Abstract List for 2016 meeting

#384: Role of Endoplasmic Reticulum Stress in Angiogenic Progenitor Cell Dysfunction in Type 1 Diabetes

Bhatta, Maulasri ¹; Chatpar, Krishna ²; Wang, Joshua J ¹; Zhang, Sarah X ¹;

¹Ross Eye Institute, Department of Ophthalmology, ²Department of Biological Sciences, SUNY University at Buffalo;

Diabetic retinopathy is characterized by progressive vascular degeneration partially attributed to defective vascular repair by circulating angiogenic cells (CACs). Our recent work has implicated endoplasmic reticulum (ER) stress in high glucose- induced dysfunction of angiogenic progenitor cells. Herein, we investigated the in vivo role of ER stress in diabetes­-induced angiogenic abnormalities using a streptozotocin (STZ) model. A significant increase in bone marrow progenitors was observed at 3 months after diabetes. In contrast, bone marrow angiogenic progenitors showed a decrease at 1 and 9 months but an increase at 3 months, CACs in peripheral blood were reduced at 1, 3, and 6 months after diabetes and were unaltered at 9 months with diabetes. Similarly, there was a reduction of CACs in the retina at 3 months with diabetes remaining unaltered at 9 months with diabetes. In BMNCs, expression of ER stress markers increased at 9 months. Moreover, expression of Il­1β was increased at months 3 and 9 with diabetes. In bone marrow­ derived EOCs, increased levels of CHOP and cleaved caspase­3 were seen at 3 months after diabetes with stunted unfolded protein response and protein quality control, suggesting reduced ER capacity. This was accompanied by reduced capacity of colony formation and migration and inhibiting ER stress by 4­phenylbutyrate (4­PBA) significantly improved the function of diabetic EOCs. Moreover, use of chemical chaperones PBA and tauroursodeoxycholic acid (TUDCA) alleviated diabetes-induced bone marrow pathology and increased angiogenic function both in vitro and in vivo. Our data demonstrate a dynamic and differential activation of ER stress signaling pathways in BMNCs and EOCs in STZ mice over 9 months of diabetes, correlating with aberrant changes of angiogenic progenitors in bone marrow, peripheral blood and the retina. Further, use of chemical chaperones restored the diabetes-induced angiogenic progenitor dysfunction.

#378: Nicotine Blocks the Acquisition of Taste Learning Associated with Ethanol Exposure

Loney, Greg C ; Meyer, Paul J ;

Department of Psychology, SUNY University at Buffalo;

Here, we examined the effects of nicotine on the palatability of ethanol (EtOH) and associative learning to EtOH. First, we tested rats in a brief-access licking paradigm to measure unconditioned licking to briefly presented, randomized concentrations of EtOH (1.25-40% v/v) in a lickometer that measures taste-guided licking while minimizing post-ingestive consequences. Curves were fit to the licks with multiple regression and the EC₅₀ was compared between saline (1.0 ml/kg) and nicotine-treated (0.4 mg/kg) rats. Nicotine had no effects on the palatability-driven licking responses relative to saline. Following baseline testing, rats were presented with an intermittent two-bottle choice tests for 4 weeks, with 20% EtOH and water while continuing to receive nicotine or saline. Subsequently, rats were again tested in the lickometer as described above. The EtOH concentration-response curve in saline-treated rats was shifted rightward from baseline, suggesting that they found EtOH less aversive after repeated exposures, while the curve in nicotine-treated rats was not (P < 0.001). To ensure that nicotine was not having any acute effects on the palatability-driven licking responses we retested all of the rats in the lickometer while switching the drugs such that saline-treated rats now received nicotine and vice versa. These switch tests revealed that nicotine had no effect on the rightward-shifted licking responses in previously saline-treated rats but removing nicotine resulted in a rightward shift in previously nicotine-treated rats (P < 0.001).  Preliminary data indicate that nicotine is increasing both the acceptance of the taste of EtOH following an EtOH-induced CTA and the number of trials initiated to EtOH. Thus, nicotine history is increasing both appetitive and consummatory behaviors following EtOH-induced illness. These data indicate that nicotine interferes with acquisition, but not expression, of taste-guided incidental and associative learning.

#400: Using functional brain states to inform surgeon-robot interactions

Shafiei, Somayeh B ¹; Guru, Khurshid A ²; Muldoon, Sarah F ³;

¹Mechanical and Aerospace Engineering, ³Mathematics, SUNY University at Buffalo; ²Urology, Roswell Park Cancer Institute;

In human-robot interactions and haptic environments, learning motor and perception skills plays an important role in both operation performance and mental workload optimization. To investigate the dynamic interaction between functional brain states and performance in robot-assisted surgery, we analyze the functional connectivity of motor, visual, and cognition areas derived from EEG data of a robot assisted surgery mentor obtained while (i) performing Urethrovesical Anastomosis (UVA) operations and (ii) observing the live performance of surgical trainees. The results show a dynamic change of the mentor’s functional brain state with relation to performance improvement, which is additionally associated with a higher modularity in all frequency bands. Further, brain state modularity is higher during operations performed by the mentor than modularity measured while the mentor observes trainees with a low quality performance. We also observe that at higher frequencies, the mentor’s brain state is composed of more functional communities. By relating brain state modularity to surgical performance, we will aid the development of a shared control environment between surgeons and robots in the next generation of robotic surgery systems. This framework is applicable to disciplines where network adaptability can be used for performance based skill assessment and cognitive trust evaluation.

#366: Monoaminergic involvment in imidazoline I2 agonist-induced analgesia

Siemian, Justin N ;

Department of Pharmacology and Toxicology, SUNY University at Buffalo, School of Medicine and Biomedical Sciences;

Chronic pain is the largest healthcare problem facing the United States, and current analgesics are inadequate for long-term chronic pain management. Thus, there is a dire clinical need for novel, safe, and effective analgesics. Recent preclinical studies have established the imidazoline I₂ receptor (I₂R) as a target to treat chronic pain. Although in vitro studies have characterized I₂Rs as allosteric inhibitory binding sites of monoamine oxidase (MAO) A and B, in vivo studies have not demonstrated the direct involvement of monoamines in the behavioral effects of I₂R ligands. This study systematically examined the analgesic effects of the selective I₂R agonist 2-BFI alone and in combination with pharmacological modulators of the serotonin (5-HT), norepinephrine (NE), and dopamine (DA) systems in male rats with chronic constriction injury (CCI)-induced neuropathic pain, as measured by the von Frey filament test. The selective serotonin reuptake inhibitor fluoxetine and the selective norepinephrine reuptake inhibitor desipramine were each ineffective when administered alone, but pretreatment with either compound potentiated 2-BFI-induced analgesia. In contrast, pharmacological depletion of either 5-HT with pCPA/fenfluramine or NE with DSP-4 suppressed 2-BFI-induced analgesia. Further investigation revealed that the selective receptor antagonists WAY100635 (5-HT_1A), MDL100907 (5-HT_2A), and WB4101 (α_1A­-adrenoceptor) caused dose-dependent rightward shifts of the 2-BFI analgesic dose-effect curve, whereas SB242084 (5-HT_2C)_, yohimbine (α₂-adrenoceptor), SCH23390 (D1), and raclopride (D2) had no effect. These results were consistent for CR4056, another selective I₂R agonist. Collectively, these data suggest that I_2­R agonist-induced analgesia is dependent upon 5-HT and NE but not DA systems, with 5-HT_1A, 5-HT_2A, and α_1A-adrenergic receptors appearing particularly important.

#373: Using brain network topological measures to study structural differences

Baidoo-Williams, Henry E ¹; Green, Clint ²; Grafton, Scott T ²; Vettel, Jean M ²; Muldoon, Sarah F ¹;

¹Department of Mathematics, SUNY University at Buffalo; ²Department of Psychological and Brain Sciences, University of California, Santa Barbara;

The spatiotemporal evolution of the states of neural populations in individual human brain networks have repeatedly been shown to correlate with temporal activities of individual subjects. Understanding how global neural populations are activated through structure-function couplings opens up important tools and measures in developing personalized brain strategies when required. To study the effects of network structure on the spatiotemporal dynamics of neural population cliques, we relate the qualitative mean field behavior of neural populations with features from the brain connectome - a connectivity map of neural streams across brain regions. We show that features which depend on the spectral radius of the connectivity matrix are able to predict the observable qualitative behavior of the system.

#387: Parsing attention and motivation in incentive cues

Baindur, Ajay N ; Wakabayashi, Ken T ; Bruno, Michael J ; Lewis, Stephen A ; Bass, Caroline E ;

Department of Pharmacology and Toxicology, SUNY University at Buffalo, School of Medicine and Biomedical Sciences;

When previously neutral cues in the environment are repeatedly paired with a reward, they can become powerful incentives for reward-seeking and thus may be a critical factor underlying the transition to addiction and relapse in people. In order to have a better understanding of the neural circuits and neurotransmitter systems involved in this kind of conditioned learning, we have developed and tested a rat model of incentive cue motivation. In this model, male rats were trained to nosepoke during an 8s intermittent tone and light stimulus, serving as an incentive cue (IC) that predicted the delivery of a liquid sucrose (~60 ml) reward upon a successful nosepoke during a 1 hour session. To gauge performance, we monitored a combination of metrics including response ratio (number of successful nosepokes/number of ICs), latency to nosepoke (seconds from ICs to nosepoke), latency to reward (seconds from nosepoke to reward cup entry) and overall accuracy (number of rewarded nosepokes/total nosepokes). Once a stable baseline level of IC response was established, we examined in separate within session tests whether trained rats were sensitive to changes in 1) the primary reinforcer by altering the volume of sucrose delivered per successful response (a manipulation sensitive to the motivation for the primary reinforcer) and 2) the predictive IC by altering the length of the IC (a change more sensitive to attention and motivation for the IC). Our results indicate that this incentive cue task is a robust model for examining the efficacy of incentive cues in modulating reward-seeking behaviors, and captures elements of motivation, attention, impulsivity and behavioral inhibition. In addition, while altering either the primary reinforcer or IC resulted in diminished task performance, changing the IC length had a greater overall effect. Our model should enable us to examine how activity within the mesolimbic circuits contributes towards responding to incentive cues.

#395: The loop region of Presenilin is essential for Glycogen synthase kinase-3β mediated axonal transport

Banerjee, Rupkatha ; Naylor, Crystal ; Gunawardena, Shermali ;

Department of Biological Sciences, SUNY University at Buffalo;

Neurons require intracellular transport of essential components for function and viability. Defects in axonal transport have been implicated in many neurodegenerative diseases. Although multiple levels of regulation of motor protein function must exist for proper transport of components within axons, little is known about these mechanisms. One possible mechanism by which transport defects can occur is by improper regulation of molecular motors. Previous work has shown that reduction of Presenilin (PS) or Glycogen synthase kinase-3β (GSK-3β) stimulated APP vesicle motility. Excess GSK-3β causes axonal transport defects and increased motor binding to membranes, while reduction of PS decreased active GSK-3β and motor binding to membranes, suggesting that PS and GSK-3β may function together during axonal transport. Since PS and GSK3β are known to interact in the β-Catenin pathway, we hypothesize that PS influences GSK3β activity for motor regulation. Using Drosophila genetics, we found that excess PS rescued GSK-3β mediated axonal blockages. Intriguingly, the catalytic region of PS, (PS loop), which is known to bind to GSK3β and β-Catenin is essential for this rescue. Disruption of PS loop (PSΔE9) exacerbated GSK3β-mediated axonal blocks, while excess of PS loop suppressed it. Together, our observations suggest that functional PS with an intact PS loop region is required to modulate GSK-3β-mediated roles during axonal transport. Perhaps, PS and GSK-3β physically interact to regulate motor activity during axonal transport similar to GSK-3β-mediated mechanisms in the β-Catenin pathway.

#401: Using data-driven computational brain models to predict individual differences in task performance

Bansal, Kanika ¹; Medaglia, John D ²; Bassett, Danielle S ³; Vettel, Jean M ⁴; Muldoon, Sarah F ¹;

¹Department of Mathematics , SUNY University at Buffalo; ²Department of Psychology, ³Department of Bioengineering , University of Pennsylvania; ⁴Department of Psychological and Brain Sciences , University of California, Santa Barbara;

The human brain connectome provides information about neural structural connectivity between the regions of the brain, thus generating a fundamental basis for our efforts in understanding the organization of the human brain as a complex and efficient network. How important is this basic structural skeleton of the brain in explaining and predicting ​individual differences at cognitive level? To address this question, we use a computational model of brain dynamics that combines structural connectivity with nonlinear oscillators representing the dynamics of regional neuronal populations. By emphasizing differences in the underlying structural connectivity, our results indicate that this relatively simple model can provide a powerful tool to differentiate the performances of individuals at basic cognitive tasks.

#412: Methamphetamine differently regulates norepinephrine and dopamine signaling in the rat brain

Bhimani, Rohan ¹; Wakabayashi, Ken T ²; Park, Jinwoo ³;

¹Neuroscience, ²Department of Pharmacology and Toxicology, ³Biotechnical and Clinical Laboratory Sciences, SUNY University at Buffalo, School of Medicine and Biomedical Sciences;

Methamphetamine (METH) is a highly addictive psychostimulant with neurotoxic effects yet still remains one of the most abused illicit drugs in the world. The psychomotor effects of METH are mediated by increased synaptic concentrations of the central catecholamines, dopamine (DA) and norepinephrine (NE), by several different dose dependent mechanisms, including inhibition of reuptake and reverse transport through their uptake transporters. Interestingly, METH has been reported to be five to nine times more potent at inhibiting the NE transporter (NET) in comparison to the DA transporter (DAT). Furthermore, the subjective effects of METH in human users are also correlated with increased NE concentrations more so than DA. Despite this evidence, relatively little is known as to how METH alters the regulation (release and clearance) of extracellular NE in the brain relative to DA. In this study, we investigated the effects of METH on NE regulation in the ventral bed nucleus of the stria terminalis (vBNST) of urethane-anesthetized and behaving rats using multichannel fast-scan cyclic voltammetry (FSCV) coupled with carbon-fiber microelectrodes. The vBNST, a small limbic brain region, receives the densest NE innervation and is critically involved in autonomic processes and behaviors related to stress as well as drug seeking. In vivo FSCV provides us with a local view of tonic and phasic NE signaling in the vBNST. These results were compared with METH effects on DA signaling in the nucleus accumbens shell (NAc), a brain region heavily implicated in the processing of reward and demonstrated that DA and NE are differently regulated by METH at behaviorally relevant doses.

#420: DMT1 is required for adequate oligodendrocyte progenitor cell maturation and myelination

Cheli, Veronica T ¹; Marziali, Leandro N ²; Santiago González, Diana A ¹; Spreuer, Vilma ¹; Pasquini, Juana M ²; Pablo, Pablo M ¹;

¹HJKRI, SUNY University at Buffalo; ²FFyB, UBA;

The Divalent Metal Transporter 1 (DMT1) is a multi-metal transporter with a primary role in iron transport. Even though DMT1 has been previously described in the CNS nothing is known about the role of DMT1 in oligodendrocyte maturation and myelination. We have found that DMT1 is upregulated during the development of the oligodendrocyte. In vitro, oligodendrocyte progenitor cells (OPCs) showed low levels of DMT1 expression but higher quantities of this metal transporter were found in mature oligodendrocytes. In the postnatal mouse brain, DMT1 was found to be highly expressed by myelinating oligodendrocytes; DMT1 immunolabeling was located in myelinated fibers and precisely colocalize with myelin proteins in the corpus callosum, cortex and striatum. To determine whether DMT1 is required for OPC maturation, we used siRNAs and the Cre/lox system to knock-down/out DMT1 expression in primary cultures of cortical OPCs. Blocking DMT1 production reduce iron uptake in OPCs and more importantly, significantly delay OPC development. DMT1 knock-down/out induced a decrease in the proportion of oligodendrocytes that expressed myelin proteins, and an increase in cells that retained immature OPC markers. Furthermore, DMT1 knock-down/out does not affect cell viability, but promotes OPC proliferation. In summary, our data suggest that DMT1 is an important multi-metal transporter for proper oligodendrocyte maturation. We have found that DMT1 is upregulated during the development of the OPC and is highly expressed by myelinating oligodendrocytes in the postnatal mouse brain.