Glucocorticoid Regulation of Stress-Induced Mineralocorticoid Receptor Gene Transcription in Vivo

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73787/1/j.1749-6632.1994.tb39292.x.pd

Forebrain Origins of Glutamatergic Innervation to the Rat Paraventricular Nucleus of the Hypothalamus: Differential Inputs to the Anterior Versus Posterior Subregions

The hypothalamic paraventricular nucleus (PVN) regulates numerous homeostatic systems and functions largely under the influence of forebrain inputs. Glutamate is a major neurotransmitter in forebrain, and glutamate neurosignaling in the PVN is known to mediate many of its functions. Previous work showed that vesicular glutamate transporters (VGluTs; specific markers for glutamatergic neurons) are expressed in forebrain sites that project to the PVN; however, the extent of this presumed glutamatergic innervation to the PVN is not clear. In the present study retrograde FluoroGold (FG) labeling of PVN-projecting neurons was combined with in situ hybridization for VGluT1 and VGluT2 mRNAs to identify forebrain regions that provide glutamatergic innervation to the PVN and its immediate surround in rats, with special consideration for the sources to the anterior versus posterior PVN. VGluT1 mRNA colocalization with retrogradely labeled FG neurons was sparse. VGluT2 mRNA colocalization with FG neurons was most abundant in the ventromedial hypothalamus after anterior PVN FG injections, and in the lateral, posterior, dorsomedial, and ventromedial hypothalamic nuclei after posterior PVN injections. Anterograde tract tracing combined with VGluT2 immunolabeling showed that 1) ventromedial nucleus-derived glutamatergic inputs occur in both the anterior and posterior PVN; 2) posterior nucleus-derived glutamatergic inputs occur predominantly in the posterior PVN; and 3) medial preoptic nucleus-derived inputs to the PVN are not glutamatergic, thereby corroborating the innervation pattern seen with retrograde tracing. The results suggest that PVN subregions are influenced by varying amounts and sources of forebrain glutamatergic regulation, consistent with functional differentiation of glutamate projections. J. Comp. Neurol. 519:1301–1319, 2011. © 2010 Wiley-Liss, Inc

Multiple Small Bowel Perforations Secondary to Cytomegalovirus in a Patient with Acquired Immunodeficiency Syndrome

Cytomegalovirus gastroenteritis can be a life-threatening infection in patients with the acquired immunodeficiency syndrome. Although gastrointestinal ulcerations from cytomegalovirus have been widely reported, our patient is only the second case reported with actual perforations in the small bowel

Emerging evidence for CHFR as a cancer biomarker : from tumor biology to precision medicine

Novel insights in the biology of cancer have switched the paradigm of a "one-size-fits-all" cancer treatment to an individualized biology-driven treatment approach. In recent years, a diversity of biomarkers and targeted therapies has been discovered. Although these examples accentuate the promise of personalized cancer treatment, for most cancers and cancer subgroups no biomarkers and effective targeted therapy are available. The great majority of patients still receive unselected standard therapies with no use of their individual molecular characteristics. Better knowledge about the underlying tumor biology will lead the way toward personalized cancer treatment. In this review, we summarize the evidence for a promising cancer biomarker: checkpoint with forkhead and ring finger domains (CHFR). CHFR is a mitotic checkpoint and tumor suppressor gene, which is inactivated in a diverse group of solid malignancies, mostly by promoter CpG island methylation. CHFR inactivation has shown to be an indicator of poor prognosis and sensitivity to taxane-based chemotherapy. Here we summarize the current knowledge of altered CHFR expression in cancer, the impact on tumor biology and implications for personalized cancer treatment

Contribution of the Ventral Subiculum to Inhibitory Regulation of the Hypothalamo-Pituitary-Adrenocortical Axis

Anatomical studies indicate that the ventral subiculum is in a prime position to mediate hippocampal inhibition of the hypothalamo-pituitary-adrenocortical (HPA) axis. The present study evaluated this hypothesis by assessing HPA function following ibotenic acid lesion of the ventral subiculum region. Rats with lesions of the ventral subiculum (vSUB) or ventral hippocampus (vHIPPO) did not show changes in basal corticosterone (CORT) secretion at either circadian peak or nadir time points when compared to sham-lesion rats (SHAM) or unoperated controls. However, rats with vSUB lesions exhibited a prolonged glucocorticoid stress response relative to all other groups. Baseline CRH mRNA levels were significantly increased in the medial parvocellular paraventricular nucleus (PVN) of the vSUB group relative to controls. CRH mRNA differences were particularly pronounced at caudal levels of the nucleus, suggesting topographic organization of vSUB interactions with PVN neurons. Notably, the vHIPPO group, which received large lesions of ventral CA1, CA3 and dentate gyrus without significant subicular damage, showed no change in stress-induced CORT secretion, suggesting that the ventral subiculum proper is principally responsible for ventral hippocampal actions on the HPA stress response. No differences in medial parvocellular PVN AVP mRNA expression were seen in either the vSUB or vHIPPO groups. The results indicate a specific inhibitory action of the ventral subiculum on HPA activation. The increase in CRH biosynthesis and stress-induced CORT secretion in the absence of changes in baseline CORT secretion or AVP mRNA expression suggests that the inhibitory actions of ventral subicular neurons affect the response capacity of the HPA axis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74632/1/j.1365-2826.1995.tb00784.x.pd

The Melanocortin-4 Receptor Integrates Circadian Light Cues and Metabolism

The melanocortin system directs diverse physiological functions from coat color to body weight homoeostasis. A commonality among melanocortin-mediated processes is that many animals modulate similar processes on a circannual basis in response to longer, summer days, suggesting an underlying link between circadian biology and the melanocortin system. Despite key neuroanatomical substrates shared by both circadian and melanocortin-signaling pathways, little is known about the relationship between the two. Here we identify a link between circadian disruption and the control of glucose homeostasis mediated through the melanocortin-4 receptor (Mc4r). Mc4r-deficient mice exhibit exaggerated circadian fluctuations in baseline blood glucose and glucose tolerance. Interestingly, exposure to lighting conditions that disrupt circadian rhythms improve their glucose tolerance. This improvement occurs through an increase in glucose clearance by skeletal muscle and is food intake and body weight independent. Restoring Mc4r expression to the paraventricular nucleus prevents the improvement in glucose tolerance, supporting a role for the paraventricular nucleus in the integration of circadian light cues and metabolism. Altogether these data suggest that Mc4r signaling plays a protective role in minimizing glucose fluctuations due to circadian rhythms and environmental light cues and demonstrate a previously undiscovered connection between circadian biology and glucose metabolism mediated through the melanocortin system

MDMA Decreases Gluatamic Acid Decarboxylase (GAD) 67-Immunoreactive Neurons in the Hippocampus and Increases Seizure Susceptibility: Role for Glutamate

3,4-Methylenedioxy-methamphetamine (MDMA) is a unique psychostimulant that continues to be a popular drug of abuse. It has been well documented that MDMA reduces markers of 5-HT axon terminals in rodents, as well as humans. A loss of parvalbumin-immunoreactive (IR) interneurons in the hippocampus following MDMA treatment has only been documented recently. In the present study, we tested the hypothesis that MDMA reduces glutamic acid decarboxylase (GAD) 67-IR, another biochemical marker of GABA neurons, in the hippocampus and that this reduction in GAD67-IR neurons and an accompanying increase in seizure susceptibility involve glutamate receptor activation. Repeated exposure to MDMA (3×10mg/kg, ip) resulted in a reduction of 37–58% of GAD67-IR cells in the dentate gyrus (DG), CA1, and CA3 regions, as well as an increased susceptibility to kainic acid-induced seizures, both of which persisted for at least 30 days following MDMA treatment. Administration of the NMDA antagonist MK-801 or the glutamate transporter type 1 (GLT-1) inducer ceftriaxone prevented both the MDMA-induced loss of GAD67-IR neurons and the increased vulnerability to kainic acid-induced seizures. The MDMA-induced increase in the extracellular concentration of glutamate in the hippocampus was significantly diminished in rats treated with ceftriaxone, thereby implicating a glutamatergic mechanism in the neuroprotective effects of ceftriaxone. In summary, the present findings support a role for increased extracellular glutamate and NMDA receptor activation in the MDMA-induced loss of hippocampal GAD67-IR neurons and the subsequent increased susceptibility to evoked seizures

End-Point Variability Is Not Noise in Saccade Adaptation

When each of many saccades is made to overshoot its target, amplitude gradually decreases in a form of motor learning called saccade adaptation. Overshoot is induced experimentally by a secondary, backwards intrasaccadic target step (ISS) triggered by the primary saccade. Surprisingly, however, no study has compared the effectiveness of different sizes of ISS in driving adaptation by systematically varying ISS amplitude across different sessions. Additionally, very few studies have examined the feasibility of adaptation with relatively small ISSs. In order to best understand saccade adaptation at a fundamental level, we addressed these two points in an experiment using a range of small, fixed ISS values (from 0° to 1° after a 10° primary target step). We found that significant adaptation occurred across subjects with an ISS as small as 0.25°. Interestingly, though only adaptation in response to 0.25° ISSs appeared to be complete (the magnitude of change in saccade amplitude was comparable to size of the ISS), further analysis revealed that a comparable proportion of the ISS was compensated for across conditions. Finally, we found that ISS size alone was sufficient to explain the magnitude of adaptation we observed; additional factors did not significantly improve explanatory power. Overall, our findings suggest that current assumptions regarding the computation of saccadic error may need to be revisited

Loss of Environmental Enrichment Elicits Behavioral and Physiological Dysregulation in Female Rats

Chronic stress drives behavioral and physiological changes associated with numerous psychiatric disease states. In rodents, the vast majority of chronic stress models involve imposition of external stressors, whereas in humans stress is often driven by internal cues, commonly associated with a sense of loss. We previously exposed groups of rats to environmental enrichment (EE) for a protracted period (1 month), followed by removal of enrichment (ER), to induce an experience of loss in male rats. ER enhanced immobility in the forced swim test (FST), led to hypothalamic pituitary adrenal (HPA) axis hypoactivity, and caused hyperphagia relative to continuously enriched (EE), single-housed (Scon) and pair-housed (Pcon) groups, most of which were reversible by antidepressant treatment (Smith et al., 2017). Here, we have applied the same approach to study enrichment loss in female rats. Similar to the males, enrichment removal in females led to an increase in the time spent immobile in the FST and increased daytime food intake compared to the single and pair-housed controls. Unlike males, ER females showed decreased sucrose preference, and showed estrus cycle-dependent HPA axis hyperactivity to an acute restraint stress. The increase in passive coping (immobility), anhedonia-like behavior in the sucrose preference test and HPA axis dysregulation suggest that enrichment removal produces a loss phenotype in females that differs from that seen in males, which may be more pronounced in nature

A Model for the Two-Phase Behavior of Fluids in Dilute Porous Media

Experiments show that the coexistence region of a vapor-liquid system or binary liquid mixture is dramatically narrowed when the fluid is confined in a dilute porous medium such as a silica aerogel. We propose a simple model of the gel as a periodic array of cylindrical strands, and study the phase behavior of an Ising system confined in this geometry. Our results suggest that the coexistence region should widen out at lower temperatures, and that the narrowness observed near the critical point may be a fluctuation-induced effect