The prefrontal cortex (PFC) mediates many executive functions including working memory, behavioral flexibility, decision making, and social cognition. The normal functioning of the PFC depends strongly on regulation by neuromodulators. Dysfunction of the PFC leads to deficits in these abilities and is a major factor in many neuropsychiatric disorders including schizophrenia and autism. Layer 5 (L5) of the PFC, a major site of dopaminergic modulation, is thought to play an important role in regulating these higher order processes. Indeed, many neurological disorders such as schizophrenia have been associated with imbalances in dopamine neurotransmission.

Prefrontal dopamine D2 receptors (D2Rs), the primary target for first generation antipsychotic drugs, specifically play a major role in tasks that are disrupted in schizophrenia. One major hypothesis is that excessive D2R activation within the PFC contributes to many of the cognitive impairments associated with schizophrenia. This dissertation investigates the mechanisms of D2R-mediated neuromodulation within the PFC and abnormalities within PFC circuitry and neuromodulation in mouse models of schizophrenia and autism.

We have previously described a phenomenon whereby D2R activation elicits afterdepolarization (ADPs) in subcortically-projecting (SC) pyramidal neurons within L5 of the PFC. Results presented in Chapter II of this dissertation show that this unusual physiological phenomenon, in which D2Rs enhance cellular excitability dependent on synaptic input, is mediated at the cellular level through the recruitment of signaling pathways associated with Gs, rather than Gi-associated mechanisms that have classically been ascribed to D2Rs.

In Chapter III, I discuss differences in D2R neuromodulation in mice with a dominant-negative mutation in disrupted in schizophrenia 1 (DISC1). DISC1 dysfunction has been associated with schizophrenia and causes deficits in working memory. Current studies, it has been shown that there is an upregulation of D2R expression and/or activity in DISC1 mouse models. Interestingly, DISC1 is also implicated in the regulation of cAMP. Here, I will show that these mice lack the quinpirole-induced Gi-independent ADP.

The medial prefrontal cortex (mPFC), particularly deep layer projection neurons, has also been implicated as a potential locus for Autism Spectrum Disorder (ASD) pathology. Previous work from our lab has shown that social exploration preferentially recruits mPRC D2R positive pyramidal neurons and that this recruitment is attenuated in three etiologically distinct mouse models of autism. In Chapter IV of this dissertation, we investigate the affects of T-brain-1 (Tbr1) selectively within layer 5 and layer 6 cortical neurons. We found that Tbr1 function is required to maintain many aspects of layer 6 identity, Tbr1 layer6 mutant neurons transform towards the identity of L5 neurons, including their transcriptome, dendritic pattern, and physiological properties. Tbr1 layer5 mutant neurons become a more homogeneous population transforming towards the identity of D2R expressing pyramidal neurons. Both Tbr1 layer6 and Tbr1 layer5 mutants have reduced excitatory and inhibitory synaptic density as well as reduced spontaneous EPSCs and IPSCs. We also present data suggesting that loss of Tbr1 function in layer 6 leads to increased anxiety and aggressive behavior whereas loss of Tbr1 function in layer 5 leads to decreased social behaviors, phenotypes consistent with different aspects of observed ASD patient behavioral characteristics.

The advancement of renewable energy technologies is critical due to the unsustainable nature of currently used energy sources and the need to meet increasing energy demands. A broad and diverse energy plan is important for long term energy independence and stability. Geothermal energy sources including hydrothermal systems and enhanced geothermal systems (EGS) should play a key role in this energy plan. Geothermal energy is the most reliable, currently developed, schedulable alternative energy source. It is estimated that improvements in these systems have the potential to provide at least 200,000 exajoules of energy to the U.S. in as little as 50 years [1]. The progress in developing this field is challenging in part due to the complex geochemical and geophysical properties of the subsurface environment. This dissertation reviews geothermal energy system limitations due to current well monitoring technologies and introduces microelectromechanical systems (MEMS) sensors as a means of optimizing well performance. Harsh environment MEMS offer an ideal alternative to macro-scale sensors due to their harsh environment material compatibility, the ability to couple MEMS with wireless RF transmission systems, and their small footprint.

In this work, harsh environment MEMS encapsulation materials are tested in simulated geothermal environments to determine their survivability. The sensors must be encapsulated to provide protection from oxidation, erosion, surface roughening, and other chemical attacks. Encapsulation materials such as silicon carbide, sapphire, vitreous carbon, and poly-crystalline diamond were tested in multiple simulated geothermal environments to determine a suitable protective layer for these MEMS devices. Once appropriate materials are determined, two temperature sensors are designed, optimized, fabricated, and tested. The first sensor improves upon existing out-of-plane MEMS capacitive temperature sensor devices by utilizing harsh environment materials. The second sensor is a novel in-plane design optimized to linearize capacitive output. These sensors are tested up to over 650 °C.

[1] Massachusetts Institute of Technology. The future of geothermal energy: Impact of enhanced geothermal systems (egs) on the united states in the 21st century. 2006