Thalamocortical Inputs Show Post-Critical-Period Plasticity

SummaryExperience-dependent plasticity in the adult brain has clinical potential for functional rehabilitation following central and peripheral nerve injuries. Here, plasticity induced by unilateral infraorbital (IO) nerve resection in 4-week-old rats was mapped using MRI and synaptic mechanisms were elucidated by slice electrophysiology. Functional MRI demonstrates a cortical potentiation compared to thalamus 2 weeks after IO nerve resection. Tracing thalamocortical (TC) projections with manganese-enhanced MRI revealed circuit changes in the spared layer 4 (L4) barrel cortex. Brain slice electrophysiology revealed TC input strengthening onto L4 stellate cells due to an increase in postsynaptic strength and the number of functional synapses. This work shows that the TC input is a site for robust plasticity after the end of the previously defined critical period for this input. Thus, TC inputs may represent a major site for adult plasticity in contrast to the consensus that adult plasticity mainly occurs at cortico-cortical connections

Technical and Conceptual Considerations for Performing and Interpreting Functional MRI Studies in Awake Rats

Functional neuroimaging studies in rodents have the potential to provide insight into neurodevelopmental and psychiatric conditions. The strength of the technique lies in its non-invasive nature that can permit longitudinal functional studies in the same animal over its adult life. The relatively good spatial and temporal resolution and the ever-growing database on the biological and biophysical basis of the blood oxygen level dependent (BOLD) signal make it a unique technique in preclinical neuroscience research. Our laboratory has used imaging to investigate brain activation in awake rats following cocaine administration and during the presentation of lactation-associated sensory stimuli. Factors that deserve attention when planning functional magnetic resonance imaging studies in rats include technical issues, animal physiology and interpretability of the resulting data. The present review discusses the pros and cons of animal imaging with a particular focus on the technical aspects of studies with awake rats. Overall, the benefits of the technique outweigh its limitations and the rapidly evolving methods will open the way for more laboratories to employ the technique in neuroscience research

Applications of manganese-enhanced magnetic resonance imaging in neuroscience

xi, 84 leaves ; 29 cmManganese-Enhanced Magnetic Resonance Imaging (MEMRI) has proven itself to be a beneficial technique in the field of Neuroscience. This thesis applies MEMRI to studies in neuroscience by first establishing the limitations concerning the use of MEMRI in live rats. Experiment 1 used an osmotic pump for manganese (Mn) delivery to the lateral ventricles for acquisition of anatomical images using MEMRI. From my knowledge, this was the first method demonstrating slow infusion of Mn to the lateral ventricles. In Experiment 2, MEMRI was used for volumetric analysis the whole brain and hippocampus of prenatally stressed rats. To my knowledge, this study was the first to investigate the effect of generational prenatal stress on the structure of a rat’s brain using MEMRI and histology. Additionally, Experiment 2 investigated the use of a subcutaneous osmotic pump to deliver Mn for MEMRI. A summary on the use of MEMRI in Neuroscience concludes this thesis, with a discussion on the methods used and related technical considerations

Magnetic Resonance Imaging in Tauopathy Animal Models

The microtubule-associated protein tau plays an important role in tauopathic diseases such as Alzheimer's disease and primary tauopathies such as progressive supranuclear palsy and corticobasal degeneration. Tauopathy animal models, such as transgenic, knock-in mouse and rat models, recapitulating tauopathy have facilitated the understanding of disease mechanisms. Aberrant accumulation of hyperphosphorylated tau contributes to synaptic deficits, neuroinflammation, and neurodegeneration, leading to cognitive impairment in animal models. Recent advances in molecular imaging using positron emission tomography (PET) and magnetic resonance imaging (MRI) have provided valuable insights into the time course of disease pathophysiology in tauopathy animal models. High-field MRI has been applied for in vivo imaging in animal models of tauopathy, including diffusion tensor imaging for white matter integrity, arterial spin labeling for cerebral blood flow, resting-state functional MRI for functional connectivity, volumetric MRI for neurodegeneration, and MR spectroscopy. In addition, MR contrast agents for non-invasive imaging of tau have been developed recently. Many preclinical MRI indicators offer excellent translational value and provide a blueprint for clinical MRI in the brains of patients with tauopathies. In this review, we summarized the recent advances in using MRI to visualize the pathophysiology of tauopathy in small animals. We discussed the outstanding challenges in brain imaging using MRI in small animals and propose a future outlook for visualizing tau-related alterations in the brains of animal models

Manganese-Enhanced Magnetic Resonance Imaging of the Spinal Cord in Rats

Manganese-enhanced magnetic resonance imaging (MEMRI) offers a novel neuroimaging method in visualizing the activity patterns of neural circuits. MEMRI is using the divalent manganese ion, which has been used as a cellular contrast agent. The present study was conducted to determine the contrast-enhancing effects of manganese ion administered into the spinal cord of rats. Manganese ion was administered into the spinal cord by lumbar puncture. Ex vivo magnetic resonance images were obtained at 6, 12, 24, and 48 hours after manganese ion injection. Although the highly contrasted images were not observed 6 or 12 hr after manganese injection, the distinctive manganese-enhanced images began to appear at 24 hours after manganese ion injection. These results suggest that the gray matter is the foci of intense paramagnetic signals and MEMRI may provide an effective technique to visualize the activity-dependent patterns in the spinal cordope

Monitoring dynamic calcium homeostasis alterations by T₁-weighted and T₁-mapping cardiac manganese enhanced MRI (MEMRI) in a murine myocardial infarction model

Manganese has been used as a T₁-weighted MRI contrast agent in a variety of applications. Because manganese ions (Mn²) enter viable myocardial cells via voltage gated calcium channels, manganese-enhanced MRI (MEMRI) is sensitive to the viability and the inotropic state of the heart. In spite of the established importance of calcium regulation in the heart both prior to, and following, myocardial injury, monitoring strategies to assess calcium homeostasis in affected cardiac tissues are limited. This study implements a T₁-mapping method to obtain quantitative information both dynamically and over a range of MnCl₂ infusion doses. In order to optimize the current manganese infusion protocols, both dose dependent and temporal washout studies were performed. A non-linear relationship between infused MnCl₂ solution dose and increase in left ventricular free wall relaxation rate (∆R₁) was observed. Control mice also exhibited significant manganese clearance over time, with approximately 50% decrease of ∆R₁ occurring in just 2.5 hours. The complicated efflux time dependence possibly suggests multiple efflux mechanisms. Using the measured relationship between infused MnCl₂ and ∆R₁, absolute Mn concentration ICP-MS data analysis provided a means to estimate the absolute heart Mn concentration in vivo. We have shown that this technique has the sensitivity to observe or monitor potential Ca²+ handling alterations in vivo due to the physiological remodeling following myocardial infarction. Left ventricular free wall ∆R₁ values were significantly lower (P = 0.005) in the adjacent zone, surrounding the injured myocardial tissue, than healthy left ventricular free wall tissue. This inferred reduction in Mn concentration can be used to estimate potentially salvageable myocardium in vivo for future therapeutic treatment or evaluation of disease progression.M.S.Committee Chair: Hu, Tom; Committee Co-Chair: Rahnema, Farzad; Committee Member: Wang, Chris; Committee Member: Yanasak, Natha

Activity Dependent Changes In Functional And Morphological Characteristics Among Presympathetic Neurons Of The Rostral Ventrolateral Medulla

A sedentary lifestyle is a major risk factor for the development of cardiovascular disease (CVD), the leading cause of death among Americans. Increasing evidence implicates increased sympathetic nerve activity (SNA) as the link between a sedentary lifestyle and CVD. The research presented in this dissertation examines the region of the brainstem known as the rostral ventrolateral medulla (RVLM) and how its regulation of SNA changes as a result of sedentary conditions. Our group has previously reported that sedentary conditions enhance splanchnic SNA in response to pharmacologically induced decreases in blood pressure or by direct activation of the RVLM via microinjection of the amino acid glutamate. More recently, our group has published the first evidence of overt structural differences in phenotypically identified RVLM neurons from sedentary versus physically active rats. Although collectively these studies suggest that a sedentary lifestyle results in increased activity and sensitivity of presympathetic RVLM neurons involved in blood pressure regulation, direct evidence of this proposed mechanism for the observed increased splanchnic SNA is lacking. The studies presented in this dissertation use in vivo characterization and juxtacellular labeling of RVLM neurons to examine the potential mechanistic connection and physiological relevance of overt changes in their structure and function and how they relate to enhanced SNA in sedentary versus physically active rats. These cross sectional studies are complemented by longitudinally based studies of in vivo neuronal activity in the RVLM utilizing manganese-enhanced magnetic resonance imaging (MEMRI). The information gained from these studies will contribute to our understanding of how a sedentary lifestyle contributes to the development of CVD and may provide information on new therapeutic targets in the brain to prevent or slow the progression of CVD