Region-specific Foxp2 deletions in cortex, striatum or cerebellum cannot explain vocalization deficits observed in spontaneous global knockouts

FOXP2 has been identified as a gene related to speech in humans, based on rare mutations that yield significant impairments in speech at the level of both motor performance and language comprehension. Disruptions of the murine orthologue Foxp2 in mouse pups have been shown to interfere with production of ultrasonic vocalizations (USVs). However, it remains unclear which structures are responsible for these deficits. Here, we show that conditional knockout mice with selective Foxp2 deletions targeting the cerebral cortex, striatum or cerebellum, three key sites of motor control with robust neural gene expression, do not recapture the profile of pup USV deficits observed in mice with global disruptions of this gene. Moreover, we observed that global Foxp2 knockout pups show substantive reductions in USV production as well as an overproduction of short broadband noise “clicks”, which was not present in the brain region-specific knockouts. These data indicate that deficits of Foxp2 expression in the cortex, striatum or cerebellum cannot solely explain the disrupted vocalization behaviours in global Foxp2 knockouts. Our findings raise the possibility that the impact of Foxp2 disruption on USV is mediated at least in part by effects of this gene on the anatomical prerequisites for vocalizing

Characterizing maternal isolation-induced ultrasonic vocalizations in a gene-environment interaction rat model for autism.

Deficits in social communication and language development belong to the earliest diagnostic criteria of autism spectrum disorders. Of the many risk factors for autism spectrum disorder, the contactin-associated protein-like 2 gene, CNTNAP2, is thought to be important for language development. The present study used a rat model to investigate the potential compounding effects of autism spectrum disorder risk gene mutation and environmental challenges, including breeding conditions or maternal immune activation during pregnancy, on early vocal communication in the offspring. Maternal isolation-induced ultrasonic vocalizations from Cntnap2 wildtype and knockout rats at selected postnatal days were analyzed for their acoustic, temporal and syntax characteristics. Cntnap2 knockout pups from heterozygous breeding showed normal numbers and largely similar temporal structures of ultrasonic vocalizations to wildtype controls, whereas both parameters were affected in homozygously bred knockouts. Homozygous breeding further exacerbated altered pitch and transitioning between call types found in Cntnap2 knockout pups from heterozygous breeding. In contrast, the effect of maternal immune activation on the offspring\u27s vocal communication was confined to call type syntax, but left ultrasonic vocalization acoustic and temporal organization intact. Our results support the double-hit hypothesis of autism spectrum disorder risk gene-environment interactions and emphasize that complex features of vocal communication are a useful tool for identifying early autistic-like features in rodent models

Vocal Expression of Emotions in Mammals: Mechanisms of Production and Evidence

Emotions play a crucial role in an animal’s life because they facilitate responses to external or internal events of significance for the organism. In social species, one of the main functions of emotional expression is to regulate social interactions. There has recently been a surge of interest in animal emotions in several disciplines, ranging from neuroscience to evolutionary zoology. Because measurements of subjective emotional experiences are not possible in animals, researchers use neurophysiological, behavioural and cognitive indicators. However, good indicators, particularly of positive emotions, are still lacking. Vocalizations are linked to the inner state of the caller. The emotional state of the caller causes changes in the muscular tension and action of its vocal apparatus, which in turn, impacts on vocal parameters of vocalizations. By considering the mode of production of vocalizations, we can understand and predict how vocal parameters should change according to the arousal (intensity) or valence (positive/negative) of emotional states. In this paper, I review the existing literature on vocal correlates of emotions in mammals. Non-human mammals could serve as ideal models to study vocal expression of emotions, because, contrary to human speech, animal vocalizations are assumed to be largely free of control and therefore direct expressions of underlying emotions. Furthermore, a comparative approach between humans and other animals would give us a better understanding of how emotion expression evolved. Additionally, these non-invasive indicators could serve various disciplines that require animal emotions to be clearly identified, including psychopharmacology and animal welfare science

Region-specific Foxp2 deletions in cortex, striatum or cerebellum cannot explain vocalization deficits observed in spontaneous global knockouts

FOXP2 has been identified as a gene related to speech in humans, based on rare mutations that yield significant impairments in speech at the level of both motor performance and language comprehension. Disruptions of the murine orthologue Foxp2 in mouse pups have been shown to interfere with production of ultrasonic vocalizations (USVs). However, it remains unclear which structures are responsible for these deficits. Here, we show that conditional knockout mice with selective Foxp2 deletions targeting the cerebral cortex, striatum or cerebellum, three key sites of motor control with robust neural gene expression, do not recapture the profile of pup USV deficits observed in mice with global disruptions of this gene. Moreover, we observed that global Foxp2 knockout pups show substantive reductions in USV production as well as an overproduction of short broadband noise “

Recent Studies of Rodent Ultrasonic Vocalizations and Their Use in Experimental Models

This book includes articles written by over 80 specialists from many countries that demonstrate the biological functions of ultrasonic vocalizations and how they are used in studies of vocal expression of emotional states and in numerous animal models of neuropsychiatric diseases and disorders. Results of investigations of emissions of ultrasonic vocalizations are useful in studies of emotional disturbances, affective disorders, autism spectrum disorders, addiction, developmental abnormalities, and many other pathologies

Phenotypic And Electrophysiologic Characterization of a Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS) is the most common form of inherited mental retardation. It is caused by a mutation in the fragile X mental retardation (FMR1) gene on the X chromosome. Many children with FXS exhibit autistic behaviors and deficits in motor coordination including speech articulation deficits. The development of the FMR1 knockout (Fmr1 KO) mouse, in which the Fmr1 gene is inactivated, has provided an animal model that can be used to investigate underlying neuro-physiological mechanisms associated with FXS as well as to evaluate potential therapeutic treatments. In this study, quantitative behavioral assays were used, such as long term fluid licking observations, measurements of ultrasonic vocalizations (USV), and 3D tracking of whisker movements to test Fmr1 KO mice for behavioral deficits compared to their Wild type (WT) littermates. Electrophysiological techniques were employed to evaluate the functional properties of the neocortex. Pyramidal neurons in the neocortex of human FXS patients and Fmr1 KO mice are characterized by abnormally long, thin and numerous dendritic spines. Multiple electrode recordings were used to study how loss of Fmr1 expression affects several aspects of the neocortical network activities in Fmr1 KO mice. Single and multi unit spike activities and local field potentials (LFPs) were recorded in the whisker barrel cortex of awake mice. Baseline spike activity was significantly lower in cortical neurons of Fmr1 KO mice. Synchronous activity at the LFP was strongly reduced in Fmr1 KO mice. Relative power in the delta range frequency band of LFP activity was significantly reduced in the neocortex of Fmr1 KO mice. Furthermore, relative power in the beta frequency band was significantly higher in Fmr1 KO compared to WT mice. Our behavioral assays identified several phenotypical differences between Fmr1 KO and WT mice. Orofacial behavioral deficits in fluid licking and USV may be comparable to speech deficits in fragile X patients. Severely impaired dynamics of neocortical network activity may be causally linked to the cognitive and sensorimotor impairments associated with fragile X syndrome

Variability in echolocation call design of 26 Swiss bat species: consequences, limits and options for automated field identification with a synergetic pattern recognition approach

Pattern recognition algorithms offer a promising approach to recognizing bat species by their echolocation calls. Automated systems like synergetic classifiers may contribute significantly to operator-independent species identification in the field. However, it necessitates the assembling of an appropriate database of reference calls, a task far from trivial. We present data on species specific flexibility in call parameters of all Swiss bat species (except Nyctalus lasiopterus and Plecotus alpinus). The selection of "training-calls" for the classifier is crucial for species identification success. We discuss this in the context of echolocation call variability differing between species and its consequences for the implementation of an automated, species specific bat activity monitoring syste

Combined behavioral and neural investigations of pup retrieval

The ability to adequately adapt to a dramatically changing environment is crucial for an animal’s survival. When female mice give birth to their offspring, their environment changes drastically and they immediately need to care for the offspring, thereby ensuring the offspring’s wellbeing. Pups completely transform the environment around the mouse, triggering a number of new behaviors, as they provide a slew of new sensory inputs, including tactile and olfactory, but also auditory. Pups emit ultrasonic vocalizations (USVs) when isolated outside the nest, triggering retrieval behavior in mothers (MTs). After pups have returned to the nest and are cared for, the USV emission ceases. Interestingly, not only MTs but also virgin mice can perform pup retrieval, provided that they either have experience with pups in their home cage or are repeatedly exposed to pups in a pup retrieval task. Those two animal groups are referred to as experienced (EVs) and naive virgins (NVs). Studies have shown that excitatory neurons in the auditory cortex of MTs and EVs respond more strongly to pup calls over time. However, these studies have been performed under head-restrained unnatural conditions. Here, we provide a framework in which MTs, EVs and NVs retrieve pups in a semi-natural, freely behaving setting. During the experiment, they carry a head-mounted miniscope that allows for imaging neural activity in multiple neurons in the auditory cortex. The entire multisensory scenery is therefore accessible to mice, which was shown to impact auditory responses to pup calls. In our study, we show differences in behavioral performances of these three groups, with MTs displaying the most skilled and fine-tuned pup retrieval behavior, already highly effective during the final pregnancy stage. EVs show slightly reduced pup retrieval abilities, but superior to NVs, which retrieve pups effectively only after a few days. Additionally, we discovered that not only pups emitted USVs, but also adult mice vocalized. Intriguingly, they vocalized significantly more when pups were present in the behavioral arena, as compared to when they were alone. Clear pup call responsive neurons in the auditory cortex of all groups were scarce. Nevertheless, the overall neuronal population showed significant responses to pup calls at least in MTs, less so in EVs and least pronounced in NVs. Strikingly, other more global and behaviorally relevant events, such as pup retrievals and nest entries and exits, showed a distinct neural signature. Despite the scarcity of clear single cell responses to pup calls, the population of auditory cortex neurons carried information about pup call presence throughout all sessions in all groups, measured by a decoding analysis. This population code could be described as a sparse and dynamic code containing a few highly informative neurons, i.e. high weight neurons, that carried most of the decoding weight in a given session. This sparsity was most pronounced in MTs and least so in NVs. Besides, these high weight neurons were largely non-overlapping with high weight neurons for other non-pup call related event types. When relating single trial pup call decoding accuracies with the associated behavioral performance in a given trial, we could identify a significant relationship in EVs that was absent in MTs and NVs, suggesting that improved single trial decoding accuracies were linked to improved pup retrieval abilities. Altogether, this study shows how different pup exposure regimes can affect the learning of an essential offspring caring behavior and, that these different learning types differently enhance the neural representations of associated sensory cues

Sensory processing in autism spectrum disorders and Fragile X syndrome-From the clinic to animal models.

Brains are constantly flooded with sensory information that needs to be filtered at the pre-attentional level and integrated into endogenous activity in order to allow for detection of salient information and an appropriate behavioral response. People with Autism Spectrum Disorder (ASD) or Fragile X Syndrome (FXS) are often over- or under-reactive to stimulation, leading to a wide range of behavioral symptoms. This altered sensitivity may be caused by disrupted sensory processing, signal integration and/or gating, and is often being neglected. Here, we review translational experimental approaches that are used to investigate sensory processing in humans with ASD and FXS, and in relevant rodent models. This includes electroencephalographic measurement of event related potentials, neural oscillations and mismatch negativity, as well as habituation and pre-pulse inhibition of startle. We outline robust evidence of disrupted sensory processing in individuals with ASD and FXS, and in respective animal models, focusing on the auditory sensory domain. Animal models provide an excellent opportunity to examine common mechanisms of sensory pathophysiology in order to develop therapeutics

Models and Analysis of Vocal Emissions for Biomedical Applications

The MAVEBA Workshop proceedings, held on a biannual basis, collect the scientific papers presented both as oral and poster contributions, during the conference. The main subjects are: development of theoretical and mechanical models as an aid to the study of main phonatory dysfunctions, as well as the biomedical engineering methods for the analysis of voice signals and images, as a support to clinical diagnosis and classification of vocal pathologies