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How Do Adult Songbirds Learn New Sounds? Using Neuromodulators to Probe the Function of the Auditory Association Cortex
No full textThe 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.Neuroscience and BehaviorDoctor of Philosophy (Ph.D.
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SEX DIFFERENCES IN ESTRADIOL SIGNALING IN THE ZEBRA FINCH (TAENIOPYGIA GUTATTA) AUDITORY CORTEX
No full textAlthough several sex differences have been described in brain structure, function, and development, sex as a biological factor is underrepresented in neuroscience studies. In the mammalian brain, there are sex differences in the mechanism of rapid estradiol actions on neuronal physiology. In the songbird, the brain is a major source of estradiol production, and estradiol rapidly modulates auditory responsiveness through dynamic changes and an unknown receptor mechanism. I set out to determine if there are sex differences in rapid estradiol modulation of auditory cortical activity, as has been shown in other systems. I tested this hypothesis through three aims: 1) to determine whether the identity of interneurons in the auditory regions of the brain differs between the sexes,2) test whether acute, endogenous estradiol production is necessary for auditory responsiveness in both sexes and 3) test whether the membrane estrogen receptor GPER1 is necessary and sufficient to shape auditory-evoked activity in both sexes. I found that male and female estrogen-producing and estrogen-sensitive cells did not differ in coexpression with interneuron subtype markers in auditory cortical regions. I also determined that more regions of the male auditory cortex depend on acute, endogenous estrogen production for auditory-induced gene expression than that of females, indicating that males are more sensitive to acute-synthesis of estrogens than females. Finally, I found that narrow-spiking (NS) neurons in the caudomedial nidopallium are more associated with auditory responses than broad-spiking (BS) neurons in males whereas in females these cell types are similar. GPER1 is necessary for the full auditory responsiveness and coding but only in NS neurons of males, indicating an alternative receptor mechanism in females. In this dissertation, I describe a mechanism by which rapid estrogen modulates auditory responsiveness in males, but females have differences in the reliance on brain derived estradiol as well as receptors that mediate estradiol’s actions. This dissertation provides a framework to study sex differences using a mechanistic approach, and highlights the importance of sex as a biological variable in physiological studies even in brain regions with anatomical similarities.Neuroscience and BehaviorDoctor of Philosophy (Ph.D.
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A Precise Steroid-responsive Centrifugal Feedback Projection to the Accessory Olfactory Bulb
No full textThe accessory olfactory bulb (AOB) processes pheromonal signals which in turn drive social behaviors. Here we identify a tract of aromatase-expressing (arom+) fibers in the dorsal lateral olfactory tract (dLOT) which terminate in the granule cell layer (GCL) of the AOB. We utilized a retrograde tracer in aromatase reporter animals to delineate the source of these fibers. We show that these input fibers emerge almost exclusively from a contiguous population of arom+ neurons that spans the bed nucleus of the accessory olfactory tract (BAOT) and posterioventral subnucleus of the medial amygdala (MeApv). This population of neurons expresses the estrogen receptor alpha and contains more aromatase neurons in male mice than female mice. Thus, this population of feedback neurons can detect neuroendocrine changes and modulate the output of AOB projection neurons in a way that is sexually dimorphic and could influence every downstream target of the AOB.Master of Science (M.S.
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AN INVESTIGATION OF THE ROLE OF AMYGDALAR CIRCUITS IN THE PRODUCTION OF SOCIAL BEHAVIOR
No full textAdaptive social behaviors allow animals to survive, thrive, and successfully reproduce. These behaviors, including mating, parenting, affiliation, and aggression, can be stereotyped in response to specific stimuli but often display sex-specific, and interoceptive-dependent variations in their execution. A conserved set of brain regions collectively known as the social behavior network (SBN) interprets sensory information about social cues and generates an appropriate behavioral response. In this dissertation I present 5 chapters. Chapter 1 introduces historical research focusing on the neural circuits that drive social behavior and the potential impact of environmental factors on the activity of these circuits. Chapter 2 describes a new technique that uses magnetohydrodynamic-based tissue clearing to investigate intact neural circuits rapidly and efficiently. Chapter 3 uses this approach to interrogate the synaptic connections of a primary hub for social sensory integration, the medial amygdala (MeA). I focused on neurons in the MeA that express an enzyme that plays an important role in the development of sex-specific social behaviors: aromatase and identified the sources of synaptic input to this population. These inputs included regions involved in maintaining metabolic homeostasis, production of socio-sexual behaviors, fear/anxiety, parenting, and aggressive behaviors –suggesting an expanded view of social behavior production. I demonstrate that the brain regions involved in the production of social behavior have broad access to internal physiological and external environmental information. Chapter 4, demonstrates the impact of external environmental factors on the behaviors produced in response to a social stimulus, as well as, on the early sensory representation of these stimuli in the AOB. Predator presence influences an animals’ responses to conspecific stimuli even when not presented concurrently. This effect was observed in males and females and in response to male and female stimuli, demonstrating a generalizable impact of environmental conditions on the sensory representation of social stimuli. Chapter 5 summarizes these findings in a broader context, arguing for an expanded role for the SBN in integrating internal and external environmental information with sensory perceptions of social stimuli to produce appropriate behavioral response for not only a specific social stimulus, but a specific environmental context.Neuroscience and BehaviorDoctor of Philosophy (Ph.D.
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ACUTE ESTROGEN SYNTHESIS AND ACTION IN THE AUDITORY CORTEX OF DEVELOPING MALE ZEBRA FINCHES (TAENIOPYGIA GUTTATA)
No full textBirdsong, as with human speech, is learned during an age- and experience-dependent sensitive period early in life. Songbirds must first memorize their parents’ song during a sensory phase, then refine their own burgeoning vocalizations to match the auditory memory of their parents’ song during a sensorimotor phase. While the error-correction aspect of the sensorimotor phase of song learning is comparatively well understood, it is largely unknown how auditory memories are formed and how auditory processing may change across development to facilitate song memorization. The songbird caudomedial nidopallium (NCM) is a brain region that encodes complex communication signals like song and is rich in aromatase (enzyme necessary for converting precursor androgens to estrogens) and estrogen receptors. In adults, acute estrogen signaling enhances auditory encoding, suggesting that one role for 17β-estradiol (E2) in NCM during development may be to enhance auditory processing and facilitate auditory memorization. Moreover, in the hippocampus of rodents, birds, and nonhuman primates, local E2 acts to enhance post-training memory consolidation. As such, I set out to determine whether this role for E2 in auditory processing and memorization occurs within the auditory cortex of juvenile songbirds. I tested this hypothesis across several experiments: I first tested how local E2 administration in NCM modulated auditory processing in developing songbirds. Next, I explored how changes in developing neural architecture and aromatase expression are aligned with distinct song learning phases. I then tested how global and local aromatase inhibition following song learning sessions impacted motor production, vocal learning, and neurophysiology in developing songbirds. Finally, using a stimulus-specific adaptation paradigm, I determined whether findings in juvenile songbirds extended to adults. Specifically, I locally blocked local E2 synthesis in NCM immediately following song exposure and subsequently measured neural recognition of the exposed song. My results showed that sensory coding is substantially enhanced in the NCM of sensory-aged birds compared to song-producing (sensorimotor-aged) juvenile birds, and that E2 exerts an age- and hemisphere-dependent effect on modulation of auditory processing. I also found that cell density in NCM peaks in sensory-aged birds, and is overall higher in dorsal vs. ventral NCM, but that aromatase and parvalbumin expression remain high and constant across development; no hemispheric differences for cell density or expression were found. Further, I found that neither circulating nor locally-derived E2 are required for tutor song memorization in development and adulthood; however, estrogen synthesis blockade can impair song production in developing birds and can also transform the lasting neural representations of autogenous and tutor song in adulthood. Taken together, this dissertation provides new insights into the pleiotropic effects of rapid steroid signaling and synthesis within the auditory cortex of developing male songbirds with implications for communication processing and sensorimotor learning.Neuroscience and BehaviorDoctor of Philosophy (Ph.D.
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Multivesicular Release in Hair Cell Ribbon Synapses in the Bullfrog Amphibian Papilla
No full textHair cell ribbon synapses in vertebrate hearing organs are capable to encode neural signals with extraordinary precision and exhibit multiple hallmark features, including multivesicular release (MVR). Compared to single vesicle releases, MVRs introduce more neurotransmitter to the synaptic cleft, but the impact of extra neurotransmitter on postsynaptic receptor activation is poorly understood. In the first part of the study, we preformed non-stationary noise analysis and examined receptor activation in spontaneous excitatory postsynaptic currents (EPSCs) recorded in hair cell ribbon synapses in the bullfrog amphibian papilla. We found that MVR activates more receptors with higher open probability within the synapse. To account for EPSCs of >300 pA, we hypothesize that MVR of high quantal content could reach and activate distant receptors in neighboring release sites. Given the geometry of these release sites, we demonstrated this is not only feasible but also consistent with multiple observations on EPSC amplitude, kinetics, and charge. Another hallmark of hair cell ribbon synapses is its remarkable temporal precision, requiring intracellular Ca2+, the trigger for synaptic vesicle releases, to be controlled precisely. In the second part of the study, we examined Ca2+ extrusion in hair cells and its implication in phase-locking. We found that Ca2+ clearance from synaptic ribbons follows a double-exponential function, and the weight of the fast component, but not the two time constants, is significantly reduced during inhibition of Ca2+ extrusion. Consistently, we found synaptic phase-locking was also disrupted in the same treatments, suggesting involvement of active Ca2+ extrusion in phase-locking. The third hallmark of hair cell ribbon synapses is the tight coupling between Ca2+ channels and docked synaptic vesicles. In the third and last part of the study, we investigated synaptic vesicle priming and fusion by manipulating Ca2+ diffusion in hair cells with dialysis of exogenous Ca2+ buffer. We found that with strong Ca2+ buffer introduced into hair cells, the reduction in priming occurred earlier than the reduction in fusion. This result, while still in its preliminary form, suggests that synaptic vesicle priming and fusion are mediated by two distinct Ca2+ sensors, possibly two different Ca2+ binding domains in otoferlin.Molecular and Cellular BiologyDoctor of Philosophy (Ph.D.
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THE ANATOMICAL AND FUNCTIONAL CONTRIBUTIONS OF VASOPRESSIN-EXPRESSING NEURONS OF THE PARAVENTRICULAR NUCLEUS
No full textArginine Vasopressin is a peptide hormone critically situated at the intersection between two essential biological responses, stress and social behavior, governed mainly by a single biological substrate, the hypothalamus. The proposed research provides a unique avenue into how AVP plays a crucial role in each both from an anatomical and functional perspective. Chapter 1 introduces historical research focusing on the role of the paraventricular nucleus of the hypothalamus (PVN) and particularly AVP-expressing neurons in the PVN and their connection with homeostatic functioning, the stress response and social behavior. Chapter 2 investigates this region and cell type from an anatomical perspective, employing retrograde synaptic tracing techniques to investigate the connections between AVP-expressing neurons and their afferent inputs. What we discovered is neuronal populations directly connected to these cells stay relatively local in thalamic and hypothalamic areas, but these input regions are known to be involved in several functions including learning and memory, social behavior, pain, feeding and the stress response. We also learned that the inputs that stay within the PVN are mostly non-peptidergic as they displayed relatively little overlap with AVP, Oxytocin (OXT) or Corticotrophin Releasing hormone (CRH). In chapter 3 we focus on the functional role of AVP in the stress response, using the optical technique fiber photometry to measure the neural activity of the global PVN alongside AVP-expressing neurons during different stress paradigms. What we discovered was that while PVN showed consistent patterns of activity during stress and nonstress recovery phases, the AVP-expressing neurons were more nuanced, displaying context dependent activity patterns including strong reactivity when a conspecific was present. In the majority of cases the PVN and AVP signals showed strongly opposite signal patterns. Chapter 4 summarizes these findings in a broader context, offering insights into the results from the perspective of a foundation from which more complex work can be built.Doctor of Philosophy (Ph.D.)2025-05-1
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SEX SPECIFIC ELECTROPHYSIOLOGY OF AROMATASE NEURONS IN THE MEDIAL AMYGDALA
No full textThe medial amygdala (MeA) is a central node in the interwoven circuits that regulate social behavior based on pheromones. Aromatase-expressing (arom+) neurons in the MeA are key for the establishment and maintenance of sex differences. Here, we characterized the intrinsic electrophysiological properties of arom+ neurons and non-aromatase (arom-) neurons in the MeA of male and female mice. Most electrophysiological properties were similar for arom+ neurons in the MeA between sexes, but the relative refractory period was twice as large in female mice. We also show that the firing pattern and firing frequency is markedly different between arom+ and arom- neurons. The activity of MeA neurons could be modulated by estradiol, which reduced activity in arom+ neurons in males. The differences between arom+ and arom- neurons were observed in both sexes suggesting that aromatase expression delineates a neural population in the MeA with similar and unique electrophysiological properties.Master of Science (M.S.
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The Effect of TGF-Beta and FGF2 on Endothelial Cells and Breast to Brain Metastasis
Get PDFMetastasis, the spread of cancer cells from the initial, or primary, site to another region of the body, accounts for 90% of cancer-related mortalities1. Of the secondary sites of metastasis, the brain is one of the hardest to treat. Treatments are complicated because of the blood-brain barrier (BBB) and the sensitivity of the brain. Our team builds upon the seed and soil hypothesis which suggests that metastasis is not random and is driven by secondary tissue remodeling in response to signals from the primary tumor which “prepare” the tissue for the eventual arrival of cancer cells. This “preparation” of the secondary site is often referred to as a pre-metastatic niche. In the brain extracellular matrix (ECM), there are many proteins that play an important role in the pre-metastatic niche and are upregulated to support breast cancer metastasis. The focus of thisproject is on transforming growth factor beta (TGF-β) and fibroblast growth factor 2 (FGF2). In literature, TGF-β and FGF2 are two growth factors that are highly discussed as important upregulated proteins to support breast to brain metastasis2,3. FGF2 supports proliferation of the disseminated tumor cells at the secondary site through angiogenesis4. TGF-β promotes endothelial to mesenchymal transition (EndMT) in endothelial cells which decreases the tight junctions in the BBB and allows for tumor cells to more easily extravasate into the brain ECM5. Despite these two proteins being heavily researched, what is not discussed as much, is how they affect each other and how this could affect the pre-metastatic niche. In endothelial cells, when FGF2 binds to its receptor, it increases miRNA-20a expression which inhibits TGF-β receptors6. I hypothesize that their interactions are important to the pre-metastatic niche by altering the BBB. By designing and applying a brain specific microvascular niche assay, I can analyze how the timing of addition for these two growth factors affects the endothelial cells, astrocytes, and the corresponding niche. Understanding brain metastasis and how circulating tumor cells extravasate through the BBB can give rise to new therapies for treating brain metastases.Master of Science (M.S.
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Sensory Representation of Social Stimuli in Aromatase Expressing Neurons in the Medial Amygdala
No full textThe ability of animals to sense, interpret, and respond appropriately to social stimuli in their environment is essential for identifying and distinguishing between members of their own species. In mammals, social interactions both within and across species play a key role in determining if an animal will live to pass on its genes to the next generation or else be removed from the gene pool. The result of this selection pressure can be observed in specialized neural circuits that respond to social stimuli and orchestrate appropriate behavioral responses. This highly conserved network of brain structures is often referred to as the Social Behavior Network (SBN). The medial amygdala (MeA) is a central node in the SBN and has been shown to be involved in transforming information from olfactory sensory systems into social and defensive behavioral responses. Previous research has shown that individual neurons in the MeA of anesthetized mice respond selectively to different chemosensory social cues, a characteristic not observed in its upstream relay, the accessory olfactory bulb (AOB). However, the cause of this stimulus selectivity in the MeA is not yet understood. Here, I hypothesize that a subpopulation of neurons in the MeA that express the enzyme aromatase are involved in the sensory representation of social stimuli in awake, behaving animals. To test this hypothesis, I designed and built a novel behavioral apparatus that allows for discrete presentations of social stimuli in a highly controllable and reproducible environment. I then injected the adeno-associated virus (AAV) AAV-Syn-Flex-GCAMP6s into the MeA of Aromatase:Cre transgenic mice and implanted a fiber optic cannula slightly above the injection site. The combination of this transgenic mouse line and conditional AAV caused GCaMP6s expression to be exclusive to aromatase-expressing neurons. By coupling my novel behavioral apparatus to a fiber photometry system, I successfully recorded the moment-to-moment activity of aromatase neurons in the MeA of awake, behaving animals as they investigated various social stimuli. Aromatase neurons in the MeA of adult male mice respond strongly to conspecific social stimuli, including live adult mice, mouse pups, and mouse urine samples. Sniffing and investigative behaviors correlated strongly with increased GCaMP6s signal in aromatase neurons, reflecting increases in their neural activity. Interestingly, after repeated investigations of the same stimuli the activity of aromatase neurons gradually diminished. Presenting a novel stimulus following repeated investigations of a familiar stimulus reinstated some, but not all of the initial GCaMP6s signal. This points to the potential role that aromatase neurons may play in the habituation to social stimuli that are consistently present in their environment. Investigations of predator stimuli did not evoke significant responses from aromatase neurons, nor did investigations of non-social stimuli. These results demonstrate that aromatase expressing neurons in the MeA of awake, behaving animals encode the sensory representation of conspecific social stimuli, and their responses are highly selective to the type of stimulus presented.Master of Science (M.S.
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