Thèse de doctorat : Neurosciences : Paris 12 : 2006. / Titre provenant de l'écran-titre. Pagination : 218 f. Bibliogr. f. 203-218.

Thèse de doctorat : Neurosciences : Paris 12 : 2004. / Version électronique uniquement consultable au sein de l'Université Paris 12 (Intranet). Titre provenant de l'écran-titre. Bibliogr. f. 133-146.

Thesis (M.S.)--State University of New York at Binghamton, Department of Psychology, 2007. / Includes bibliographical references (leaves 38-49).

The ability to switch between different forms of locomotion is critical to many aspects of survival, whether it is switching from walking to running to evade predators, or switching to a slower gait to obtain food. Uncovering the mechanisms behind gait transitions has implications for many fields, from treating Parkinson Disease to understanding the impact of drugs of abuse on movement. However, the mechanisms of gait transitions are not well understood. The experiments outlined in this thesis sought to understand the neuronal basis for gait switching. This work employed the nematode Caenorhabditis elegans, a unique model organism chosen for its genetic tractability and fully characterized nervous system. C. elegans displays different forms of motion: crawling on land and swimming in liquid. First, I sought to determine the mechanisms for switching between these forms of motion in collaboration with Dr. Andres Vidal-Gadea. In the process, we discovered that crawling and swimming actually represent distinct gaits in contrast to recent reports that suggested they were merely a single gait. We further elucidated mechanisms for gait transition in C. elegans. For instance, we found that the transition to crawling required viii the D1-like dopamine receptors DOP-1 and DOP-4; and activation of dopamine neurons via the light-activated cation channel Channelrhodopsin2 was sufficient to induce crawling behavior in worms immersed in liquid. Conversely, photoactivation of serotonergic neurons expressing Channelrhodopsin2 induced swim-like behavior on land. Finally, laser microablation of dopaminergic or serotonergic neurons was sufficient to impair the transition to crawl or swim, respectively. Together these results show that transitions to crawling and swimming are controlled by dopamine and serotonin respectively. Next I wanted to better understand how gait transitions are impaired by a drug of abuse, alcohol. I found that, as in other organisms, ethanol disrupts gait transitions, causing worms in water to inappropriately transition from swim to crawl and to display other land-specific behaviors. Animals lacking the D1-like dopamine receptor DOP-1 were resistant to the ethanol-induced transition to crawl. Finally, I found that several interneurons required for the transition to crawl. Specifically, laser microablation of the DOP-4 receptor-expressing neuron RID or the DOP-1-expressing neurons PQR or RIS resulted in a significant impairment in the time to crawl onset. Overall, the findings presented in this thesis represent the first evidence that C. elegans uses an evolutionarily conserved mechanism to transition between gaits and provides the beginning of a molecular description of gait transitions. / text

Functional asymmetries, most commonly associated in humans with population-level hand preference and lateralization in language processing, are complex, heterogeneous traits with poorly understood biological and genetic bases. Notably, functional asymmetries are also associated with familial non-right handedness suggesting that common genetic factors influence both handedness and functional lateralization. This dissertation has two aims. The first is the development of a specific biological hypothesis that may partially account for the consistent co-lateralization of hand preference and prefrontal language function. I argue that asymmetries in local neural properties that affect the excitability and signal-to-noise ratio of neural assemblies can produce a bias in the direction and, to some extent, the degree of functional lateralization for complex functions. At a high level of representation, this hypothesis is similar to long-standing theories of hemispheric differences, but differs from these by providing a single biological difference between hemispheres that influences both motor and prefrontal asymmetries. Specifically, I propose that a hemispheric asymmetry in the ratio of activity at D1 and D2 dopamine receptors can account for both forms of asymmetry. The second aim is to identify novel electrophysiological and behavioral correlates of genetic effects linked to handedness. By applying a standard genetic model to familial handedness data, I obtain an estimate of these genetic effects for individual research participants that may improve sensitivity over previous studies that have primarily used categorical classifications to study familial handedness effects. Two EEG studies of executive function provide evidence for computational changes associated with familial handedness. The first, an auditory oddball paradigm, suggests that cortical noise is increased in conjunction with estimated genetic effects associated with left handedness. In the second study, a go-nogo task, a dissociation between response inhibition and response conflict processing was found with respect to estimated genetic effects associated with left handedness. In addition to bearing on current theories of conflict processing, these results may provide indirect evidence for dopaminergic contributions to neurological and behavioral differences associated with familial sinistrality. Additional studies of resting EEG and behavioral responses to Necker cube viewing provide additional evidence for broad effects of familial sinistrality.

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Illicit drug abuse and addiction is a major problem in New Zealand and worldwide with approximately 12% of illicit drug users classified as having drug dependence or drug-use disorders. The chronically relapsing nature of drug addiction is a prominent feature of this disorder and a significant barrier to treating addiction. Amphetamine-type drugs, more than any other class of drugs, have seen an increase in global usage since the early 1990's. The lack of approved medications for the treatment of stimulant addiction together with an increasing treatment demand drives the need for pharmaceutical intervention. Substitute treatment approaches primarily focus on the dopamine (DA) system. However, several lines of research implicate a dual role for serotonin (5-HT). Using a benztropine (BZT) analogue, JHW 007 (JHW), and an atypical antidepressant, trazodone (TRAZ), we sought to test whether the combined modulation of DA and 5-HT during a period of extinction produced greater attenuation to drug-induced reinstatement compared to either DA or 5-HT alone. One hundred and two (102) male Long Evans rats were tested using an extinction-reinstatement model of methamphetamine (MA) addiction in conditioned place preference (CPP) (n=72) and self-administration (n=30) experimental designs. We hypothesised that a combined DA/5-HT treatment would further attenuate MA-induced reinstatement. Findings showed that JHW significantly attenuated MA-induced reinstatement in our self-administration model but not CPP, while TRAZ failed to significantly attenuate reinstatement in both experiments. The combination treatment group showed a mild attenuation to drug seeking with CPP, but this finding was not significant. Due to time restrictions, we did not test the combination group using a self-administration procedure. Unfortunately we were unable to fully address our initially proposed hypothesis, but our results with JHW add further support to this BZT analogue as a promising stimulant abuse medication.

Stimulant medications such as D-amphetamine, mixed-salts (75% D- and25% L-) amphetamine; Adderall®, and methylphenidate are first-line treatmentsfor Attention-Deficit/Hyperactivity Disorder (ADHD). In vivo studies havepredominantly focused on these stimulants in the context of drug abuse, andtheir therapeutic mechanistic properties are only theoretical. Previously, in vivotechniques have been limited by poor temporal and spatial resolution, andcharacterizations of these medications in rodent models have not been possibleat low, clinically relevant levels. In order to address these issues, our laboratoryused in vivo high speed chronoamperometric microelectrodes to characterize theeffects of local applications of D-amphetamine, L-amphetamine, D,Lamphetamine,and Adderall® at low levels in the striatum and nucleusaccumbens of 3-6 month old, male Fischer 344 (F344) rats. Our results showedsignificant differences between the faster kinetics of dopamine (DA) releasesignals caused by D,L-amphetamine and the slower kinetics resulting from Damphetamine.These data support that resulting DA concentrations evoked by DandD,L-amphetamine are correlated with the amount of D-amphetamine in thedrug and only the time courses of the signals are affected by L-amphetamine.Additionally, locally applied D- and L-amphetamine caused DA release signalswith similar amplitudes or concentrations of evoked DA; however, the signalswere significantly faster for L-amphetamine. Adderall® caused significantlygreater DA release that lasted over a longer time course compared to DA releasecaused by D- or D,L-amphetamine. These data support the hypothesis thatamphetamine isomers, alone or in combination, interact differently with the DAtransporter (DAT) to subsequently cause reversal of transport of DA out ofpresynaptic membranes of DA neuronal projections. Finally, reversemicrodialysis studies were carried out to assess low levels of D-amphetamine,Adderall® (75% D-, 25% L-amphetamine), methylphenidate, and a new mixedsaltsamphetamine that we referred to as Reverse Adderall (75% L-, 25% Damphetamine)in the striatum of F344 rats. These data reveal a stimulantconcentration-response curve for DA with double plateaus that may be explainedby dual mechanisms of reverse transport of DA through the DAT. In addition,reverse microdialysis of methylphenidate caused DA overflow similar to theeffects of the other stimulants.