Recurrent impairments in visual perception and place avoidance across autism models are causally linked in the haploinsufficiency model of intellectual disabilitySetd5

Abstract

Autism spectrum disorders (ASD) include a range of neurodevelopmental conditions characterised by social and communication difficulties, often co-occurring with sensory processing abnormalities. The neural origins of these impairments are thought to reside in cortical circuits. Here we demonstrate that a subcortical node required to initiate efficient and timely responses to visual threats is disrupted across genetic models of ASD. Although mutant animals can detect visual threat stimuli, they require longer to evaluate them and respond with less vigour than their wild-type siblings. These delays in perceptual judgement are linked to reduced place-aversion to visual threats. Visual responses and other motor properties remain unaffected, overall indicating cognitive rather than sensory or motor impairments. Focusing on one of the models (Setd5), we show that these behavioural deficits are recapitulated following optogenetic activation of excitatory deep medial collicular neurons, known to initiate threat responses by exciting the dorsal periaqueductal gray (dPAG). Consistently, ex vivo patch-clamp recordings of Setd5 mutant dPAG neurons revealed a stark hypoexcitability phenotype mediated by misregulation of a voltage-gated potassium channel. Our results show that the timing of perceptual decision-making is regulated via intrinsic excitability, mechanistically dissecting a cognitive disorder through an instinctive behaviour.

The neural basis of defensive behaviour evolution inPeromyscusmice

“…Third, the properties of excitatory neurons or their circuit connections may be different in the two species. For example, the intrinsic excitability of neurons could differ (BURNETT et al 2022), or be held at different levels through long-range inhibitory projections from other brain regions (TOVOTE et al 2016;FADOK et al 2017;FRATZL et al 2021;SALAY AND HUBERMAN 2021;LI et al 2022). Alternatively, the role of the dPAG in the circuit could be reversed, for example, through changes in local wiring or in longrange projections, such that exposure to the same threat triggers distinct neural computations and defensive responses.…”

A new family of statistical tests for neuronal spiking and autocorrelated timeseries data

“…It is particularly well suited to detecting whether cells are driven by optogenetic stimulation in opto-tagging experiments (Dudok et al, 2021; Schneider et al, 2023; Spyropoulos et al, 2023; Szadzinska et al, 2021). It has also been used to detect response onset latencies (Oude Lohuis et al, 2022), and to quantify somatosensory and visual stimulus responsiveness (Burnett et al, 2023; Montijn et al, 2023; Qin et al, 2023; Ziegler et al, 2023). While the ZETA-test works well for spiking data, an important shortcoming is that it can only be applied to point events, such as spike times.…”