| Popis: |
The brain is a complicated structure that receives copious amounts of information at any given time. The pedunculopontine tegmental nucleus (PPTg) is involved in many innate functions like arousal, rapid eye-movement (REM) sleep, reward association and sensorimotor gating. Although commonly referred to as a cholinergic structure, it also contains glutamatergic and GABAergic neurons. Based on chronic PPTg lesions that disrupted PPI, cholinergic PPTg neurons were long assumed to mediate prepulse inhibition (PPI) of startle, a measure of sensorimotor gating. Deficits of PPI are observed in a variety of neurological disorders, including Autism Spectrum Disorder (ASD), Obsessive-Compulsive Disorder (OCD), and is considered an endophenotype of Schizophrenia. The PPTg has also been shown to play a crucial role in reward association. The main goal of this thesis is to explore PPTg neuronal projections to the startle-mediating caudal pontine reticular nucleus (PnC) and to assess how distinct PPTg neuronal populations influence startle and its modulations. I employed fluorescent tracing methods, chemogenetics (DREADDs; designer receptors exclusively activated by designer drugs), fluorescence in situ hybridization (FISH) RNAscope analyses, among various behavioural assays, that resulted in the discoveries that 1) PPTg glutamatergic and cholinergic neuronal populations are mostly distinct neuron-types; 2) efferent pathways arising from PPTg glutamate-releasing neurons directly innervate and terminate on PnC giant neurons; 3) transient inhibition of all or specifically glutamatergic PPTg neurons – but not cholinergic PPTg neurons – disrupts PPI of startle; and 4) transient inhibition of cholinergic PPTg neurons - but not glutamatergic PPTg neurons - disrupts reward associative learning, tested by morphine-conditioned place preference. In conclusion, my work shows a double dissociation between the role of glutamatergic and cholinergic PPTg neurons in startle modulation and reward association, respectively. It also provides valuable new insights into the clinically relevant theoretical neural circuitry underlying PPI, which is disrupted in various neuropsychiatric and neurological diseases. |
