The Molecular Correlates of Auditory Cortical Plasticity from Social Auditory Experience Open Access

Moreno, Amielle (Fall 2019)

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While infant cues are often assumed to innately possess behavioral significance to elicit maternal response in mothers, recent research highlights how cue processing is enhanced through plasticity events in the sensory cortex. Evidence from mice suggests experience caring for pups induces plasticity in the auditory cortex (AC), which improves pup-vocalization detection and processing. Neuromodulators such as norepinephrine and estrogens are associated with experience-dependent plasticity and social sound processing. Differences in sensorineural representations of novel versus familiar vocalizations and how experience encourages this transition, are still being explored at the molecular level. Here, I used ovariectomized and estradiol (E2) or blank implanted virgin female mice to delve into the behavior and AC molecular changes induced by pup-calls when novel, first paired with pup-caring, or familiar through experience. I addressed whether pup-calls engaged the AC and the noradrenergic locus coeruleus (LC) based on the subject’s prior pup experience or E2 availability, using the cellular activity and plasticity marker, the immediate early gene c-Fos. Transcription of the memory-associated gene brain derived neurotrophic factor’s (Bdnf’s) was altered by the playback of pup-calls depending on social context. While E2 influenced the rate of maternal behavior at initial exposure, it did not influence the number of neurons expressing c-Fos (c-Fos-IR) in the AC or total AC Bdnf mRNA transcription. Social pup experience had a main effect decreasing AC c-Fos-IR in pup-familiar subjects, perhaps maintaining auditory representations of familiar vocalizations. Initial pup experience increased Bdnf mRNA transcription throughout the AC in an isoform specific manner. In the LC, E2 and pup experience interacted, increasing c-Fos-IR and locomotion during playback, consistent with the neuromodulatory center’s activity reflecting both hormonal and experience-dependent influences on arousal. Experience and not hormones affected molecular response to social sounds in the AC. My data suggests that the engagement of sensory and neuromodulatory areas is situationally dependent and depends differentially on both internal physiology like hormones and the long lasting changes left by prior experience. This research expands our understanding of the molecular response to salient social sounds and is the first time Bdnf is associated with processing social stimuli in the AC.

Table of Contents

1.   Chapter 1: Introduction to Maternal Auditory Processing and Auditory Cortex Plasticity  1

1.1  Familiar Versus Novel Sound Processing. 6

1.2  The Maternal Experience. 10

1.2.1   The Maternal Physiological State.. 13

1.2.2   The Neural Circuitry of Motherhood.. 18

1.2.3   Behavioral Response to Infant Cues.. 24

1.3  Plasticity of the Auditory Cortex. 33

1.4  Advantages of the Mouse Maternal Model for Studying Auditory Plasticity. 38

1.5  Sensory Cortical Plasticity for Infant Vocalizations. 43

1.6  Molecular Mechanisms of Learning and Memory in the Auditory Cortex. 48

1.6.1   RNA Translation and Localization.. 49

1.6.2   Immediate Early Genes.. 51

1.6.3   Protein Synthesis. 55

1.6.4   Neurotrophic Factors.. 58

1.6.5   Epigenetic Regulation.. 60

1.6.6   Estrogen in Auditory Processing.. 64

1.6.7   Norepinephrine in Auditory Processing.. 72

1.7  Significance of My Research. 75

2   Chapter 2: Familiarity with Social Sounds Alters c-Fos Expression in Auditory Cortex and Interacts with Estrogen in Locus Coeruleus. 77

2.2  Abstract. 79

2.3  Introduction. 80

2.4  Materials and Methods. 83

2.4.1   Animals.. 84

2.4.2   Hormonal Manipulation.. 85

2.4.3   Pup Experience Manipulation.. 86

2.4.4   Stimulus Presentation.. 87

2.4.5   Immunohistochemistry for Tyrosine Hydroxylase and c-Fos.. 88

2.4.6   Electrophysiological Mapping.. 90

2.4.7   Quantification.. 94

2.4.8   Behavior Analyses.. 97

2.4.9   Statistical Analysis.. 98

2.5  Results. 101

2.5.1   Differential impact of experience and hormone on pup-call-induced LC and AC c-Fos-IR... 103

2.5.2   GLMM Analysis Confirms Differential Effects of Experience and Hormone on LC and AC.. 108

2.5.3   Differential effects of experience and hormone on behavioral response to pup-call playback.. 113

2.6  Discussion.. 115

2.6.1   LC processing of infant cues.. 116

2.6.2   Experience-dependent changes in AC.. 119

2.6.3   Correlation among brain regions. 122

2.7  Conclusion. 124

3   Bdnf Transcription in Response to Infant Auditory Experience in the Female Mouse Auditory Cortex  125

3.1  Abstract. 126

3.2  Highlights. 128

3.3  Introduction. 128

3.4  Methods. 133

3.4.1   Animal Use.. 133

3.4.2   Hormonal Manipulations.. 133

3.4.3   Auditory Stimulus.. 135

3.4.4   Habituation.. 136

3.4.5   Sound Stimuli Playback and Context. 136

3.4.6   Behavior Assessment. 138

3.4.7   Tissue Collection and Processing.. 142

3.4.8   Statistical Analysis.. 144

3.5  Results. 146

3.5.1   Behavior.. 147

3.5.2   Bdnf Expression.. 153

3.6  Discussion.. 158

3.6.1   Auditory Plasticity Induced by BDNF.. 159

3.6.2   Effect of Estrogens on Auditory Processing.. 161

3.6.3   Linking Behavior Findings to Behavior and Circuitry.. 165

3.6.4   Ventral Hippocampus and Social Memory.. 166

3.7  Conclusion. 168

4   General Discussion and Future Directions:. 170

4.1  Memory in the Sensory Cortex: How does the research here broaden the field?. 171

4.2  Sparse Encoding of AC Stimuli and Memories. 180

4.3  The Immediate Molecular Changes with Initial Pup Experience. 185

4.4  Long-Term Changes of Bdnf Transcription: Epigenetic Changes. 189

4.5  Applications: Female Post-Menopausal Memory Deficits. 194

5   Appendix. 198

5.1  Advice for Future Researchers. 198

5.1.1   qPCR Housekeeping Genes.. 198

Figure Table of Contents

Figure 1‑1 Sound in a Naïve versus Familiar Context. 5

Figure 1‑2 Maternal Circuitry Schematic. 18

Figure 2‑1 Animal experimental conditions and timelines. 85

Figure 2‑2 TH/c-Fos immunohistochemistry, quantification and methodological steps for the cortical c-Fos-IR neuron counting in the AC. 93

Figure 2‑3 LC c-Fos-IR expression varies between stimuli, with pup-call playback producing differences in expression dependent on pup experience and hormone treatment. 102

Figure 2‑4 C-Fos-IR expression in response to pup-call playback varies within layers V/VI of the Auditory Cortex, and depends on pup experience and hormone treatment. 105

Figure 2‑5 Correlation between brain regions. 107

Figure 2‑6 GLMM analysis verifies majority of ANOVA findings. 110

Figure 2‑7 Behavior during 10 minute playback. 113

Figure 3‑1 Hormonal treatment and pup-vocalization exposure, with or without pup experience. 134

Figure 3‑2 The presence of pups and E2 affected the behavior displayed by subjects. 148

Figure 3‑3 There were specific maternal behavior differences between PxE2 and PxBk subjects (n =43) during the first 45 min of pup experience. 150

Figure 3‑4 Latency to Retrieve All 3 Pups Per Retrieval Trial. 152

Figure 3‑5 No effect of 2x2 conditions on Bdnf mRNA levels in AC or VH.. 156

Figure 3‑6 When subject hormone condition was collapsed within experience group, a transcript specific effect was found in the AC. 157

Figure 4‑1 Estrogen-Sensitive Molecular Pathways. 186

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