Performance motor errors trigger animals’ adaptive learning behaviors to improve the accuracy and efficiency of the movement. The cerebellum is one of the key brain centers for encoding motor performance and motor learning. Climbing fibers relay information related to motor errors to the cerebellar cortex, evoking elevation of intracellular Ca2+ signals at Purkinje cell dendrites and inducing plasticity at coactive parallel fiber synapses, ultimately recalibrating sensorimotor associations to alter behavior. Molecular layer interneurons (MLIs) inhibit Purkinje cells to modulate dendritic excitability and action potential output. How MLIs contribute to the regulation and encoding of climbing fiber-evoked adaptive movements remains poorly understood. In this dissertation, I used genetic tools to manipulate the activity of MLIs while monitoring Purkinje cell dendritic activity during a cerebellum-dependent motor learning task with different contexts to evaluate how MLIs are involved in this process. The results show that by suppressing dendritic Ca2+ signals in Purkinje cells, MLI activity coincident with climbing fiber-mediated excitation prevents the occurrence of learning when adaptation is not necessary. On the other hand, with error signals present, disinhibition onto Purkinje cells, mediated by MLI-MLI microcircuit, unlocked the ability of climbing fibers to induce plasticity and motor learning. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2020. / FAU Electronic Theses and Dissertations Collection

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Yes / Background:With current treatments for Alzheimer’s disease (AD) only providing temporary symptomatic benefits, disease modifying drugs are urgently required. This approach relies on improved understanding of the early pathophysiology of AD. A new hypothesis has emerged, in which early memory loss is considered a synapse failure caused by soluble amyloid-β oligomers (Aβo). These small soluble Aβo, which precede the formation of larger fibrillar assemblies, may be the main cause of early AD pathologies. Objective:The aim of the current study was to investigate the effect of acute administration of stabilized low-n amyloid-β1-42 oligomers (Aβo1-42) on cognitive, inflammatory, synaptic, and neuronal markers in the rat. Methods:Female and male Lister Hooded rats received acute intracerebroventricular (ICV) administration of either vehicle or 5 nmol of Aβo1-42 (10μL). Cognition was assessed in the novel object recognition (NOR) paradigm at different time points. Levels of inflammatory (IL-1β, IL-6, TNF-α), synaptic (PSD-95, SNAP-25), and neuronal (n-acetylaspartate, parvalbumin-positive cells) markers were investigated in different brain regions (prefrontal and frontal cortex, striatum, dorsal and ventral hippocampus). Results:Acute ICV administration of Aβo1-42 induced robust and enduring NOR deficits. These deficits were reversed by acute administration of donepezil and rolipram but not risperidone. Postmortem analysis revealed an increase in inflammatory markers, a decrease in synaptic markers and parvalbumin containing interneurons in the frontal cortex, with no evidence of widespread neuronal loss. Conclusion:Taken together the results suggest that acute administration of soluble low-n Aβo may be a useful model to study the early mechanisms involved in AD and provide us with a platform for testing novel therapeutic approaches that target the early underlying synaptic pathology.

No / Acute administration of the psychotomimetic phencyclidine (PCP) can mimic some features of schizophrenia, while a repeated treatment regimen of PCP may provide a more effective way to model in animals the enduring cognitive dysfunction observed in many schizophrenic patients. The present study aims to investigate behavioural and neuropathological effects of sub-chronic PCP administration. The cognitive deficit induced by sub-chronic PCP was examined using a previously established operant reversal-learning paradigm. Subsequently, the effect of sub-chronic PCP on parvalbumin-immunoreactive (parvalbumin-IR) neurons was assessed using immunohistochemical techniques. Rats were trained to respond for food in an operant reversal-learning paradigm for approximately 6 weeks, followed by sub-chronic administration of PCP (2mg/kg) or vehicle twice daily for 7 days followed 7 days later by behavioural testing. Six weeks post PCP, brains were analysed using immunohistochemical techniques to determine the size and density of parvalbumin-IR in the frontal cortex and hippocampus. Sub-chronic PCP significantly reduced (p <0.001) percentage correct responding in the reversal phase relative to the initial phase, an effect that persisted throughout the experimental period (4 weeks). The density of parvalbumin-IR neurons was reduced in the hippocampus, with significant reductions in the dentate gyrus and CA2/3 regions (p <0.001). There were significant changes in the frontal cortex, with a reduction (p <0.01) in the M1 (motor area 1) region and increases in the M2 (motor area 2) region and cingulate cortex (p <0.01-p <0.001). These results parallel findings of profound hippocampal and more subtle cortical deficits of parvalbumin-IR neurons in schizophrenia, and provide evidence to suggest that sub-chronic PCP can induce a lasting cognitive deficit, an effect that may be related to the observed neuronal deficits.

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Replay of spike sequences can be seen during sharp wave – ripple population burst activity in the hippocampus. It is thought that this activity, which occurs during rest and sleep, is involved in memory consolidation. The cellular mechanisms underlying the initiation of these replay events are not well understood. To investigate this, a hippocampal slice model, showing spontaneous sharp wave – ripple activity, and a combination of planar multi-electrode array recordings and whole-cell patch-clamp recordings of anatomically identified hippocampal neurons were used. Firstly, the spatial and temporal profile of sharp waves in vitro was analysed in detail. Sharp waves were generated by changing subpopulations of pyramidal neurons in the CA3 region and had characteristics similar to those found in vivo. Secondly, four major receptor types present in hippocampal CA3, namely NMDA, AMPA, GABAA and GABAB receptors, were investigated for their involvement in sharp wave generation. Surprisingly, not only AMPA receptor-mediated events, but also phasic GABAA receptor-mediated inhibition, were necessary for sharp wave generation. Thirdly, single perisomatic-targeting interneurons were activated. This experiment showed that induced spiking activity of an individual perisomatic-targeting interneuron can both suppress and subsequently enhance local sharp wave generation. Spiking activity of other neuron types (i.e. pyramidal neurons, dendritic-targeting interneurons and interneuron-selective interneurons) had no significant effect on sharp wave incidence. Finally, it is suggested that this post-inhibitory enhancement of sharp wave generation can be mediated by a transient increase in the ratio of excitation to inhibition in the local network. In conclusion, these results suggest a new role for perisomatic-targeting interneurons in controlling the local initiation of sharp waves by selectively suppressing and subsequently enhancing recruitment of a subpopulation of pyramidal neurons. These results further imply that interneurons may play an integral part in the local information processing that takes place in the hippocampal network.

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Neuregulin 1 (NRG1) is a growth factor implicated in neurodevelopment and postnatal maintenance of synaptic circuits. Its gene has been associated with schizophrenia, and the expression of the type I isoform (NRG1tyI) is increased in patients’ brains. Earlier behavioural phenotyping of mice over-expressing NRG1tyI revealed impairment in hippocampus-dependent spatial working memory. This present work investigates the effects of increased NRG1tyI expression on hippocampal network functioning in these mice. Fast network oscillations, specifically at gamma frequencies, were studied in CA3 hippocampal slices in a carbachol model using cellular and extracellular microelectrode recording techniques. The peak frequency of field potential oscillations was significantly reduced in slices from NRG1tyI mice compared to wild-type littermates. In addition, NRG1tyI mouse slices were more prone to develop epileptiform activity. During rhythmic activity, the balance of phasic excitation and inhibition was significantly altered in principal cells of NRG1tyI mice. Inhibitory synaptic input was more sustained, while excitatory synaptic currents were kinetically unchanged but larger and more variable in amplitude. Together, these data suggest altered functioning of the GABAergic inhibitory circuits that generate and maintain gamma oscillations. Because parvalbumin-expressing (PV+) interneurons are a major target of NRG1 signalling, the inhibition from PV+ interneurons to pyramidal cells was examined next. Channelrhodopsin-2-mediated photostimulation of PV+ cell axons failed to show changes in GABAergic inhibition of CA3 pyramidal cells in NRG1tyI mice. However, synaptic miniature glutamatergic neurotransmission was reduced in identified PV+ basket cells (BCs) and axo-axonic cells (AACs) but not in pyramidal cells. The change was expressed postsynaptically, affecting NMDA receptor- but not AMPA receptor-mediated currents. The data suggest that NRG1tyI over-expression results in alterations in PV+ interneuron types, particularly at the glutamatergic synapses that excite these cells. These changes and the altered gamma oscillations are already evident in late adolescence — before the age at which cognitive deficits are detectable.