Thesis
Impact of environmental risk factors for schizophrenia on the developing brain : characterisation of the effects of polyIC and THC on functional neural systems and behaviour
- Creator
- Awarding institution
- University of Strathclyde
- Date of award
- 2012
- Thesis identifier
- T13455
- Qualification Level
- Qualification Name
- Department, School or Faculty
- Abstract
- Cannabis abuse can produce deficits in cognition and has been implicated as a 'late' environmental risk factor in the pathogenesis of the poly-factorial disorder schizophrenia. Evidence suggests an age-related susceptibility to the deleterious effects of cannabis as early onset of use may increase the vulnerability of the brain to the adverse consequences of cannabis abuse. Animal models are crucial for exploration of mechanistic and causative theories, and long-term behavioural consequences of adolescent cannabis abuse in a controlled experimental environment. This thesis evaluates the vulnerability of the adolescent/peripubertal brain to Δ9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis, and explores the potential interplay between this schizophrenia-related 'late' environmental risk factor and an 'early' environmental risk factor (prenatal infection - maternal immune activation (MIA)) on functional neural systems and behaviours relevant to schizophrenia. Cannabinoid CB1 receptor ontogeny (activated in the brain by the receptor ligand THC) within important cognitive substrates, the prefrontal cortex (PFC) and hippocampus, was investigated to delineate a period of neurodevelopmental vulnerability for peripubertal THC treatment. CB1 receptor ligand binding revealed that the PFC and hippocampus follow differential late maturational trajectories throughout the peripubertal period. The 'vulnerability window' for peripubertal THC treatment was defined as post-natal day (PD) 35-56 to encompass the dynamic peripubertal ontogenetic patterns of the CB1 receptor in both these regions. Furthermore, age-related alterations in cerebral metabolism and regional functional connectivity profiles were evident in the hippocampus and important neuromodulatory nuclei including the ventral tegmental area, dorsal raphe, locus coeruleus and the diagonal band of Broca.;Acute THC administration (5mg/kg) produced hypometabolism in the thalamus and an altered functional connectivity profile between thalamic nuclei and the PFC, hippocampus and the nucleus accumbens. THC-induced anomalistic neural activity was evident in key neuromodulatory nuclei and produced perturbed functional connectivity within acetylcholine, noradrenaline, and dopamine neural pathways. Acute THC treatment resulted in alterations in cerebral metabolism in the amygdala and aberrant functional connectivity profiles between amygdaloid nuclei and the hippocampus, PFC and nucleus accumbens. There appeared to be an age-related sensitivity to THC in several thalamic, neuromodulatory and amygdaloid nuclei. Peripubertal low-dose intermittent THC (3.5mg/kg, 3 times a week), mimetic of light, recreational adolescent cannabis use, produced long-term cognitive inflexibility, as measured by the attentional-set shifting task, perturbed cerebral metabolism in the dorsolateral orbital cortex and the nucleus accumbens core and altered functional coupling between both these regions and neural substrates subserving reward-related learning including prefrontal, septal and amygdala subfields. High-dose daily THC (7mg/kg) throughout the peripubertal period, mimetic of heavy daily cannabis abuse, did not precipitate any schizophrenia-related behaviours in adulthood. MIA induced by prenatal exposure to the immune-stimulating agent polyriboinosinic-polyribocytidilic acid (PolyIC) did not produce any schizophrenia-related phenotypes in adulthood. However, prenatal PolyIC exposure produced residual hypermetabolism within discrete components of the prefrontal cortex dorsolateral orbital and cingulate cortices and hypometabolism within the CA3 subfield of the hippocampus. The functional connectivity signatures of all these regions indicated a unified MIA effect of aberrant mesocorticolimbic functional coupling in adulthood. Furthermore, chronic intermittent treatment with low-dose THC during the peripubertal period caused an increase in sensitivity to amphetamine (indicative of aberrant mesolimbic dopamine transmission) in PolyIC-treated offspring compared to PBS-treated offspring, suggestive of a synergistic effect of these two environmental risk factors. In conclusion, the findings presented in this thesis have provided clear evidence of dose-specific detrimental effects of 'adolescent' THC exposure on behaviour and the functional neural systems that may underpin these deficits which impact on behaviour and neural systems into adulthood.
- Resource Type
- Note
- Strathclyde theses - ask staff. Thesis no. : T13455
- DOI
- Date Created
- 2012
- Former identifier
- 991367
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