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Author ORCID Identifier

https://orcid.org/0000-0003-3536-3736

Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Neuroscience and Behavior

Year Degree Awarded

2020

Month Degree Awarded

May

First Advisor

Luke Remage-Healey

Subject Categories

Behavioral Neurobiology | Comparative and Evolutionary Physiology | Endocrinology | Evolution | Laboratory and Basic Science Research | Molecular and Cellular Neuroscience | Systems Neuroscience

Abstract

The ability to associate sounds and outcomes is vital in the life history of many species. Animals constantly assess the soundscape for cues associated with threats, competitors, allies, mates or prey, and experience is crucial for those associations. For vocal learning species such as humans and songbirds, learning sounds (i.e. perception and association learning) is also the first step in the process of vocal learning. Auditory learning is thought to depend on high-order cortical brain structures, where sounds and meaning are bound. In songbirds, the caudomedial nidopallium (NCM) is part of the auditory association cortex and is known to be involved in sound learning and perception. During songbird development, NCM plays a role in song learning, but in adulthood, NCM’s role is less clear and a matter of controversy in the literature. Furthermore, NCM is a site of action of neuromodulators including neuroestradiol (E2) and dopamine (DA). E2 is known to be produced by NCM neurons that contain the enzyme aromatase, which converts testosterone into E2. E2 production is also known to increase in the NCM during social interactions, and exogenous E2 modulates neuronal firing, but its effects on auditory behavior have not been pinpointed. Effects of E2 within the mammalian and avian hippocampus had been previously reported to support spatial learning. My main goal in this dissertation was to clarify the role of NCM in adult zebra finches (Taeniopygia guttata). Towards this end, I developed experiments in which I manipulated and thus documented the effects of two neuromodulatory systems, E2 and DA. I first examined the role of E2 in auditory-dependent behavior. For this, I developed a novel operant conditioning task with social reinforcement. Using this task, I showed that inhibiting E2 production within NCM during learning impairs acquisition of auditory associations. However, after the learning process was completed, I found that E2 production and even NCM activity were no longer required for maintaining high auditory performance, suggesting that NCM does not play a role in memory retrieval or auditory discrimination in adults. These findings led me to develop the hypothesis that E2 in NCM modulates online associative learning signals. In mammals, plasticity in virtually all learning-related brain regions is dependent on dopamine (DA) regulation and E2-DA interactions have been reported in several of these regions. Much is known about DA signaling in brain areas involved in decision-making and reinforcement learning. I here review the literature on motor and, especially, sensory cortical regions and provide a comprehensive review of the current knowledge of DA’s roles in cortical regions involved in sensory and motor learning, paying especial attention to non-mammalian vertebrates. I found that this literature is surprisingly limited in mammals, and often non-existent in non-mammalian vertebrates. Then, I hypothesized that E2 could be operating on dopaminergic (DAergic) signaling in NCM, in which D1 receptor (D1R) mRNA had been reported. Since there were no data on the anatomical and functional effects of these receptors, I investigated whether D1R protein could be detected and D1R-mediated signaling modulated synaptic plasticity in NCM. Specifically, I found that D1R protein is prevalent in NCM neurons, especially in aromatase-, GABA-, and parvalbumin-positive neurons. Activating D1R in vitro reduced the amplitude of spontaneous GABAergic and glutamatergic currents and increased the frequency of the latter. Similarly, activating D1R in vivo reduced firing of putative-inhibitory interneurons, but increased firing of putative-excitatory projection neurons. Finally, I showed that D1R activation disrupted stimulus-specific adaptation of NCM neurons, a phenomenon reflective of active auditory memory formation. In conclusion, this dissertation advances the literature by providing direct evidence that E2 production within the auditory cortex affects sensory learning, potentially by tapping into the DAergic system, which itself modulates plasticity mechanisms associated with learning and memory. I propose that these findings could apply to other vertebrates that contain aromatase and DA receptors in their auditory cortex, including humans.

Available for download on Saturday, May 08, 2021

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