Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Neuroscience

Supervisor

Schmid, Susanne

Abstract

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.

Summary for Lay Audience

Our brain receives incessant information at any given time, even while asleep, making it arguably the most complicated organ to study. To perform its countless functions, the brain needs to sort out the important from the useless information. For example, Sensorimotor gating is a form of sensory filter used by a wide range of species and can be easily measured through a test called prepulse inhibition (PPI) of the startle reflex. Disruptions of PPI are observed in many neurological disorders including Autism Spectrum Disorder (ASD), Obsessive Compulsion Disorder (OCD), and are considered a hallmark of Schizophrenia. As scientists studied PPI in the mid to late 20th century, they became particularly interested in the pedunculopontine tegmental nucleus (PPTg), a small area in the brain located in the phylogenetically old part of the brain, and found in almost every vertebrate, including humans. Beyond its involvement in basic functions like arousal, sleep, and reward association, the PPTg has been shown to be important for sensorimotor gating and sensory filtering.

This Dissertation focuses on the PPTg, the various different types of brain cells (neurons) it is made of, and how each kind of cell may influence PPI and reward association. There are three main neuron types found in the PPTg: cholinergic, glutamatergic, and GABAergic, based on the neurotransmitter that they release to communicate to other neurons. Of these, the cholinergic population has received considerable attention as mediators of PPI and reward association, while the former two cell types have been largely neglected. In this thesis, I aimed to understand how distinct PPTg neuronal populations influence PPI by studying their impact on the well-known startle-mediating brain region (the caudal pontine reticular nucleus (PnC). The results of this work suggest that 1) the glutamatergic PPTg cell population may be more important than the cholinergic cells for PPI, whereas the cholinergic PPTg population is crucial for reward-associative learning; 2) PPTg glutamatergic and cholinergic neuronal populations, previously thought to be related to each other, are mostly distinct neuron-types. In conclusion, my work provides insights into the clinically relevant theoretical neural circuitry of PPI, which is disrupted in various neuropsychiatric and neurological diseases. This work sheds light on potential therapeutic mechanisms that can be explored further to improve sensory filtering disruptions in patients, which lead to an overload of information to the brain.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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