Thesis (Ph.D.). / Written for the Dept. of Neurology & Neurosurgery. Title from title page of PDF (viewed ). Errata sheets included. Includes bibliographical references.

published_or_final_version / Human Performance / Doctoral / Doctor of Philosophy

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While the extrinsic factors regulating neurogenesis in the developing forebrain have been widely studied, the mechanisms downstream of the various signaling pathways are relatively ill-defined. In particular, we focused on proteins that have been implicated in cognitive dysfunction. Here, we ask what role two cell intrinsic factors play in the development of two different neurogenic compartments in the forebrain. In the first part of the thesis, the transcription factor FoxP2, which is mutated in individuals who have specific language deficits, was identified to regulate neurogenesis in the developing cortex, in part by regulating the transition from the radial precursors to the transit amplifying intermediate progenitors. Moreover, we found that ectopic expression of the human homologue of the protein promotes neurogenesis in the murine cortex, thereby acting as a gain-of-function isoform. In the second part of the thesis, the histone acetyltransferase CREB-binding protein (CBP) was identified as regulating the generation of neurons from medial ganglionic eminence precursors, similar to its role in the developing cortex. But CBP also plays a more substantial role in the expression of late interneuron markers, suggesting that it is continuously required for the various stages of neurogenesis at least in the ventral neurogenic niche. Finally, similar to cortical precursors, the function of CBP in the ventral forebrain precursors is also dependent on histone acetylation. Together, these studies shed light on some of the key intrinsic players that regulate the differentiation of neural precursors in the embryonic murine forebrain, and they also suggest potential mechanisms for the pathogenesis of various cognitive dysfunctions.

The posterior parietal cortex (PPC) is a cortical region receiving inputs from different sensory modalities which has been shown to subserve a visuospatial function. The potential contribution of PPC in audiospatial behaviours and recognition of amodal spatial correspondences were postulated and assessed in the present study. Adult male Long- Evans rats received PPC lesions by aspiration, and they were compared to sham operated control rats on three behavioural tasks. In the Morris water maze, the rats had to learn to use the distal visual cues to locate an escape platform hidden in the pool. In an open field task, the rats were assessed on their reactions to a spatial relocation of a visual or an auditory object. In a spatial cross-modal transfer (CMT) task (Tees & Buhrmann, 1989), rats were trained to respond to light signals using spatial rules, and were then subjected to transfer tests using comparable sound signals. Results from the Morris water maze, the open field, and the initial training phase of the spatial CMT task confirmed a visuospatial deficit in PPC lesioned rats. However, if given sufficient training, PPC lesioned rats could learn the location of a hidden platform in the Morris water maze, and they could also acquire spatial rules in the CMT task. Such results indicated that the visuospatial deficits in PPC lesioned rats were less severe than previously thought. On the other hand, a persistent navigational difficulty characterized by a looping pattern of movement was observed in the PPC lesioned rats in the Morris water maze. Results from the open field indicated that PPC was less involved in audiospatial behaviours. Moreover, results also indicated that PPC was not necessary for spatial CMT. Hence, data from the present study did not support the idea that PPC played an essential role in supramodal spatial abilities in the rats. Instead, data from the spatial CMT task seemed to imply a role of PPC in managing conflicting spatial information coming from different sensory modalities.

Although a plethora of data exists on the role of the prefrontal cortex in memory retrieval, it has been difficult to relate specific aspects of retrieval processing to the different prefrontal regions. The present thesis consists of one behavioural experiment and three functional neuroimaging studies that aimed at elucidating the role of the mid-ventrolateral region of the prefrontal cortex in memory retrieval. We hypothesized that the mid-ventrolateral prefrontal cortex, through its anatomical connections with posterior association areas, is in a key position to exert control over posterior association areas where information is processed and stored for the active retrieval of mnemonic information. In contrast to automatic retrieval, active retrieval is necessary when a person retrieves based on his/her plans and intentions a specific memory amongst multiple related mnemonic traces. / Previously, we had demonstrated that the mid-ventrolateral prefrontal cortex in the right hemisphere controls active retrieval of non-verbal stimuli. More specifically, we reported activity increases within this region during the delay period that followed the presentation of a retrieval cue. We proposed that these activity increases reflect the top-down control exerted by the mid-ventrolateral prefrontal cortex to focus attention on relevant aspects of encoded memories in preparation for the decision. The first study of my thesis focuses on the behavioural correlates of this active retrieval process. The results indicate that the subjects' performance improves (i.e. becomes faster) with longer retrieval periods. Thus, some aspect of retrieval is initiated during the delay before the presentation of a test stimulus for the decision. The results, however, also indicate that retrieval continues after the presentation of the test stimulus. / The three event-related fMRI studies that make up chapters three, four, and five of the thesis were designed on the basis of the results obtained in the behavioural study described in chapter two. For all three fMRI studies, we used an experimental paradigm in which the retrieval cue coincided with the test stimulus presentation. The experimental design for the three neuroimaging studies was similar but examined the retrieval of mnemonic information from different sensory modalities. A separate group of subjects was tested for each study with a common hypothesis: when subjects are performing active retrieval trials, selective activity increases will be observed within the mid-ventrolateral prefrontal cortex. The study presented in chapter three examined verbal active retrieval, the study presented in chapter four examined tactile active retrieval, and the one in chapter five examined active retrieval for auditory stimuli. Selective activity increases were reported within the mid-ventrolateral prefrontal cortex during the active retrieval trials in all three studies. Activity increases were stronger in the left mid-ventrolateral prefrontal cortex when subjects retrieved verbal information. For tactile and auditory stimuli, the activity increases were bilateral. Importantly, within the prefrontal cortex, there were no other activity increases, indicating that the role of the mid-ventrolateral prefrontal cortex in memory retrieval is specific and distinct from that of other prefrontal regions. Thus it can be concluded that, across sensory modalities, the mid-ventrolateral prefrontal cortex plays a key role in the top-down control necessary for the disambiguation of information in memory during retrieval.

While the extrinsic factors regulating neurogenesis in the developing forebrain have been widely studied, the mechanisms downstream of the various signaling pathways are relatively ill-defined. In particular, we focused on proteins that have been implicated in cognitive dysfunction. Here, we ask what role two cell intrinsic factors play in the development of two different neurogenic compartments in the forebrain. In the first part of the thesis, the transcription factor FoxP2, which is mutated in individuals who have specific language deficits, was identified to regulate neurogenesis in the developing cortex, in part by regulating the transition from the radial precursors to the transit amplifying intermediate progenitors. Moreover, we found that ectopic expression of the human homologue of the protein promotes neurogenesis in the murine cortex, thereby acting as a gain-of-function isoform. In the second part of the thesis, the histone acetyltransferase CREB-binding protein (CBP) was identified as regulating the generation of neurons from medial ganglionic eminence precursors, similar to its role in the developing cortex. But CBP also plays a more substantial role in the expression of late interneuron markers, suggesting that it is continuously required for the various stages of neurogenesis at least in the ventral neurogenic niche. Finally, similar to cortical precursors, the function of CBP in the ventral forebrain precursors is also dependent on histone acetylation. Together, these studies shed light on some of the key intrinsic players that regulate the differentiation of neural precursors in the embryonic murine forebrain, and they also suggest potential mechanisms for the pathogenesis of various cognitive dysfunctions.

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This work includes several studies exploring functional specialization of human primary and anterior secondary auditory cortex (AC) in the two hemispheres. It was hypothesized that the left hemisphere prepotency for linguistic processing is based, in part, on specialized mechanisms within this hemisphere for the processing of acoustic transients relevant to speech. Evidence supporting this idea was obtained in a positron emission tomography study (PET). Since nonlinguistic stimuli were used, the observed left-hemispheric activation cannot be specific to the speech system, but must reflect a more general processing mechanism. A reanalysis of data from six auditory PET studies revealed that the peak focus of auditory activation was significantly posterior to Heschl's gyrus (HG) in the right hemisphere, while it encompassed HG in the left. The cause of this asymmetry is unknown, but it appears to hold true for other auditory functional imaging studies in the literature. Functional specialization in auditory regions was also explored by testing patients with anterior temporal-lobe resections from either the left (LT) or right (RT) hemisphere and normal volunteers on several linguistic and nonlinguistic auditory tasks. The excisions in these patients always included some secondary AC, and sometimes included primary AC (HG). I had speculated that anterior. secondary AC in the left hemisphere was specialized for processing word-sounds, but patients with excisions in this area were unimpaired in their ability to use such information to retrieve items from the mental lexicon. Furthermore these patients did not show a disproportionate impairment on a lexical decision task, when items were presented aurally instead of visually, compared to normal subjects. With few exceptions, a battery of psychophysical tests of auditory processes were performed normally by all groups. The notable exception was an impairment in the group of RT patients with lesions that included HG on a ta