Doctoral thesis
Open access

The impact of sensory processing on social motivation in autism spectrum disorder animal models

Number of pages168
Imprimatur date2022-11-24
Defense date2022-11-10

Social deficits and dysfunctional sensory processes are cardinal behavioural deficits found in autism spectrum disorder (ASD) patients. Although these two behavioural phenotypes are often considered independent, it is possible that the aberrant integration of sensory stimuli during social interaction affects sociability. Recent studies identified the Ventral Tegmental Area (VTA) as a major regulator of social motivation (Gunaydin et al., 2014; Solié, Girard, et al., 2022). However, little is known about how brain areas that process sensory modalities control this important midbrain structure during specific aspects of social interaction. In order to contribute to this research field, I firstly dissected the involvement of isolated sensory modalities in driving mice sociability using a modified version of the three-chamber sociability test. I observed that mainly social odor cues elicit social behavior and increase the firing rate of dopaminergic (DA) neurons of the VTA during the three-chamber test (Contestabile et al., 2021). In a second instance, I investigated the projections to the VTA from a sensory processing brain region: the superior colliculus (SC, Solié, Contestabile, et al., 2022). Using in vitro patch clamp techniques coupled with optogenetic tools, I quantified the SC monosynaptic inputs onto GABAergic (42.31%) and DA (25.73%) neurons of the VTA. At the functional level, in vivo fiber photometry experiments revealed that SC-VTA neurons display social interaction anticipatory calcium activity, which correlates with orienting responses towards an unfamiliar conspecific or a moving object. Remarkably, I causally demonstrated the role of SC-VTA pathway modulating the activity of this pathway in vivo. I noticed that protracted phasic stimulation of SC-VTA pathway promoted head/body movements and decreased social orientation and interaction. On the other hand, inhibition of this pathway increased social interaction. After studying neuronal circuit function in wild-type animals, I focused my attention on investigating social dysfunctions in a ASD-related mouse model, Shank3 deficient mice. I designed new ways to study social behavior in mice, and I deeply investigated the effects of a postnatal (P5-6) downregulation of Shank3 in the VTA or nucleus accumbens (NAc). I demonstrated that VTA Shank3 downregulated animals presented an altered habituation to a non-familiar conspecific during conditioning and an accelerated extinction of social-induced conditioned responses (Bariselli, Contestabile, et al., 2018). On the other hand, the downregulation of Shank3 in the NAc provoked impaired sociability during the three-chamber test (Tzanoulinou, Musardo, Contestabile, et al., 2022). Interestingly and confirming these results, general Shank3 KO mice (Shank3-/- ) presented an altered sociability and a dysfunctional social interaction probably caused by a reduced social orienting response. Since Shank3 KO mice showed deficits in social orientation, I investigated SC-VTA pathway which, as previously demonstrated in wild-type animas, controls orienting responses. Calcium signals of SC neurons projecting to the VTA recorded through a miniscope revealed a dramatic decrease of correlated neurons and a lack of synchronicity during orienting responses in Shank3-/- mice. These dysfunctions at the neuronal level could explain social orienting and interaction deficits in this model of ASDs.

  • Social orientation
  • Autism Spectrum Disorder
  • Shank3
  • Sensory processing
  • Social motivation
  • Superior Colliculus
  • Ventral Tegmental Area
  • Nucleus accumbens
Citation (ISO format)
CONTESTABILE, Alessandro. The impact of sensory processing on social motivation in autism spectrum disorder animal models. 2022. doi: 10.13097/archive-ouverte/unige:165942
Main files (2)
Thesis - Thesis and Imprimatur

Technical informations

Creation12/05/2022 3:13:00 PM
First validation12/05/2022 3:13:00 PM
Update time03/16/2023 10:19:11 AM
Status update03/16/2023 10:19:08 AM
Last indexation09/18/2023 9:42:29 PM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack