Destination Area: Adaptive Brain and Behavior (ABB)
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This destination area focuses broadly on how brains change and adapt over the life course, how they change following traumatic events or diseases, and how social and societal forces are affected by and affect brains and individuals. ABB brings together humanities, social sciences, and neuroscience to analyze adaptive changes across multiple levels of inquiry from molecules to individuals, families, and communities. This destination area has three organizational sub-themes:
• Healthy and Unhealthy Brain Development: Characterizing healthy brain development first – including cognition, stress, emotion, and decision-making – allows researchers to better identify and understand unhealthy brain development with wide-ranging complex and interactive effects for people and communities. Virginia Tech has recognized leaders in research on focused brain and behavioral development.
• Brain Trauma: Damage occurs to the brain not only due to injury, but also genetics or psychological/emotional causes such as PTSD, abuse, or neglect. Virginia Tech is a recognized leader for research and education to help recognize, respond to, and recover from brain trauma.
• Brain Cancer: Affecting more than 200,000 people each year in the U.S. alone, brain cancer is a major health crisis. Virginia Tech has a strong contingent of internationally recognized investigators whose research is informing society on cancer biology, etiology, disease mechanisms, and experimental treatments.
[http://provost.vt.edu/destination-areas/da-brain.htm]
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Browsing Destination Area: Adaptive Brain and Behavior (ABB) by Subject "1103 Clinical Sciences"
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- Alzheimer's Disease-Like Neurodegeneration in Porphyromonas gingivalis Infected Neurons with Persistent Expression of Active GingipainsHaditsch, Ursula; Roth, Theresa; Rodriguez, Leo; Hancock, Sandy; Cecere, Thomas E.; Nguyen, Mai; Arastu-Kapur, Shirin; Broce, Sean; Raha, Debasish; Lynch, Casey C.; Holsinger, Leslie J.; Dominy, Stephen S.; Ermini, Florian (IOS Press, 2020-01-01)Background: Porphyromonas gingivalis (P. gingivalis) and its gingipain virulence factors have been identified as pathogenic effectors in Alzheimer's disease (AD). In a recent study we demonstrated the presence of gingipains in over 90% of postmortem AD brains, with gingipains localizing to the cytoplasm of neurons. However, infection of neurons by P. gingivalis has not been previously reported. Objective: To demonstrate intraneuronal P. gingivalis and gingipain expression in vitro after infecting neurons derived from human inducible pluripotent stem cells (iPSC) with P. gingivalis for 24, 48, and 72 h. Methods: Infection was characterized by transmission electron microscopy, confocal microscopy, and bacterial colony forming unit assays. Gingipain expression was monitored by immunofluorescence and RT-qPCR, and protease activity monitored with activity-based probes. Neurodegenerative endpoints were assessed by immunofluorescence, western blot, and ELISA. Results: Neurons survived the initial infection and showed time dependent, infection induced cell death. P. gingivalis was found free in the cytoplasm or in lysosomes. Infected neurons displayed an accumulation of autophagic vacuoles and multivesicular bodies. Tau protein was strongly degraded, and phosphorylation increased at T231. Over time, the density of presynaptic boutons was decreased. Conclusion: P. gingivalis can invade and persist in mature neurons. Infected neurons display signs of AD-like neuropathology including the accumulation of autophagic vacuoles and multivesicular bodies, cytoskeleton disruption, an increase in phospho-tau/tau ratio, and synapse loss. Infection of iPSC-derived mature neurons by P. gingivalis provides a novel model system to study the cellular mechanisms leading to AD and to investigate the potential of new therapeutic approaches.
- Connexin 43 peptidic medicine for glioblastoma stem cellsSheng, Zhi (Elsevier, 2021-02-01)
- Effects of Chronic Social Stress and Maternal Intranasal Oxytocin and Vasopressin on Offspring Interferon-gamma and BehaviorMurgatroyd, Christopher A.; Hicks-Nelson, Alexandria; Fink, Alexandria; Beamer, Gillian; Gurel, Kursat; Elnady, Fawzy; Pittet, Florent; Nephew, Benjamin C. (Frontiers, 2016-12-14)Recent studies support the hypothesis that the adverse effects of early-life adversity and transgenerational stress on neural plasticity and behavior are mediated by inflammation. The objective of the present study was to investigate the immune and behavioral programing effects of intranasal (IN) vasopressin (AVP) and oxytocin (OXT) treatment of chronic social stress (CSS)-exposed F1 dams on F2 juvenile female offspring. It was hypothesized that maternal AVP and OXT treatment would have preventative effects on social stress-induced deficits in offspring anxiety and social behavior and that these effects would be associated with changes in interferon-γ (IFNγ). Control and CSS-exposed F1 dams were administered IN saline, AVP, or OXT during lactation and the F2 juvenile female offspring were assessed for basal plasma IFNγ and perseverative, anxiety, and social behavior. CSS F2 female juvenile offspring had elevated IFNγ levels and exhibited increased repetitive/perseverative and anxiety behaviors and deficits in social behavior. These effects were modulated by AVP and OXT in a context- and behavior-dependent manner, with OXT exhibiting preventative effects on repetitive and anxiety behaviors and AVP possessing preventative effects on social behavior deficits and anxiety. Basal IFNγ levels were elevated in the F2 offspring of OXT-treated F1 dams, but IFNγ was not correlated with the behavioral effects. These results support the hypothesis that maternal AVP and OXT treatment have context- and behavior-specific effects on peripheral IFNγ levels and perseverative, anxiety, and social behaviors in the female offspring of early-life social stress-exposed dams. Both maternal AVP and OXT are effective at preventing social stress-induced increases in self-directed measures of anxiety, and AVP is particularly effective at preventing impairments in overall social contact. OXT is specifically effective at preventing repetitive/perseverative behaviors, yet is ineffective at preventing deficits in overall social behavior.
- Glioma-induced peritumoral hyperexcitability in a pediatric glioma modelChaunsali, Lata; Tewari, Bhanu P.; Gallucci, Allison; Thompson, Emily G.; Savoia, Andrew; Feld, Noah; Campbell, Susan L. (Wiley, 2020-10-01)Epileptic seizures are among the most common presenting symptom in patients with glioma. The etiology of glioma-related seizures is complex and not completely understood. Studies using adult glioma patient tissue and adult glioma mouse models, show that neurons adjacent to the tumor mass, peritumoral neurons, are hyperexcitable and contribute to seizures. Although it is established that there are phenotypic and genotypic distinctions in gliomas from adult and pediatric patients, it is unknown whether these established differences in pediatric glioma biology and the microenvironment in which these glioma cells harbor, the developing brain, differentially impacts surrounding neurons. In the present study, we examine the effect of patient-derived pediatric glioma cells on the function of peritumoral neurons using two pediatric glioma models. Pediatric glioma cells were intracranially injected into the cerebrum of postnatal days 2 and 3 (p2/3) mouse pups for 7 days. Electrophysiological recordings showed that cortical layer 2/3 peritumoral neurons exhibited significant differences in their intrinsic properties compared to those of sham control neurons. Peritumoral neurons fired significantly more action potentials in response to smaller current injection and exhibited a depolarization block in response to higher current injection. The threshold for eliciting an action potential and pharmacologically induced epileptiform activity was lower in peritumoral neurons compared to sham. Our findings suggest that pediatric glioma cells increase excitability in the developing peritumoral neurons by exhibiting early onset of depolarization block, which was not previously observed in adult glioma peritumoral neurons.
- Maltreatment and brain development: The effects of abuse and neglect on longitudinal trajectories of neural activation during risk processing and cognitive controlKim-Spoon, Jungmeen; Herd, Toria; Brieant, Alexis; Peviani, Kristin; Deater-Deckard, Kirby; Lauharatanahirun, Nina; Lee, Jacob; Casas, Brooks (Elsevier, 2021-04-01)The profound effects of child maltreatment on brain functioning have been documented. Yet, little is known about whether distinct maltreatment experiences are differentially related to underlying neural processes of risky decision making: valuation and control. Using conditional growth curve modeling, we compared a cumulative approach versus a dimensional approach (relative effects of abuse and neglect) to examine the link between child maltreatment and brain development. The sample included 167 adolescents (13–14 years at Time 1, 53 % male), assessed annually four times. Risk processing was assessed by blood-oxygen-level-dependent responses (BOLD) during a lottery choice task, and cognitive control by BOLD responses during the Multi-Source Interference Task. Cumulative maltreatment effects on insula and dorsolateral anterior cingulate cortex (dACC) activation during risk processing were not significant. However, neglect (but not abuse) was associated with slower developmental increases in insula and dACC activation. In contrast, cumulative maltreatment effects on fronto-parietal activation during cognitive control were significant, and abuse (but not neglect) was associated with steeper developmental decreases in fronto-parietal activation. The results suggest neglect effects on detrimental neurodevelopment of the valuation system and abuse effects on accelerated neurodevelopment of the control system, highlighting differential effects of distinct neglect versus abuse adverse experiences on neurodevelopment.
- Processes linking socioeconomic disadvantage and neural correlates of cognitive control in adolescenceBrieant, Alexis; Herd, Toria; Deater-Deckard, Kirby; Lee, Jacob; Casas, Brooks; Kim-Spoon, Jungmeen (Elsevier, 2021-04-01)Socioeconomic status (SES) is broadly associated with self-regulatory abilities across childhood and adolescence. However, there is limited understanding of the mechanisms underlying this association, especially during adolescence when individuals are particularly sensitive to environmental influences. The current study tested perceived stress, household chaos, parent cognitive control, and parent-adolescent relationship quality as potential proximal mediators of the association between family SES and neural correlates of cognitive control. A sample of 167 adolescents and their primary caregivers participated in a longitudinal study across four years. SES was indexed by caregivers’ education and income-to-needs ratio at Time 1. At Time 2, adolescents reported on their perceived stress, household chaos, and relationship with parents, and parents completed a cognitive control task. Two years later, adolescents completed the same cognitive control task while blood-oxygenation-level-dependent (BOLD) response was monitored with functional magnetic resonance imaging (fMRI). A parallel mediation model indicated that parent cognitive control, but not other proximal factors, explained the relation between SES and adolescents’ activation in the middle frontal gyrus during a cognitive control task. The results suggest potential targets for intervention and prevention efforts that may positively alter neurocognitive outcomes related to socioeconomic disadvantage.
- Prospective impact of COVID-19 on mental health functioning in adolescents with and without ADHD: protective role of emotion regulation abilitiesBreaux, Rosanna; Dvorsky, Melissa R.; Marsh, Nicholas P.; Green, Cathrin D.; Cash, Annah R.; Shroff, Delshad M.; Buchen, Natalie; Langberg, Joshua M.; Becker, Stephen P. (Wiley, 2021-02-04)Background: The impact of chronic stressors like the COVID-19 pandemic is likely to be magnified in adolescents with pre-existing mental health risk, such as attention-deficit/hyperactivity disorder (ADHD). This study examined changes in and predictors of adolescent mental health from before to during the COVID-19 pandemic in the Southeastern and Midwestern United States. Methods: Participants include 238 adolescents (132 males; ages 15–17; 118 with ADHD). Parents and adolescents provided ratings of mental health symptoms shortly before the COVID-19 pandemic and in spring and summer 2020. Results: Adolescents on average experienced an increase in depression, anxiety, sluggish cognitive tempo, inattentive, and oppositional/defiant symptoms from pre-COVID-19 to spring 2020; however, with the exception of inattention, these symptoms decreased from spring to summer 2020. Adolescents with ADHD were more likely than adolescents without ADHD to experience an increase in inattentive, hyperactive/impulsive, and oppositional/defiant symptoms. Adolescents with poorer pre-COVID-19 emotion regulation abilities were at-risk for experiencing increases in all mental health symptoms relative to adolescents with better pre-COVID-19 emotion regulation abilities. Interactive risk based on ADHD status and pre-COVID-19 emotion regulation abilities was found for inattention and hyperactivity/impulsivity, such that adolescents with ADHD and poor pre-COVID-19 emotion regulation displayed the highest symptomatology across timepoints. Lower family income related to increases in inattention but higher family income related to increases in oppositional/defiant symptoms. Conclusions: The early observed increases in adolescent mental health symptoms during the COVID-19 pandemic do not on average appear to be sustained following the lift of stay-at-home orders, though studies evaluating mental health across longer periods of time are needed. Emotion dysregulation and ADHD increase risk for sustained negative mental health functioning and highlight the need for interventions for these populations during chronic stressors. Results and clinical implications should be considered within the context of our predominately White, middle class sample.
- Proteomic Analysis Reveals Sex-Specific Protein Degradation Targets in the Amygdala During Fear Memory FormationFarrell, Kayla; Musaus, Madeline; Navabpour, Shaghayegh; Martin, Kiley; Ray, W. Keith; Helm, Richard F.; Jarome, Timothy J. (Frontiers, 2021-09-29)Ubiquitin-proteasome mediated protein degradation has been widely implicated in fear memory formation in the amygdala. However, to date, the protein targets of the proteasome remain largely unknown, limiting our understanding of the functional significance for protein degradation in fear memory formation. Additionally, whether similar proteins are targeted by the proteasome between sexes has yet to be explored. Here, we combined a degradation-specific K48 Tandem Ubiquitin Binding Entity (TUBE) with liquid chromatography mass spectrometry (LC/MS) to identify the target substrates of the protein degradation process in the amygdala of male and female rats following contextual fear conditioning. We found that males (43) and females (77) differed in the total number of proteins that had significant changes in K48 polyubiquitin targeting in the amygdala following fear conditioning. Many of the identified proteins (106) had significantly reduced levels in the K48-purified samples 1 h after fear conditioning, suggesting active degradation of the substrate due to learning. Interestingly, only 3 proteins overlapped between sexes, suggesting that targets of the protein degradation process may be sex-specific. In females, many proteins with altered abundance in the K48-purified samples were involved in vesicle transport or are associated with microtubules. Conversely, in males, proteins involved in the cytoskeleton, ATP synthesis and cell signaling were found to have significantly altered abundance. Only 1 protein had an opposite directional change in abundance between sexes, LENG1, which was significantly enhanced in males while lower in females. This suggests a more rapid degradation of this protein in females during fear memory formation. Interestingly, GFAP, a critical component of astrocyte structure, was a target of K48 polyubiquitination in both males and females, indicating that protein degradation is likely occurring in astrocytes following fear conditioning. Western blot assays revealed reduced levels of these target substrates following fear conditioning in both sexes, confirming that the K48 polyubiquitin was targeting these proteins for degradation. Collectively, this study provides strong evidence that sex differences exist in the protein targets of the degradation process in the amygdala following fear conditioning and critical information regarding how ubiquitin-proteasome mediated protein degradation may contribute to fear memory formation in the brain.
- Survival of a male patient harboring CASK Arg27Ter mutation to adolescenceMukherjee, Konark; Patel, Paras A.; Rajan, Deepa S.; LaConte, Leslie E. W.; Srivastava, Sarika (Wiley, 2020-07-21)Background: CASK is an X-linked gene in mammals and its deletion in males is incompatible with life. CASK heterozygous mutations in female patients associate with intellectual disability, microcephaly, pontocerebellar hypoplasia, and optic nerve hypoplasia, whereas CASK hemizygous mutations in males manifest as early infantile epileptic encephalopathy with a grim prognosis. Here, we report a rare case of survival of a male patient harboring a CASK null mutation to adolescent age. Methods: Trio whole exome sequencing analysis was performed from blood genomic DNA. Magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and electroencephalogram (EEG) analyses were performed to determine anomalies in brain development, metabolite concentrations, and electrical activity, respectively. Results: Trio-WES analysis identified a de novo c.79C>T (p.Arginine27Ter) mutation in CASK causing a premature translation termination at the very N-terminus of the protein. The 17-years, and 11-month-old male patient displayed profound intellectual disability, microcephaly, dysmorphism, ponto-cerebellar hypoplasia, and intractable epilepsy. His systemic symptoms included overall reduced somatic growth, dysautonomia, ventilator and G tube dependence, and severe osteopenia. Brain MRI revealed a severe cerebellar and brain stem hypoplasia with progressive cerebral atrophy. EEG spectral analysis revealed a global functional defect with generalized background slowing and delta waves dominating even in the awake state. Conclusion: This case study is the first to report survival of a male patient carrying a CASK loss-of-function mutation to adolescence and highlights that improved palliative care could extend survival. Moreover, the genomic position encoding Arg27 in CASK may possess an increased susceptibility to mutations.