In the United States, one in six teenagers has driven under the influence of marijuana. Despite the fact that marijuana use is less common than alcohol use, driving under their influence is equally prevalent. Previous research has shown that the effects of marijuana on driving performance are more subtle than those of alcohol. Despite the knowledge that many drugs affect men and women differently, fewer than 25% of studies exploring the effects of marijuana use on driving performance have included women. Findings from both animal and human studies suggest marijuana may have more deleterious effects on women than men. This study examined gender differences in the acute effects of marijuana on cognition and driving performance. While no gender differences were found, marijuana did impair tasks of selective and divided attention, time estimation, and executive function. Participants under the influence of marijuana performed comparably to those who received a placebo cigarette on the driving assessment.

MED12 is an X– chromosome member of the Mediator complex that is a key regulator of tissue specific gene expression and moderates intracellular signaling via multiple developmental pathways. Sequence variation in the carboxy– terminus of MED12, which contains a PQL and Opa domain, is associated with X– linked mental retardation behavioral syndromes and schizophrenia. Unfortunately, the mechanism(s) through which sequence variation in the carboxy– terminus could alter vulnerability to neurodevelopmental and neuropsychiatric illnesses is yet unclear. In order to elucidate a better understanding of this process, we examined the role of the MED12 carboxy– terminus in cell cycle and gene expression with a full– length overexpression construct, domain deleted overexpression constructs and RNA interference using a HEK293 cell model. Our results show that MED12 overexpression leads to G1 cell cycle exit, whereas deletion of the PQL domain and MED12 RNA interference results in cell cycle progression. Our data also show that MED12 expression level differentially affects early response antiviral gene expression and stress response mechanisms. These results are consistent with prior studies showing that MED12 has a key role in determining neuronal cell fate and with the theoretical understanding of the biological basis of psychosis. These results also lend further insight upon the pathways through which MED12 exerts its effects upon differentiation and disease pathogenesis, which may lead to new approaches to the treatment of MED12– related disorders.

Γ-protocadherins (Γ-Pcdhs) are important for neuronal development and regular nervous system patterning. Much of this work is based on the assumption that this family of 22 cadherin-like adhesion molecules acts in the manner of Roger Sperry's hypothesized "molecular code", with homophilic adhesion allowing neurons to find their proper neuronal partners during development. Therefore, most research has focused on the expression and roles of these adhesion molecules in neurons and glia. Although these molecules have been almost exclusively studied in neurons, there is evidence that Γ-Pcdhs are also expressed and play important roles in other cells. The work done for this thesis focuses on the roles of Γ-Pcdhs in the choroid plexus (CP), a brain epithelial tissue that produces the cerebrospinal fluid, as well as potential roles in neuro-immune interactions. The importance of the CP for proper nervous system development, maintenance, function, and neuro-immunosurveillance has largely been overlooked in the past. Prior to this research, the presence, let alone the function of Γ-Pcdhs in the CP was not documented. Here, we show that each epithelial cell of the CP expresses a subset of Γ-Pcdhs at high levels, and that restricted disruption of this gene family in the CP and in the adjacent ependymal epithelia of mice results in reduced cerebroventricular volume. Furthermore, we show that CP-restricted mutant mice have altered gene expression in the CP, including groups of genes associated with immune function and with TGFΒ signaling pathways, suggesting novel roles for the Γ-Pcdhs. Finally, we present preliminary data indicating that expression of the Γ-Pcdhs is up-regulated in the CP following an immune challenge (experimental autoimmune encephalomyelitis, a mouse model for multiple sclerosis) and that they are expressed in other non-neuronal tissues, which, like the CP, play roles in immunosurveillance.

Levodopa-induced dyskinesias (LIDs) are abnormal involuntary movements that limit the effectiveness of treatments for Parkinson’s disease. Although dyskinesias involve the striatum, it is unclear how striatal neurons are involved in dyskinetic movements. Here we record from striatal neurons in mice during levodopa-induced axial dyskinesias. We developed an automated 3-dimensional motion tracking system to capture the development of axial dyskinesias at ~10 ms resolution, and correlated these movements with neuronal activity of striatal medium spiny neurons and fast spiking interneurons. The average firing rate of medium spiny neurons increased as axial dyskinesias developed, and both medium spiny neurons and fast spiking interneurons were modulated around axial dyskinesias. We also found that delta field potential power increased in the striatum with dyskinesia, and that this increased delta power coupled with striatal neurons. Secondly, we studied the role of the two main types of dopamine receptors. We pharmacologically inhibited either the D1 or D2 receptors while recording from neuronal ensembles in the striatum and measuring LIDs in high temporal resolution. We found that inhibiting the D1, but not the D2, receptor led to a decrease in axial dyskinesias. Interestingly, both types of antagonist attenuated the strong modulation of MSNs around axial dyskinesias when compared to levodopa alone. These results suggest that LIDs are modulated through activity in D1-MSNs. Lastly, we selectively targeted the D1 receptor expressing neurons (D1-MSNs) with optogenetics. With this technique, we can specifically activate or inhibit certain neuronal populations. We found that stimulating the D1-MSNs led to dyskinetic events only after levodopa priming. However, inhibiting these neurons was not sufficient to attenuate dyskinesias following levodopa administration. We also found that putative D1-MSNs are more strongly modulated around axial dyskinesias than other MSNs. Together, our findings provide novel insight into how striatal networks change as LIDs develop, and suggest that increased medium spiny neuron firing, that D1-MSNs are strongly modulated around LIDs, and that D1-MSN activity is sufficient to drive dyskinesias. These data could help clarify the role of the striatum in the pathogenesis of dyskinesias in Parkinson’s disease.

Experience-dependent plasticity is the adaptability of brain circuits as a result of changes in neural activity, a phenomenon that has been proposed as the neural basis for important brain function in health and disease. The underlying mechanisms of experience-dependent plasticity can take different forms, depending on the organisms and brain areas under investigation. A better understanding of these mechanisms will help to interpret normal brain function as well as to guide therapies for neurological diseases. Mouse vibrissa system offers great experimental advantages to studying experience-dependent plasticity and the underlying molecular mechanisms at different levels. Using sensory experience paradigms of unbalanced whisker activity, we find that sensory experience induces rapid synaptic strengthening at excitatory synapses converged onto single layer 2/3 pyramidal neurons, although the plasticity at these synapses displays remarkable input specificity. Furthermore, we discover that recently potentiated layer 4-2/3 excitatory synapses are labile and subject to activity-dependent weakening in vitro. Calcium-permeable AMPARs (CP-AMPARs) that are sometimes associated with synaptic strengthening are not essential for activity-induced synaptic weakening. Finally, we demonstrate that ongoing sensory experience triggers distinct phases of synaptic plasticity, which are tightly correlated with changes in NMDAR properties and function. Taken together, the results from this thesis show distinct manifestations and mechanisms of how sensory experience modulates synaptic properties and neuronal function that may provide insights into information processing and coding in the neocortex.

This dissertation examines the representation of Alzheimer's Disease (AD) neuronarratives (NN), works that centralize the brain or consciousness in the plot, in multiple modalities to support that argument that neuronarratives should be expanded into a transmedia genre. These modalities include neurogames, neurocomics, and neuromemoirs. These three modalities were analyzed to determine how selfhood and social networks are represented by characters or authors with Alzheimer's Disease. As AD is often viewed as the loss of selfhood and is associated with isolation, these works combat these stigmas and complicate representations of the disease. The use of images was also examined in neurogames and neurocomics as a means of expressing complex emotions without relying on text. As the selected neurocomics were written by carers or based on experiences with AD patients and the neuromemoirs were written by AD patients, these works were also analyzed as a means to provide agency for AD patients and carers. This dissertation approaches these neuronarratives through the lens and medium of hypertext. Applying this approach complicates the concept of fragmentation and memory in AD NN and reveals that selfhood in these works are constructed through the creation of many selves rather than one cohesive self or a dual self that represents the healthy and ill AD patient. Regardless of the medium, these selves remain in conversation with each other, emphasizing the active process of creating selfhood by the author's themselves and by the player or reader. Comparing the affordances and limitations of the medium reveal conversations between the digital and print mediums that may not be initially apparent. Viewing these works through hypertext de-centers AD at the core of the narrative and instead emphasizes the personhood of the patient. Expanding analytical approaches to transmedia NN provides new means of exploring selfhood and consciousness by writers, artists, and developers.

Physiological measurements have become more popular in Psychological research over the past ten years. These advancements allowed different objective sensors to become another measurement tool in a scientific arsenal of collecting data. Traditionally, performance and after task subjective measures have been used for most studies in Psychological research. With the opportunity to use these subjective measures along with objective measures, more data can be collected during research and therefore potentially produce better quality conclusions. Eye Tracking (ET), functional near infrared (fNIR), transcranial Doppler ultrasound (TCD), electrocardiogram (EKG) and the electroencephalogram (EEG) have shown great promise in their ability to produce reliable and powerful objective data for research. Consequently, these devices are being used at the same time. The simultaneous use has the potential for interference between devices. Further, these devices are used on human subjects who can find these devices uncomfortable. These issues have the ability to skew data simply due to the measurement devices used. The effort of this study was to determine if the above devices could be used simultaneously without affecting their data quality, determine if difference combinations are more or less beneficial and determine if the combination of sensors have an effect on participant experience. A negative effect from discomfort has the potential to effect data. A study was conducted utilizing the ET, EEG, EKG, fNIR and TCD together in various combinations and also alone to determine if data is compromised and to determine if the combinations have an effect on participant experience.

<p>Centrally active peptides have increasingly been implicated in diverse neuro-psychiatric disorders in humans. Although several clinical studies have attested to the therapeutic potential of L-Prolyl-L-Leucyl-Glycinamide (PLG) in Parkinson's disease, no unifying hypothesis concerning its mode of action can be formulated. The present critical analysis of the pharmacological property of PLG was predicated on the hypothesis that there exist putative receptor sites of PLG manifesting differential modulatory effects on dopaminergic neurotransmission.</p> <p>The action of PLG was examined in behavioral paradihms reflecting dopamine dependent extrapyramidal motor dysfunction: haloperidol-and morphine-induced catalepsy in rats. Chronic, but not acute, treatment of PLG significantly antagonized hoth morphine and haloperidol catalepsy.</p> <p>The influence of PLG on in vitro dopamine receptor function was evaluated, and the resutls showed that PLG selectively enhanced the affinity of the specific binding of the agonist H-apomorphine to doapmine receptors in rat striatum. PLG, however, failed to alter ³H-spiroperidol binding in vitro.</p> <p>A radioligand binding assay was developed to identify specific putative binding sites of PLG in normal rat and human brain. ³H-PLG bound to membrane homogenates from both human and rat striatum with high affinity and in a saturable manner. The regional distribution profile of the specific ³H-PLG binding demonstrated that human substantia nigra exhibited thehighest level of ³H-PLG binding sites, followed by the striatum and hypothalamus. In the rat brain, the striatum was highly enriched with PLG binding sites. Pharmacologically active analogues of PLG completed for specific ³H-PLG binding with relative potencies paralleling their in vitro biological activities.</p> <p>The potential anti-dyskinetic activity of PLG was evaluated in the pharmacological animal model of tardive dyskinesia. In rats, PLG, when administered concurrently with haloperidol of chlorpromazine, antagonized the enhancements in specific ³H-spiroperidol binding in the striatum as associated with chronic neuroleptic treatment.</p> <p>The results of the present study support the hypothesis that putative PLG binding sites are functionally coupled to dopamine/neuroleptic adenylate cyclase complex and raise the issue as to the feasibility of specific peptidergic dysfunction and peptide replacement therapy in neuro-psychiatric disorders.</p> / Doctor of Philosophy (PhD)

Speech perception is challenging because the acoustic input is extremely variable. This variability partially stems from differences in how talkers pronounce words. For example, Voice Onset Time (VOT) is the primary cue that distinguishes /b/ from /p/. Women tend to use longer Voice Onset Times (VOTs) than men. A VOT of 20 msec could thus be a /b/ spoken by a woman and a /p/ spoken by a man. A critical question is how listeners deal with this variability. Previous research shows that listeners use these regularities (e.g., the systematic relationship between gender and VOT) to compensate for variability. For example, listeners adjust their phoneme category boundary based on talker gender. However, it is unclear the exact mechanisms by which talker gender information influences speech processing. Talker gender could influence only later stages of speech processing, like phoneme categorization. Alternatively, talker gender could modulate the earliest stage: acoustic cue encoding. I use event-related potentials, eye-tracking in the visual world paradigm, and electrocorticography to isolate the specific role of talker gender in speech perception. The results show that the auditory system influences the earliest stage of speech perception by allowing cues to be encoded relative to prior expectations about gender and that gender is integrated with acoustic cues during lexical activation. These experiments give insight into how the brain deals effectively with variability during categorization.

Thesis (Ph.D.)--University of California, San Francisco, 2009. / Source: Dissertation Abstracts International, Volume: 71-02, Section: B, page: . Adviser: Graeme W. Davis.