Travel Grant Recipients to Neuroscience 2017 Announced

• Kevin Beier, PhD

• Postdoctoral Fellow
• Stanford University
• Stanford, CA, USA

Research Summary

“My research vision is to understand how drugs of abuse and stress trigger divergent behavioral outcomes – drug addiction and mood disorders - through common neuroanatomical substrates. The ventral tegmental area dopamine (VTA-DA) neurons have been proposed as a final common pathway for many disorders. Most studies have focused on common excitatory synaptic changes onto VTA-DA neurons triggered by both drugs and stressors. However, given the differing behavioral consequences of these stimuli, the most straightforward explanation is that these experiences induce as-yet undiscovered changes in other brain circuits unique to the experience. What are these changes? Where do they occur? Which are common to both drugs and stress, and which are distinctive for each experience? I will present a novel methodology by which we can uncover these changes in an unbiased manner.”

• Nicola Corbett, PhD

• Postdoctoral Fellow
• University of Manchester
• Manchester, UK

Research Summary

“I will be presenting my data in a nanosymposium session entitled “Alzheimer's Disease: APP and Its Processing” (session number 544). My research looks at the effects, and the signalling of, a non-amyloidogenic cleavage product of the amyloid precursor protein (APP), known as soluble amyloid precursor protein α (sAPPα). The research that I will be presenting will concentrate on sAPPα at the synapse of cortical neurons that we have derived from human induced pluripotent stem cells.”

• Dimitri Yousef Yengej

• PhD Candidate
• University of Amsterdam - Swammerdam Institute for Life Sciences
• Amsterdam, Netherlands

Research Summary

Activity driven homeostatic scaling of excitability is a well-documented way of keeping neuronal firing within working range. CA1 pyramidal neurons in the rat hippocampus adjust their excitability by upscaling hyperpolarization activated cyclic nucleotide–gated (HCN) channels in the membrane (van Welie et al., 2004; Noam, et al., 2010). H-current (Ih) was also found in CA1 interneurons and while scaling of their current could have similar effects at the cellular level, the outcome at circuit level will be more complex. In this study, we investigated Ih scaling in stratum Oriens-Laconusum-Moleculare (OLM) interneurons as a result of enhanced synaptic drive. Whole cell patch-clamp recordings were performed in sagittal brain slices of 4-6 weeks old male mice. OLM neurons were recognized based on location, morphology and high firing rate (>150 Hz). Ih was quantified in voltage clamp by stepwise hyperpolarization. The voltage-dependent activation obeyed a Boltzmann function. Alpha-Latrotoxin (LTX, 0.15 nM) was used to upregulate spontaneous synaptic release, which was confirmed by an enhanced presence of miniature post synaptic currents. As a consequence of the enhanced activation of the glutamatergic input, Ih was upregulated in about 15 min. by approximately 51% (±11% SEM, n=9) in CA1 OLM-interneurons, in a way comparable to what has been described for Ih upregulation in CA1 pyramidal neurons. The change was best described by amplitude scaling and did not affect the voltage dependent properties of Ih. Neuronal sub-threshold resonance was measured by injecting a chirp current (0.5 – 20Hz) and recording the resulting membrane voltage response. Resonance was voltage dependent and most prominent around -80 mV membrane potential; it was blocked by the HCN channel blocker ZD7288 (20 µM). Preliminary results indicate that Ih scaling is associated with a change in resonance in OLM interneurons: The peak frequency of the resonance shifted with Ih upregulation from ~2.0 Hz to ~2.9 Hz (n=3). We conclude that OLM interneurons present activity induced scaling of the Ih which modulates intrinsic excitability, firing rate and subthreshold neuronal resonance. Ih modulation in OLM interneurons will affect theta frequency and power (Neymotin, et al., 2013). Disruptions of this process could result in several disorders, including epilepsy.

• Lindsay Rizzardi, PhD

• Postdoctoral Fellow
• Johns Hopkins School of Medicine - Molecular Medicine
• Baltimore, MD, USA

Research Summary

DNA methylation is an epigenetic modification that can mediate gene-environment interactions resulting in altered gene regulation. Many methylation changes occur during normal brain development and can be associated with neuropsychiatric diseases including schizophrenia, Alzheimer’s, and multiple mood disorders. To understand how these altered epigenetic states influence neurological processes, we have performed whole genome bisulfite sequencing on neuronal nuclei (NeuN+) isolated from many different post-mortem brain regions in individuals with no history of neurological disease. We have found substantial methylation differences between brain regions attributable to the varied composition of neuronal subtypes present in each region. Combining this information with gene expression data from these same regions/individuals allows us to identify distinct functional networks being regulated through this epigenetic mechanism in diverse areas of the brain. Her work will be presented during session 555 - Genetics of Neurodevelopmental Disease.

• Wendy Gold

• Research Officer
• Kids Research Institute - Rett Syndrome Group
• Westmead, Australia

Research Summary

The focus of my research is the role of the cytoskeleton in mitochondrial trafficking in Rett syndrome. Rett syndrome is a devastating neurodevelopmental disorder, predominantly caused by genetic mutations in the transcriptional regulator Methyl-CpG-binding protein 2 (MECP2). A predominance of neuronal and synaptic dysfunction is an overarching feature of Rett syndrome. Defective microtubule dynamics and concomitant aberrant trafficking of brain derived neurotrophic factor (BDNF) has recently been described in Rett syndrome, highlighting the importance of the microtubule network. Reduced microtubule stability and defective trafficking of mitochondria has been reported in other neurological disorders such as Alzheimer’s Disease. Thus, since a stable microtubule network is essential for the trafficking of mitochondria to critical regions of the cell, such as the synapse, it is possible that mitochondria may be aberrantly trafficked in Rett syndrome.

• Yifei Cai

• PhD Candidate
• Peking University - Shenzhen PKU-HKUST Medical Center
• Shenzhen, China

Research Summary

Autism is a highly complex neurodevelopmental disorder. Eph receptors have been linked to autism because the dimerization of these receptors control growth cone collapse by regulating Rho-GTPase. Recent genetic studies identified two autism-associated de novo mutations on EphB2, including a de novo premature stop codon (Q858X) on the C-terminus of the kinase domain. Truncation of the kinase domain-SAM-PDZ binding motif (KSP)in EphB2 disrupted multiple neurodevelopmental events, including synapse density and spine formation. The SAM-PDZ binding motif (SP) is conserved across evolution. Research has shown that truncation of SP domains in multiple EphA family members alter receptor dimerization propensity and kinase activity in various ways, indicating that KSP domains perform individual functions in signal transportation. However, the role of SP domains in the EphB family is still unclear. We are interested in how the SP domain regulates Eph receptor dimerization and its function during neurodevelopment.

“Our research has shown that both the Q858X de novo mutation and SAM domain regulate EphB2 kinase activity. Our experiements were done both with and without ligand Ephrin B1 or B2 (R&D Systems) stimulation, as well as with a point mutation in the SAM domain. Our results suggest that the SAM domain negatively regulates kinase activity in a stereo-inhibition manner. We are now investigating receptor dimerization propensity, downstream signaling pathways, and morphological study in neurons to support this hypothesis.”

• Erik Dustrude, PhD

• Postdoctoral Fellow
• Indiana University School of Medicine
• Indianapolis, IN, USA

Research Summary

“At Sfn 2017, I will present a poster detailing my research on basolateral amygdala (BLA) input from the perifornical hypothalamus (PeF) during fear behaviors. My laboratory’s previous work has demonstrated that disinhibition of the PeF produces a ‘panic-vulnerable’ state and that augmented panic vulnerability increases excitation of BLA neurons. In my current research, I have used optogenetic techniques to specifically activate an excitatory PeF-BLA circuit in order to isolate the role of this circuit in fear acquisition, fear extinction, and reinstatement of fear. This work advances my laboratory’s goal of understanding circuit-level contributions to phobia development. My poster will be on display on Monday November 13^th, 2017 from 8:00 AM - 12:00 PM as part of session #328.”

• Magdalena Skonieczna

• Professor
• Silesian University of Technology, Poland
• Gilwice, Poland

Research Summary

Cellular responses to stressing conditions are highly dependent on the physiological status of mitochondria and the permeability of its membrane. In this work, the effect of inhibiting mitochondrial membrane voltage-dependent anion channels (VDACs), by the inhibitor 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS), on survival and response to radiation of human lymphoblastoid K562 cells was studied. DIDS treatment caused a stepwise decrease of mitochondrial membrane potential and about 50% increase in cell death 48 h after treatment. This was accompanied by a significant increase in the activity of caspase 3, with the activities of caspases 1, 8, and 9 less influenced. The differences between DIDS-treated and -untreated cells were more pronounced after exposure to X-irradiation. K562 cells exposed to 4 Gy of 6 MV X-ray photons arrested the cell cycle and showed the highest number of cells in G2 phase 12 h after irradiation. Inhibition of the cell cycle in DIDS-treated and irradiated cells was less pronounced with lower G2/G1 cell number ratio. Treatment with DIDS did not significantly change the level of reactive oxygen species (ROS) in control cells, but DIDS treated and irradiated cells showed significantly higher levels of ROS 24 h after exposure and the levels of nitric oxide (NO) were lower in these cells than in irradiated without DIDS treatment. Obtained results suggest that the status of voltage dependent anion channels may influence the cell cycle checkpoints and the cellular response to ionizing radiation through modulation of the NO- and ROS-dependent signaling pathways.

• Fernanda Barros-Aragão

• PhD Candidate
• Federal University of Rio de Janeiro
• Rio de Janeiro, Brazil

Research Summary

“The recent outbreak of the mosquito-born exanthematic disease caused by the Zika virus (ZIKV) has brought worldwide caution due to its association with severe neurological complications in the fetus during pregnancy. In adults, ZIKV infection has also been linked to rare neurological manifestations, including acute myelitis, encephalitis and meningoencephalitis. Nevertheless, little is known about ZIKV infection in the adult human brain and its possible consequences. In our study, we aimed to evaluate if ZIKV is able to infect human adult brain tissue and its possible consequences for higher cognition. We found that ZIKV infects ex-vivo human adult cortical tissue, increasing infectious particles released to the medium and the cytokine interleukin-6 (IL-6) levels in a time-dependent manner. Moreover, when injected into the lateral ventricle of wild-type Swiss mice, ZIKV replicates in brain tissue, accumulating in areas central to memory and cognition, including the hippocampus and frontal cortex. While not inducing neuronal death, this infection leads to synaptic loss and increased cytokine mRNA levels, as well as increased IBA-1 positive cells. Furthermore, infected animals performed poorly in the novel object recognition memory task as soon as one day post-infection (dpi) until 30 dpi. Therefore, our results indicate that ZIKV successfully replicates in adult human and mice neural tissue in sites unrelated to neurogenesis but key to memory, and this viral infection induces brain inflammation, synapse loss and memory impairment in mice.”

• Ajibola Meraiyebu, PhD

• Senior Lecturer
• Bingham University
• Abuja, Nigeria

Research Summary

“My research is targeted at the role of cholesterol in neurodegenerative disorders and how excessive intake of cholesterol crossing the BBB can be hydrolysed. Studies have shown that individuals who consume high levels of cholesterol, especially LDL, are more prone to neurodegenerative disorders. Amyloid plaques are being studied and compared in rats feed with increased levels of Cholesterol to determine their action on brain cells using immunohistochemistry.”