Scholarly Works, School of Neuroscience

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Adenosine Signaling through A1 Receptors Inhibits Chemosensitive Neurons in the Retrotrapezoid Nucleus
James, S. D.; Hawkins, V. E.; Falquetto, B.; Ruskin, D. N.; Masino, S. A.; Moreira, T. S.; Olsen, Michelle L.; Mulkey, D. K. (Society for Neuroscience, 2018)
A subset of neurons in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors by regulating depth and frequency of breathing in response to changes in tissue CO2/H. The activity of chemosensitive RTN neurons is also subject to modulation by CO2/H-dependent purinergic signaling. However, mechanisms contributing to purinergic regulation of RTN chemoreceptors are not entirely clear. Recent evidence suggests adenosine inhibits RTN chemoreception in vivo by activation of A1 receptors. The goal of this study was to characterize effects of adenosine on chemosensitive RTN neurons and identify intrinsic and synaptic mechanisms underlying this response. Cell-attached recordings from RTN chemoreceptors in slices from rat or wild-type mouse pups (mixed sex) show that exposure to adenosine (1 M) inhibits chemoreceptor activity by an A1 receptor-dependent mechanism. However, exposure to a selective A1 receptor antagonist (8-cyclopentyl-1,3- dipropylxanthine, DPCPX; 30 nM) alone did not potentiate CO2/H-stimulated activity, suggesting activation of A1 receptors does not limit chemoreceptor activity under these reduced conditions. Whole-cell voltage-clamp from chemosensitive RTN neurons shows that exposure to adenosine activated an inward rectifying K conductance, and at the network level, adenosine preferentially decreased frequency of EPSCs but not IPSCs. These results show that adenosine activation of A1 receptors inhibits chemosensitive RTN neurons by direct activation of a G-protein-regulated inward-rectifier K (GIRK)-like conductance, and presynaptically, by suppression of excitatory synaptic input to chemoreceptors.
Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome
Kiraly, D. D.; Horn, S. R.; Van Dam, N. T.; Costi, S.; Schwartz, J.; Kim-Schulze, S.; Patel, M.; Hodes, Georgia E.; Russo, Scott J.; Merad, Miriam; Iosifescu, D. V.; Charney, D. S.; Murrough, J.W. (2017-03-21)
A subset of patients with depression have elevated levels of inflammatory cytokines, and some studies demonstrate interaction between inflammatory factors and treatment outcome. However, most studies focus on only a narrow subset of factors in a patient sample. In the current study, we analyzed broad immune profiles in blood from patients with treatment-resistant depression (TRD) at baseline and following treatment with the glutamate modulator ketamine. Serum was analyzed from 26 healthy control and 33 actively depressed TRD patients free of antidepressant medication, and matched for age, sex and body mass index. All subjects provided baseline blood samples, and TRD subjects had additional blood draw at 4 and 24 h following intravenous infusion of ketamine (0.5 mg kg-1). Samples underwent multiplex analysis of 41 cytokines, chemokines and growth factors using quantitative immunoassay technology. Our a priori hypothesis was that TRD patients would show elevations in canonical pro-inflammatory cytokines; analyses demonstrated significant elevation of the pro-inflammatory cytokine interleukin-6. Further exploratory analyses revealed significant regulation of four additional soluble factors in patients with TRD. Several cytokines showed transient changes in level after ketamine, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response. In sum, we found that patients with TRD demonstrate a unique pattern of increased inflammatory mediators, chemokines and colony-stimulating factors, providing support for the immune hypothesis of TRD. These patterns suggest novel treatment targets for the subset of patients with TRD who evidence dysregulated immune functioning.
Assessment of Ketamine and Its Enantiomers in an Organophosphate-Based Rat Model for Features of Gulf War Illness
Zhu, Jackie; Hawkins, Elisa; Phillips, Kristin; Deshpande, Laxmikant S. (MDPI, 2020-06-30)
Approximately 33% of U.S. soldiers from the first Gulf War suffer from a multi-system disorder known as the Gulf War Illness (GWI). GW veterans suffer from a cluster of symptoms that prominently include fatigue and can include mood-related symptoms. Compared to traditional antidepressants, ketamine (KET) produces a fast-onset and long-lasting antidepressant response, but assessments of KET for GWI-related depression are lacking. The etiology of GWI is multi-factorial and exposure to organophosphates (OP) during deployment is one of the factors underlying GWI development. Here, male Sprague-Dawley rats were repeatedly exposed to an OP DFP and three months later these rats, when assessed on a battery of rodent behavioral assays, displayed signs consistent with aspects of GWI characteristics. When treated with a sub-anesthetic dose of KET (3, 5, or 10 mg/kg, i.p.), DFP-treated rats exhibited a significant improvement in immobility time, open-arm exploration, and sucrose consumption as early as 1 h and much of these effects persisted at 24-h post-KET injection. KET’s stereoisomers, R-KET and S-KET, also exhibited such effects in DFP rats, with R-KET being the more potent isomer. Our studies provide a starting point for further assessment of KET for GWI depression.
Astrocyte morphogenesis is dependent on BDNF signaling via astrocytic TrkB.T1
Holt, Leanne M.; Hernandez, Raymundo D.; Pacheco, Natasha L.; Ceja, Beatriz Torres; Hossain, Muhannah; Olsen, Michelle L. (2019-08-21)
Brain-derived neurotrophic factor (BDNF) is a critical growth factor involved in the maturation of the CNS, including neuronal morphology and synapse refinement. Herein, we demonstrate astrocytes express high levels of BDNF's receptor, TrkB (in the top 20 of protein-coding transcripts), with nearly exclusive expression of the truncated isoform, TrkB.T1, which peaks in expression during astrocyte morphological maturation. Using a novel culture paradigm, we show that astrocyte morphological complexity is increased in the presence of BDNF and is dependent upon BDNF/TrkB.T1 signaling. Deletion of TrkB.T1, globally and astrocyte-specifically, in mice revealed morphologically immature astrocytes with significantly reduced volume, as well as dysregulated expression of perisynaptic genes associated with mature astrocyte function. Indicating a role for functional astrocyte maturation via BDNF/TrkB.T1 signaling, TrkB.T1 KO astrocytes do not support normal excitatory synaptogenesis or function. These data suggest a significant role for BDNF/TrkB.T1 signaling in astrocyte morphological maturation, a critical process for CNS development.
Building Interdisciplinary Partnerships for Community-Engaged Environmental Health Research in Appalachian Virginia
Satterwhite, Emily M.; Bell, Shannon E.; Marr, Linsey C.; Thompson, Christopher K.; Prussin, Aaron J. II; Buttling, Lauren G.; Pan, Jin; Gohlke, Julia M. (MDPI, 2020-03-05)
This article describes a collaboration among a group of university faculty, undergraduate students, local governments, local residents, and U.S. Army staff to address long-standing concerns about the environmental health effects of an Army ammunition plant. The authors describe community-responsive scientific pilot studies that examined potential environmental contamination and a related undergraduate research course that documented residents’ concerns, contextualized those concerns, and developed recommendations. We make a case for the value of resource-intensive university–community partnerships that promote the production of knowledge through collaborations across disciplinary paradigms (natural/physical sciences, social sciences, health sciences, and humanities) in response to questions raised by local residents. Our experience also suggests that enacting this type of research through a university class may help promote researchers’ adoption of “epistemological pluralism”, and thereby facilitate the movement of a study from being “multidisciplinary” to “transdisciplinary”.
Case study on the use of intensive pediatric neurorehabilitation in the treatment of kernicterus
Mann, Jessie; Wallace, Dory A.; DeLuca, Stephanie C. (2020-02-03)
Background Kernicterus Spectrum Disorder (KSD) is the result of prolonged bilirubin toxicity resulting in widespread neurological injury. Once the bilirubin levels are normalized the encephalopathy becomes static, however the consequences of the injury can have life-long effects. The sequelae of KSD include motor impairments, auditory deficits, dental dysplasia, and potentially cognitive impairments. While KSD is a rare diagnosis, particularly in developed countries, there is evidence that there may be a global increase in incidence (Hansen, Semin Neonatol 7:103–9, 2002; Johnson, J Perinatol 29:S25–45, 2009; Kaplan etal. Neonatology 100:354–62, 2011; Maisels, Early Hum Dev 85:727–32, 2009; Olusanya etal., Arch Dis Child 99:1117–21, 2014; Steffensrud, Newborn Infant Nurs Rev 4:191–200, 2004). The literature on the treatment of various specific sequelae of KSD is varied, but in general specific therapeutic efforts to improve motor skills are not evidenced-based. The following is a case report on the use of Acquire therapy, an intensive neuromotor intervention, to ameliorate some of the motor-function deficits secondary to KSD. Case presentation This case-report presents the results of two intensive therapeutic intervention sessions in one male child with KSD. Treatments occurred at 28 and 34 months. The child presented with fine and gross motor deficits as well as communication delays. Each session consisted of daily therapy for 4 h each weekday for 3 weeks. The child was assessed before and after treatment with 2 standardized measures, the Gross Motor Function Measure (GMFM) and The Bayley Scales of Infant and Toddler Development (Bayley). Conclusions The GMFM at the 1st assessment was 34, 74at the 2nd assessment (after intervention 1), and 64 at the third assessment and 104 at the 4th assessment (after intervention 2). The Bayley at the 3rd assessment was 18, and 38 at the 4th assessment (after intervention 2).
A Collision Coupling Model Governs the Activation of Neuronal GIRK1/2 Channels by Muscarinic-2 Receptors
Berlin, Shai; Artzy, Etay; Handklo-Jamal, Reem; Kahanovitch, Uri; Parnas, Hanna; Dascal, Nathan; Yakubovich, Daniel (2020-08-12)
The G protein-activated Inwardly Rectifying K+-channel (GIRK) modulates heart rate and neuronal excitability. Following G-Protein Coupled Receptor (GPCR)-mediated activation of heterotrimeric G proteins (G alpha beta gamma), opening of the channel is obtained by direct binding of G beta gamma subunits. Interestingly, GIRKs are solely activated by G beta gamma subunits released from G alpha(i/o)-coupled GPCRs, despite the fact that all receptor types, for instance G alpha(q)-coupled, are also able to provide G beta gamma subunits. It is proposed that this specificity and fast kinetics of activation stem from pre-coupling (or pre-assembly) of proteins within this signaling cascade. However, many studies, including our own, point towards a diffusion-limited mechanism, namely collision coupling. Here, we set out to address this long-standing question by combining electrophysiology, imaging, and mathematical modeling. Muscarinic-2 receptors (M2R) and neuronal GIRK1/2 channels were coexpressed inXenopus laevisoocytes, where we monitored protein surface expression, current amplitude, and activation kinetics. Densities of expressed M2R were assessed using a fluorescently labeled GIRK channel as a molecular ruler. We then incorporated our results, along with available kinetic data reported for the G-protein cycle and for GIRK1/2 activation, to generate a comprehensive mathematical model for the M2R-G-protein-GIRK1/2 signaling cascade. We find that, without assuming any irreversible interactions, our collision coupling kinetic model faithfully reproduces the rate of channel activation, the changes in agonist-evoked currents and the acceleration of channel activation by increased receptor densities.
Corticotropin-Releasing Factor Receptor-1 Neurons in the Lateral Amygdala Display Selective Sensitivity to Acute and Chronic Ethanol Exposure
Agoglia, Abigail E.; Zhu, ManHua; Ying, Rose; Sidhu, Harpreet; Natividad, Luis A.; Wolfe, Sarah A.; Buczynski, Matthew W.; Contet, Candice; Parsons, Loren H.; Roberto, Marisa; Herman, Melissa A. (2020-03)
The lateral amygdala (LA) serves as the point of entry for sensory information within the amygdala complex, a structure that plays a critical role in emotional processes and has been implicated in alcohol use disorders. Within the amygdala, the corticotropin-releasing factor (CRF) system has been shown to mediate some of the effects of both stress and ethanol, but the effects of ethanol on specific CRF1 receptor circuits in the amygdala have not been fully established. We used male CRF1:GFP reporter mice to characterize CRF1-expressing (CRF1(+)) and nonexpressing (CRF1(-)) LA neurons and investigate the effects of acute and chronic ethanol exposure on these populations. The CRF1(+) population was found to be composed predominantly of glutamatergic projection neurons with a minority subpopulation of interneurons. CRF1(+) neurons exhibited a tonic conductance that was insensitive to acute ethanol. CRF1(-) neurons did not display a basal tonic conductance, but the application of acute ethanol induced a delta GABA(A) receptor subunit-dependent tonic conductance and enhanced phasic GABA release onto these cells. Chronic ethanol increased CRF1(+) neuronal excitability but did not significantly alter phasic or tonic GABA signaling in either CRF1(+) or CRF1(-) cells. Chronic ethanol and withdrawal also did not alter basal extracellular GABA or glutamate transmitter levels in the LA/BLA and did not alter the sensitivity of GABA or glutamate to acute ethanol-induced increases in transmitter release. Together, these results provide the first characterization of the CRF1(+) population of LA neurons and suggest mechanisms for differential acute ethanol sensitivity within this region.
A developmental sex difference in hippocampal neurogenesis is mediated by endogenous Oestradiol
Bowers, J. Michael; Waddell, Jaylyn; McCarthy, Margaret M. (BMC, 2010)
Background: Oestradiol is a steroid hormone that exerts extensive influence on brain development and is a powerful modulator of hippocampal structure and function. The hippocampus is a critical brain region regulating complex cognitive and emotional responses and is implicated in the aetiology of several mental health disorders, many of which exhibit some degree of sex difference. Many sex differences in the adult rat brain are determined by oestradiol action during a sensitive period of development. We had previously reported a sex difference in rates of cell genesis in the developing hippocampus of the laboratory rat. Males generate more new cells on average than females. The current study explored the effects of both exogenous and endogenous oestradiol on this sex difference. Methods: New born male and female rat pups were injected with the mitotic marker 5-bromo-2-deoxyuridine (BrdU) and oestradiol or agents that antagonize oestradiol action. The effects on cell number, proliferation, differentiation and survival were assessed at several time points. Significant differences between groups were determined by two- or thee-Way ANOVA. Results: Newborn males had higher rates of cell proliferation than females. Oestradiol treatment increased cell proliferation in neonatal females, but not males, and in the CA1 region many of these cells differentiated into neurons. The increased rate of proliferation induced by neonatal oestradiol persisted until at least 3 weeks of age, suggesting an organizational effect. Administering the aromatase inhibitor, formestane, or the oestrogen receptor antagonist, tamoxifen, significantly decreased the number of new cells in males but not females. Conclusion: Endogenous oestradiol increased the rate of cell proliferation observed in newborn males compared to females. This sex difference in neonatal neurogenesis may have implications for adult differences in learning strategy, stress responsivity or vulnerability to damage or disease.
Differential stress induced c-Fos expression and identification of region-specific miRNA-mRNA networks in the dorsal raphe and amygdala of high-responder/low-responder rats
Cohen, Joshua L.; Ata, Anoosha E.; Jackson, Nateka L.; Rahn, Elizabeth J.; Ramaker, Ryne C.; Cooper, Sara; Kerman, Ilan A.; Clinton, Sarah M. (2017-02)
Chronic stress triggers a variety of physical and mental health problems, and how individuals 2 cope with stress influences risk for emotional disorders. To investigate molecular mechanisms 3 underlying distinct stress coping styles, we utilized rats that were selectively-bred for differences 4 in emotionality and stress reactivity. We show that high novelty responding (HR) rats readily 5 bury a shock probe in the defensive burying test, a measure of proactive stress coping behavior, 6 while low novelty responding (LR) rats exhibit enhanced immobility, a measure of reactive 7 coping. Shock exposure in the defensive burying test elicited greater activation of HR rats’ 8 caudal dorsal raphe serotonergic cells compared to LRs, but lead to more pronounced 9 activation throughout LRs’ amygdala (lateral, basolateral, central, and basomedial nuclei) 10 compared to HRs. RNA-sequencing revealed 271 mRNA transcripts and 33 microRNA species 11 that were differentially expressed in HR/LR raphe and amygdala. We mapped potential 12 microRNA-mRNA networks by correlating and clustering mRNA and microRNA expression and 13 identified networks that differed in either the HR/LR dorsal raphe or amygdala. A dorsal raphe 14 network linked three microRNAs which were down-regulated in LRs (miR-206-3p, miR-3559-5p, 15 and miR-378a-3p) to repression of genes related to microglia and immune response (Cd74, 16 Cyth4, Nckap1l, and Rac2), the genes themselves were up-regulated in LR dorsal raphe. In the 17 amygdala, another network linked miR-124-5p, miR-146a-5p, miR-3068-3p, miR-380-5p, miR-18 539-3p, and miR-7a-1-3p with repression of chromatin remodeling-related genes (Cenpk, 19 Cenpq, Itgb3bp, and Mis18a). Overall this work highlights potential drivers of gene-networks 20 and downstream molecular pathways within the raphe and amygdala that contribute to 21 individual differences in stress coping styles and stress vulnerabilities.
Divergent age-dependent peripheral immune transcriptomic profile following traumatic brain injury
Hazy, Amanda; Bochicchio, Lauren; Oliver, Andrea; Xie, Eric; Geng, Shuo; Brickler, Thomas; Xie, Hehuang David; Li, Liwu; Allen, Irving C.; Theus, Michelle H. (Springer Nature, 2019-06-12)
The peripheral immune system is a major regulator of the pathophysiology associated with traumatic brain injury (TBI). While age-at-injury influences recovery from TBI, the differential effects on the peripheral immune response remain unknown. Here, we investigated the effects of TBI on gene expression changes in murine whole blood using RNAseq analysis, gene ontology and network topology-based key driver analysis. Genome-wide comparison of CCI-injured peripheral whole blood showed a significant increase in genes involved in proteolysis and oxidative-reduction processes in juvenile compared to adult. Conversely, a greater number of genes, involved in migration, cytokine-mediated signaling and adhesion, were found reduced in CCI-injured juvenile compared to CCI-injured adult immune cells. Key driver analysis also identified G-protein coupled and novel pattern recognition receptor (PRR), P2RY10, as a central regulator of these genes. Lastly, we found Dectin-1, a c-type lectin PRR to be reduced at the protein level in both naive neutrophils and on infiltrating immune cells in the CCI-injured juvenile cortex. These findings demonstrate a distinct peripheral inflammatory profile in juvenile mice, which may impact the injury and repair response to brain trauma.
Diverse GABAergic neurons organize into subtype-specific sublaminae in the ventral lateral geniculate nucleus
Sabbagh, Ubadah; Govindaiah, Gubbi; Somaiya, Rachana D.; Ha, Ryan V.; Wei, Jessica C.; Guido, William; Fox, Michael A. (Wiley, 2020-05-19)
In the visual system, retinal axons convey visual information from the outside world to dozens of distinct retinorecipient brain regions and organize that information at several levels, including either at the level of retinal afferents, cytoarchitecture of intrinsic retinorecipient neurons, or a combination of the two. Two major retinorecipient nuclei which are densely innervated by retinal axons are the dorsal lateral geniculate nucleus, which is important for classical image-forming vision, and ventral LGN (vLGN), which is associated with non-image-forming vision. The neurochemistry, cytoarchitecture, and retinothalamic connectivity in vLGN remain unresolved, raising fundamental questions of how it receives and processes visual information. To shed light on these important questions, used in situ hybridization, immunohistochemistry, and genetic reporter lines to identify and characterize novel neuronal cell types in mouse vLGN. Not only were a high percentage of these cells GABAergic, we discovered transcriptomically distinct GABAergic cell types reside in the two major laminae of vLGN, the retinorecipient, external vLGN (vLGNe) and the non-retinorecipient, internal vLGN (vLGNi). Furthermore, within vLGNe, we identified transcriptionally distinct subtypes of GABAergic cells that are distributed into four adjacent sublaminae. Using trans-synaptic viral tracing and in vitro electrophysiology, we found cells in each these vLGNe sublaminae receive monosynaptic inputs from retina. These results not only identify novel subtypes of GABAergic cells in vLGN, they suggest the subtype-specific laminar distribution of retinorecipient cells in vLGNe may be important for receiving, processing, and transmitting light-derived signals in parallel channels of the subcortical visual system.
DNA Double-Strand Breaks Are a Critical Regulator of Fear Memory Reconsolidation
Navabpour, Shaghayegh; Rogers, Jessie; McFadden, Taylor; Jarome, Timothy J. (MDPI, 2020-11-26)
Numerous studies have shown that following retrieval, a previously consolidated memory requires increased transcriptional regulation in order to be reconsolidated. Previously, it was reported that histone H3 lysine-4 trimethylation (H3K4me3), a marker of active transcription, is increased in the hippocampus after the retrieval of contextual fear memory. However, it is currently unknown how this epigenetic mark is regulated during the reconsolidation process. Furthermore, though recent evidence suggests that neuronal activity triggers DNA double-strand breaks (DSBs) in some early-response genes, it is currently unknown if DSBs contribute to the reconsolidation of a memory following retrieval. Here, using chromatin immunoprecipitation (ChIP) analyses, we report a significant overlap between DSBs and H3K4me3 in area CA1 of the hippocampus during the reconsolidation process. We found an increase in phosphorylation of histone H2A.X at serine 139 (H2A.XpS139), a marker of DSB, in the Npas4, but not c-fos, promoter region 5 min after retrieval, which correlated with increased H3K4me3 levels, suggesting that the two epigenetic marks may work in concert during the reconsolidation process. Consistent with this, in vivo siRNA-mediated knockdown of topoisomerase II β, the enzyme responsible for DSB, prior to retrieval, reduced Npas4 promoter-specific H2A.XpS139 and H3K4me3 levels and impaired long-term memory, indicating an indispensable role of DSBs in the memory reconsolidation process. Collectively, our data propose a novel mechanism for memory reconsolidation through increases in epigenetic-mediated transcriptional control via DNA double-strand breaks.
Dual color optogenetic control of neural populations using low-noise, multishank optoelectrodes
Kampasi, Komal; English, Daniel Fine; Seymour, John; Stark, Eran; McKenzie, Sam; Vöröslakos, Mihály; Buzsáki, György; Wise, Kensall D.; Yoon, Euisik (Nature, 2018)
Optogenetics allows for optical manipulation of neuronal activity and has been increasingly combined with intracellular and extracellular electrophysiological recordings. Genetically-identified classes of neurons are optically manipulated, though the versatility of optogenetics would be increased if independent control of distinct neural populations could be achieved on a sufficient spatial and temporal resolution. We report a scalable multisite optoelectrode design that allows simultaneous optogenetic control of two spatially intermingled neuronal populations in vivo. We describe the design, fabrication, and assembly of low-noise, multisite/multicolor optoelectrodes. Each shank of the four-shank assembly is monolithically integrated with 8 recording sites and a dualcolor waveguide mixer with a 7 × 30 μm cross-section, coupled to 405 nm and 635 nm injection laser diodes (ILDs) via gradient-index (GRIN) lenses to meet optical and thermal design requirements. To better understand noise on the recording channels generated during diode-based activation, we developed a lumped-circuit modeling approach for EMI coupling mechanisms and used it to limit artifacts to amplitudes under 100 μV upto an optical output power of 450 μW. We implanted the packaged devices into the CA1 pyramidal layer of awake mice, expressing Channelrhodopsin-2 in pyramidal cells and ChrimsonR in paravalbumin-expressing interneurons, and achieved optical excitation of each cell type using sub-mW illumination. We highlight the potential use of this technology for functional dissection of neural circuits.
Early-Life Stress Induced Epigenetic Changes of Corticotropin-Releasing Factor Gene in Anorexic Low Body Weight–Selected Chicks
Xiao, Yang; Wang, Jinxin; Siegel, Paul B.; Cline, Mark A.; Gilbert, Elizabeth R. (MDPI, 2020-04-27)
The expression of neuropeptide Y (NPY) in the arcuate nucleus (ARC) and corticotropin-releasing factor (CRF) in the paraventricular nucleus (PVN) were increased when low body weight–selected (LWS) line chicks, which are predisposed to anorexia, were subjected to a combination of nutritional and thermal stressors at hatch. We hypothesized that such changes resulted from epigenetic modifications. We determined global DNA methylation, DNA methyltransferase (DNMT) activity, and methylation near the promoter regions of NPY and CRF, in the hypothalamus of LWS chicks on day 5 post-hatch. Stress exposure at hatch induced global hypermethylation and increased DNMT activity in the ARC but not PVN. In the PVN of stressed LWS chicks, there was decreased methylation of a CpG site located at the core binding domain of methyl cytosine binding domain protein 2 (MBD2), near the CRF gene promoter. We then demonstrated that this was associated with disrupted binding of MBD2. There was also reduced utilization of yolk reserves and lean and fat masses in chicks that were stress-exposed. These findings provide novel insights on molecular mechanisms through which stressful events induce or intensify anorexia in predisposed individuals and a novel molecular target for further studies.
Estrogen receptor α drives pro-resilient transcription in mouse models of depression
Lorsch, Zachary S.; Loh, Yong-Hwee Eddie; Purushothaman, Immanuel; Walker, Deena M.; Parise, Eric M.; Salery, Marine; Cahill, Michael E.; Hodes, Georgia E.; Pfau, Madeline L.; Kronman, Hope; Hamilton, Peter J.; Issler, Orna; Labonte, Benoit; Symonds, Ann E.; Zucker, Matthew; Zhang, Tie Yuan; Meaney, Michael J.; Russo, Scott J.; Shen, Li; Bagot, Rosemary C.; Nestler, Eric J. (Nature Publishing Group, 2018-03-16)
Most people exposed to stress do not develop depression. Animal models have shown that stress resilience is an active state that requires broad transcriptional adaptations, but how this homeostatic process is regulated remains poorly understood. In this study, we analyze upstream regulators of genes differentially expressed after chronic social defeat stress. We identify estrogen receptor α (ERα) as the top regulator of pro-resilient transcriptional changes in the nucleus accumbens (NAc), a key brain reward region implicated in depression. In accordance with these findings, nuclear ERα protein levels are altered by stress in male and female mice. Further, overexpression of ERα in the NAc promotes stress resilience in both sexes. Subsequent RNA-sequencing reveals that ERα overexpression in NAc reproduces the transcriptional signature of resilience in male, but not female, mice. These results indicate that NAc ERα is an important regulator of pro-resilient transcriptional changes, but with sex-specific downstream targets.
Focal stimulation of the temporoparietal junction improves rationality in prosocial decision‑making
Li, Flora; Ball, Sheryl B.; Zhang, Xiaomeng; Smith, Alexander Charles (Nature Research, 2020)
We tested the hypothesis that modulation of neurocomputational inputs to value-based decisionmaking affects the rationality of economic choices. The brain’s right temporoparietal junction (rTPJ) has been functionally associated with both social behavior and with domain-general information processing and attention. To identify the causal function of rTPJ in prosocial decisions, we administered focal high definition transcranial direct current stimulation (HD-tDCS) while participants allocated money between themselves and a charity in a modified dictator game. Anodal stimulation led to improved rationality as well as increased charitable giving and egalitarianism, resulting in more consistent and efficient choices and increased sensitivity to the price of giving. These results are consistent with the theory that anodal stimulation of the rTPJ increases the precision of value computations in social decision-making. Our results demonstrate that theories of rTPJ function should account for the multifaceted role of the rTPJ in the representation of social inputs into value-based decisions.
From Synapse to Function: A Perspective on the Role of Neuroproteomics in Elucidating Mechanisms of Drug Addiction
Natividad, Luis A.; Buczynski, Matthew W.; McClatchy, Daniel B.; Yates, John R. (MDPI, 2018-12-09)
Drug addiction is a complex disorder driven by dysregulation in molecular signaling across several different brain regions. Limited therapeutic options currently exist for treating drug addiction and related psychiatric disorders in clinical populations, largely due to our incomplete understanding of the molecular pathways that influence addiction pathology. Recent work provides strong evidence that addiction-related behaviors emerge from the convergence of many subtle changes in molecular signaling networks that include neuropeptides (neuropeptidome), protein-protein interactions (interactome) and post-translational modifications such as protein phosphorylation (phosphoproteome). Advancements in mass spectrometry methodology are well positioned to identify these novel molecular underpinnings of addiction and further translate these findings into druggable targets for therapeutic development. In this review, we provide a general perspective of the utility of novel mass spectrometry-based approaches for addressing critical questions in addiction neuroscience, highlighting recent innovative studies that exemplify how functional assessments of the neuroproteome can provide insight into the mechanisms of drug addiction.
Frontal beta-theta network during REM sleep
Vijayan, Sujith; Lepage, Kyle Q.; Kopell, Nancy J.; Cash, Sydney S. (eLife Sciences Publications, 2017-01-25)
We lack detailed knowledge about the spatio-temporal physiological signatures of REM sleep, especially in humans. By analyzing intracranial electrode data from humans, we demonstrate for the first time that there are prominent beta (15–35 Hz) and theta (4–8 Hz) oscillations in both the anterior cingulate cortex (ACC) and the DLPFC during REM sleep. We further show that these theta and beta activities in the ACC and the DLPFC, two relatively distant but reciprocally connected regions, are coherent. These findings suggest that, counter to current prevailing thought, the DLPFC is active during REM sleep and likely interacting with other areas. Since the DLPFC and the ACC are implicated in memory and emotional regulation, and the ACC has motor areas and is thought to be important for error detection, the dialogue between these two areas could play a role in the regulation of emotions and in procedural motor and emotional memory consolidation.
Functional changes in glutamate transporters and astrocyte biophysical properties in a rodent model of focal cortical dysplasia
Campbell, Susan L.; Hablitz, John J.; Olsen, Michelle L. (Frontiers, 2014-12-17)
Cortical dysplasia is associated with intractable epilepsy and developmental delay in young children. Recent work with the rat freeze-induced focal cortical dysplasia (FCD) model has demonstrated that hyperexcitability in the dysplastic cortex is due in part to higher levels of extracellular glutamate. Astrocyte glutamate transporters play a pivotal role in cortical maintaining extracellular glutamate concentrations. Here we examined the function of astrocytic glutamate transporters in a FCD model in rats. Neocortical freeze lesions were made in postnatal day (PN) 1 rat pups and whole cell electrophysiological recordings and biochemical studies were performed at PN 21–28. Synaptically evoked glutamate transporter currents in astrocytes showed a near 10-fold reduction in amplitude compared to sham operated controls. Astrocyte glutamate transporter currents from lesioned animals were also significantly reduced when challenged exogenously applied glutamate. Reduced astrocytic glutamate transport clearance contributed to increased NMDA receptor-mediated current decay kinetics in lesioned animals. The electrophysiological profile of astrocytes in the lesion group was also markedly changed compared to sham operated animals. Control astrocytes demonstrate large-amplitude linear leak currents in response to voltage-steps whereas astrocytes in lesioned animals demonstrated significantly smaller voltage-activated inward and outward currents. Significant decreases in astrocyte resting membrane potential and increases in input resistance were observed in lesioned animals. However, Western blotting, immunohistochemistry and quantitative PCR demonstrated no differences in the expression of the astrocytic glutamate transporter GLT-1 in lesioned animals relative to controls. These data suggest that, in the absence of changes in protein or mRNA expression levels, functional changes in astrocytic glutamate transporters contribute to neuronal hyperexcitability in the FCD model.

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