UC Irvine

Primary cilia are microtubule-based, non-motile organelles that extend from the surface of nearly all mammalian neurons and concentrate G protein-coupled receptors, including dopamine D1 and D2 receptors, melanin-concentrating hormone receptor 1, and adenosine A2A receptor, within a physically restricted signaling compartment. Although these receptors are established regulators of circadian behavior, motivation, and social engagement, whether the ciliary organelle itself contributes functionally to these behaviors, and whether it does so uniformly or through specific neuronal populations, was unknown. This dissertation addresses this question in the mouse nucleus accumbens core (NAcC), a ventral striatal region that integrates dopaminergic input from the ventral tegmental area with glutamatergic input from prefrontal, hippocampal, and amygdala circuits to drive goal-directed, social, and circadian behavior.The first study established the structural foundation for this work by generating a high-throughput, brain-wide atlas of primary cilia across 22 mouse brain regions. Using automated image analysis applied to coronal sections collected at twelve time points across a 24-hour period, over 10 million individual cilia were measured for length and orientation, yielding the largest spatiotemporal atlas of ciliary structure assembled to date. Cilia length and orientation varied substantially by brain region and were not static: length fluctuated significantly across the light-dark cycle in the majority of regions examined, and the NAcC was among five regions, alongside the arcuate nucleus, dorsomedial and ventromedial hypothalamus, and somatosensory cortex, showing statistically significant circadian rhythmicity in cilia length, with peak length occurring in the hours preceding the onset of the active phase. Building on this structural rationale, primary cilia were selectively ablated from CaMKII-expressing NAcC neurons in adult mice via stereotaxic AAV-Cre delivery to Ift88-floxed animals, removing the intraflagellar transport protein required for ciliary maintenance. This manipulation was assessed across two independent behavioral domains. In the circadian domain, cilia-ablated mice showed a selective reduction in dark-phase wheel running, decreased total NREM sleep, and increased wakefulness measured by 48-hour EEG/EMG recording, while the timing, phase, and day-to-day stability of the light-dark-entrained rhythm, along with food intake, remained statistically indistinguishable from controls, indicating a deficit in the amplitude, or gain, of circadian behavioral output rather than in the clock mechanism itself. In the social domain, the same ablation abolished normal social approach preference and social novelty recognition, and altered corticolimbic network dynamics recorded via local field potential during social interaction, including a selective reduction in parietal theta power, changes in delta-centered phase-amplitude coupling, elevated frontal-parietal coherence, and elevated baseline motor output prior to social exposure.Because the CaMKII-driven manipulation targets a heterogeneous neuronal population encompassing D1- and D2-expressing medium spiny neurons and interneurons, a third study tested whether either phenotype could be attributed to a single, genetically defined cell type: D1 receptor-expressing medium spiny neurons (D1-MSNs). Using D1-Cre-dependent AAV deletion of IFT88 to ablate cilia specifically from NAcC D1-MSNs, this study found a complete loss of social approach preference and social novelty recognition, with discrimination indices indistinguishable from zero in both assays, alongside a distinct frontal cortical EEG signature, a steeper aperiodic spectral slope, reduced spectral entropy, and increased signal regularity, that was present even before social stimulus exposure, suggesting an altered baseline motivational or arousal state rather than a stimulus-locked encoding deficit. In marked contrast to the broader CaMKII manipulation, circadian locomotor rhythms and feeding rhythms were fully preserved in D1-MSN-specific knockouts, and sleep architecture was largely intact, with only a modest redistribution of wakefulness across the light phase and no change in total sleep amount or spectral power.Together, these findings demonstrate that primary cilia in the NAcC are structurally dynamic across the circadian cycle and functionally necessary for both circadian behavioral gain and social behavior, but that these two functions are mediated by dissociable neuronal populations: D1-MSN cilia are selectively required for social approach and recognition memory, while the circadian gain phenotype produced by broader ciliary ablation depends on a distinct, non-D1 population within the NAcC. This dissertation establishes primary cilia as a cell-type-specific subcellular mechanism through which a single neural circuit achieves functionally distinct behavioral outputs, offering a new framework for understanding how compartmentalized organelle signaling contributes to the flexibility and specificity of adult neural circuit function.