Characterizing the HIV Brain during Rest using Neuroimaging
Recent studies have shown that 35-70% of patients infected with the human immunodeficiency virus type one (HIV) exhibit at least some form of neuropsychological impairment. These impairments are generally referred to as HIV-associated neurocognitive disorders (HAND) and are formally categorized into three levels. Importantly, although neuropsychological studies have shown that HAND affects a wide array of cognitive functions, a formal diagnosis is still based on the exclusion of opportunistic infections and other common ailments, as no specific tests or biomarkers are currently available. The primary goal in the current study was to use magnetoencephalography (MEG), which is a noninvasive and direct measure of neural activity with millisecond temporal resolution and millimeter spatial precision, to identify cortical regions where there was reduced neuronal firing in HIV-infected participants compared with controls, and to decipher whether activity in these regions was predictive of neuropsychological functioning. Reductions in neural activity likely indicate reduced neuronal synchronization within specific brain areas. Potentially, such functional indices of neural activity may be more sensitive to early cortical changes than structural-based measures, and thus provide improved options for early detection of HAND.
The study team used MEG imaging to measure neural activity during rest (i.e., when the participants were not engaged in any task) in 15 HIV-infected patients and a matched group of 15 uninfected controls. Their primary findings were that HIV-infected persons exhibited decreased beta (14-30 Hz) oscillations in several brain regions, including the supplementary motor area, paracentral lobule, posterior cingulate, and bilateral regions of the superior parietal lobule relative to healthy controls. Beta oscillations in the posterior cingulate, a critical component of the default mode network, were also positively correlated with patient scores on the memory recall aspect of the Hopkins Verbal Learning Test-Revised. These results demonstrate that chronic HIV infection does not uniformly disturb cortical function, and that neuronal populations in dorso-medial motor and parietal cortices are especially affected. These findings also suggest that resting-state MEG recordings may hold significant promise as a functional biomarker for identifying HAND and monitoring disease progression.
The full abstract of the paper, as well as a link to the full text can be found here
Oxytocin facilitates fidelity in marmosets
Marmosets are one of the few primate species (other than humans) in which males and females form and maintain long-term social relationships, otherwise known as 'pair-bonds.' These relationships in marmosets, like human romantic relationships, are characterized by marmoset couples spending lots of time together doing similar activities, and showing high levels of affiliative and sexual behavior with their long-term partner. In addition, marmoset couples tend to avoid interactions with opposite-sex strangers, which also is important for maintaining fidelity among couples. Cavanaugh tested whether the neuropeptide oxytocin, a hormone known to promote social behavior, affected the nature of the social and sexual relationship in marmoset couples. Marmosets were given either an intranasal 'spritz' of oxytocin, or a saline spray, and then given an opportunity to interact with their long-term pairmate or an opposite-sex stranger. Oxytocin treatment did not change the relationship between existing marmoset couples, and marmosets spent the same amount of time nearby or in contact with their partner, and similar rates of courtship and sexual behavior whether treated with oxytocin or saline. However, while marmosets (maybe like human beings!) show some level of interest in attractive strangers of the opposite sex, treatment with oxytocin reduced the time spent 'checking out' these strangers, and delayed the expression of sexual solicitation behaviors that constitute the marmoset equivalent of 'flirting' with strangers. These results show that oxytocin plays a role in promoting marmoset pair-bonds, not by making partners 'love' each other more, but rather by decreasing interest in interactions with opposite-sex strangers. Thus, oxytocin does appear to play a role in marmoset monogamy, by decreasing the potential that a marmoset may stray from its long-term partner. The results also highlight that there are at least two mechanisms for maintaining social and sexual fidelity with a long-term partner: attraction TO the partner, and avoidance OF interactions with potential strangers of the opposite sex. In marmosets, oxytocin appears to affect the second mechanism, which nevertheless leads to good marmoset couples. This research was supported by funds from the National Institutes of Health (HD42882) awarded to Jeff French and UNO's Graduate Research and Creative Activity (GRACA) awarded to Jon Cavanaugh.
An abstract of the paper can be found here: http://tiny.cc/marmoset_couples
Contact: Jon Cavanaugh – firstname.lastname@example.org
Two members of the neuroscience group, Postdoctoral Research Fellow Dongren Ren and Neuroscience Program Director, Dr. Jeff French, were part of a research team that recently published a paper on molecular genetics in the marmoset monkey. Collaborators included Drs. Robert Norgren (UNMC) Etsuko Moriyama (UNL), and UNO undergraduate bioinformatics major Mnirnal Maudhoo, who served as first author on the paper. The research used Next-Generation ("Next-Gen") sequencing techniques to characterize the marmoset transcriptome, or mRNA sequences, expressed in five different tissues. The transcriptome differs from the traditional genome, because it provides information above and beyond the gene sequences that are found in every cell, and can specify which genes are active and being expressed in different tissues of the body. The paper was published in the Biomed Central journal, Gigascience, on 19 September 2014.
The research identifies over 10,000 genes in the marmoset, and further characterizes over 2,000 genes that had not previously been described in the recently-published marmoset genome (July 2014 issue of Nature Genetics). The paper includes links to a database that contains over 30 billion base pairs from the marmoset transcriptome that are publically accessible to scientists. The data will be useful for scientists who are interested in primate evolution, and animal models of immunology, physiology, and reproduction. Because the transcriptomic data includes mRNA sequences from the cerebellum, hippocampus, and cerebral cortex, the data will also be of particular interest for neuroscientists.
A full-text, open access copy of the paper can be found here: http://www.gigasciencejournal.com/content/3/1/14 and the paper contains links to the publically-accessible database for the marmoset transcriptome.
Biology and Sex Differences Redux
A recent Pew survey showed that in 40% of American households with children, women were the major 'bread-winners'. In an interview on Fox News, conservative political blogger Erick Erickson responded to this survey by stating that it was "anti-science" for society to accept this role for women. "When you look at biology, when you look at the natural world – the roles of a male and a female in society and in other animals, the male typically is the dominant role. The female, it's not antithesis, or it's not competing, it's a complementary role", said Erickson. These statements ignited anew the discussion regarding "biologically-determined" sex roles in men and women.
An upcoming scientific paper by a group of UNO scientists in the College of Arts and Sciences has clearly shown that 'science' has no rigid proscriptions for what male and female roles are or what they should be in nature. The group, led by Jeff French, Varner Professor of Psychology, Biology, and Neuroscience at UNO, reviewed the published literature on species of mammals (the taxonomic group to which human beings belong) in which females are not only more aggressive than males, but in many cases are socially dominant over males. "In a host of species, females are clearly dominant to males in feeding competitions, in access to preferred locations for resting and sleeping, and in many other facets of social life", said French. Species in which females "rule the roost" include spotted hyenas, rock hyrax (a close relative of elephants), ring-tailed lemurs, marmosets, and hamsters.
In their paper, French and his group, including graduate students Aaryn Mustoe and Jon Cavanaugh, and research technician Andrew Birnie, also presented information on the biological origins of this sex-reversed pattern of dominance and aggression. In many cases, exposure to high levels of androgen hormones (like testosterone) during gestation or shortly after birth can 'program' the brain centers involved in regulating aggression and dominance in females, thus shaping the nature of aggression later in adulthood. In addition, the ability to form complex coalitions among females, particularly among related individuals (mothers, daughters, and granddaughters) can provide an important social route to female dominance in some species.
"In contrast to Mr. Erickson's characterization of male and female roles, our work shows that having simply having XX or XY chromosomes (the sex-determining chromosomes in female and male mammals, respectively) does not dictate what an individual's social role, social status, or aggression level will be", concluded French. "Nature has multiple ways of shaping sex roles, and our review confirms that evolution produces remarkable diversity in animals. This includes diversity in sex-typical patterns of dominance and aggression, including many cases where females are both more aggressive and more dominant than males." The paper will be published in an upcoming issue of the Proceedings of the Royal Society B – Biological Sciences.
Contact: Jeffrey A. French email@example.com
This study used magnetoencephalography (MEG) to investigate neural population-level responses, and other oscillatory activity, during a motor task in un-medicated patients with Parkinson's Disease (PD) and a matched-group of healthy adults. The goal of the study was to investigate the locus of motor deficits in patients with PD during each phase of movement: planning, execution, and termination. During the study, patients and controls performed a simple finger-tapping task, while their brain activity was recorded in real-time. Each of the movement phases was independently examined using beamforming to distinguish the brain areas and movement stages where pathological brain activity exists during motor control. Patients with PD exhibited significantly diminished pre-movement neural activity, which indicates that these patients have difficulty demonstrating the proper brain response during movement planning. This is likely to contribute to their diminished movement capacities. This study provides important evidence of aberrant cortical oscillations in patients with PD during movement, and suggests that advanced MEG techniques may be a promising method to explore neurophysiological markers of PD symptomatology. A full pdf copy of the paper can be found here.
The study addressed the important question of feeding intolerance (FI) in premature infants. Some proportion of 'premies' develop an inability to appropriately process food delivered orally, and the problem can lead to long-term developmental morbidity in infants or even death. Moore's study evaluated the potential for predicting whether a premature infant would develop FI based on metabolic biomarkers measured in noninvasively collected samples (urine and saliva). Infants that ultimately developed FI had significantly lower levels of the metabolically-important hormone CORTISOL on the first day of life, and tended to have lower levels of 8-OHdG (8-hydroxydeoxyguanasine) a marker of oxidative stress at the same time point. Although the sample size was small, the results point to the potential usefulness of these noninvasively collected biomarkers for predicting health outcomes (especially feeding intolerance) in the remarkably at-risk population of premature infants.
In most primate species, including humans, exposure of developing fetuses to high levels of male-like hormones (androgens) masculinizes both external genitalia in sex-specific patterns, and sex-typical play patterns. Primate fetuses that are exposed to higher levels of prenatal androgens exhibit higher levels of rough-and-tumble play, and choose male-typical play objects. We monitored gestational levels of androgens in pregnant female marmoset monkeys, and looked for associations with postnatal play patterns. Unlike humans and rhesus monkeys, juveniles born to mothers with higher gestational levels of androgen hormones received fewer play initiations from other group members overall, received fewer play initiations from siblings, engaged in less overall play with siblings, and initiated fewer play bouts with male siblings. High levels of aggressive-like play in juveniles (and aggression in adulthood) may be incompatible with prosocial behavior that is critical for pair-bond formation and parental care in marmosets. Therefore, marmosets may employ mechanisms by which increased exposure to gestational androgens can facilitate both physical and behavioral characteristics that favor a monogamous and biparental social structure.
UNO Neuroscience majors were featured in the College of Arts and Sciences 2012 Newsletter. Link to article.
Rosemary Strasser, a UNO faculty member in the Neuroscience Program, was a co-author on a recent paper in the international journal Age. The study evaluated the impact of variation in early testosterone exposure on lifespan in the house sparrow, a common North American songbird. A summary of the paper follows below, and a link to the paper can be found here:http://tinyurl.com/6qd7ezu
The presence or absence of certain hormones during prenatal development can organize the brain and influence the future behavior of offspring. Many mothers "program" the development of their offspring through the transmission of maternal steroid hormones to their young. These early maternal hormones can have long-lasting effects on the growth, development, behavior, and survival of their young. Birds are an excellent model system to study these maternal effects because the mothers naturally vary the amount of steroid hormones they deposit into their eggs and the young develop outside the mother. In many bird species, the concentration of these maternal steroids, mostly androgens like testosterone, can "organize" the brain and influence the behavior of the offspring well into adulthood. In a recent publication, we report that injections of a physiological dose of testosterone (T) into yolks of freshly laid eggs of a small, seasonally breeding songbird, the house sparrow (Passer domesticus), increased survivorship during the first years of life. In addition, survival effects of developmental T exposure were sex-dependent, with males generally having a higher risk of death their first year. T treatment resulted in higher body mass at 3–4months of age which subsequently influenced mortality risk. This study suggest that although testosterone-enhanced survivorship could potentially increase lifetime reproductive success, there is a “cost” associated with this. Specifically, testosterone may increase mortality risk from extrinsic factors in young male house sparrows by altering adult sexual and aggressive behavior, by increasing the risk of exposure to infectious disease, predation, and injury, or by alterations in physiology early in life that could, in turn, affect health, physiological function and survivorship later in life.
Tony Wilson, a UNMC faculty member with an Courtesy Appointment with the Neuroscience Program at UNO, and Beth Heinrichs-Graham, an M.A. student in psychobiology at UNO, have recently published a paper in the journal Human Brain Mapping exploring the relationship between brain function in a unique brain circuit called the default-mode network, and attention deficit disorder. A brief summary follows, and a copy of the original paper can be found here.
The default-mode network (DMN) is a group of brain structures that are active when a person engages in processes such as self-reflection or mind wandering. The DMN includes the medial prefrontal cortex (MPFC), the posterior cingulate/precuneus cortices (PCC), and the mediolateral inferior parietal cortices bilaterally (RIPL and LIPL). Dysfunction in these areas may be associated with Attention Deficit/Hyperactivity Disorder, a disorder characterized by inattention and hyperactivity/impulsivity. One consistent finding is that there is reduced functional connectivity between the MPFC and the PCC cortices in patients with ADHD during the resting-state. This study evaluates neurophysiological function within cortices of the DMN during a period of awake rest using magnetoencephalography (MEG) in unmedicated and medicated adults with ADHD (predrug/postdrug), as well as group of adults without ADHD. Findings included a global reduction of high-frequency activity in the DMN in unmedicated adults with ADHD, and a particularly robust decrease of neuronal activity in the MPFC of adults with ADHD that was frequency-nonspecific. The unmedicated patients also exhibited significantly stronger activation in posterior nodes (LIPL and RIPL) than the anterior MPFC at lower frequencies. The administration of ADHD medication suppressed the cross-frequency gamma coupling and significantly normalized 8–14 Hz alpha activity in the MPFC of adults with ADHD. However, neuronal activity in all other frequency bins remained abnormal. This study improves knowledge of the DMN as it is the first to demonstrate broadband (not just low-frequency) abnormalities in patients with ADHD, as well as provides insight into the frequency-specific pharmacological effects of ADHD medication on adults with ADHD.
Dr. Bruce Chase, Professor of Biology and a member of the Neuroscience faculty, was recently a co-author on a scientific paper that describes a potential link between a genetic mutation and the neurodegenerative condition known as Parkinson’s disease, or Parkinsonism. He summarizes the work below: Most cases of Parkinson's Disease are sporadic and have an unknown cause. However, a few percent of cases result from dominant or recessive mutations. Studying these rare inherited mutations has led to the identification of about a dozen genes. In turn, their analysis has led to substantial insights into the causes of Parkinson's Disease. The first gene to be identified was that for alpha-synuclein. Alpha-synuclein accumulates in most forms of Parkinson's disease as well as in several other neurodegenerative disorders, including Alzheimer Disease. This paper presents an analysis of a Swedish kindred with an A53T alpha-synuclein mutation. By comparing the genetic region containing the alpha-synuclein gene in the Swedish kindred to that in Greek kindreds that also have the A53T mutation, it shows that the A53T mutation has arisen independently in different human lineages. This supports the idea that the A53T mutation itself, and not some other nearby genetic variant, causes disease. By comparing the parkinsonian phenotype in the Swedish kindred to that seen in other kindreds, this paper also shows that the A53T mutation is associated with different parkinsonian phenotypes in different individuals. One possible explanation for this is that phenotypic differences arise from genetic variation at genes other than alpha-synuclein. Understanding how differences at other genes can modify a parkinsonian phenotype holds promise for developing therapeutic interventions that can delay or prevent the onset of sporadic Parkinson's disease. A link to the full-text article can be found here: http://tinyurl.com/3nzfoss
The black tufted-ear marmoset is helping the psychobiology lab of Dr. Jeffrey French at UNO understand the ways in which hormones and social interactions can influence health and well-being.
Maternal gestational androgen levels in female marmosets (Callithrix geoffroyi) vary across trimesters but do not vary with the sex ratio of litters. General and comparative endocrinology 2010;165(2):309-14.French Jeffrey A; Smith Adam S; Birnie Andrew K
Maternal hormones can dramatically modify offspring phenotypes via organizational actions on morphological and behavioral development. In placental mammals, there is the possibility that some portion of hormones in maternal circulation may be derived from fetal origin. We tested the possibility that maternal androgens in pregnant female marmosets reflected, in part, contributions from male fetuses by comparing levels of urinary androgens across pregnancy in females carrying varying numbers of male offspring. We monitored urinary androgen excretion in 18 pregnancies from five female white-faced marmosets (Callithrix geoffroyi). Androgen levels rose significantly in the first trimester of pregnancy, reached a peak in the middle of the second trimester, and then declined gradually until parturition. At no point in pregnancy were levels of urinary androgens higher in females carrying litters that had 50% or more males than in females carrying litters that were less than 50% male. Levels of maternal androgens were not associated with litter size, the number of males in the litter, or with the proportion of the litter that was male. The high levels of androgen in pregnant females are therefore likely of strictly maternal origin, and any modification of fetal growth and development can be considered a 'maternal effect'.