Wöhr, M. | bioRxiv Science

bioRxiv2024

Altered Socio-Affective Communication and Amygdala Development in mice with Protocadherin10-deficient Interneurons

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental conditions associated with deficits in social interaction and communication, together with repetitive behaviors. The cell adhesion molecule Protocadherin10 (Pcdh10) has been implicated in the etiology of ASD. Pcdh10 is expressed in the nervous system during embryonic and early postnatal development and has been linked to neural circuit formation. Here, we show strong expression of Pcdh10 in the ganglionic eminences and in the basolateral complex of the amygdala at mid and late embryonic stages, respectively. Both inhibitory and excitatory neurons expressed Pcdh10 in the basolateral complex at perinatal stages and genes linked to vocalization behavior were enriched in Pcdh10- expressing neurons in adult mice. To further investigate the involvement of Pcdh10 in neurodevelopment with relevance to ASD, and to assess the functional and behavioral consequences of loss of Pcdh10 in basolateral amygdala interneurons, we combined a ubiquitous and a conditional Pcdh10 knockout mouse model. Conditional knockout of Pcdh10 reduced the number of interneurons in the basolateral complex. Both models exhibited altered developmental trajectories of socio-affective communication through isolation-induced ultrasonic vocalizations in neonatal pups, characterized by increased emission rates in heterozygous pups. Furthermore, acoustic call features were affected and heterozygous conditional knockout pups emitted calls characterized by reduced peak frequencies but increased frequency modulation. Additionally, we identified distinct clusters of call subtypes with specific developmental trajectories, suggesting the vocalization repertoire is extensive and dynamic during early life. The nuanced alterations in socio-affective communication at the level of call emission rates, acoustic call features, and clustering of call subtypes were primarily seen in heterozygous pups of the conditional knockout and less prominent in the ubiquitous Pcdh10 knockout, suggesting that changes in anxiety levels associated with Gsh2-lineage interneurons might drive the observed behavioral effects. Together, this demonstrates that loss of Pcdh10 specifically in interneurons contributes to behavioral alterations in socio-affective communication with relevance to ASD.

neuroscience↗

bioRxiv2022

Correlations across timing cues in natural vocalizations predict judging synthetic sound burst durations.

It is well known that animals rely on multiple sources of information in order to successfully identify sounds in natural environments, to make decisions that are optimal for their survival. For example, rats use duration and pitch cues to respond appropriately to prosocial and distress vocalizations (Saito et al., 2019). Vocalization duration cues are known to co-vary with other temporal cues (Khatami et al., 2018), yet little is known about whether animals rely upon such co-variations to successfully discriminate sounds. In the current study, we find natural alarm vocalizations in rats have onset and offset slopes that are correlated with their duration. Accordingly, vocalizations with faster onset slopes are more likely to have shorter durations. Given that vocalization slopes begin and end within milliseconds, they could provide rapid perceptual cues for predicting and discriminating vocalization duration. To examine this possibility, we train rodents to discriminate duration differences in sequences of synthetic vocalizations and examine how artificially changing the slope impacts duration judgments. We find animals are biased to misjudge a range of synthetic vocalizations as being shorter in duration when the onset and offset slopes are artificially fast. Moreover, this bias is reduced when rats are exposed to multiple synthetic vocalization bursts. The observed perceptual bias is accurately captured by a Bayesian decision-theoretic model that utilizes the empirical joint distribution of duration and onset slopes in natural vocalizations as a prior during duration judgements of synthetic vocalizations. This model also explains why the bias is reduced when more evidence is accumulated across multiple bursts, reducing the priors influence. These results support the theory that animals are sensitive to fine-grained statistical co-variations in auditory timing cues and integrate this information optimally with incoming sensory evidence to guide their decisions.

animal behavior and cognition↗