Thesis (Ph.D.)--Biomedical Engineering, Georgia Institute of Technology, 2007. / Committee Chair: Potter, Steve; Committee Member: Butera, Robert; Committee Member: DeWeerth, Stephen; Committee Member: Schumacher, Eric; Committee Member: Wenner, Pete.

Thesis (M.S.)--Georgia State University, 2009. / Title from title page (Digital Archive@GSU, viewed July 20, 2010) Andrey Shilnikov, Robert Clewley, Gennady Cymbalyuk, committee co-chairs; Igor Belykh, Vladimir Bondarenko, Mukesh Dhamala, Michael Stewart, committee members. Includes bibliographical references (p. 65-67).

Thesis (Ph. D.)--Ohio State University, 2007. / Title from first page of PDF file. Includes bibliographical references (p. 144-147).

Thesis (M. S.)--Psychology, Georgia Institute of Technology, 2007. / Schumacher, Eric, Committee Chair ; Corballis, Paul, Committee Member ; Jacko, Julie, Committee Member.

Part I abstract: Genetic methods for inducibly and reversibly inhibiting neuronal activity of specific neurons are critical for exploring the functions of neuronal circuits. The engineered human glycine receptor, called ivermectin (IVM)-gated silencing receptor (IVMR), has been shown to possess this ability in vitro, which abolish the binding with endogenous glycine and improve the sensitivity to ivermectin. Based on that, we constructed the knock-in plasmid which put IVMR in the downstream of a loxP-flanked STOP cassette. The Rosa26-IVMR mouse line was generated by inserting the plasmid into the Rosa26 locus though homologous recombination. IVMR expression can be induced by crossing with specific Cre mouse line or stereotactic injection of Cre-expressing virus. When expressing IVMR in unilateral striatal by injecting Cre-expressing virus, APO-induced rotation behavior was observed after inactivation of unilateral striatal neurons by administering ivermectin. Furthermore, 10mg/kg and 5mg/kg IVM are the effective ligand concentrations as they are able to induce obvious rotational behavior, but the effect last longer for 10mg/kg IVM than that for 5mg/kg. The physiological recording in vivo exhibited that neuron firing dramatically decreased in IVM-treated freely moving Rosa26-IVMR; Emx1-Cre mice and neuronal excitability in brain slice showed a substantial reduction as shown by increased threshold of the current needed to evoke the action potential and the reduced frequency of the action potential. In conclusion, our mouse line can inactivate the neuronal activity effectively in an inducible and reversible way with systemic administration of the ligand. So it provides a powerful tool for exploring selective circuit functions in freely behaving mice. Part II abstract: Schizophrenia is a chronic and severe mental disease which affects around 0.5%-1% population. However, the underlying cause are complex and remain unclear. Genetic abnormalities are considered to be the main risky factor. Although the typical symptoms start to occur between 18 and 30 age, the disturbance of neurodevelopmental process at earlier age is believed to be involved. To date, only a few of susceptibility genes are confirmed in human patients. Previously, through a meta-analysis of copy number variants (CNV) data from the International Schizophrenia Consortium and in vitro studies, we found a novel serine/threonine kinase gene, unc-51-like kinase 4 (Ulk4), as a risk factor for major mental disorders including schizophrenia. To investigate the Ulk4's roles in corticogenesis, Ulk4 knockout mice was employed. Though analyzing a series of developmental process during corticogenesis including laminar specification, neuronal migration in Ulk4 deficient mice, we found that Ulk4 loss led to the thinner layer II-IV, delayed neuronal migration and increased cell death in layer II-IV but did not affect the proliferation of progenitors which later give rise to the projection neurons in layer II-IV. Meantime the influence of Ulk4 deficiency on the deep layer (layer V and layer VI) development was limited. In conclusion, Ulk4 plays a crucial role on corticogenesis and regulates a variety of neurodevelopmental processes. When defective, this will lead to the increased risk of neurodevelopment disorders and also might be involved in the onset of mental disease including schizophrenia at early adolescence.

No description available.

Hemoglobin, the oxygen-carrying component of red blood cells, is known as a nitric oxide (NO) chelating agent. For this reason, hemoglobin has been used widely in studying the role of nitric oxide in long-term potentiation (LTP) and excitotoxicity. However, the direct electrophysiological actions of hemoglobin has not been examined. In this investigation, the actions of hemoglobin on rat hippocampal CAl neurons were studied since hemoglobin may be present in hemorrhagic stroke and other head injuries. Superfusion of rat hippocampal slices with 0.1 mM of bovine hemoglobin for 15 minutes was induced a significant depolarization associated with an increase in the input resistance. In addition, hemoglobin suppressed the evoked synaptic responses and increased the depolarization-induced discharge of action potentials, of rat hippocampal CAl neurons. These hemoglobin-mediated changes usually recovered partially 30 minutes after the removal of hemoglobin. While the depolarizing action of hemoglobin was enhanced in a calcium-free medium, it was not significantly changed by 2-amino-5-phosphonovalerate (APV) and 6- cyano-7-nitroquinoxaline-2,3-dione (CNQX). These observations suggest that the depolarizing action of hemoglobin is independent of the presence of extracellular calcium and activations of the excitatory amino acid receptors. Because hemoglobin has been observed to suppress the depolarizing action of glutamate, it is possible that hemoglobin suppresses the EPSP by interfering with the actions of glutamate. Although hemoglobin has been suggested to suppress LTP and excitability by scavenging nitric oxide (Garthwaite et al., 1988; Haley et al., 1992; 0’ Dell et al., 1991; Schuman and Madison, 1991), the reported actions of hemoglobin were not removed by pre-treatment with 100 pM or 500 pM of No-nitro-L-arginine, a nitric oxide synthase inhibitor. Similar to the scavenging property of hemoglobin, the iron content of hemoglobin probably did not contribute to the actions of hemoglobin since 0.4 mM or 2.0 mM of ferric chloride did not simulate the effects of hemoglobin. Because neurons can be exposed to hemoglobin in hemorrhagic stroke and head injuries, the electrophysiological actions of hemoglobin on rat hippocampal CAl neurons may be relevant to the neurological complications associated with intracranial hemorrhage and head injuries. Further studies on mechanisms of the electrophysiological actions of hemoglobin are necessary for understanding the role of hemoglobin in neuronal damages associated with hemorrhagic stroke and other head injuries. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

The effects of cannabinoid agonists on spontaneous neuronal network activity were characterized in murine spinal cord and auditory cortical cultures with multichannel extracellular recording using photoetched electrode arrays. Different cultures responded reproducibly with global decreases of spiking and bursting to anandamide and methanandamide, but each agonist showed unique minor effects on network activity. The two tissues responded in a tissue-specific manner. Spontaneous activity in spinal tissue was terminated by 1 μM anandamide and 6.1 μM methanandamide. Cortical activity ceased at 3.5 μM and 2.8 μM respectively. Irreversible cessation of activity was observed beyond 8 μM for both tissues and test substances. Palmitoylethanolamide, demonstrated that CB2 receptors were not present or not responsive. However, the data strongly suggested the presence of CB1 receptors.

The hippocampus (HPC) is a brain area in the medial temporal lobe involved in spatial navigation, as well as the formation of episodic memories. A subset of the principal cells of the HPC, known as place cells, are active in specific locations of an environment, called the place fields. Dorsal hippocampal area CA1 contains place fields that are known to change their firing during spatial tasks where animals learn the location of a reward, known as goal-oriented learning (GOL) – CA1 place fields shift toward rewarded locations. Previous studies suggest that this preferentially occurs at novel rewarded locations in a familiar environment, but the mechanism is unknown. The locus coeruleus (LC) is a neuromodulatory nucleus in the brainstem that projects throughout the brain and releases norepinephrine and a small amount of dopamine. Stimulating locus coeruleus-hippocampal area CA1 projections (LC-CA1) was recently shown to improve performance on spatial memory tasks. Since performance on the GOL task is correlated with the degree of overrepresentation of rewarded locations, we hypothesized that the LC-CA1 projection was involved in reward-related place field reorganization. Using in vivo two photon calcium imaging, we recorded the activity of the LC-CA1 projection during a head fixed GOL task with two phases – during the first phase, a water reward was presented in one location (RZ1), and in the second phase, it was moved to a novel location (RZ2). In the first phase of the task, the LC-CA1 axons were correlated with running, but in the second phase they showed an increase in activity preceding RZ2. To determine whether the LC-CA1 is involved in place field reorganization that normally occurs in RZ2, we optogenetically activated the projection just before RZ1, and saw a pronounced place field reorganization right before the reward. Conversely, inhibition of LC-CA1 at RZ2 attenuated place field reorganization at this site. Finally, LC-CA1 stimulation away from the reward did not lead to place field reorganization, indicating that the LC influences place field shifts in conjunction with other signals that are differentially active around rewards. A full account of the effects of neuromodulation should also include astrocytes, since they respond to neuromodulators with large calcium signals that may be able to affect the function of neurons. We also recorded HPC astrocyte calcium activity during different behavioral tasks. Astrocytes showed occasional large calcium signals, with some differences in synchronicity and activity levels between hippocampal layers and behavioral paradigms. Future studies should determine whether the LC-CA1 projection affects place fields directly by affecting neural activity, indirectly via astrocytes, or both.

Modularity plays a pivotal role in evolution, as the compartmentalization of components of a system allows their independent optimization in isolation, minimizing the effect on the system as a whole. As a manifestation of this universal design principle, evidence suggests modularity plays a key role in the function of the brain as well, allowing the compartmentalization of specific structural and functional units before their integration. Despite this, it’s unknown how modularity arises during the development of neural circuits. Accordingly, observing the development of the modularity of the nervous system and correlating this with the emergence of specific behaviors has the potential to highlight features of the functional role of modularity in the mature nervous system. To explore this issue, we work with the small cnidarian Hydra vulgaris, a representative of some of the simplest nervous systems in evolution. Depending on the size of the animal, Hydra’s isometrically scaling nervous system of 300-2,000 neurons is organized in two independent nerve nets in its ectoderm and endoderm and is distributed through the body of the animal without any cephalization or ganglia. Moreover, under the right conditions Hydra can reassemble itself into a normal animal after complete dissociation into individual cells. Using transgenic Hydra which express the calcium sensor GCaMP6s in every neuron (Dupre and Yuste, 2017) we have imaged the neuronal activity of dissociated preparations as they re-aggregate then regenerate over a period of several days. We demonstrate the robust synchronization of Hydra’s neural nets during the process. Of the possible routes toward synchronization, we observe that an initially random structure takes on a hierarchical organization as small groups of neurons synchronize. As these proto-circuits further synchronize, the modularity of the system increases, accompanied by a loss of the hierarchical depth of the network structure as normal behavioral rhythms resume during regeneration.