Neurodevelopmental disorders (NDDs) manifest during early childhood and have
deleterious effects on development, leading to lifelong conditions affecting attention,
cognition, motor abilities, communication and social domains, often alongside
physical ailments such as gastrointestinal issues and epilepsy. With a worldwide
reported prevalence of around 1%, NDDs either directly or indirectly affect a large
proportion of the population.
Rodent models of monogenic forms of NDD provide a means for unravelling
mechanisms and developing targeted therapeutics for debilitating aspects of NDDs.
However, modelling social and emotional facets of NDDs such as autism spectrum
disorder (ASD) remains a challenge. The rat makes a good model species for the
social and emotional facets of NDDs as rats are highly social, experience a sensitive
period of social and emotional development, and exhibit a behavioural repertoire
that is flexible and sensitive to context. The aim of this thesis was to develop a welfarefriendly,
robust assay of socio-emotional phenotype in rat models of NDD.
Play behaviour appears to be a critical aspect of the developmental process in many
highly social species, including both rats and humans. Children develop social skills
and emotional regulation through playful peer interactions. For individuals with
NDDs, including ASD, social challenges often emerge from a very young age and
impair playful interactions with peers. In juvenile rats, play experience is crucial for
social, emotional, and sensorimotor development. Therefore, disruptions in social
and emotional function in rat models of NDD may be observable in juvenile play
behaviour. While juvenile play has been well-characterised in wild-type (WT) rats, it
has not yet been thoroughly investigated in rat models of NDDs.
Some aspects of rat social play can be mimicked during playful interactions with
humans in which the rat is ‘pinned’ by gently flipping onto the back and tickling using
fine-scale tickle movements of the fingers on the ventral surface. During tickle, rats
produce ultrasonic vocalisations (USVs) indicative of a positive affective state which
can be used as a proxy measure of tickle responsiveness. Number of successful pin
and tickle events per tickle session was used as a behavioural measure of
responsiveness as rats were only pinned if they engaged with the experimenter’s
hand. As an assay of social responsiveness, I investigated behavioural and USV
responses to tickle in three different rat models of NDD associated with ASD: Fragile
X Syndrome, SYGNAP1 haploinsufficiency, and CDKL5 Deficiency Disorder.
Tickle response varied between models of NDD. Tickle response in the Fragile X
Syndrome model (Fmr1-/y) was very similar to WT littermate controls, with high rates
of both USVs and pin/tickle events during tickle sessions in both genotypes. In
contrast, for models of SYNGAP1 haploinsufficiency (Syngap1+/DGAP and Syngap1+/-),
the tickle protocol was almost impossible to carry out due to climbing behaviour by
the SYNGAP1 model rats, and very few USVs were emitted during tickle sessions.
WTs were receptive to tickle and emitted USVs at high rates during tickle sessions. In
the CDKL5 Deficiency Disorder model (Cdkl5-/y), both WT and Cdkl5-/y rats emitted
very few USVs, and behavioural and USV responses were more variable in Cdkl5-/y
than in WTs. Because the tickle paradigm involves habituation to a novel environment
and experimenter handling, reduced tickle responsiveness may not be indicative of
playfulness or social responsiveness in general but could instead reflect an
impairment in habituation, since tickle response is highly sensitive to emotional state.
To address this possibility, I developed a novel paradigm which allows all
experimental manipulations and observations to be carried out in a spatially complex
home environment, minimising handling and exposure to novel experimental
environments. Play behaviour was observed for the first 2 hours of the dark phase
over a 4-week period following three experimental conditions: 24hr isolation, a
negative control condition, and an undisturbed condition.
In WT rats, brief isolation reliably elicits a transient increase in play, termed the
rebound effect. As isolation is stressful, the rebound effect is thought to reflect an
immediate benefit of play as a behavioural stress-reduction mechanism. I
hypothesised that Cdkl5-/y rats may not use this behavioural strategy to reduce stress
following isolation, or alternatively, that they would not find social isolation as stressful
as their WT littermates. I predicted that Cdkl5-/y pairs would show less of a play
rebound effect than their WT littermates.
Unexpectedly, my results suggest that both WT and Cdkl5-/y pairs exhibit the
expected rebound effect in response to brief (24hr) isolation. Further characterisation
of play behaviour revealed that pairs of Cdkl5-/y rats engage in more frequent play
bouts, but play for a similar amount of time as WT littermate pairs, and these
parameters were affected differently by treatment condition in WT and Cdkl5-/y pairs.
Detailed snapshot and longitudinal analysis of play behaviour indicates that the
temporal dynamics and sequencing of play in Cdkl5-/y pairs differs from WT
littermates, and that the developmental trajectory of play behaviour may diverge from
WT in Cdkl5-/y pairs.
Overall, this thesis provides evidence that rat models of NDD behave differently in
social contexts than WT animals and highlights the benefit of ethologically relevant
outcome measures and minimally invasive test environments for uncovering subtle
social and emotional phenotypes in rat models of NDD
