Perturbations in neural stem cell function during a neurotropic viral infection in juvenile mice.

Viral infections of the central nervous system (CNS) often cause worse neurological outcomes in younger hosts. Throughout childhood, the brain undergoes extensive development and refinement to produce functional neural networks. Network function is maintained partly with the help of neural stem cells (NSCs) that replace neuronal and glia subtypes in the two neurogenic niches of the brain (the hippocampus and subventricular zone). Accumulating evidence suggests that viruses disrupt NSC function in adulthood and infancy, but the in vivo impact of childhood infections on acute and long-term NSC function is unknown. Using a juvenile mouse model of measles virus (MeV) infection, where only mature neurons in the brain are infected, we defined the effects of the antiviral immune response on NSCs from juvenile to adult stages of life. We found that (a) virus persists in the brains of survivors despite an anti-viral immune response; (b) NSC numbers decrease dramatically during early infection, but ultimately stabilize in adult survivors; (c) infection is associated with mild apoptosis throughout the juvenile brain, but NSC proliferation is unchanged; (d) the loss of NSC numbers is dependent upon the stage of NSC differentiation; and (e) immature neurons increase early during infection, concurrent with depletion of NSC pools. Collectively, we show that NSCs are exquisitely sensitive to the inflammatory microenvironment created during neuron-restricted MeV infection in juveniles, responding with an early loss of NSCs but increased neurogenesis. These studies provide insight into potential cellular mechanisms associated with long-term neurological deficits in survivors of childhood CNS infections.

The anti-viral immune response of the adult host robustly modulates neural stem cell activity in spatial, temporal, and sex-specific manners.

Viruses induce a wide range of neurological sequelae through the dysfunction and death of infected cells and persistent inflammation in the brain. Neural stem cells (NSCs) are often disturbed during viral infections. Although some viruses directly infect and kill NSCs, the antiviral immune response may also indirectly affect NSCs. To better understand how NSCs are influenced by a productive immune response, where the virus is successfully resolved and the host survives, we used the CD46+ mouse model of neuron-restricted measles virus (MeV) infection. As NSCs are spared from direct infection in this model, they serve as bystanders to the antiviral immune response initiated by selective infection of mature neurons. MeV-infected mice showed distinct regional and temporal changes in NSCs in the primary neurogenic niches of the brain, the hippocampus and subventricular zone (SVZ). Hippocampal NSCs increased throughout the infection (7 and 60 days post-infection; dpi), while mature neurons transiently declined at 7 dpi and then rebounded to basal levels by 60 dpi. In the SVZ, NSC numbers were unchanged, but mature neurons declined even after the infection was controlled at 60 dpi. Further analyses demonstrated sex, temporal, and region-specific changes in NSC proliferation and neurogenesis throughout the infection. A relatively long-term increase in NSC proliferation and neurogenesis was observed in the hippocampus; however, neurogenesis was reduced in the SVZ. This decline in SVZ neurogenesis was associated with increased immature neurons in the olfactory bulb in female, but not male mice, suggesting potential migration of newly-made neurons out of the female SVZ. These sex differences in SVZ neurogenesis were accompanied by higher infiltration of B cells and greater expression of interferon-gamma and interleukin-6 in female mice. Learning, memory, and olfaction tests revealed no overt behavioral changes after the acute infection subsided. These results indicate that antiviral immunity modulates NSC activity in adult mice without inducing gross behavioral deficits among those tested, suggestive of mechanisms to restore neurons and maintain adaptive behavior, but also revealing the potential for robust NSC disruption in subclinical infections.

A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes.

Reactive microglia are observed with aging and in Lewy body disorders, including within the olfactory bulb of men with Parkinson's disease. However, the functional impact of microglia in these disorders is still debated. Resetting these reactive cells by a brief dietary pulse of the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 may hold therapeutic potential against Lewy-related pathologies. To our knowledge, withdrawal of PLX5622 after short-term exposure has not been tested in the preformed α-synuclein fibril (PFF) model, including in aged mice of both sexes. Compared to aged female mice, we report that aged males on the control diet showed higher numbers of phosphorylated α-synuclein+ inclusions in the limbic rhinencephalon after PFFs were injected in the posterior olfactory bulb. However, aged females displayed larger inclusion sizes compared to males. Short-term (14-day) dietary exposure to PLX5622 followed by control chow reduced inclusion numbers and levels of insoluble α-synuclein in aged males-but not females-and unexpectedly raised inclusion sizes in both sexes. Transient delivery of PLX5622 also improved spatial reference memory in PFF-infused aged mice, as evidenced by an increase in novel arm entries in a Y-maze. Superior memory was positively correlated with inclusion sizes but negatively correlated with inclusion numbers. Although we caution that PLX5622 delivery must be tested further in models of α-synucleinopathy, our data suggest that larger-sized-but fewer-α-synucleinopathic structures are associated with better neurological outcomes in PFF-infused aged mice.

Neural Stem Cells: What Happens When They Go Viral?

Viruses that infect the central nervous system (CNS) are associated with developmental abnormalities as well as neuropsychiatric and degenerative conditions. Many of these viruses such as Zika virus (ZIKV), cytomegalovirus (CMV), and herpes simplex virus (HSV) demonstrate tropism for neural stem cells (NSCs). NSCs are the multipotent progenitor cells of the brain that have the ability to form neurons, astrocytes, and oligodendrocytes. Viral infections often alter the function of NSCs, with profound impacts on the growth and repair of the brain. There are a wide spectrum of effects on NSCs, which differ by the type of virus, the model system, the cell types studied, and the age of the host. Thus, it is a challenge to predict and define the consequences of interactions between viruses and NSCs. The purpose of this review is to dissect the mechanisms by which viruses can affect survival, proliferation, and differentiation of NSCs. This review also sheds light on the contribution of key antiviral cytokines in the impairment of NSC activity during a viral infection, revealing a complex interplay between NSCs, viruses, and the immune system.

Type II interferon signaling in the brain during a viral infection with age-dependent pathogenesis.

Viral infections of the central nervous system (CNS) often cause disease in an age-dependent manner, with greater neuropathology during the fetal and neonatal periods. Transgenic CD46+ mice model these age-dependent outcomes through a measles virus infection of CNS neurons. Adult CD46+ mice control viral spread and survive the infection in an interferon gamma (IFNγ)-dependent manner, whereas neonatal CD46+ mice succumb despite similar IFNγ expression in the brain. Thus, we hypothesized that IFNγ signaling in the adult brain may be more robust, potentially due to greater basal expression of IFNγ signaling proteins. To test this hypothesis, we evaluated the expression of canonical IFNγ signaling proteins in the neonatal and adult brain, including the IFNγ receptor, Janus kinase (JAK) 1/2, and signal transducer and activator of transcription-1 (STAT1) in the absence of infection. We also analyzed the expression and activation of STAT1 and IFNγ-stimulated genes during MV infection. We found that neonatal brains have equivalent or greater JAK/STAT1 expression in the hippocampus and the cerebellum than adults. IFNγ receptor expression varied by cell type in the brain but was widely expressed on neuronal and glial cells. During MV infection, increased STAT1 expression and activation correlated with viral load in the hippocampus regardless of age, but not in the cerebellum where viral load was consistently undetectable in adults. These results suggest the neonatal brain is capable of initiating IFNγ signaling during a viral infection, but that downstream STAT1 activation is insufficient to limit viral spread.

Long weekend sleep is linked to stronger academic performance in male but not female pharmacy students.

Poor sleep hygiene portends loss of physical and mental stamina. Therefore, maintaining a regular sleep/wake schedule on both weekdays and weekends is highly recommended. However, this advice runs contrary to the habits of university students who sleep late on weekends. Pharmacy students at Duquesne University sit for frequent examinations, typically commencing at 7:30 AM, and they complain about mental fatigue. Here, we tested the central hypothesis that longer sleep durations on both weekdays and weekends are linked to stronger academic performance in men and women. Students in their first professional year were administered three surveys to collect data on sleep habits and factors that might influence sleep, such as roommates, long commute times, and sleep interruptions. Grade point averages (GPAs) were collected from the Dean's office, with individual permissions from the students. Longer weekend-but not weekday-sleep durations were significantly correlated with higher cumulative GPAs in men and not in women. Women achieved slightly higher cumulative GPAs than men. Students who fell asleep within 15 min of going to bed had higher professional-phase GPAs than those who fell asleep after an hour or more. Our observations cannot establish causal links, but, given the body of prior evidence on the salutary properties of sleep, men may reap more benefit from recovery sleep on weekends. Rather than recommending that students force themselves awake early on weekends in an attempt to maintain a consistent sleep routine, the real-life habits of students should also be given consideration.

Understanding the Role of Antiviral Cytokines and Chemokines on Neural Stem/Progenitor Cell Activity and Survival.

Viral infections of the central nervous system are accompanied by the expression of cytokines and chemokines that can be critical for the control of viral replication in the brain. The outcomes of cytokine/chemokine signaling in neural cells vary widely, with cell-specific effects on cellular activity, proliferation, and survival. Neural stem/progenitor cells (NSPCs) are often altered during viral infections, through direct infection by the virus or by the influence of immune cell activity or cytokine/chemokine signaling. However, it has been challenging to dissect the contribution of the virus and specific inflammatory mediators during an infection. In addition to initiating an antiviral program in infected NSPCs, cytokines/chemokines can induce multiple changes in NSPC behavior that can perturb NSPC numbers, differentiation into other neural cells, and migration to sites of injury, and ultimately brain development and repair. The focus of this review was to dissect the effects of common antiviral cytokines and chemokines on NSPC activity, and to consider the subsequent pathological consequences for the host from changes in NSPC function.

The neonatal anti-viral response fails to control measles virus spread in neurons despite interferon-gamma expression and a Th1-like cytokine profile.

Neonates are highly susceptible to viral infections in the periphery, potentially due to deviant cytokine responses. Here, we investigated the role of interferon-gamma (IFNγ), a key anti-viral in the neonatal brain. We found that (i) IFNγ, which is critical for viral control and survival in adults, delays mortality in neonates, (ii) IFNγ limits infiltration of macrophages, neutrophils, and T cells in the neonatal brain, (iii) neonates and adults differentially express pathogen recognition receptors and Type I interferons in response to the infection, (iv) both neonates and adults express IFNγ and other Th1-related factors, but expression of many cytokines/chemokines and IFNγ-responsive genes is age-dependent, and (v) administration of IFNγ extends survival and reduces CD4 T cell infiltration in the neonatal brain. Our findings suggest age-dependent expression of cytokine/chemokine profiles in the brain and distinct dynamic interplays between lymphocyte populations and cytokines/chemokines in MV-infected neonates.