Thesis (Ph. D.)--Ohio State University, 2005. / Title from first page of PDF file. Includes bibliographical references (p. 94-97).

One goal of the neurophysiological approach to the study of nervous systems is to analyze neuronal circuitry in terms of the synaptic actions of one cell on another, particularly in instances in which both cells are functionally identifiable and components of a circuit whose overall structural and functional properties can be analyzed with experimental techniques. The present project contributed to this type of effort by providing an analysis of the recurrent Renshaw circuit, a prominent pathway in the mammalian spinal cord which includes recurrent motoneuronal collaterals, Renshaw cells and other interneurons, which, in turn, project to motoneurons. The project describes the use of a relatively new data processing technique, spike-triggered averaging, to study the effects of the single impulses of single motor axons on the postsynaptic activity of single motoneurons which were responsive to the test impulses by way of components of the recurrent Renshaw circuit. The experimental paradigm involved intracellular recording from single motoneurons in low-spinal cats, either anesthetized with chloralose-urethane or unanesthetized after their ischemic decapitation. The synaptic noise recorded in each motoneuron served as the input to a signal averager which was triggered by brief electrical shocks used to activate single antidromic impulses in single motor axons, either by way of an intra-axonally positioned microelectrode in the muscle nerve or by microstimulation of the muscle supplied by the axon. The resultant average revealed the motoneuron's response to each single antidromic impulse; a recurrent inhibitory postsynaptic potential, recorded for the first-ever time in this project and termed a single-axon RIPSP. The experimental results described in the report include: first, the measurement, incidence and characterization of single-axon RIPSPs; and second, their use to test a hypothesis concerned with the distribution of Renshaw-cell effects within the spinal cord. The single-axon RIPSP measurement was shown to be the clearest example yet provided in the neurophysiological literature that spike-triggered averaging can be used to detect synaptic activity crossing two or more synapses within the central nervous system. Furthermore, the hypothesis was confirmed that Renshaw-cell effects within a single spinal motor nucleus are distributed according to the principle of topographic specificity.

Project report (M.S.)--Virginia Polytechnic Institute and State University, 1991. / Abstract. Includes bibliographical references (leaves 68-70). Also available via the Internet.

Thesis (M. S.)--Psychology, Georgia Institute of Technology, 2009. / Committee Chair: Dr. Paul Corballis, Ph.D.; Committee Member: Dr. Daniel Spieler, Ph.D.; Committee Member: Dr. Eric Schumacher, Ph.D.; Committee Member: Dr. Krish Sathian, M.D., Ph.D.; Committee Member: Dr. Randall Engle, Ph.D.

My project has been involved in analysing a class of interneuron that expresses the calcium‐binding protein parvalbumin (PV). In my thesis, I will describe the application of a method that involves the local injection of Creactivated recombinant adeno-associated viruses (AAVs) into a transgenic mouse line that expresses Cre recombinase in PV positive cells. This will drive the expression of a transgene specifically in PV positive cells, at a specific brain region. In the first part of my project, I used this method to introduce the molecular trans-synaptic tracer proteins wheat germ agglutinin and tetanus toxin heavy chain specifically to PV positive neurons to visualize their postand pre‐synaptic connections, respectively. What I found is that while our technique of combining Cre-activated AAVs in transgenic mice has allowed specific labelling of neurons in a brain region and cell type specific manner, we could not definitively identify trans-synaptically traced neurons. In the second part of my project I have used these novel AAV‐based techniques in mice to introduce tetanus toxin light chain (TeLC) to PV neurons in the dentate gyrus. This has been previously used to functionally remove PV neurons from the CA1 of the hippocampus. This protein inhibits neurotransmitter release by cleaving the vesicle docking protein, VAMP2. The DG has been implicated in the separation of sensory inputs (pattern separation) which increases the resolution of the encoded memory and thereby assists in the accurate recall. The lateral inhibition of excitatory activity in the DG is believed to aid accurate encoding. Using our AAV method, I found that PV positive interneurons are required for spatial working and reference memory. Using a new behavioural assay that I developed, I could also show that these neurons are needed to enhance the resolution of spatial information. However, I also discovered that long term expression of TeLC could result in neuronal cell death. I have therefore demonstrated that local injection of Cre recombinase activated AAVs allows for a quick, versatile method of genetic manipulation, provided long term expression (greater than 2 months) is not required.

A key role in simplified models of neural circuitry (Wilson and Cowan, 1972) is played by the matrix of synaptic weights, also called connectivity matrix, whose elements describe the amount of influence the firing of one neuron has on another. Biologically, this matrix evolves over time whether or not sensory inputs are present, and symmetries possessed by the internal dynamics of the network may break up spontaneously, as found in the development of the visual cortex (Hubel and Wiesel, 1977). In this thesis, a full analytical treatment is provided for the simplest case of such a biological phenomenon, a single dendritic arbor driven by correlation-based dynamics (Linsker, 1988). Borrowing methods from the theory of Schrödinger operators, a complete study of the model is performed, analytically describing the break-up of rotational symmetry that leads to the functional specialization of cells. The structure of the eigenfunctions is calculated, lower bounds are derived on the critical value of the correlation length, and explicit expressions are obtained for the long-term profile of receptive fields, i.e. the dependence of neural activity on external inputs. The emergence of a functional architecture of orientation preferences in the cortex is another crucial feature of visual information processing. This is discussed through a model consisting of large neural layers connected by an infinite number of Hebb-evolved arbors. Ohshiro and Weiliky (2006), in their study of developing ferrets, found correlation profiles of neural activity in contradiction with previous theories of the phenomenon (Miller, 1994; Wimbauer, 1998). The theory proposed herein, based upon the type of correlations they measured, leads to the emergence of three different symmetry classes. The contours of a highly structured phase diagram are traced analytically, and observables concerning the various phases are estimated in every phase by means of perturbative, asymptotic and variational methods. The proper modeling of axonal competition proves to be key to reproducing basic phenomenological features. While these models describe the long-term effect of synaptic plasticity, plasticity itself makes the connectivity matrix highly dependent on particular histories, hence its stochasticity cannot be considered perturbatively. The problem is tackled by carrying out a detailed treatment of the spectral properties of synaptic-weight matrices with an arbitrary distribution of disorder. Results include a proof of the asymptotic compactness of random spectra, calculations of the shape of supports and of the density profiles, a fresh analysis of the problem of spectral outliers, a study of the link between eigenvalue density and the pseudospectrum of the mean connectivity, and applications of these general results to a variety of biologically relevant examples. The strong non-normality of synaptic-weight matrices (biologically engineered through Dale’s law) is believed to play important functional roles in cortical operations (Murphy and Miller, 2009; Goldman, 2009). Accordingly, a comprehensive study is dedicated to its effect on the transient dynamics of large disordered networks. This is done by adapting standard field-theoretical methods (such as the summation of ladder diagrams) to the non-Hermitian case. Transient amplification of activity can be measured from the average norm squared; this is calculated explicitly for a number of cases, showing that transients are typically amplified by disorder. Explicit expressions for the power spectrum of response are derived and applied to a number of biologically plausible networks, yielding insights into the interplay between disorder and non-normality. The fluctuations of the covariance of noisy neural activity are also briefly discussed. Recent optogenetic measurements have raised questions on the link between synaptic structure and the response of disordered networks to targeted perturbations. Answering to these developments, formulae are derived that establish the operational regime of networks through their response to specific perturbations, and a minimal threshold is found to exist for counterintuitive responses of an inhibitory-stabilized circuit such as have been reported in Ozeki et al. (2016), Adesnik (2016), Kato et al. (2017). Experimental advances are also bringing to light unsuspected differences between various neuron types, which appear to translate into different roles in network function (Pfeffer et al., 2013; Tremblay et al., 2016). Accordingly, the last part of the thesis focuses on networks with an arbitrary number of neuronal types, and predictions are provided for the response of networks with a multipopulation structure to targeted input perturbations.

This thesis focuses on my work using optical techniques to study different brain regions in vivo. The ability to optically study neurons and the circuits they comprise in vivo is an important method to better understand their role in the healthy brain and their dysfunction in disease. The first part of my thesis focuses on my work using on a collaborative project using a new optical probe to study norepinephrine synapses in vivo. In this work we were able to observe the effects of amphetamine on norepinephrine release in vivo and observed some evidence of potential silent synapses. I also describe a new method of cranial window surgery I developed for optical imaging. This technique called PHASOR, is faster, and has a higher success rate, than traditional surgical methods. The improvements demonstrated in this new surgical technique may enable more widespread use of optical imaging methods. In the second part of my thesis, I used optical techniques to study the dorsal striatum in vivo in awake behaving mice. The direct and indirect paths of the dorsal striatum play an important role in motor behavior and motor learning. Dysfunction in these paths has been implicated in motor diseases as well as in mood disorders. In this thesis, I provide a review of the anatomy and physiology of the neurons that comprise the dorsal striatum, and the circuits that they form. The next chapters describe my work using optical techniques to record from these neurons in vivo. In my first set of experiments, I recorded from the direct and indirect paths during a behavioral task of anxiety and observed differential firing depending on the anxiety state of the mouse. Finally, in a preliminary set of experiments, I record from the direct and indirect paths during tasks of motor learning. I found that both paths show changes in firing during motor learning and that these changes differ between the dorsolateral and dorsomedial striatum.

No description available.

Appropriately organized synaptic connections are essential for proper neural circuit function. Prior to forming and refining synaptic connections, axons of projection neurons must first navigate long distances to their targets. Research in the axon guidance field has generated a great deal of knowledge about how axons successfully navigate through intermediate choice points and form initial connections with their synaptic targets. One aspect of neural circuit development that has been less well studied is whether axons are organized within their tracts. Axons could be highly ordered, or arranged haphazardly, to be sorted out within their destination target zone. Findings from several systems indicate that axon tracts are organized and, furthermore, that pre-target organization is important for accurate targeting. Chapter 1 will survey these findings as an introduction to my thesis. The remaining chapters present my research in the mouse retinogeniculate pathway, in which I examine three aspects of pre-target axon organization: the organization of cohorts of retinal ganglion cell (RGC) axons in the optic nerve and tract; the role of axon self association in tract organization; and the relationship between tract order and targeting. RGC axons project either ipsi- or contralaterally at the optic chiasm. In the first thalamic target, the dorsal lateral geniculate nucleus (dLGN), RGC axon terminals are organized based on retinotopy and laterality (i.e., into ipsi- and contralateral zones). Chapter 2 presents my findings on the organization of ipsilateral (ipsi) and contralateral (contra) RGC axons in the optic nerve and tract. Ipsilateral RGC axons cluster together in the optic nerve, are less tightly bundled in the optic chiasm, and once in the optic tract, again bundle together and are segregated from contralateral axons. Topographic and ipsi/contra axon order in the optic tract are largely in register, although ipsi- and contralateral axons from the same topographic region maintain distinct ipsi/contra segregation in the tract. Chapter 3 explores one potential mechanism involved in creating the organization between ipsi and contra RGC axons in the tract: differential fasciculation behavior between RGC axon cohorts. I used in vitro retinal explant culture systems to test the hypothesis that ipsilateral RGC axons have a greater preference to self-fasciculate than contralateral axons. Ipsilateral neurites display greater self-association/fasciculation than contralateral neurites, indicating an axon-intrinsic mechanism of ipsilateral-specific self-association. Chapter 4 examines tract organization and fasciculation in the EphB1 mutant retinogeniculate pathway. EphB1 is expressed exclusively by ipsilateral RGCs, and loss of EphB1 leads to a reduced ipsilateral projection and increased contralateral projection. However, aberrantly crossing axons project to the ipsilateral zone in the dLGN. Given its combination of an aberrant decussation phenotype with a grossly normal targeting phenotype, I used this mutant to explore the relationship between midline choice, tract organization, and targeting. First, remaining ipsilateral axons in the EphB1-/- optic tract largely retain their position in the lateral optic tract, but appear splayed apart, suggestive of aberrant fasciculation. In vitro, EphB1-/- ipsilateral neurites still bundle more than EphB1-/- contralateral neurites, although the magnitude of this difference is less striking than in wild-type retinal explants. Thus, EphB1 may be involved in preferential ipsilateral RGC axon fasciculation. In vivo, the aberrantly crossing axons in the EphB1 mutant grossly maintain their position in the ipsilateral zone of the optic tract (i.e., the lateral aspect), indicating a preservation of ipsilateral segregation in the tract. This is in line with a model in which bundling partners in the tract may help guide axons to the correct zone in the target. The data presented in this thesis detail two organizational modes of RGC axons in the developing optic nerve and tract, eye-specific (typographic) and topographic, and suggest that axon-intrinsic factors mediate ipsilateral-specific self-association. Axon-intrinsic factors likely act alongside extrinsic cellular and molecular cues in the developing retinogeniculate pathway to facilitate pre-target axon organization, which may in turn facilitate accurate formation of synaptic connections in the dLGN.

Thesis (M.S.)--Oregon Graduate Center, 1988.