Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Neuroscience

Supervisor

Bussey, Tim

2nd Supervisor

Saksida, Lisa

Co-Supervisor

Abstract

Gamma rhythms (30 – 100hz) emerge in the prefrontal cortex (PFC) during engagement in cognitive tests of attention, working memory, and task switching. Further, abnormalities in prefrontal gamma synchrony are present during cognitive testing in patients with neuropsychiatric diseases such as schizophrenia. A subset of GABAergic neurons expressing the protein parvalbumin (PVNs), are known to facilitate local gamma synchrony, are abnormal in the PFC of schizophrenia patients, and contribute to various forms of PFC-dependent cognition in rodents.

This thesis aimed to evaluate the role of prefrontal PVNs in cognitive processes relevant to schizophrenia, namely working memory and attention. Mice were tested using touchscreen-based cognitive tasks designed to mirror human paradigms more closely. PVNs were assessed using calcium imaging and manipulated using excitatory and inhibitory optogenetics during cognitive testing. Due to the role of PVNs in gamma band activity, activation was performed at both gamma (30hz) and theta (5hz) frequencies to induce optimal or aberrant local oscillatory activity, respectively.

First, we optimized a touchscreen-based task of working memory and confirmed its dependence on intact mPFC functioning. We further show that perturbing PVN activity outside the gamma range induces deficits in both working memory and attention, and that PVN contributions are strongly modulated by cognitive load. We observed that PVN activity is effectively shaped by learning, differentially recruited depending on task demands, and confers information regarding the outcome of behavioral responses. Finally, we observed reduced prefrontal PVN activity in a mouse model of neuropsychiatric disease that displayed attention deficits. Interestingly, stimulating PVNs at the gamma frequency rescued these impairments.

Our findings indicate the PVNs play a flexible role in PFC-dependent cognition, and aid task performance depending on the unique demands of a given task. Importantly, PVNs do not appear to modulate specific domains of cognition, but underlie the integrated functions of the PFC. This role is tightly associated with gamma band activity, as inhibiting or sub-optimal stimulation of PVNs induced cognitive deficits, while gamma stimulation had pro-cognitive effects. We also show that targeting PVN and restoring PFC gamma synchrony may provide a therapeutic avenue to future treatment options.

Summary for Lay Audience

In schizophrenia, patients experience treatment-resistant disruptions in cognition. These symptoms include distractibility, trouble switching between tasks, and issues with short-term memory. When patients with schizophrenia perform cognitive tests in a laboratory setting, brain-imaging studies have shown reduced activity in a brain region called the prefrontal cortex (PFC). The PFC is important for many different brain functions and behavior, and impaired function of this area could contribute to the cognitive issues observed in schizophrenia.

While communication across the brain is carried in electrical signals, this activity is tightly organized and often takes a rhythmic form, known as brain waves. Brain waves result from the balance of two types of neuron signals, an excitatory “Go” signal and an inhibitory “Stop” signal. Importantly, brain waves can occur quickly or more slowly, which differentially contribute to types of cognition. Fast brain waves are especially important for things like attention and memory, and heavily rely on organized Stop signals. Unfortunately, patients with schizophrenia also have less fast wave signals in the PFC. This has led researchers to wonder how brain waves aid cognition and if restoring them could reduce the cognitive impairments.

We were interested in how neurons that are important for the Stop signal behave during cognition, and if targeting them could be an option for future treatment strategies. To do so, we assessed mice on tests of attention and memory using touchscreens, which let us test animals in the same way we do humans. Additionally, we used techniques that allowed us target Stop neurons in PFC and turn them on or off while mice were performing the cognitive tasks. Interestingly, we found that turning these cells off resulted in mice with poorer cognition. Alternatively, turning them on at a specific frequency (to match fast brain waves) enhanced their cognition. Moreover, when we applied this manipulation to a mouse model of schizophrenia, we were able to improve their cognitive impairments. All together, our data shows that specific PFC cells that control fast brain waves regulate multiple aspects of cognition, and that improving their activity could offer treatment options for cognitive symptoms in schizophrenia.

While communication across the brain is carried in electrical signals, this activity is tightly organized and often takes a rhythmic form, known as brain waves. Brain waves result from the balance of two types of neuron signals, an excitatory “Go” signal and an inhibitory “Stop” signal. Importantly, brain waves can occur quickly or more slowly, which differentially contribute to types of cognition. Fast brain waves are especially important for things like attention and memory, and heavily rely on organized Stop signals. Unfortunately, patients with schizophrenia also have less fast wave signals in the PFC. This has led researchers to wonder how brain waves aid cognition and if restoring them could reduce the cognitive impairments.

We were interested in how neurons that are important for the Stop signal behave during cognition, and if targeting them could be an option for future treatment strategies. To do so, we assessed mice on tests of attention and memory using touchscreens, which let us test animals in the same way we do humans. Additionally, we used techniques that allowed us target Stop neurons in PFC and turn them on or off while mice were performing the cognitive tasks. Interestingly, we found that turning these cells off resulted in mice with poorer cognition. Alternatively, turning them on at a specific frequency (to match fast brain waves) enhanced their cognition. Moreover, when we applied this manipulation to a mouse model of schizophrenia, we were able to improve their cognitive impairments. All together, our data shows that specific PFC cells that control fast brain waves regulate multiple aspects of cognition, and that improving their activity could offer treatment options for cognitive symptoms in schizophrenia.

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Available for download on Wednesday, May 01, 2024

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