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 "1109 Neurosciences"
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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.
- 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.
- Potassium and glutamate transport is impaired in scar-forming tumor-associated astrocytesCampbell, Susan C.; Muñoz-Ballester, Carmen; Chaunsali, Lata; Mills, William A.; Yang, Jennifer H.; Sontheimer, Harald; Robel, Stefanie (Elsevier, 2019-12-09)Unprovoked recurrent seizures are a serious comorbidity affecting most patients who suffer from glioma, a primary brain tumor composed of malignant glial cells. Cellular mechanisms contributing to the development of recurrent spontaneous seizures include the release of the excitatory neurotransmitter glutamate from glioma into extracellular space. Under physiological conditions, astrocytes express two high affinity glutamate transporters, Glt-1 and Glast, which are responsible for the removal of excess extracellular glutamate. In the context of neurological disease or brain injury, astrocytes become reactive which can negatively affect neuronal function, causing hyperexcitability and/or death. Using electrophysiology, immunohistochemistry, fluorescent in situ hybridization, and Western blot analysis in different orthotopic xenograft and allograft models of human and mouse gliomas, we find that peritumoral astrocytes exhibit astrocyte scar formation characterized by proliferation, cellular hypertrophy, process elongation, and increased GFAP and pSTAT3. Overall, peritumoral reactive astrocytes show a significant reduction in glutamate and potassium uptake, as well as decreased glutamine synthetase activity. A subset of peritumoral astrocytes displayed a depolarized resting membrane potential, further contributing to reduced potassium and glutamate homeostasis. These changes may contribute to the propagation of peritumoral neuronal hyperexcitability and excitotoxic death.
- 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.
- 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.
- Sex-Specific Linear Polyubiquitination Is a Critical Regulator of Contextual Fear Memory FormationMusaus, Madeline; Farrell, Kayla; Navabpour, Shaghayegh; Ray, W. Keith; Helm, Richard F.; Jarome, Timothy J. (Frontiers, 2021-07-09)Strong evidence supports that protein ubiquitination is a critical regulator of fear memory formation. However, as this work has focused on protein degradation, it is currently unknown whether polyubiquitin modifications that are independent of the proteasome are involved in learning-dependent synaptic plasticity. Here, we present the first evidence that atypical linear (M1) polyubiquitination, the only ubiquitin chain that does not occur at a lysine site and is largely independent of the proteasome, is critically involved in contextual fear memory formation in the amygdala in a sex-specific manner. Using immunoblot and unbiased proteomic analyses, we found that male (49) and female (14) rats both had increased levels of linear polyubiquitinated substrates following fear conditioning, though none of these protein targets overlapped between sexes. In males, target protein functions involved cell junction and axonal guidance signaling, while in females the primary target was Adiponectin A, a critical regulator of neuroinflammation, synaptic plasticity, and memory, suggesting sex-dependent functional roles for linear polyubiquitination during fear memory formation. Consistent with these increases, in vivo siRNA-mediated knockdown of Rnf31, an essential component of the linear polyubiquitin E3 complex LUBAC, in the amygdala impaired contextual fear memory in both sexes without affecting memory retrieval. Collectively, these results provide the first evidence that proteasome-independent linear polyubiquitination is a critical regulator of fear memory formation, expanding the potential roles of ubiquitin-signaling in learning-dependent synaptic plasticity. Importantly, our data identify a novel sex difference in the functional role of, but not a requirement for, linear polyubiquitination in fear memory formation.