Reduced human activity during COVID-19 alters avian land use across North America.

The COVID-19 pandemic resulted in extraordinary declines in human mobility, which, in turn, may affect wildlife. Using records of more than 4.3 million birds observed by volunteers from March to May 2017­2020 across Canada and the United States, we found that counts of 66 (80%) of 82 focal bird species changed in pandemic-altered areas, usually increasing in comparison to prepandemic abundances in urban habitat, near major roads and airports, and in counties where lockdowns were more pronounced or occurred at the same time as peak bird migration. Our results indicate that human activity affects many of North America's birds and suggest that we could make urban spaces more attractive to birds by reducing traffic and mitigating the disturbance from human transportation after we emerge from the pandemic.

Carvedilol alleviates diabetic cardiomyopathy in diabetic rats.

Diabetic cardiomyopathy (DCM) is characterized by structural and functional changes in the myocardium. Several studies have revealed that myocardial apoptosis and fibrosis occur during DCM. Studies have also indicated that oxidative stress may be a major factor associated with the development of DCM. Protein kinase C (PKC)ß2 has been demonstrated to be activated in diabetic rats, and overexpression of PKCß2 in the myocardium may result in cardiac hypertrophy and fibrosis. The P66shc adaptor protein, which is mediated by PKCß, serves an important role in apoptosis during oxidative stress. The aim of the present study was to investigate whether the PKCß2/P66shc oxidative stress pathway is associated with DCM, and to investigate the role and mechanisms of carvedilol in preserving cardiac function. Experimental diabetic rat models were induced by streptozotocin treatment accompanied by high energy intake. Carvedilol was orally administrated at a dose of 1 or 10 mg/kg/day. Cardiac function was evaluated by serum N-terminal pro-B-type natriuretic peptide level and cardiac ultrasound. Myocardial inflammation, oxidative stress, apoptosis and fibrosis were assessed by histopathological and echocardiographic analyses and tests for oxidative markers. Associated proteins and factors were examined by immunohistochemical and western blot analyses. Rats in the diabetes mellitus group exhibited significantly decreased systolic cardiac function along with elevated expression levels of phosphorylated (p)-PKCß2, phos-P66shc, caspase-3, malondialdehyde, collagen type I, tumor necrosis factor-α and interleukin-1ß, which were accompanied by disorder in metabolic processes. Treatment with carvedilol reversed these changes. Thus, the present results suggest that the PKCß2/P66shc signaling pathway may be associated with diabetic cardiomyopathy; furthermore, carvedilol, as a novel ß-receptor blocker, may protect the myocardium from injury by suppressing the myocardial inflammatory response, fibrosis, P66shc-mediated oxidative stress and subsequent apoptosis in myocardial tissue. Consequently, carvedilol may have potential as a therapy for the treatment of DCM.

Effects of bilateral anterior agranular insula lesions on food anticipatory activity in rats.

Food anticipatory activity (FAA) refers to a daily rhythm of locomotor activity that emerges under conditions of food restriction, whereby animals develop an intense, predictable period of activity in the few hours leading up to a predictable, daily delivery of food. The neural mechanisms by which FAA is regulated are not yet fully understood. Although a number of brain regions appear to be involved in regulating the development and expression of FAA, there is little evidence to date concerning the role of the anterior agranular insular cortex (AICa). The AICa plays a critical role in integrating the perception of visceral states with motivational behaviour such as feeding. We assessed the effect of bilateral electrolytic or ibotenic acid lesions of the AICa on FAA in male Wistar rats receiving food for varying lengths of time (2 h, 3 h, or 5 h) during the middle of the light phase (starting at either ZT4 or ZT6). Contrary to our initial expectations, we found that both electrolytic and ibotenic acid lesions significantly increased, rather than decreased, the amount of FAA expressed in lesioned rats. Despite increased FAA, lesioned rats did not eat significantly more during restricted feeding (RF) periods than control rats. Similar to controls, AlCa-lesioned rats showed negligible anticipatory activity to a restricted treat suggesting that the increased anticipatory activity in lesioned rats is associated with food restriction, rather than the appetitive value of the meal. Monitoring behaviour in an open field indicated that increased FAA in AlCa-lesioned rats was not explained by a general increase in locomotor activity. Together, these findings suggest that the AICa contributes to the network of brain regions involved in FAA.

The Effects of Carvedilol on Cardiac Function and the AKT/XIAP Signaling Pathway in Diabetic Cardiomyopathy Rats.

OBJECTIVES: Diabetic cardiomyopathy (DCM) is characterized by cardiac dysfunction, myocardial inflammation, interstitial fibrosis and cardiomyocytes apoptosis. The present study aimed to investigate the effects of carvedilol on cardiac function and the AKT/XIAP signaling pathway in DCM rats. METHODS: Male Wistar rats were randomly divided into 3 groups: the control group, diabetic mellitus (DM) group and DM with carvedilol treatment group. DM rats were induced by streptozotocin accompanied by high energy intake. Carvedilol was orally administered at a dose of 10 mg/kg/day. After 16 weeks, the interrelated blood data were detected by biochemical analysis. Cardiac function was evaluated by echocardiography and the serum NT-proBNP level. The changes of myocardium ultrastructural and fibrosis were determined by electron microscopy and Masson's staining. Apoptotic cells were examined by TUNEL staining and interrelated proteins were measured by immunohistochemical and Western blots. RESULTS: Rats in the DM group showed significant serum elevation of glucose, cholesterol, triglyceride, NT-proBNP, IL-1ß and TNF-α, along with decreased cardiac function. Moreover, in the DM group, the levels of myocardial apoptosis and fibrosis were all increased accompanied by upregulation of caspase-3 and downregulation of phos-AKT and phos-XIAP, whereas carvedilol treatment prevented or reversed all the changes without influencing plasma levels of glucose, cholesterol and triglyceride. CONCLUSIONS: The AKT/XIAP signaling pathway may be involved in DCM. Carvedilol can improve cardiac function, possibly not only by upregulating the AKT/XIAP antiapoptotic signaling pathway and subsequently attenuating myocardial fibrosis, but also through suppressing the myocardial inflammation response.

Stress-induced changes in the expression of the clock protein PERIOD1 in the rat limbic forebrain and hypothalamus: role of stress type, time of day, and predictability.

Stressful events can disrupt circadian rhythms in mammals but mechanisms underlying this disruption remain largely unknown. One hypothesis is that stress alters circadian protein expression in the forebrain, leading to functional dysregulation of the brain circadian network and consequent disruption of circadian physiological and behavioral rhythms. Here we characterized the effects of several different stressors on the expression of the core clock protein, PER1 and the activity marker, FOS in select forebrain and hypothalamic nuclei in rats. We found that acute exposure to processive stressors, restraint and forced swim, elevated PER1 and FOS expression in the paraventricular and dorsomedial hypothalamic nuclei and piriform cortex but suppressed PER1 and FOS levels exclusively in the central nucleus of the amygdala (CEAl) and oval nucleus of the bed nucleus of the stria terminalis (BNSTov). Conversely, systemic stressors, interleukin-1ß and 2-Deoxy-D-glucose, increased PER1 and FOS levels in all regions studied, including the CEAl and BNSTov. PER1 levels in the suprachiasmatic nucleus (SCN), the master pacemaker, were unaffected by any of the stress manipulations. The effect of stress on PER1 and FOS was modulated by time of day and, in the case of daily restraint, by predictability. These results demonstrate that the expression of PER1 in the forebrain is modulated by stress, consistent with the hypothesis that PER1 serves as a link between stress and the brain circadian network. Furthermore, the results show that the mechanisms that control PER1 and FOS expression in CEAl and BNSTov are uniquely sensitive to differences in the type of stressor. Finally, the finding that the effect of stress on PER1 parallels its effect on FOS supports the idea that Per1 functions as an immediate-early gene. Our observations point to a novel role for PER1 as a key player in the interface between stress and circadian rhythms.

The influence of weather and lemmings on spatiotemporal variation in the abundance of multiple avian guilds in the arctic.

Climate change is occurring more rapidly in the Arctic than other places in the world, which is likely to alter the distribution and abundance of migratory birds breeding there. A warming climate can provide benefits to birds by decreasing spring snow cover, but increases in the frequency of summer rainstorms, another product of climate change, may reduce foraging opportunities for insectivorous birds. Cyclic lemming populations in the Arctic also influence bird abundance because Arctic foxes begin consuming bird eggs when lemmings decline. The complex interaction between summer temperature, precipitation, and the lemming cycle hinder our ability to predict how Arctic-breeding birds will respond to climate change. The main objective of this study was to investigate the relationship between annual variation in weather, spring snow cover, lemming abundance and spatiotemporal variation in the abundance of multiple avian guilds in a tundra ecosystem in central Nunavut, Canada: songbirds, shorebirds, gulls, loons, and geese. We spatially stratified our study area based on vegetation productivity, terrain ruggedness, and freshwater abundance, and conducted distance sampling to estimate strata-specific densities of each guild during the summers of 2010-2012. We also monitored temperature, rainfall, spring snow cover, and lemming abundance each year. Spatial variation in bird abundance matched what was expected based on previous ecological knowledge, but weather and lemming abundance also significantly influenced the abundance of some guilds. In particular, songbirds were less abundant during the cool, wet summer with moderate snow cover, and shorebirds and gulls declined with lemming abundance. The abundance of geese did not vary over time, possibly because benefits created by moderate spring snow cover were offset by increased fox predation when lemmings were scarce. Our study provides an example of a simple way to monitor the correlation between weather, spring snow cover, lemming abundance, and spatiotemporal variations in Arctic-breeding birds.

Phase differences in expression of circadian clock genes in the central nucleus of the amygdala, dentate gyrus, and suprachiasmatic nucleus in the rat.

We performed a high temporal resolution analysis of the transcript level of two core clock genes, Period2 (Per2) and Bmal1, and a clock output gene, Dbp, in the suprachiasmatic nucleus (SCN), the master circadian clock, and in two forebrain regions, the lateral part of the central nucleus of the amygdala (CEAl), and dentate gyrus (DG), in rats. These regions, as we have shown previously, exhibit opposite rhythms in expression of the core clock protein, PERIOD2 (PER2). We found that the expression of Per2, Bmal1 and Dbp follow a diurnal rhythm in all three regions but the phase and amplitude of the rhythms of each gene vary across regions, revealing important regional differences in temporal dynamics underlying local daily rhythm generation in the mammalian forebrain. These findings underscore the complex temporal organization of subordinate circadian oscillators in the forebrain and raise interesting questions about the functional connection of these oscillators with the master SCN clock.

Comprehensive mapping of regional expression of the clock protein PERIOD2 in rat forebrain across the 24-h day.

In mammals, a light-entrainable clock located in the suprachiasmatic nucleus (SCN) regulates circadian rhythms by synchronizing oscillators throughout the brain and body. Notably, the nature of the relation between the SCN clock and subordinate oscillators in the rest of the brain is not well defined. We performed a high temporal resolution analysis of the expression of the circadian clock protein PERIOD2 (PER2) in the rat forebrain to characterize the distribution, amplitude and phase of PER2 rhythms across different regions. Eighty-four LEW/Crl male rats were entrained to a 12-h: 12-h light/dark cycle, and subsequently perfused every 30 min across the 24-h day for a total of 48 time-points. PER2 expression was assessed with immunohistochemistry and analyzed using automated cell counts. We report the presence of PER2 expression in 20 forebrain areas important for a wide range of motivated and appetitive behaviors including the SCN, bed nucleus, and several regions of the amygdala, hippocampus, striatum, and cortex. Eighteen areas displayed significant PER2 rhythms, which peaked at different times of day. Our data demonstrate a previously uncharacterized regional distribution of rhythms of a clock protein expression in the brain that provides a sound basis for future studies of circadian clock function in animal models of disease.

Translational control of entrainment and synchrony of the suprachiasmatic circadian clock by mTOR/4E-BP1 signaling.

Protein synthesis is critical for circadian clock function, but little is known of how translational regulation controls the master pacemaker in mammals, the suprachiasmatic nucleus (SCN). Here we demonstrate that the pivotal translational repressor, the eukaryotic translational initiation factor 4E binding protein 1 (4E-BP1), is rhythmically regulated via the mechanistic target of rapamycin (mTOR) signaling in the SCN and preferentially represses vasoactive intestinal peptide (Vip) mRNA translation. Knockout (KO) of Eif4ebp1 (gene encoding 4E-BP1) leads to upregulation of VIP and higher amplitude of molecular rhythms in the SCN. Consequently, the 4E-BP1 null mice exhibit accelerated re-entrainment to a shifted light/dark cycle and are more resistant to the rhythm-disruptive effects of constant light. Conversely, in Mtor(+/-) mice VIP expression is decreased and susceptibility to the effects of constant light is increased. These results reveal a key role for mTOR/4E-BP1-mediated translational control in regulating entrainment and synchrony of the master clock.

Rapid localized spread and immunologic containment define Herpes simplex virus-2 reactivation in the human genital tract.

Herpes simplex virus-2 (HSV-2) is shed episodically, leading to occasional genital ulcers and efficient transmission. The biology explaining highly variable shedding patterns, in an infected person over time, is poorly understood. We sampled the genital tract for HSV DNA at several time intervals and concurrently at multiple sites, and derived a spatial mathematical model to characterize dynamics of HSV-2 reactivation. The model reproduced heterogeneity in shedding episode duration and viral production, and predicted rapid early viral expansion, rapid late decay, and wide spatial dispersion of HSV replication during episodes. In simulations, HSV-2 spread locally within single ulcers to thousands of epithelial cells in <12 hr, but host immune responses eliminated infected cells in <24 hr; secondary ulcers formed following spatial propagation of cell-free HSV-2, allowing for episode prolongation. We conclude that HSV-2 infection is characterized by extremely rapid virological growth and containment at multiple contemporaneous sites within genital epithelium. DOI:http://dx.doi.org/10.7554/eLife.00288.001.

Peripheral circadian clocks--a conserved phenotype?

The circadian system of mammals regulates the timing of occurrence of behavioral and physiological events, thereby optimizing adaptation to their surroundings. This system is composed of a single master pacemaker located in the suprachiasmatic nucleus (SCN) and a population of peripheral clocks. The SCN integrates time information from exogenous sources and, in turn, synchronizes the downstream peripheral clocks. It is assumed that under normal conditions, the circadian phenotype of different peripheral clocks would be conserved with respect to its period and robustness. To study this idea, we measured the daily wheel-running activity (WRA; a marker of the SCN output) in 84 male inbred LEW/Crl rats housed under a 12 h:12 h light-dark cycle. In addition, we assessed the mRNA expression of two clock genes, rPer2 and rBmal1, and one clock-controlled gene, rDbp, in four tissues that have the access to time cues other than those emanating from the SCN: olfactory bulbs (OBs), liver, tail skin, and white blood cells (WBCs). In contrast with the assumption stated above, we found that circadian clocks in peripheral tissues differ in the temporal pattern of the expression of circadian clock genes, in the robustness of the rhythms, and possibly in the number of functional ~24-h-clock cells. Based on the tissue diversity in the robustness of the clock output, the hepatic clock is likely to house the highest number of functional ~24-h-clock cells, and the OBs, the fewest number. Thus, the phenotype of the circadian clock in the periphery is tissue specific and may depend not only on the SCN but also on the sensitivity of the tissue to non-SCN-derived time cues. In the OBs and liver, the circadian clock phenotypes seem to be dominantly shaped by the SCN output. However, in the tail skin and WBC, other time cues participate in the phenotype design. Finally, our study suggests that the basic phenotype of the circadian clock is constructed at the transcript level of the core clock genes. Yet, additional posttranscriptional and translational events can contribute to the robustness and periodicity of the clock output.

Recording and analysis of circadian rhythms in running-wheel activity in rodents.

When rodents have free access to a running wheel in their home cage, voluntary use of this wheel will depend on the time of day. Nocturnal rodents, including rats, hamsters, and mice, are active during the night and relatively inactive during the day. Many other behavioral and physiological measures also exhibit daily rhythms, but in rodents, running-wheel activity serves as a particularly reliable and convenient measure of the output of the master circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus. In general, through a process called entrainment, the daily pattern of running-wheel activity will naturally align with the environmental light-dark cycle (LD cycle; e.g. 12 hr-light:12 hr-dark). However circadian rhythms are endogenously generated patterns in behavior that exhibit a ~24 hr period, and persist in constant darkness. Thus, in the absence of an LD cycle, the recording and analysis of running-wheel activity can be used to determine the subjective time-of-day. Because these rhythms are directed by the circadian clock the subjective time-of-day is referred to as the circadian time (CT). In contrast, when an LD cycle is present, the time-of-day that is determined by the environmental LD cycle is called the zeitgeber time (ZT). Although circadian rhythms in running-wheel activity are typically linked to the SCN clock, circadian oscillators in many other regions of the brain and body could also be involved in the regulation of daily activity rhythms. For instance, daily rhythms in food-anticipatory activity do not require the SCN and instead, are correlated with changes in the activity of extra-SCN oscillators. Thus, running-wheel activity recordings can provide important behavioral information not only about the output of the master SCN clock, but also on the activity of extra-SCN oscillators. Below we describe the equipment and methods used to record, analyze and display circadian locomotor activity rhythms in laboratory rodents.

Vaginal langerhans cells nonproductively transporting HIV-1 mediate infection of T cells.

Although implied by other models, proof that Langerhans cells (LCs) in the human vagina participate in dissemination of infectious human immunodeficiency virus type 1 (HIV-1) has been lacking. Here, we show that LCs migrate from HIV-1-exposed vaginal epithelia and pass infectious virus to CD4+ T cells without being productively infected themselves, and we point to a pathway that might enable HIV-1 to avoid degradation in vaginal LCs. Transport by migratory LCs to local lymphatics in a nonproductive but infectious form may aid HIV-1 in evasion of topical microbicides that target its intracellular productive life cycle.

Variations in daily expression of the circadian clock protein, PER2, in the rat limbic forebrain during stable entrainment to a long light cycle.

The circadian clock in the mammalian suprachiasmatic nucleus (SCN) can be entrained by light cycles longer than the normal 24-h light/dark (LD) cycle, but little is known about the effect of such cycles on circadian clocks outside the SCN. Here we examined the effect of exposure to a 26-h T cycle (T26, 1 h:25 h LD) on patterns of expression of the clock protein, PERIOD2 (PER2), in the SCN and in four regions of the limbic forebrain known to exhibit robust circadian oscillations in PER2: the oval nucleus of the bed nucleus of the stria terminalis (BNSTov), central nucleus of the amygdala (CEA), basolateral amygdala (BLA), and dentate gyrus (DG). All rats showed stable entrainment of running wheel activity rhythms to the T26 cycle. As previously shown, PER2 expression in the SCN was stably entrained, peaking around the onset of locomotor activity. In contrast, exposure to the T26 cycle uncoupled the rhythms of PER2 expression in the BNSTov and CEA from that of the SCN, whereas PER2 rhythms in the BLA and DG were unaffected. These results show that exposure to long light cycles can uncouple circadian oscillators in select nuclei of the limbic forebrain from the SCN clock and suggest that such cycles may be used to study the functional consequences of coupling and uncoupling of brain circadian oscillators.

Endogenous dopamine regulates the rhythm of expression of the clock protein PER2 in the rat dorsal striatum via daily activation of D2 dopamine receptors.

A role for dopamine (DA) in the regulation of clock genes in the mammalian brain is suggested by evidence that manipulations of DA receptors can alter the expression of some clock genes outside the suprachiasmatic nucleus (SCN), the master circadian clock. The role of endogenous DA in the regulation of clock gene expression is unknown. Here, we demonstrate a direct relationship between extracellular DA levels and the rhythm of expression of the clock protein PERIOD2 (PER2) in the dorsal striatum of the male Wistar rat. Specifically, we show that the peak of the daily rhythm of extracellular DA in the dorsal striatum precedes the peak of PER2 by ∼6 h and that depletion of striatal DA by 6-hydroxydopamine or α-methyl-para-tyrosine or blockade of D(2) DA receptors by raclopride blunts the rhythm of striatal PER2. Furthermore, timed daily activation of D(2) DA receptors, but not D(1) DA receptors, restores and entrains the PER2 rhythm in the DA-depleted striatum. None of these manipulations had any effect on the PER2 rhythm in the SCN. Our findings are consistent with the idea that the rhythm of expression of PER2 in the dorsal striatum depends on daily dopaminergic activation of D(2) DA receptors. These observations may have implications for circadian abnormalities seen in Parkinson's disease.

Are migrant and resident elk (Cervus elaphus) exposed to similar forage and predation risk on their sympatric winter range?

Partially migratory populations, where one portion of a population conducts seasonal migrations (migrants) while the other remains on a single range (residents), are common in ungulates. Studies that assess trade-offs between migratory strategies typically compare the amount of predation risk and forage resources migrants and residents are exposed to only while on separate ranges and assume both groups intermix completely while on sympatric ranges. Here we provide one of the first tests of this assumption by comparing the amount of overlap between home ranges of GPS-collared migrant and resident elk and fine-scale exposure to wolf predation risk and forage biomass at telemetry locations on a sympatric winter range in west-central Alberta, Canada. Overlap between migrant and resident home ranges increased throughout the winter, and both groups were generally intermixed and exposed to equal forage biomass. During the day, both migrants and residents avoided predation risk by remaining in areas far from timber with high human activity, which wolves avoided. However, at night wolves moved onto the grasslands close to humans and away from timber. Resident elk were consistently closer to areas of human activity and further from timber than migrants, possibly because of a habituation to humans. As a result, resident elk were exposed to higher night-time predation risk than migrants. Our study does not support the assumption that migrant and resident elk are exposed to equal predation risk on their sympatric range when human presence alters predation risk dynamics and habituation to humans is unequal between migratory strategies.

Ex vivo comparison of microbicide efficacies for preventing HIV-1 genomic integration in intraepithelial vaginal cells.

Vaginally applied microbicides hold promise as a strategy to prevent sexual HIV transmission. Several nonspecific microbicides, including the polyanion cellulose sulfate, have been evaluated in large-scale clinical trials but have failed to show significant efficacy. These findings have prompted a renewed search for preclinical testing systems that can predict negative outcomes of microbicide trials. Moreover, the pipeline of potential topical microbicides has been expanded to include antiretroviral agents, such as reverse transcriptase, fusion, and integrase inhibitors. Using a novel ex vivo model of vaginal HIV-1 infection, we compared the prophylactic potentials of two forms of the fusion inhibitor T-20, the CCR5 antagonist TAK-778, the integrase inhibitor 118-D-24, and cellulose sulfate (Ushercell). The T-20 peptide with free N- and C-terminal amino acids was the most efficacious compound, causing significantly greater inhibition of viral genomic integration in intraepithelial vaginal leukocytes, measured by an optimized real-time PCR assay, than the more water-soluble N-acetylated T-20 peptide (Fuzeon) (50% inhibitory concentration [IC50], 0.153 microM versus 51.2 microM [0.687 ng/ml versus 230 ng/ml]; P<0.0001). In contrast, no significant difference in IC50s was noted in peripheral blood cells (IC50, 13.58 microM versus 7.57 microM [61 ng/ml versus 34 ng/ml]; P=0.0614). Cellulose sulfate was the least effective of all the compounds tested (IC50, 1.8 microg/ml). These results highlight the merit of our model for screening the mucosal efficacies of novel microbicides and their formulations and potentially rank ordering candidates for clinical evaluation.

Differential effects of HIV infected macrophages on dorsal root ganglia neurons and axons.

Human immunodeficiency virus-associated distal-symmetric neuropathy (HIV-DSP) is the most common neurological complication of HIV infection. The pathophysiology of HIV-DSP is poorly understood and no treatment is available for this entity. The dorsal root ganglia (DRG) are the principal sites of neuronal damage and are associated with reactive mononuclear phagocytes as well as HIV-infected macrophages. To determine the role of HIV-infected macrophages in the pathogenesis of HIV-DSP, we developed a technique for culturing human DRG's. When the dissociated DRG neurons were exposed to supernatants from macrophages infected with CXCR4 or CCR5 tropic HIV-1 strains axonal retraction was observed without neuronal cell death but there was mitochondrial dysfunction in the neuronal cell body. Even though CXCR4 and CCR5 were expressed on the DRG neurons, the effects were independent of these receptors. Antioxidants rescued the neuronal cell body but not the axon from the toxic effects of the culture supernatants. Further, peripheral nerves of HIV-infected patients obtained at autopsy did not show evidence of increased oxidative stress. These observations suggest a differential effect on the axon and cell body. Different mechanisms of injury may be operative in these two structures.

Nucleoside reverse transcriptase inhibitors and human immunodeficiency virus proteins cause axonal injury in human dorsal root ganglia cultures.

Distal symmetric polyneuropathy (DSP) has emerged as the most common complication of human immunodeficiency virus (HIV) infection, which is associated with neuronal injury in the dorsal root ganglion (DRG). With the advent of highly active antiretroviral therapy, especially nucleoside analogs, patients are living longer. Some of the antiretroviral drugs used to treat HIV infection have been associated with neuropathies. The pathogenesis of these neuropathies remains poorly understood. Utilizing a human fetal DRG model of predominantly nociceptive fibers, the authors investigated the effects of HIV gp120 and Tat(1-72), alone or in combination with nucleoside analogs on both morphological and ultra-structural changes in DRG neurons. Nucleoside analogs and HIV proteins both caused a significant decrease in the mean axonal length. However, ddI was the most potent, followed by ddC, d4T, and AZT. Despite the combined exposure to toxic dosages of HIV proteins and nucleoside analogs, there appeared to be a ceiling effect on the amount of axonal retraction, indicating that the proximal and distal axon are differentially regulated. In conclusion, both HIV proteins and nucleoside reverse transcriptase inhibitors (NRTIs) cause axonal damage by inducing mitochondrial injury and rearrangement of microtubules.

Thyroidectomy alters the daily pattern of expression of the clock protein, PER2, in the oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala in rats.

A role for thyroid hormones in the regulation of the rhythmic expression of circadian clock genes is suggested by the finding that surgical removal of the thyroid gland alters circadian behavioral and endocrine rhythms in rodents. Virtually nothing is known about the role of thyroid hormones in the regulation of clock genes responsible for the generation of circadian rhythmicity. To study this issue, we assessed in rats the effect of thyroidectomy/parathyrodectomy (TPX) on the expression of the clock protein, PER2, in the suprachiasmatic nucleus (SCN), the master circadian clock, and in a number of key limbic forebrain structures, the oval nucleus of the bed nucleus of the stria terminalis (BNSTov), the central nucleus of the amygdala (CEA), the basolateral amygdala (BLA) and the dentate gyrus (DG). TPX significantly altered the normal daily pattern of PER2 expression in the BNSTov and CEA, but had no effect on PER2 expression in the SCN, BLA and DG. Thus, although thyroid hormones modulate PER2 expression in the brain, the effect is tissue specific and therefore likely not to be mediated by a direct effect of the hormone on gene expression.