Partial inhibition of mitochondrial complex I ameliorates Alzheimer\u27s disease pathology and cognition in APP/PS1 female mice.

Alzheimer\u27s Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership-AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients

Functional Connectivity of the Rodent Striatum

The striatum serves as the major input nucleus of the basal ganglia circuitry, important for its varied roles in cognition, motivation, and sensorimotor function. Despite decades of study, fundamental features of the striatum’s functional organization and broader role(s) within the basal ganglia circuitry remain contentious and/or poorly defined. Given the diverse and critical roles of striatal activity in normal brain function and a multitude of disease states (including neurodegenerative and psychiatric disorders), a better understanding of this nucleus’ functional organization is imperative. The use of electrophysiological tools, which predominate the field, allow for in-depth characterizations of discrete, pre-selected brain regions, but are not appropriate for delineating functional neural circuit interactions on large spatial scales in an unbiased manner. A complementary approach to these studies is the use of functional magnetic resonance imaging (fMRI), which provides global, unbiased measures of functional neural circuit and network connectivity. In the first two studies described herein (Chapters 2 and 3), we used fMRI to map the functional response patterns to electrical DBS of the rat nucleus accumbens (NAc; ventral striatum), as well as the dual striatal outputs: external globus pallidus (GPe), and substantia nigra pars reticulata. Notable findings included the presence of negative fMRI signals in striatum during stimulation of each nuclei, robust prefrontal cortical modulation by NAc- and GPe-DBS, and marked functional connectivity changes by high frequency DBS. We next used optogenetic tools to more selectively map the brain-wide responses to stimulation of GPe neurons in healthy and Parkinson’s disease model rats (Chapter 4), as well as dorsal striatal neurons and their motor cortical inputs (Chapter 5). Optogenetic stimulation of each nuclei elicited an intriguing dorsal striatal negative fMRI signal, observed during direct striatal stimulation as well as putative recruitment of both excitatory both inhibitory striatal inputs, and thus suggestive of neurovascular uncoupling. Additionally, results from our GPe experiments revealed that this signal may be compromised in certain neurological disease states (e.g., Parkinson’s disease). Collectively, the studies described in this dissertation have exploited fMRI tools to reveal novel features of striatal connectivity, which may shed light on striatal function in health and disease.Doctor of Philosoph

Treatment During Abstinence from Methamphetamine in a Rat Model of Methamphetamine Use Disorder

Indiana University-Purdue University Indianapolis (IUPUI)Methamphetamine (METH) is a psychostimulant with high abuse potential. Currently there are no pharmacological treatments specific for relapse to METH use disorder. Chronic METH abuse has been associated with changes to the dopamine and glutamate neurotransmitter systems, as well as inflammation. Phosphodiesterase-4 inhibitors are known to affect cAMP involved in dopaminergic and glutamatergic neurotransmission, as well as having anti-inflammatory action. In pre-clinical models, phosphodiesterase inhibitors can reduce behaviors associated with the self-administration of drugs of abuse if given directly before tests of relapse-like behavior. However, they have not been examined in the more clinically relevant context as a treatment for use during abstinence from drugs of abuse. To address this gap, a METH self-administration model in the rat was used in which roflumilast, a phosphodiesterase 4 inhibitor, was administered during the abstinence period before a relapse test. The overarching hypothesis was that roflumilast inhibited inflammation associated with METH self-administration abstinence to reduce subsequent relapse-like behaviors. A detailed behavioral analysis showed that the chronic treatment with roflumilast during 7 days of forced abstinence reduced relapse-like behavior to METH seeking and METH taking. Roflumilast treatment during 7 days of forced abstinence did not affect subsequent sucrose seeking and sucrose taking behaviors. Biochemical analyses of proteins related to dopamine and glutamate neurotransmission did not reveal changes in these neurotransmitter systems, nor was there evidence of overt inflammation. These data suggest that roflumilast may be a treatment for METH use disorder that is effective when taken during abstinence, but further studies related to the mechanism of action of roflumilast are needed

Use of functional neuroimaging and optogenetics to explore deep brain stimulation targets for the treatment of Parkinson's disease and epilepsy

Deep brain stimulation (DBS) is a neurosurgical therapy for Parkinson’s disease and epilepsy. In DBS, an electrode is stereotactically implanted in a specific region of the brain and electrical pulses are delivered using a subcutaneous pacemaker-like stimulator. DBS-therapy has proven to effectively suppress tremor or seizures in pharmaco-resistant Parkinson’s disease and epilepsy patients respectively. It is most commonly applied in the subthalamic nucleus for Parkinson’s disease, or in the anterior thalamic nucleus for epilepsy. Despite the rapidly growing use of DBS at these classic brain structures, there are still non-responders to the treatment. This creates a need to explore other brain structures as potential DBS-targets. However, research in patients is restricted mainly because of ethical reasons. Therefore, in order to search for potential new DBS targets, animal research is indispensable. Previous animal studies of DBS-relevant circuitry largely relied on electrophysiological recordings at predefined brain areas with assumed relevance to DBS therapy. Due to their inherent regional biases, such experimental techniques prevent the identification of less recognized brain structures that might be suitable DBS targets. Therefore, functional neuroimaging techniques, such as functional Magnetic Resonance Imaging and Positron Emission Tomography, were used in this thesis because they allow to visualize and to analyze the whole brain during DBS. Additionally, optogenetics, a new technique that uses light instead of electricity, was employed to manipulate brain cells with unprecedented selectivity

Developing neurostimulation techniques to investigate antidepressant and mood modulating behaviors / by Rajas Prakash Kale

 My PhD consisted of a multidisciplinary approach towards primary research in the field of translational neuroscience. Incorporation of preclinical research, behavioral neuroscience, translational psychiatry, neural engineering, and biomedical device development techniques drives my continuing passion towards helping patients through innovation