Doctor of Philosophy

dissertationHippocampal network oscillations are important for learning and memory. Theta rhythms are involved in attention, navigation, and memory encoding, whereas sharp wave-ripple complexes (ripples) are involved in memory consolidation. Cholinergic neurons in the medial septum-diagonal band of Broca (MS-DB) influence both types of hippocampal oscillations, promoting theta rhythms and suppressing ripples. They also receive frequency-dependent hyperpolarizing feedback from hippocamposeptal connections, potentially affecting their role as neuromodulators in the septohippocampal circuit. However, little is known about how the integration properties of cholinergic MS-DB neurons change with hyperpolarization. By potentially altering firing behavior in cholinergic neurons, hyperpolarizing feedback from the hippocampal neurons may, in turn, change hippocampal network activity. To study how hyperpolarizing inputs change in membrane integration properties, we used whole-cell patch-clamp recordings targeting genetically labeled, choline acetyltransferase-positive neurons in mouse medial septal brain slices. Hyperpolarization of cholinergic MS-DB neurons resulted in a long-lasting decrease in spike firing rate and input-output gain. Additionally, voltage-clamp measures implicated a slowly inactivating, 4-AP-insensitive, outward K+ conductance. Using a conductance-based model of cholinergic MS-DB neurons, we show that the ability of this conductance to modulate firing rate and gain depends on the expression of an experimentally verified shallow intrinsic spike frequency-voltage relationship. Finally, we show that cholinergic suppression of hippocampal ripples can be achieved through an imbalance in drive, caused by cholinergic modulation, to hippocampal excitatory and inhibitory neurons. Together, these findings show possible mechanisms through which cholinergic MS-DB neurons may both influence and be influenced by hippocampal rhythms

Fluorescence anisotropy of diphenylhexatriene and its cationic Trimethylamino derivative in liquid dipalmitoylphosphatidylcholine liposomes: opposing responses to isoflurane

<p>Abstract</p> <p>Background</p> <p>The mechanism of action of volatile general anesthetics has not yet been resolved. In order to identify the effects of isoflurane on the membrane, we measured the steady-state anisotropy of two fluorescent probes that reside at different depths. Incorporation of anesthetic was confirmed by shifting of the main phase transition temperature.</p> <p>Results</p> <p>In liquid crystalline dipalmitoylphosphatidylcholine liposomes, isoflurane (7-25 mM in the bath) increases trimethylammonium-diphenylhexatriene fluorescence anisotropy by ~0.02 units and decreases diphenylhexatriene anisotropy by the same amount.</p> <p>Conclusions</p> <p>The anisotropy data suggest that isoflurane decreases non-axial dye mobility in the headgroup region, while increasing it in the tail region. We propose that these results reflect changes in the lateral pressure profile of the membrane.</p

Voxel-based morphometry (VBM) studies in schizophrenia—can white matter changes be reliably detected with VBM?

Voxel-Based Morphometry (VBM) is a hypothesis-free, whole-brain, voxel-by-voxel analytic method that attempts to compare imaging data between populations. Schizophrenia studies have utilized this method to localize differences in Diffusion Tensor Imaging (DTI) derived Fractional Anisotropy (FA), a measure of white matter integrity, between patients and healthy controls. The number of publications has grown, although it is unclear how reliable and reproducible this method is, given the subtle white matter abnormalities expected in schizophrenia. Here we analyze and combine results from 23 studies published to date that use VBM to study schizophrenia in order to evaluate the reproducibility of this method in DTI analysis. Coordinates of each region reported in DTI VBM studies published thus far in schizophrenia were plotted onto a Montreal Neurological Institute atlas, and their anatomical locations were recorded. Results indicated that the reductions of FA in patients with schizophrenia were scattered across the brain. Moreover, even the most consistently reported regions were reported independently in less than 35% of the papers studied. Other instances of reduced FA were replicated at an even lower rate. Our findings demonstrate striking inconsistency, with none of the regions reported in much more than a third of the published papers. Poor replication rate suggests that the application of VBM to DTI data may not be the optimal way for studying the subtle microstructural abnormalities that are being hypothesized in schizophrenia

D-Amphetamine Rapidly Reverses Dexmedetomidine-Induced Unconsciousness in Rats

D-amphetamine induces emergence from sevoflurane and propofol anesthesia in rats. Dexmedetomidine is an alpha2-adrenoreceptor agonist that is commonly used for procedural sedation, whereas ketamine is an anesthetic that acts primarily by inhibiting NMDA-type glutamate receptors. These drugs have different molecular mechanisms of action from propofol and volatile anesthetics that enhance inhibitory neurotransmission mediated by GABAA receptors. In this study, we tested the hypothesis that d-amphetamine accelerates recovery of consciousness after dexmedetomidine and ketamine. Sixteen rats (Eight males, eight females) were used in a randomized, blinded, crossover experimental design and all drugs were administered intravenously. Six additional rats with pre-implanted electrodes in the prefrontal cortex (PFC) were used to analyze changes in neurophysiology. After dexmedetomidine, d-amphetamine dramatically decreased mean time to emergence compared to saline (saline:112.8 +/- 37.2 min; d-amphetamine:1.8 +/- 0.6 min, p \u3c 0.0001). This arousal effect was abolished by pre-administration of the D1/D5 dopamine receptor antagonist, SCH-23390. After ketamine, d-amphetamine did not significantly accelerate time to emergence compared to saline (saline:19.7 +/- 18.0 min; d-amphetamine:20.3 +/- 16.5 min, p = 1.00). Prefrontal cortex local field potential recordings revealed that d-amphetamine broadly decreased spectral power at frequencies \u3c 25 Hz and restored an awake-like pattern after dexmedetomidine. However, d-amphetamine did not produce significant spectral changes after ketamine. The duration of unconsciousness was significantly longer in females for both dexmedetomidine and ketamine. In conclusion, d-amphetamine rapidly restores consciousness following dexmedetomidine, but not ketamine. Dexmedetomidine reversal by d-amphetamine is inhibited by SCH-23390, suggesting that the arousal effect is mediated by D1 and/or D5 receptors. These findings suggest that d-amphetamine may be clinically useful as a reversal agent for dexmedetomidine

Phosphatase and tensin homologue on chromosome ten (PTEN) directs prostaglandin E2-mediated fibroblast responses via regulation of E prostanoid 2 receptor expression

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90013/1/white-phosphatase_tensin.pd