Familiarity with social sounds alters c-Fos expression in auditory cortex and interacts with estradiol in locus coeruleus.

When a social sound category initially gains behavioral significance to an animal, plasticity events presumably enhance the ability to recognize that sound category in the future. In the context of learning natural social stimuli, neuromodulators such as norepinephrine and estrogen have been associated with experience-dependent plasticity and processing of newly salient social cues, yet continued plasticity once stimuli are familiar could disrupt the stability of sensorineural representations. Here we employed a maternal mouse model of natural sensory cortical plasticity for infant vocalizations to ask whether the engagement of the noradrenergic locus coeruleus (LC) by the playback of pup-calls is affected by either prior experience with the sounds or estrogen availability, using a well-studied cellular activity and plasticity marker, the immediate early gene c-Fos. We counted call-induced c-Fos immunoreactive (c-Fos-IR) cells in both LC and physiologically validated fields within the auditory cortex (AC) of estradiol or blank-implanted virgin female mice with either 0 or 5-days prior experience caring for vocalizing pups. Estradiol and pup experience interacted both in the induction of c-Fos-IR in the LC, as well as in behavioral measures of locomotion during playback, consistent with the neuromodulatory center's activity being an online reflection of both hormonal and experience-dependent influences on arousal. Throughout core AC, as well as in a high frequency sub-region of AC and in secondary AC, a main effect of pup experience was to reduce call-induced c-Fos-IR, irrespective of estradiol availability. This is consistent with the hypothesis that sound familiarity leads to less c-Fos-mediated plasticity, and less disrupted sensory representations of a meaningful call category. Taken together, our data support the view that any coupling between these sensory and neuromodulatory areas is situationally dependent, and their engagement depends differentially on both internal state factors like hormones and external state factors like prior experience.

Contrast Enhancement without Transient Map Expansion for Species-Specific Vocalizations in Core Auditory Cortex during Learning.

Tonotopic map plasticity in the adult auditory cortex (AC) is a well established and oft-cited measure of auditory associative learning in classical conditioning paradigms. However, its necessity as an enduring memory trace has been debated, especially given a recent finding that the areal expansion of core AC tuned to a newly relevant frequency range may arise only transiently to support auditory learning. This has been reinforced by an ethological paradigm showing that map expansion is not observed for ultrasonic vocalizations (USVs) or for ultrasound frequencies in postweaning dams for whom USVs emitted by pups acquire behavioral relevance. However, whether transient expansion occurs during maternal experience is not known, and could help to reveal the generality of cortical map expansion as a correlate for auditory learning. We thus mapped the auditory cortices of maternal mice at postnatal time points surrounding the peak in pup USV emission, but found no evidence of frequency map expansion for the behaviorally relevant high ultrasound range in AC. Instead, regions tuned to low frequencies outside of the ultrasound range show progressively greater suppression of activity in response to the playback of ultrasounds or pup USVs for maternally experienced animals assessed at their pups' postnatal day 9 (P9) to P10, or postweaning. This provides new evidence for a lateral-band suppression mechanism elicited by behaviorally meaningful USVs, likely enhancing their population-level signal-to-noise ratio. These results demonstrate that tonotopic map enlargement has limits as a construct for conceptualizing how experience leaves neural memory traces within sensory cortex in the context of ethological auditory learning.

An Overrepresentation of High Frequencies in the Mouse Inferior Colliculus Supports the Processing of Ultrasonic Vocalizations.

Mice are of paramount importance in biomedical research and their vocalizations are a subject of interest for researchers across a wide range of health-related disciplines due to their increasingly important value as a phenotyping tool in models of neural, speech and language disorders. However, the mechanisms underlying the auditory processing of vocalizations in mice are not well understood. The mouse audiogram shows a peak in sensitivity at frequencies between 15-25 kHz, but weaker sensitivity for the higher ultrasonic frequencies at which they typically vocalize. To investigate the auditory processing of vocalizations in mice, we measured evoked potential, single-unit, and multi-unit responses to tones and vocalizations at three different stages along the auditory pathway: the auditory nerve and the cochlear nucleus in the periphery, and the inferior colliculus in the midbrain. Auditory brainstem response measurements suggested stronger responses in the midbrain relative to the periphery for frequencies higher than 32 kHz. This result was confirmed by single- and multi-unit recordings showing that high ultrasonic frequency tones and vocalizations elicited responses from only a small fraction of cells in the periphery, while a much larger fraction of cells responded in the inferior colliculus. These results suggest that the processing of communication calls in mice is supported by a specialization of the auditory system for high frequencies that emerges at central stations of the auditory pathway.

Norepinephrine is necessary for experience-dependent plasticity in the developing mouse auditory cortex.

Critical periods are developmental windows during which the stimuli an animal encounters can reshape response properties in the affected system to a profound degree. Despite this window's importance, the neural mechanisms that regulate it are not completely understood. Pioneering studies in visual cortex initially indicated that norepinephrine (NE) permits ocular dominance column plasticity during the critical period, but later research has suggested otherwise. More recent work implicating NE in experience-dependent plasticity in the adult auditory cortex led us to re-examine the role of NE in critical period plasticity. Here, we exposed dopamine ß-hydroxylase knock-out (Dbh(-/-)) mice, which lack NE completely from birth, to a biased acoustic environment during the auditory cortical critical period. This manipulation led to a redistribution of best frequencies (BFs) across auditory cortex in our control mice, consistent with prior work. By contrast, Dbh(-/-) mice failed to exhibit the expected redistribution of BFs, even though NE-deficient and NE-competent mice showed comparable auditory cortical organization when reared in a quiet colony environment. These data suggest that while intrinsic tonotopic patterning of auditory cortical circuitry occurs independently from NE, NE is required for critical period plasticity in auditory cortex.

Behavioral relevance helps untangle natural vocal categories in a specific subset of core auditory cortical pyramidal neurons.

Sound categorization is essential for auditory behaviors like acoustic communication, but its genesis within the auditory pathway is not well understood-especially for learned natural categories like vocalizations, which often share overlapping acoustic features that must be distinguished (e.g., speech). We use electrophysiological mapping and single-unit recordings in mice to investigate how representations of natural vocal categories within core auditory cortex are modulated when one category acquires enhanced behavioral relevance. Taking advantage of a maternal mouse model of acoustic communication, we found no long-term auditory cortical map expansion to represent a behaviorally relevant pup vocalization category-contrary to expectations from the cortical plasticity literature on conditioning with pure tones. Instead, we observed plasticity that improved the separation between acoustically similar pup and adult vocalization categories among a physiologically defined subset of late-onset, putative pyramidal neurons, but not among putative interneurons. Additionally, a larger proportion of these putative pyramidal neurons in maternal animals compared with nonmaternal animals responded to the individual pup call exemplars having combinations of acoustic features most typical of that category. Together, these data suggest that higher-order representations of acoustic categories arise from a subset of core auditory cortical pyramidal neurons that become biased toward the combination of acoustic features statistically predictive of membership to a behaviorally relevant sound category.

Adult plasticity in the subcortical auditory pathway of the maternal mouse.

Subcortical auditory nuclei were traditionally viewed as non-plastic in adulthood so that acoustic information could be stably conveyed to higher auditory areas. Studies in a variety of species, including humans, now suggest that prolonged acoustic training can drive long-lasting brainstem plasticity. The neurobiological mechanisms for such changes are not well understood in natural behavioral contexts due to a relative dearth of in vivo animal models in which to study this. Here, we demonstrate in a mouse model that a natural life experience with increased demands on the auditory system - motherhood - is associated with improved temporal processing in the subcortical auditory pathway. We measured the auditory brainstem response to test whether mothers and pup-naïve virgin mice differed in temporal responses to both broadband and tone stimuli, including ultrasonic frequencies found in mouse pup vocalizations. Mothers had shorter latencies for early ABR peaks, indicating plasticity in the auditory nerve and the cochlear nucleus. Shorter interpeak latency between waves IV and V also suggest plasticity in the inferior colliculus. Hormone manipulations revealed that these cannot be explained solely by estrogen levels experienced during pregnancy and parturition in mothers. In contrast, we found that pup-care experience, independent of pregnancy and parturition, contributes to shortening auditory brainstem response latencies. These results suggest that acoustic experience in the maternal context imparts plasticity on early auditory processing that lasts beyond pup weaning. In addition to establishing an animal model for exploring adult auditory brainstem plasticity in a neuroethological context, our results have broader implications for models of perceptual, behavioral and neural changes that arise during maternity, where subcortical sensorineural plasticity has not previously been considered.

Diet choice, cortisol reactivity, and emotional feeding in socially housed rhesus monkeys.

Chronic psychosocial stress produces an array of adverse health consequences that are highly comorbid, including emotional eating, affective disorders, and metabolic syndrome. The consumption of high caloric diets (HCDs) is thought to provide comfort in the face of unrelenting psychosocial stress. Using social subordination in female rhesus monkeys as a model of continual exposure to daily stressors in women, we tested the hypothesis that subordinate females would consume significantly more calories from a HCD compared to dominant females, and this pattern of food intake would be associated with reduced cortisol release and reduced frequency of anxiety-like behaviors. Food intake, parameters of cortisol secretion, and socio-emotional behavior were assessed for 3 weeks during a no choice phase when only a low caloric diet (LCD) was available and during a choice condition when both a LCD and HCD were available. While all animals preferred the HCD, subordinate females consumed significantly more of the HCD than did dominant females. A flattening of the diurnal cortisol rhythm and a greater increase in serum cortisol to an acute social separation occurred during the diet choice condition in all females. Furthermore, the rate of anxiety-like behavior progressively declined during the 3-week choice condition in subordinate but not dominant females. These data provide support for the hypothesis that daily exposure to psychosocial stress increases consumption of calorically dense foods. Furthermore, consumption of HCDs may be a metabolic stressor that synergizes with the psychosocial stress of subordination to further increase the consumption of these diets.

Genetic, epigenetic and environmental impact on sex differences in social behavior.

The field of behavioral neuroendocrinology has generated thousands of studies that indicate differences in brain structure and reactivity to gonadal steroids that produce sex-specific patterns of social behavior. However, rapidly emerging evidence shows that genetic polymorphisms and resulting differences in the expression of neuroactive peptides and receptors as well as early-life experience and epigenetic changes are important modifiers of social behavior. Furthermore, due to its inherent complexity, the neurochemical mechanisms underlying sex differences in social behavior are usually studied in a tightly regulated laboratory setting rather than in complex environments. Importantly, specific hormones may elicit a range of different behaviors depending on the cues present in these environments. For example, individuals exposed to a psychosocial stressor may respond differently to the effects of a gonadal steroid than those not exposed to chronic stress. The objective of this review is not to re-examine the activational effects of hormones on sex differences in social behavior but rather to consider how genetic and environmental factors modify the effects of hormones on behavior. We will focus on estrogen and its receptors but consideration is also given to the role of androgens. Furthermore, we have limited our discussions to the importance of oxytocin and vasopressin as targets of gonadal steroids and how these effects are modified by genetic and experiential situations. Taken together, the data clearly underscore the need to expand research initiatives to consider gene-environment interactions for better understanding of the neurobiology of sex differences in social behavior.