex and peri-infarct regions. Thus, BP changes synchronous with tasks in fMRI studies can result in MR signal changes consistent with a loss of cerebral blood flow (CBF) autoregulation rather than neuronal activation in necrotic brain. After stroke, the use of stressful tasks associated with BP changes in fMRI studies should be limited or the BP change should be considered as a potential source of MR signal changes.

Altered chloride homeostasis removes synaptic inhibitory constraint of the stress axis.

In mammals, stress elicits a stereotyped endocrine response that requires an increase in the activity of hypothalamic parvocellular neuroendocrine neurons. The output of these cells is normally constrained by powerful GABA-mediated synaptic inhibition. We found that acute restraint stress in rats released the system from inhibitory synaptic drive in vivo by down-regulating the transmembrane anion transporter KCC2. This manifested as a depolarizing shift in the reversal potential of GABA(A)-mediated synaptic currents that rendered GABA inputs largely ineffective. Notably, repetitive activation of GABA synapses after stress resulted in a more rapid collapse of the anion gradient and was sufficient to increase the activity of neuroendocrine cells. Our data indicate that hypothalamic neurons integrate psychological cues to mount the endocrine response to stress by regulating anion gradients.

Increased metabolism in the R6/2 mouse model of Huntington's disease.

Huntington's disease (HD) is a hereditary disorder characterized by personality changes, chorea, dementia and weight loss. The cause of this weight loss is unknown. The aim of this study was to examine body weight changes and weight-regulating factors in HD using the R6/2 mouse model as a tool. We found that R6/2 mice started losing weight at 9 weeks of age. Total locomotor activity was unaltered and caloric intake was not decreased until 11 weeks of age, which led us to hypothesize that increased metabolism might underlie the weight loss. Indeed, oxygen consumption in R6/2 mice was elevated from 6 weeks of age, indicative of an increased metabolism. Several organ systems that regulate weight and metabolism, including the hypothalamus, the stomach and adipose tissue displayed abnormalities in R6/2 mice. Together, these data demonstrate that weight loss in R6/2 mice is associated with increased metabolism and changes in several weight-regulating factors.

Transient blood pressure changes affect the functional magnetic resonance imaging detection of cerebral activation.

Functional magnetic resonance imaging (fMRI) provides an indirect measure of cerebral activation that could be altered by factors directly affecting cerebral blood flow independent of changes in neuronal activation. Presently, we investigate how changes in blood pressure (BP) affect the activation detected with fMRI. fMRI scans were acquired in 33 rats under control conditions and following transient BP increases (norepinephrine, IV) or decreases (arfonad, IV) with and without electrical stimulation of the forepaw. Voxels correlating to either the stimulation or the change in BP time courses were identified. During transient hypertension, irrespective of forepaw stimulation, BP increases (i.e., >10 mm Hg) produced a transient increase in the blood oxygen level-dependent (BOLD) intensity resulting in a significant numbers of voxels correlating to the BP time courses (P < 0.05), and the number of these voxels increased as BP increased, becoming substantial at BP > 30 mm Hg. The activation patterns with BP increases and stimulation overlapped spatially resulting in an enhanced cerebral activation to simultaneous forepaw stimulation (P < 0.05). BP decreases (>10 mm Hg) produced corresponding decreases in BOLD intensity, causing significant numbers of voxels correlating to the BP decreases (P < 0.005), and these numbers increased as BP decreased (P < 0.001). The BP decreases and stimulation time courses and responses were distinct, and hypotension did not affect the detection of the activation response to forepaw stimulation. The results indicate that substantial hypertension accompanying a stimulation paradigm produces a BOLD response that enhances the cerebral activation detected, whereas hypotension does not affect the detection of neuronal activation but does produce responses that could be interpreted as a 'deactivation'.