Student Theses and Dissertations

Date of Award

2024

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Rajasethupathy Laboratory

Abstract

Animals are constantly bombarded by any number of sensory inputs but have a limited capacity with which to process them. A mechanism for filtering, prioritizing, and directing mental assets is required to prevent sensory overload, enable meaningful comprehension, and allow for further action. Attention is the process of directing cognitive resources toward specific stimuli, which can be dispensed in a top-down manner to carry out higher-order cognitive functions. However, despite extensive and careful study at the molecular, cellular, and, circuit scales, unifying principles have been challenging to elicit. In this thesis, I aimed to provide a new perspective by taking a forward genetics approach to identify genes with prominent contributions to attentional performance. We studied 200 mice from a highly genetically diverse, multi parent mouse population on measures of pre-attentive processing and through genetic mapping identified a small locus on chromosome 13 (95%CI: 92.22-94.09 Mb) driving substantial variation (19%) in this trait. After identifying the parental genomic contributions driving this variation, we validated that the locus also drove variation in attention, but not other related cognitive processes, using similarly diverse mice homozygous for the appropriate founder haplotypes. Further characterization of the locus revealed Homer1, encoding a synaptic protein, as the causative gene. Further analysis determined that down-regulation in the prefrontal cortex (PFC) only during a developmental critical period of two short, activity-dependent isoforms Homer1a and Ania3 led to significant improvements in multiple measures of attentional performance in the adult. Subsequent single-cell RNA seq experiments revealed that prefrontal Homer1 down regulation in excitatory neurons is associated with GABAergic receptor upregulation in those same cells. Moreover, physiological studies demonstrated that this increase in GABAergic receptors corresponded to strong inhibitory tone in PFC. This enhanced inhibitory influence, together with dynamic neuromodulatory coupling, led to strikingly low PFC activity at baseline periods of an attention task but targeted elevations at cue onset, predicting short-latency correct choices. Notably high-Homer1, low-attentional performers, exhibited uniformly elevated prefrontal activity throughout the task. We thus identify a single gene with a large effect on attention–Homer1 –and find that it improves prefrontal inhibitory tone and signal-to-noise (SNR) to enhance attentional performance. Complementary to older models focused mainly on uniformly amplifying PFC activity, this work provides a new paradigm of attentional control–one in which reduced prefrontal activity can improve SNR.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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