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A potent gene transcription regulator, retinoic acid (RA) is known to influence more than 500 genes, whose functions include regulation of neuronal differentiation and patterning of the developing nervous system. Furthermore, its ability to stimulate neurite outgrowth has been documented in primary neurons such as postnatal cerebellar granule neurons, adult cortical neurons, or embryonic and adult dorsal root ganglia neurons (DRGs) (Corcoran et al. 2000, Wong et al. 2006, Yip et al. 2006, Puttagunta et al. 2011). It has been previously proposed that RA synthesis takes place only in the cytoplasm mediated by three retinaldehyde dehydrogenases (Raldhs) namely Raldh1, Raldh2 and Raldh3. From this cytoplasmic location RA is then transported to the nucleus where RA receptors (RAR) α, β and γ initiate gene transcription. RA is then removed from the nucleus and degraded by microsomal cytochrome 450 (Cyp26) A1, B1 or C1 enzymes. New studies have pointed to additional roles for RARs in the cytoplasm to regulate kinase function. Thus, as well as being a highly potent gene regulator, RA might act on several different levels involving separate mechanisms all converging towards its pro-regenerative abilities. The starting hypothesis for this thesis was that neurons in culture that re-grow dendrites and axons following their removal from their previously interconnected state in the brain activate intrinsic RA signalling mechanisms. Neurons that regenerate in culture following dissection of CNS were termed throughout the thesis as “regenerating neurons” by extrapolation from a similar terminology used for neurons cultured from the dissected CNS of Lymnea stagnalis (Farrar et al. 2009). The aim of this thesis was to determine if the synthesis of RA occurs within these neurons and, if so, where such synthesis is localised within sub-regions of the regenerating neuron. Such localisation of RA signalling can be genomic (RAR control of nuclear transcription) or non-genomic (RAR control of cytoplasmic kinases). Three types of neurons from hippocampus, cortex and retina, as well as the tissue of origin, were analysed by means of immunochemistry for the expression of Raldh1 and Raldh2 as well as RAR α, β and γ. Since many genes can be regulated by RA, a possible candidate gene, and effects of its inhibition on neurite outgrowth with or without RA, was investigated. Considering the promising results that appear on the horizon concerning the potential therapeutic effects that RA may have on neuronal regeneration, various retinoids were tested for genomic and non-genomic activity. The genomic activity was determined using a reporter cell line that has lac-Z driven by a RA response element while the non-genomic activity was assessed though an assay performed with MCF-7 cells that measured the phosphorylation of Erk1/2 as one of the potential RA-regulated downstream kinases. The main finding of this thesis was that in-vivo, neurons in postnatal hippocampus, cortex and retina showed very little expression of the components for RA synthesis while expression of RARs seemed to decrease dramatically within days of postnatal life. Nevertheless neurons from all these regions, when regenerating in culture, possessed the ability to synthesize RA as well as responding to it due to the up regulation of the necessary receptors. This thesis also suggested that the Raldhs, the main enzymes responsible for RA synthesis, are much more dynamic than previously considered and their location as well as intensity can change over time, or as a response to typical neuronal plasticity manipulation. Since all regenerating neurons switch on RA signalling within a couple of days of culture, this suggests that RA could be therefore the decisive factor that tips the balance between the two possible outcomes for a neuron that has its neurites cut away: to live and regenerate or to die. In the attempt to identify potential retinoids with greater effect in stimulating the ability of neurons to regenerate, it was found that some retinoids appeared to have a substantial influence on neurite outgrowth while different retinoids had unique combinations of genomic and non-genomic potencies.

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Sensory gating is a mechanism by which irrelevant sensory information is filtered in the brain, enabling efficient information processing. The auditory conditioning-test paradigm, an index of sensory gating, measures the reduction in the auditory-evoked response (AER) produced by a test stimulus following an initial conditioning stimulus. Schizophrenic patients demonstrate a lack of attenuation of the test response measured in the P50 component of the cortical auditory-evoked potential. The N2/N40 auditory-evoked potential recorded from rat hippocampus is considered homologous to the human P50 wave. Altered glutamatergic neurotransmission and the endocannabinoid system have been implicated in the pathogenesis of schizophrenia with structural and functional abnormalities in the hippocampus and the medial prefrontal cortex (mPFC). The current study examined sensory gating using auditory conditioning-test paradigm in the dentate gyrus (DG) and the CA3 region of the hippocampus and in the medial prefrontal cortex (mPFC) before and after administration of N-Methyl- D-Aspartate (NMDA) receptor antagonist phencyclidine (PCP; 1 mg/kg, i.p) or the cannabinoid agonist WIN55,212-2 (1.2mg/kg, i.p). Electrophysiological recordings were conducted in Lister hooded rats, under isoflurane anaesthesia, during the presentation of paired auditory stimuli. Extracellular action potential spikes and local field potentials (LFPs) were recorded simultaneously using multi-electrode arrays and the effects of acute administration of PCP (1 mg/kg, i.p) or WIN55,212-2 (1.2mg/kg, i.p) was determined. Gating of the N2 wave was assessed by measuring the ratio of the Test to Conditioning response amplitude (T/C ratio); T/C ratio ≤ 50% was indicative of gating. Robust auditory-evoked potentials were recorded from the hippocampal CA3 and DG regions and the mPFC; some rats demonstrated auditory gating while others failed to. In rats that demonstrated gating of N2, mPFC showed higher T/C ratios and shorter conditioning response latencies compared to DG and CA3. PCP disrupted auditory gating in all three areas with a significant increase in test response amplitudes in the gating rats. PCP had no effect on T/C ratios in the non-gating rats. The atypical antipsychotic clozapine (5mg/kg, i.p) prevented PCP induced disruption of gating in the CA3, DG and mPFC. WIN55,212-2 disrupted auditory gating with a significant increase in test response amplitudes in the gating rats. WIN55,212-2 had no effect on T/C ratios in the non-gating rats. The cannabinoid receptor (CB1) antagonist SR141716A (1mg/kg, i.p) prevented WIN55,212-2 induced disruption of gating. Neither clozapine nor SR141716A had any effects on the non-gating rats. Both PCP and WIN55,212- 2 disrupted gating of the single-unit responses in the CA3, DG and mPFC, effects which were prevented by the pre- administration of clozapine or SR141716A. The non-gating rats may model some inhibitory deficits observed in schizophrenic patients. Administration of PCP disrupted auditory gating which was prevented by clozapine; similar deficits are observed in schizophrenic patients. Furthermore, cannabinoid receptor activation disrupted auditory gating which was prevented by CB1 receptor antagonism, suggesting the endocannabinoid system as a potential target for future clinical research in the treatment in schizophrenia.

The profile of caregivers to Alzheizner’s disease victims in Georgia was examined. The sample population consisted of 377 caregivers (20% of the registered members of the 16 Alzheimer’s Support Groups across the state). The findings revealed that, the majority of the caregivers are between the ages of 45 and 74 years old, they tend to be the spouse of the victim, live on a fixed income, and is experiencing emotional, physical and financial stress. The findings were analyzed utilizing tables and percent comparisons.

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