Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Neuroscience

Supervisor

Martinez-Trujillo, Julio C

2nd Supervisor

Palaniyappan, L

Affiliation

McGill University

Co-Supervisor

Abstract

Neural activity in the primate lateral prefrontal cortex (LPFC) has been causally linked to working memory (WM) ⁠— the brief maintenance and mental manipulation of information. Primates use WM to perform tasks in complex contexts; however, neural mechanisms of WM and the pathophysiology related to WM deficits have traditionally been studied using simple tasks that deviate from naturalistic conditions. This raises the question, how is WM processed in naturalistic conditions? To explore this, I trained two macaque monkeys on a spatial WM task set in a naturalistic virtual environment. During the task, a target was presented in 1 of 9 locations in a virtual arena. The target then disappeared and following a 2-second delay period, subjects navigated to the cued target location using a joystick. I recorded single neuron activity using two 96-channel Utah Arrays implanted in LPFC (areas 9/46 & 8a). During this task, single neurons are spatially selective for remembered target locations and neural populations contain large amounts of information about the target location over the duration of the task. Neural coding for WM is robust and distinct from signals related to perception and eye movement. Using ketamine to model the pathophysiology of schizophrenia, I demonstrate drastic deficits in WM performance. The decrease in performance is related to differential effects on putative excitatory and inhibitory neurons. Inhibitory neurons decrease their firing rate for their preferred location after ketamine injection, thus disinhibiting excitatory cells, resulting in distorted WM representations. Finally, I demonstrate a new neural code for maintaining WM in naturalistic conditions. Precise temporal patterns of population activity contain large amounts of information about target location and target trajectories in our virtual task. Ketamine distorts these neural sequences and their relationship to behavior. Together, these findings demonstrate that the LPFC relies on a robust neural code that uses firing rate and temporal information to maintain WM representations in the presence of incoming sensory signals and eye movement. These findings detail how the primate LPFC encodes WM representations in naturalistic conditions and models how WM deficits may arise in day-to-day life.

Summary for Lay Audience

Working memory is the cognitive process that allows us to maintain information from our environment for the span of seconds to a few minutes. For example, if I were to read you a phone number to dial, you must be able to briefly remember the number to successfully make the call. However, after the call is made and the information is no longer relevant to your task, the number will fade from memory. For this thesis. I developed a working memory task set in a virtual environment that is meant to resemble how we use working memory in real life – in complex and dynamic environments. During this task, I recorded from neurons in the prefrontal cortex of macaque monkeys, an area clearly involved in working memory. I demonstrate that neurons in the prefrontal cortex robustly represent the locations of targets after they disappeared. Moreover, neurons that represent working memory information are separate from neurons that represent eye position and visual perception, allowing for robust memory despite eye movement or potential distractors in the environment. Next, I explore how naturalistic working memory is affected by ketamine, a drug that mimics the symptoms of schizophrenia. Here, I show that ketamine reduces the specificity of neurons for representing target location so that neurons are similarly active for all targets – limiting the ability of animals to precisely remember a location. Finally, I explore the possibility that not only is the number of action potentials that neurons fire important, but also when the action potentials are fired. I explore temporal patterns of neural activity and show that single neurons fire around the same time in each trial and that the population of neurons form complex temporal patterns that were closely related to naturalistic working memory behavior. Overall, I demonstrate how the brain processes working memory in naturalistic conditions and how working memory deficits may occur in patients in complex environments that reflect how they would use working memory in real life.

Creative Commons License

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

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Available for download on Friday, September 08, 2023

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