Cholinergic Modulation of Parvalbumin Neurons in Cognition Relevant to Schizophrenia

Hamidullah, Shahnaza

Cholinergic Modulation of Parvalbumin Neurons in Cognition Relevant to Schizophrenia

Files

Hamidullah_Shahnaza_PhD_2025_thesis.pdf (7.69 MB)

Date

2025-12-03

Authors

Hamidullah, Shahnaza

Abstract

Cognitive impairments, particularly deficits in attention and working memory, are a hallmark of schizophrenia and related disorders. These impairments significantly impact daily life and are among the strongest predictors of poor functional outcomes. Understanding the neural mechanisms underlying attention and working memory is crucial for developing therapeutic strategies to improve the quality of life for patients with these disorders. These aspects of cognition rely on the balance between excitatory and inhibitory neurotransmission, particularly in the prefrontal cortex (PFC), where inhibitory parvalbumin neurons (PVNs) play a key role. PVN activity, in turn is subject to modulation by neuromodulators such as acetylcholine (ACh).

This work examines how cholinergic signaling and PVNs in the PFC contribute to cognition. Using fibre photometry, we first characterized ACh and PVN dynamics in attention using the rodent continuous performance task (rCPT). ACh and PVN signals showed highly similar event-related patterns, suggesting coordinated activity during attentional processing. These findings support a model in which cholinergic modulation enhances PVN recruitment to facilitate attention. Next, we investigated the receptor mechanisms underlying this modulation. Broad muscarinic receptor (mAChR) blockade with scopolamine impaired discrimination between targets and non-targets and reduced PVN activity, indicating a causal link between muscarinic signaling and PVN recruitment. Selective targeting revealed that M1, but not M4, mAChR antagonism reproduced these effects, identifying M1 mAChRs as critical for sustaining attention by maintaining excitation–inhibition balance. Nicotinic blockade produced only modest effects, suggesting a lesser role on modulation of PVN activity and attention.

Finally, we explored the role of PVNs in working memory using the trial-unique delayed nonmatching-to-location (TUNL) task. We found that PVN activity was associated with greater task demands, particularly when delay length or interference was increased. Furthermore, optogenetic inhibition impaired performance under demanding conditions, whereas gamma-frequency stimulation improved accuracy. Together, these findings demonstrate that PVNs are recruited in a demand-dependent manner during working memory performance.

Our findings indicate that M1 mAChR modulation of PVNs plays a key role in cognition relevant to schizophrenia and related disorders. Targeting specific mAChRs may provide a promising therapeutic avenue for these conditions.

Summary for Lay Audience

Schizophrenia is a devastating brain disorder that affects 1 out of 100 Canadians. Some symptoms that patients may experience, such as hallucinations and emotional blunting, have effective treatments. However, cognitive symptoms, such as impairments in attention and memory, are not well treated. These cognitive symptoms have a negative impact on quality of life so it is essential to develop therapies to manage them. To develop new treatments, we need to understand the relevant brain changes. Research indicates two types of brain changes underlie cognitive impairments in schizophrenia. The first change involves dysfunction in a specific kind of brain cell called a 'parvalbumin-positive neuron (PVN)'. The second change consists of the dysfunction of chemical neuromodulators, such as acetylcholine (ACh), that modulate the activity of brain cells. Although there is considerable work looking at how these mechanisms individually affect cognition in schizophrenia, we don't know much about how the two types of brain dysfunction may intersect. Studying how these mechanisms overlap can help identify the underlying causes of cognitive deficits and guide the development of treatments that target both systems more effectively. I will use mice to study the interaction between PVNs and ACh as they allow us to investigate brain changes precisely, using techniques that would not be possible in humans. These techniques will allow me to observe and manipulate PVN and ACh activity while the mice engage in touchscreen-based cognitive tasks identical to those used in humans, allowing me to translate my findings to patients more successfully. Understanding brain changes behind cognitive impairments will help discover better treatment options for cognitive symptoms and, ultimately, improve the quality of life for patients with schizophrenia.

Keywords

Attention, executive function, schizophrenia, cognitive deficits, excitation-inhibition balance, parvalbumin interneurons, GABAergic inhibition, prefrontal cortex, cortical microcircuits, gamma oscillations, acetylcholine, muscarinic receptors, M1 receptor, M4 receptor, basal forebrain, neuromodulation, fibre photometry, touchscreen cognitive testing, continuous performance task, calcium imaging, intracranial drug infusion, xanomeline, telenzepine, mecamylamine, muscarinic agonist, muscarinic antagonist, rodent models, in vivo neural activity, behavioural neuroscience